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1. Risk of hypoglycemia associated with repaglinide combined with clopidogrel, a retrospective cohort study

Author

Yuuki Akagi, Akiko Iketaki, Haruna Kimura, Yuki Matsudaira, Takami Yoshida, Takahiro Nishimura, Yohei Kawano, Yasunari Mano, Erina Shigematsu, and Makoto Ujihara

Subjects
Repaglinide, Clopidogrel, Drug-drug interaction, Hypoglycemia, Cytochrome P450 2C8, Mitiglinide, Therapeutics. Pharmacology, RM1-950, Pharmacy and materia medica, RS1-441
Abstract

Abstract Background Repaglinide is widely prescribed to reduce postprandial hyperglycemia and elevated glycated hemoglobin (HbA1c) levels associated with type 2 diabetes, and clopidogrel is a thienopyridine antiplatelet agent and widely used in cardiovascular and cerebrovascular diseases. It has been suggested that the concomitant use of repaglinide with clopidogrel may inhibit repaglinide metabolism, because repaglinide is a substrate of cytochrome P450 2C8 (CYP2C8) and the main metabolite of clopidogrel acyl-β-D-glucuronide inhibits CYP2C8 activity. In this study, we retrospectively investigated the effect of clopidogrel with repaglinide on plasma glucose and the risk of hypoglycemia associated with the combination of both drugs. Method Patients were taking clopidogrel (75 mg/day) and started taking glinide (1.5 mg/day repaglinide or 30 mg/day mitiglinide) for the first time from April 2012 to March 2017. We targeted subjects who were hospitalized at the start of glinide and whose preprandial plasma glucose was measured by a nurse. The glucose levels were collected for up to 5 days before and after the glinide start date. Results Average fasting plasma glucose levels (before breakfast) in the repaglinide and clopidogrel group before and after starting repaglinide were 180.1±35.5 and 136.5 ± 44.1 mg/dL, with a mean decrease of 43.6 ± 33.6 mg/dL. In contrast, there was only a moderate decrease of 11.6 ± 30.0 mg/dL in the mitiglinide and clopidogrel group. Minimum plasma glucose levels in the repaglinide and clopidogrel group before and after starting repaglinide were 145.2 ± 42.9 and 93.3 ± 36.3 mg/dL, respectively. Decrease in minimum levels after starting glinide in the repaglinide and clopidogrel group (51.9 ± 47.5 mg/dL) was more significant than those in the mitiglinide and clopidogrel group (only 2.1 ± 29.1 mg/dL), and the repaglinide group (without clopidogrel, 15.5 ± 20.0 mg/dL). Hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, but only 1 of 15 patients in the mitiglinide and clopidogrel group, and no patients in the repaglinide group. Conclusion These findings indicate that minimum plasma glucose levels were significantly decreased in patients taking repaglinide and clopidogrel. Considering the risk of hypoglycemia associated with taking repaglinide and clopidogrel, when a glinide is required in patients taking clopidogrel, mitiglinide may be a better choice.

Published
2020
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2. Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

Author

Hiroshi Maegawa, Masahiro Yamazaki, Takashi Akamizu, Rimei Nishimura, Takashi Doi, Kazuhiko Sakaguchi, Akihito Otsuka, Fumihiko Sato, Masahiro Matsumoto, Hirotaka Watada, Yoshiaki Okubo, Masakazu Kobayashi, Yoshihiro Miyamoto, Takuya Awata, Hirohito Sone, Hideaki Miyoshi, Haruhiko Osawa, Kazuki Fukui, Makoto Nakamura, Kohjiro Ueki, Daisuke Koya, Takanori Miura, Akihiro Isogawa, Ryo Suzuki, Takashi Kadowaki, Iichiro Shimomura, Yoshihito Atsumi, Hiroshi Yamaguchi, Yoshiyuki Nagai, Udai Nakamura, Eiichi Araki, Kohei Ogawa, Akira Shimada, Naoki Matsuoka, Hitoshi Shimano, Junko Sato, Satoru Yamada, Yukio Tanizawa, Jiro Nakamura, Yuichiro Yamada, Nobuya Inagaki, Atsuko Abiko, Hideki Katagiri, Michio Hayashi, Keiko Naruse, Shimpei Fujimoto, Masazumi Fujiwara, Kenichi Shikata, Yosuke Okada, Tsutomu Yamazaki, Sou Nagai, Katsuyuki Yanagisawa, Hiromichi Kijima, Shinji Taneda, Shigeyuki Saitoh, Daisuke Ikeda, Fuminori Hirano, Haruhiko Yoshimura, Mitsutaka Inoue, Masahiko Katoh, Osamu Nakagaki, Chiho Yamamoto, Akitsuki Morikawa, Kazuhiro Yoshida, Shin Furukawa, Takeshi Koshiya, Hajime Sugawara, Takumi Uchida, Noe Takakubo, Yasushi Ishigaki, Susumu Suzuki, Takashi Shimotomai, Naoki Tamasawa, Jun Matsui, Takashi Goto, Toshihide Oizumi, Shinji Susa, Makoto Daimon, Hiroshi Murakami, Takashi Sugawara, Hiroaki Akai, Mari Nakamura, Yoshiji Ogawa, Takao Yokoshima, Tsuyoshi Watanabe, Michio Shimabukuro, Kazuhisa Tsukamoto, Motoei Kunimi, Jo Satoh, Atushi Okuyama, Kazutaka Ogawa, Hideyuki Eguchi, Mamoru Kimura, Hiroshi Kouno, Yohei Horikawa, Shin Ikejima, Masaru Saitoh, Naoyoshi Minami, Akihiro Sekikawa, Toyoyoshi Uchida, Toshihide Kawai, Nobuya Fujita, Ken Tomotsune, Shigeo Yamashita, Motoji Naka, Toru Hiyoshi, Tomotaka Katoh, Kumiko Hamano, Kouichi Inukai, Takuma Kondo, Kazuhiro Tsumura, Yoko Matsuzawa, Masahiro Mimura, Masahiko Kawasumi, Izumi Takei, Masafumi Matsuda, Ichiro Tatsuno, Nobuyuki Banba, Akihiko Ando, Masao Toyoda, Daisuke Suzuki, Takahiro Iijima, Yasumichi Mori, Yutaka Uehara, Yoshihiko Satoh, Kazuaki Yahata, Yoshimasa Asoh, Koichiro Kuwabara, Souichi Takizawa, Yasushi Tanaka, Koutaroh Yokote, Masako Tohgo, Takanobu Itoi, Shigeru Miyazaki, Hiroshi Itoh, Teruo Shiba, Takahisa Hirose, Mariko Higa, Masanobu Yamada, Osamu Ogawa, Masatoshi Kuroki, Shinobu Satoh, Makoto Ujihara, Kenjiroh Yamanaka, Hajime Koyano, Tadashi Yamakawa, Kenichiroh Takahashi, Kazuki Orime, Tsutomu Hirano, Jiroh Morimoto, Takashi Itoh, Yuzoh Mizuno, Naoyuki Yamamoto, Han Miyatake, Mina Yamaguchi, Kenji Yamane, Masahiko Kure, Satoko Kawabe, Masahumi Kakei, Masashi Yoshida, Hiroyuki Itoh, Nobuaki Minami, Kazuki Kobayashi, Yusuke Fujino, Makoto Shibuya, Midori Hosokawa, Isao Nozaki, Chigure Nawa, Tamio Ieiri, Takayuki Watanabe, Yoshio Katoh, Takuyuki Katabami, Michiko Handa, Issei Shimada, Kenichi Ohya, Yoshihiro Ogawa, Takanobu Yoshimoto, Jiroh Nakamura, Naotsuka Okayama, Kenro Imaeda, Syuko Yoshioka, Masako Murakami, Takashi Murase, Yoshihiko Yamada, Yutaka Yano, Hiromitsu Sasaki, Yasuhiro Sumida, Osamu Yonaha, Hiroshi Sobajima, Mitsuyasu Ito, Atushi Suzuki, Atsuko Ishikawa, Takehiko Ichikawa, Shogo Asano, Shinobu Goto, Sakuma Hiroya, Hiroshi Murase, Shozo Ogawa, Hideki Okamoto, Kotaro Nagai, Koji Nagayama, Masanori Yoshida, Norio Takahashi, Kazuhisa Takami, Tsuneo Ono, Takanobu Morihiro, Daisuke Tanaka, Noriko Takahara, Satoshi Miyata, Mamiko Tsugawa, Koichiro Yasuda, Seiji Muro, Masanori Emoto, Ikuo Mineo, Ichiro Shiojima, Takeshi Kurose, Makoto Ohashi, Yumiko Kawabata, Mitsushige Nishikawa, Emiko Nomura, Yasuyuki Nishimura, Yasuhiro Ono, Yasuhisa Yamamoto, Keigo Naka, Taizo Yamamoto, Rika Usuda, Hiroshi Akahori, Seika Kato, Hiroyuki Konya, Yutaka Umayahara, Takashi Seta, Hideki Taki, Masashi Sekiya, Shinichi Mogami, Sumie Fujii, Toshiyuki Hibuse, Shingo Tsuji, Hirofumi Sumi, Yasuro Kumeda, Akinori Kogure, Kenji Furukawa, Akira Kuroe, Hideaki Sawaki, Narihiro Hibiki, Yoshihiro Kitagawa, Yukihiro Bando, Akira Ono, Rikako Uenaka, Seitaro Omoto, Yuki Kita, Eiko Ri, Ryutaro Numaguchi, Sachiko Kawashima, Ichiro Kisimoto, Kiminori Hosoda, Yoshihiko Araki, Tetsuroh Arimura, Mitsuru Hashiramoto, Koumei Takeda, Akira Matsutani, Yasushi Inoue, Fumio Sawano, Nozomu Kamei, Yasuo Ito, Miwa Morita, Yoshiaki Oda, Rui Kishimoto, Katsuhiro Hatao, Tomoatsu Mune, Fumiko Kawasaki, Hiroki Teragawa, Ken Yaga, Keita Ishii, Kyouji Hirata, Tatsuaki Nakatou, Yutaka Nitta, Naoki Fujita, Masayasu Yoneda, Masatoshi Tsuru, Shinichirou Ando, Toshiaki Kakiba, Michihiro Toyoshige, Tsuguka Shiwa, Hiroaki Miyaoka, Yasumi Shintani, Takenori Sakai, Tetsuji Niiya, Shinpei Fujimoto, Hisaka Minami, Yoshihiko Noma, Masaaki Tamaru, Yoshitaka Sayou, Tomoyo Oyama, Masamoto Torisu, Yuichi Fujinaka, Yoshitaka Kumon, Shozo Miyauchi, Morikazu Onji, Toru Nakamura, Yoichi Hiasa, Yousuke Okada, Toshihiko Yanase, Kenro Nishida, Syuji Nakamura, Kunihisa Kobayashi, Nobuhiko Wada, Moritake Higa, Koji Matsushita, Yoshihiko Nishio, Ryoji Fujimoto, Yasuyuki Kihara, Shinichiro Mine, Tadashi Arao, Hiromi Tasaki, Yasuto Matsuo, Hirofumi Matsuda, Kohei Uriu, Kazuko Kanda, Kazuo Ibaraki, Yoshio Kaku, Yasuhiro Takaki, Iwaho Hazekawa, Kenji Ebihara, Eiichiro Watanabe, Iku Sakurada, Kazuhisa Muraishi, Tamami Oshige, Junichi Yasuda, Toyoshi Iguchi, Noriyuki Sonoda, Masahiro Adachi, Isao Ichino, Yuko Horiuchi, Souichi Uekihara, Shingo Morimitsu, Mitsuhiro Nakazawa, Tadashi Seguchi, and Kengo Kaneko

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Introduction Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methods We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.Results Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.Conclusions Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Published
2021
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3. A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing’s syndrome other than Cushing’s disease

Author

Akira Shimatsu, Sanae Midorikawa, Tamami Takeda, Akina Suzuki, Makoto Ujihara, Fumitoshi Satoh, Tomomi Kaneko, Tomoaki Tanaka, and Masahiko Sato

Subjects
Adult, Male, medicine.medical_specialty, Pyridines, Endocrinology, Diabetes and Metabolism, Population, Phases of clinical research, 030209 endocrinology & metabolism, Gastroenterology, Drug Administration Schedule, Malaise, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Japan, Internal medicine, medicine, Adrenal insufficiency, Clinical endpoint, Humans, Pituitary ACTH Hypersecretion, education, Adverse effect, Cushing Syndrome, Osilodrostat, Aged, education.field_of_study, Dose-Response Relationship, Drug, business.industry, Imidazoles, Cushing's disease, Middle Aged, medicine.disease, Treatment Outcome, 030220 oncology & carcinogenesis, Female, medicine.symptom, business
Abstract

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11β-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable.

Published
2020
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4. Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

Author

Masakazu Kobayashi, Hirohito Sone, Haruhiko Osawa, Daisuke Koya, Takanori Miura, Yoshihito Atsumi, Udai Nakamura, Eiichi Araki, Hitoshi Shimano, Yukio Tanizawa, Jiro Nakamura, Yuichiro Yamada, Nobuya Inagaki, Atsuko Abiko, Hideki Katagiri, Michio Hayashi, Keiko Naruse, Shimpei Fujimoto, Masazumi Fujiwara, Kenichi Shikata, Yosuke Okada, Tsutomu Yamazaki, Sou Nagai, Katsuyuki Yanagisawa, Hiromichi Kijima, Shinji Taneda, Shigeyuki Saitoh, Daisuke Ikeda, Fuminori Hirano, Haruhiko Yoshimura, Mitsutaka Inoue, Masahiko Katoh, Osamu Nakagaki, Chiho Yamamoto, Akitsuki Morikawa, Shin Furukawa, Takeshi Koshiya, Hajime Sugawara, Takumi Uchida, Noe Takakubo, Yasushi Ishigaki, Susumu Suzuki, Takashi Shimotomai, Naoki Tamasawa, Jun Matsui, Takashi Goto, Toshihide Oizumi, Shinji Susa, Makoto Daimon, Hiroshi Murakami, Takashi Sugawara, Hiroaki Akai, Mari Nakamura, Yoshiji Ogawa, Takao Yokoshima, Tsuyoshi Watanabe, Michio Shimabukuro, Kazuhisa Tsukamoto, Motoei Kunimi, Jo Satoh, Atushi Okuyama, Kazutaka Ogawa, Hideyuki Eguchi, Mamoru Kimura, Hiroshi Kouno, Yohei Horikawa, Shin Ikejima, Masaru Saitoh, Naoyoshi Minami, Akihiro Sekikawa, Toyoyoshi Uchida, Toshihide Kawai, Nobuya Fujita, Ken Tomotsune, Shigeo Yamashita, Motoji Naka, Toru Hiyoshi, Tomotaka Katoh, Kumiko Hamano, Kouichi Inukai, Takuma Kondo, Kazuhiro Tsumura, Yoko Matsuzawa, Masahiro Mimura, Masahiko Kawasumi, Izumi Takei, Masafumi Matsuda, Ichiro Tatsuno, Nobuyuki Banba, Akihiko Ando, Masao Toyoda, Daisuke Suzuki, Takahiro Iijima, Yasumichi Mori, Yutaka Uehara, Yoshihiko Satoh, Kazuaki Yahata, Yoshimasa Asoh, Koichiro Kuwabara, Souichi Takizawa, Yasushi Tanaka, Koutaroh Yokote, Masako Tohgo, Takanobu Itoi, Shigeru Miyazaki, Hiroshi Itoh, Teruo Shiba, Takahisa Hirose, Mariko Higa, Masanobu Yamada, Osamu Ogawa, Masatoshi Kuroki, Shinobu Satoh, Makoto Ujihara, Kenjiroh Yamanaka, Hajime Koyano, Tadashi Yamakawa, Kenichiroh Takahashi, Kazuki Orime, Tsutomu Hirano, Jiroh Morimoto, Takashi Itoh, Yuzoh Mizuno, Naoyuki Yamamoto, Han Miyatake, Mina Yamaguchi, Kenji Yamane, Masahiko Kure, Satoko Kawabe, Masahumi Kakei, Masashi Yoshida, Hiroyuki Itoh, Nobuaki Minami, Kazuki Kobayashi, Yusuke Fujino, Makoto Shibuya, Midori Hosokawa, Isao Nozaki, Chigure Nawa, Tamio Ieiri, Takayuki Watanabe, Yoshio Katoh, Takuyuki Katabami, Michiko Handa, Issei Shimada, Kenichi Ohya, Yoshihiro Ogawa, Takanobu Yoshimoto, Jiroh Nakamura, Naotsuka Okayama, Kenro Imaeda, Syuko Yoshioka, Masako Murakami, Takashi Murase, Yoshihiko Yamada, Yutaka Yano, Hiromitsu Sasaki, Yasuhiro Sumida, Osamu Yonaha, Hiroshi Sobajima, Mitsuyasu Ito, Atushi Suzuki, Atsuko Ishikawa, Takehiko Ichikawa, Shogo Asano, Shinobu Goto, Sakuma Hiroya, Hiroshi Murase, Shozo Ogawa, Hideki Okamoto, Kotaro Nagai, Koji Nagayama, Masanori Yoshida, Norio Takahashi, Kazuhisa Takami, Tsuneo Ono, Takanobu Morihiro, Daisuke Tanaka, Noriko Takahara, Satoshi Miyata, Mamiko Tsugawa, Koichiro Yasuda, Seiji Muro, Masanori Emoto, Ikuo Mineo, Ichiro Shiojima, Takeshi Kurose, Makoto Ohashi, Yumiko Kawabata, Mitsushige Nishikawa, Emiko Nomura, Yasuyuki Nishimura, Yasuhiro Ono, Yasuhisa Yamamoto, Keigo Naka, Taizo Yamamoto, Rika Usuda, Hiroshi Akahori, Seika Kato, Hiroyuki Konya, Yutaka Umayahara, Takashi Seta, Hideki Taki, Masashi Sekiya, Shinichi Mogami, Sumie Fujii, Toshiyuki Hibuse, Shingo Tsuji, Hirofumi Sumi, Yasuro Kumeda, Akinori Kogure, Kenji Furukawa, Akira Kuroe, Hideaki Sawaki, Narihiro Hibiki, Yoshihiro Kitagawa, Yukihiro Bando, Akira Ono, Rikako Uenaka, Seitaro Omoto, Yuki Kita, Eiko Ri, Ryutaro Numaguchi, Sachiko Kawashima, Ichiro Kisimoto, Kiminori Hosoda, Yoshihiko Araki, Tetsuroh Arimura, Mitsuru Hashiramoto, Koumei Takeda, Akira Matsutani, Yasushi Inoue, Fumio Sawano, Nozomu Kamei, Yasuo Ito, Miwa Morita, Yoshiaki Oda, Rui Kishimoto, Katsuhiro Hatao, Tomoatsu Mune, Fumiko Kawasaki, Hiroki Teragawa, Ken Yaga, Keita Ishii, Kyouji Hirata, Tatsuaki Nakatou, Yutaka Nitta, Naoki Fujita, Masayasu Yoneda, Masatoshi Tsuru, Shinichirou Ando, Toshiaki Kakiba, Michihiro Toyoshige, Tsuguka Shiwa, Hiroaki Miyaoka, Yasumi Shintani, Takenori Sakai, Tetsuji Niiya, Shinpei Fujimoto, Hisaka Minami, Yoshihiko Noma, Masaaki Tamaru, Yoshitaka Sayou, Tomoyo Oyama, Masamoto Torisu, Yuichi Fujinaka, Yoshitaka Kumon, Shozo Miyauchi, Morikazu Onji, Toru Nakamura, Yousuke Okada, Toshihiko Yanase, Kenro Nishida, Syuji Nakamura, Kunihisa Kobayashi, Nobuhiko Wada, Moritake Higa, Koji Matsushita, Yoshihiko Nishio, Ryoji Fujimoto, Yasuyuki Kihara, Shinichiro Mine, Tadashi Arao, Hiromi Tasaki, Yasuto Matsuo, Hirofumi Matsuda, Kohei Uriu, Kazuko Kanda, Kazuo Ibaraki, Yoshio Kaku, Yasuhiro Takaki, Iwaho Hazekawa, Kenji Ebihara, Eiichiro Watanabe, Iku Sakurada, Kazuhisa Muraishi, Tamami Oshige, Junichi Yasuda, Toyoshi Iguchi, Noriyuki Sonoda, Masahiro Adachi, Isao Ichino, Yuko Horiuchi, Souichi Uekihara, Shingo Morimitsu, Mitsuhiro Nakazawa, Tadashi Seguchi, and Kengo Kaneko

Subjects
Blood Glucose, safety, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Hypoglycemia, Group B, Diseases of the endocrine glands. Clinical endocrinology, dipeptidyl peptidase 4, Japan, Piperidines, Internal medicine, Diabetes mellitus, medicine, Humans, Hypoglycemic Agents, Prospective Studies, Adverse effect, Uracil, Aged, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Incidence (epidemiology), Type 2 Diabetes Mellitus, registries, medicine.disease, RC648-665, Diabetes Mellitus, Type 2, type 2, diabetes mellitus, Clinical care/Education/Nutrition, business, Alogliptin
Abstract

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Published
2020

5. Risk of hypoglycemia associated with repaglinide combined with clopidogrel, a retrospective cohort study

Author

Takahiro Nishimura, Yuuki Akagi, Takami Yoshida, Erina Shigematsu, Akiko Iketaki, Haruna Kimura, Makoto Ujihara, Yasunari Mano, Yuki Matsudaira, and Yohei Kawano

Subjects
Mitiglinide, lcsh:RS1-441, 030209 endocrinology & metabolism, Pharmacology (nursing), Type 2 diabetes, Pharmacology, Hypoglycemia, 030226 pharmacology & pharmacy, lcsh:Pharmacy and materia medica, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cytochrome P450 2C8, medicine, Pharmacology (medical), cardiovascular diseases, CYP2C8, business.industry, lcsh:RM1-950, Clopidogrel, medicine.disease, Repaglinide, lcsh:Therapeutics. Pharmacology, Postprandial, chemistry, Glycated hemoglobin, business, medicine.drug, circulatory and respiratory physiology, Research Article, Drug-drug interaction
Abstract

Background Repaglinide is widely prescribed to reduce postprandial hyperglycemia and elevated glycated hemoglobin (HbA1c) levels associated with type 2 diabetes, and clopidogrel is a thienopyridine antiplatelet agent and widely used in cardiovascular and cerebrovascular diseases. It has been suggested that the concomitant use of repaglinide with clopidogrel may inhibit repaglinide metabolism, because repaglinide is a substrate of cytochrome P450 2C8 (CYP2C8) and the main metabolite of clopidogrel acyl-β-D-glucuronide inhibits CYP2C8 activity. In this study, we retrospectively investigated the effect of clopidogrel with repaglinide on plasma glucose and the risk of hypoglycemia associated with the combination of both drugs. Method Patients were taking clopidogrel (75 mg/day) and started taking glinide (1.5 mg/day repaglinide or 30 mg/day mitiglinide) for the first time from April 2012 to March 2017. We targeted subjects who were hospitalized at the start of glinide and whose preprandial plasma glucose was measured by a nurse. The glucose levels were collected for up to 5 days before and after the glinide start date. Results Average fasting plasma glucose levels (before breakfast) in the repaglinide and clopidogrel group before and after starting repaglinide were 180.1±35.5 and 136.5 ± 44.1 mg/dL, with a mean decrease of 43.6 ± 33.6 mg/dL. In contrast, there was only a moderate decrease of 11.6 ± 30.0 mg/dL in the mitiglinide and clopidogrel group. Minimum plasma glucose levels in the repaglinide and clopidogrel group before and after starting repaglinide were 145.2 ± 42.9 and 93.3 ± 36.3 mg/dL, respectively. Decrease in minimum levels after starting glinide in the repaglinide and clopidogrel group (51.9 ± 47.5 mg/dL) was more significant than those in the mitiglinide and clopidogrel group (only 2.1 ± 29.1 mg/dL), and the repaglinide group (without clopidogrel, 15.5 ± 20.0 mg/dL). Hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, but only 1 of 15 patients in the mitiglinide and clopidogrel group, and no patients in the repaglinide group. Conclusion These findings indicate that minimum plasma glucose levels were significantly decreased in patients taking repaglinide and clopidogrel. Considering the risk of hypoglycemia associated with taking repaglinide and clopidogrel, when a glinide is required in patients taking clopidogrel, mitiglinide may be a better choice.

Published
2019

6. Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial

Author

Ruilope, Luis M, Agarwal, Rajiv, Anker, Stefan D, Bakris, George L, Filippatos, Gerasimos, Nowack, Christina, Kolkhof, Peter, Joseph, Amer, Mentenich, Nicole, Pitt, Bertram, Diego, Besada, Alfredo, Wassermann, Julio, Bittar, Alicia, Elbert, Augusto, Vallejos, Gloria, Viñes, Hugo, Sanabria, Federico Pérez Manghi, Alberto, Liberman, Inés, Bartolacci, Diego, Aizenberg, Mariano, Chahin, Laura, Maffei, Elizabeth, Gelersztein, Bernhard, Ludvik, Hans-Robert, Schönherr, Heinz, Drexel, Wolfgang, Preiß, Ursula, Hanusch, Peter, Neudorfer, Friedrich, Prischl, Bernhard, Paulweber, Christoph, Ebenbichler, Rudolf, Prager, Harald, Sourij, Gerit-Holger, Schernthaner, Martin, Clodi, Evelyn, Fliesser-Görzer, Elif, Ekinci, Richard, Macisaac, David, Packham, Hugo, Stephenson, Michael, Suranyi, Gary, Wittert, Katie-Jane, Wynne, Alexia, Pape, Duncan, Topliss, Peter, Colman, Craig, Nelson, James, Vandeleur, David, Colquhoun, Simon, Roger, Peak Mann Mah, Walter, Abhayaratna, Luc VAN Gaal, Pieter, Gillard, Jean-Michel, Hougardy, Marijn, Speeckaert, Koen, Stas, Wendy, Engelen, Francis, Duyck, André, Scheen, Hilde, Vanbelleghem, Peter, Doubel, Svetla, Vasileva, Rosen, Rashkov, Boyan, Nonchev, Theodora, Temelkova-Kurktschieva, Mariana, Yoncheva-Mihaylova, Rangel, Rangelov, Neli, Klyuchkova, Pavel, Stanchev, Zhivko, Tagarev, Radostina, Boshnyashka, Petya, Manova, Zhulieta, Prakova, Mariya, Lucheva, Valentina, Gushterova, Ghassan, Farah, Dimitar, Georgiev, Mariyana, Pichmanova, Dotska, Minkova, Bilyana, Stoyanovska-Elencheva, Maria Eugenia Canziani, Miguel, Hissa, Irene, Noronha, Joao Eduardo Salles, Daniela, Antunes, Freddy, Eliaschewitz, Carlos Eduardo Figueiredo, Rogerio de Paula, Luis, Canani, Maurilo Leite Jr, Bruno, Paolino, Rosangela, Rea, Sergio, Vencio, Claudia, Brito, Raphael, Paschoalin, Roberto Pecoits Filho, Eduardo, Vasconcellos, Nathalia, Paschoalin, Adriana, Forti, Roberto, Botelho, Miguel, Riella, Dalton, Precoma, Maria, Cerqueira, Lilia, Maia, Evandro, Portes, Marcio, Pereira, Joanne, Liutkus, Dennis, O Keefe, Richard, Tytus, Brian, Carlson, James, Conway, Michael, Walsh, Igor, Wilderman, Andrew, Steele, Sheldon, Tobe, Louise, Vitou, Karthik, Tennankore, Valdemar, Martinho, Philip, Mcfarlane, Daniel, Shu, Serge, Cournoyer, Richard, Dumas, Giuseppe, Mazza, Guy, Tellier, George, Tsoukas, Stanley, Weisnagel, Jean-Francois, Yale, Sameh, Fikry, Randolph, Hart, Pavel, Hamet, Francois, Madore, Paul, Barre, Daniel, Schwartz, Allan, Kelly, Ivor, Teitelbaum, Sean, Peterson, Sam, Henein, Richard, Goluch, Gregoire, Wuerzner, Markus, Laimer, Stefan, Bilz, Marc, Donath, Gottfried, Rudofsky, Christopher, Strey, Antoinette, Pechère-Bertschi, Paola, Varleta, Fernando, González, Marcelo, Medina, Carmen, Romero, Victor, Saavedra, Juan Carlos Prieto, Eliana, Reyes, Juan Carlos Palma, Jorge, Cobos, Zhihong, Liu, Dalong, Zhu, Nan, Chen, Fang, Liu, Wang, Li, Qing, Su, Bingyin, Shi, Aiping, Yin, Hao, Wang, Yan, Li, Jianying, Niu, Chaoqing, Wu, Xinjun, Wang, Ying, Zhang, Peng, Ai, Jianhua, Ma, Yuxiu, Li, Hongguang, Zheng, Minxiang, Lei, Zhaohui, Mo, Nanwei, Tong, Jinluo, Cheng, Youping, Dong, Xudong, Xu, Qinkai, Chen, Tianjun, Guan, Gang, Long, Changying, Xing, Ling, Li, Yinghong, Liu, Hao, Zhang, Ling, Zhong, Zhonghe, Li, Longyi, Zeng, Jiali, Wei, Hanqing, Cai, Tianfeng, Wu, Weiping, Lu, Ning, Xu, Yibing, Lu, Dejun, Chen, Ruifang, Bu, Jiansong, Shen, Junwu, Dong, Zhiquan, Zhao, Fei, Xiong, Fangfang, Jiang, Jinkui, Yang, Jian, Kuang, Guoyuan, Lu, Lihua, Wang, Yanlin, Zhang, Shuifu, Tang, Weiying, Guo, Jian, Liu, Sheng, Jiang, Fang, Yi, Yuming, Du, Zhuxing, Sun, Yuantao, Liu, Liyong, Zhong, Dongmei, Li, Hongmei, Li, Chuanming, Hao, Feixia, Shen, Jianqin, Wang, Jingmei, Li, Dora, Molina, Carlos, Cure, Jaime, Ibarra, Gustavo, Aroca, Hernán, Yupanqui, Eric, Hernández, Mónica, López, Gregorio, Sánchez, Germán, Barreto, Edgar, Arcos, Miguel, Urina, William, Kattah, Carlos, Durán, Clara, Arango, Julian, Coronel, Guillermo, Blanco, Mónica, Terront, Gustavo, Guzmán, Luis, García, Carlos, Jaramillo, Manuel, Liévano, Diego, Benitez, Tatiana, Cárdenas, Iván, Villegas, Sandra, Barrera, Nicolás, Jaramillo, Rodrigo, Botero, Nelly Beltrán López, Freddy, Trujillo, Martin, Prazny, Jitka Hasalova Zapletalova, Libor, Okenka, Dino, Alferi, Tomas, Edelsberger, Pavel, Tomanek, Jiri, Brezina, Olga, Hola, Jana, Houdova, Petr, Bucek, David, Karasek, Sarka, Kopecka, Richard, Kovar, Michal, Brada, Lucie, Hornova, Eva, Krcova, Hana, Lubanda, Vlasta, Kutejova, Jiri, Kuchar, Helena, Hrmova, Jiri, Pumprla, Magdalena, Mokrejsova, Drahomira, Gulakova, Ivo, Matyasek, Thilo, Krüger, Hermann, Haller, Thorsten, Koch, Ludger, Rose, Diethelm, Tschöpe, Lutz, Stemler, Volker, Schettler, Andreas, Pfützner, Karl, Derwahl, Thomas, Horacek, Helena, Sigal, Heidrun, Täschner, Ingolf, Schiefke, Andreas, Hagenow, Andreas, Birkenfeld, Christoph, Axthelm, Christoph, Wanner, Klaus, Busch, Heike, Schlichthaar, Christoph, Hasslacher, Stefan, Degenhardt, Markus van der Giet, Georg, Strack, Norbert, Schöll, Bernhard, R Winkelmann, Lars, Rump, Ruth, Nischik, Bernd, Schröppel, Thomas, Giebel, Achim, Ulmer, Andrea, Rinke, Christel, Contzen, Wolfgang, Jungmair, Nicole, Toursarkissian, Christof, Kloos, Joachim, Müller, Thomas, Schürholz, Hermann, Braun, Frank, Pistrosch, Per, Poulsen, Claus, Juhl, Joan, Nielsen, Jesper, Bech, Ole, Rasmussen, Peter, Rossing, Jens, Faber, Thure, Krarup, Morten, Lindhardt, Ulrik Pedersen-Bjergaard Pedersen-Bjergaard, Karoline, Schousboe, Jørgen, Hangaard, Sten, Madsbad, Gunnar, Gislason, Grzegorz Jaroslaw Pacyk, Olga González Albarrán, Carlos Sánchez Juan, José Julián Segura de la Morena, Secundino Cigarrán Guldris, Francisco Martínez Deben, José María Pascual Izuel, Julio Pascual Santos, Francesca, Calero, Alfonso, Soto, Manuel Polaina Rusillo, Josep, Redón, Josep, Galcerán, Juan, Mediavilla, Mª Dolores Martínez Esteban, Alfredo, Michán, Fernando de Álvaro, Javier Escalada San Martín, Josep Cruzado Garrit, Cristina, Castro, Fernando Cereto Castro, Rafael Santamaría Olmo, Esteban, Poch, Judith, Martins, Julio Hernández Jaras, Meritxell, Ibernón, Daniel, Seron, Hanane, Bouarich, Maribel, Troya, Jorma, Strand, Ilkka, Kantola, Sakari, Nieminen, Arvo, Koistinen, Kristiina, Kananen, Sakari, Sulosaari, Mikko, Honkasalo, Pirkko, Korsoff, Tuomo, Nieminen, Karita, Sadeharju, Kari, Humaloja, Jorma, Lahtela, Philippe, Zaoui, Jean-Pierre, Fauvel, Ronan, Roussel, Didier, Gouet, Pierre, Serusclat, Sylvaine, Clavel, Bruno, Guerci, Bruno, Verges, Olivier, Moranne, Arnaud, Monier, Alexandre, Klein, François, Chantrel, Yannick LE Meur, Rafik, Mesbah, Bertrand, Cariou, Dominique, Guerrot, Karim, Gallouj, Kieran, Mccafferty, Arutchelvam, Vijayaraman, Yuk-Ki, Wong, Dhanya, Kalathil, Sam, Rice, Sui Phi Kon, Hassan, Kahal, Cuong, Dang, Fahmy, Hanna, Christina, Kyriakidou, Imrozia, Arif, Anne, Kilvert, Pauline, Swift, Ioannis, Stefanidis, Ploumis, Passadakis, Aikaterini, Papagianni, Erifili, Hatziagelaki, Dorothea, Papadopoulou, Ioannis, Boletis, Ioanna, Makriniotou, Theodora, Kounadi, Ioannis, Ioannidis, Paul, Lee, Ching Wan Ronald Ma, Vincent, Yeung, Tai Pang Ip, Ebrahim, Noori, Julianna, Kiss, Eleonora, Harcsa, Albert, Szocs, Szilard, Vasas, Krisztina, Wudi, Robert, Kirschner, Dora, Bajcsi, Beata, Lamboy, Botond, Literati-Nagy, Gabor, Nyirati, Gizella, Petro, Karoly, Schneider, Katalin, Keltai, Akos, Kalina, Peter, Danos, Szilvia, Kazup, Zsolt, Zilahi, Judit, Simon, Laszlo, Kovacs, Marianna, Zsom, Margit, Mileder, Laszlo, Nagy, Yoram, Yagil, Julio, Wainstein, Ofri, Mosenzon, Rosane Abramof Ness, Sydney Ben Chetrit, Faiad, Adawi, Idit, Liberty, Ehud, Grossman, Mazen, Elias, Zaher, Armaly, Evgeny, Farber, Assy, Nimer, Amir, Bashkin, Gil, Chernin, Shai, Efrati, Doron, Schwartz, Noa Berar Yanay, Mariela, Glandt, Robert, Zukermann, Majdi, Halabi, Shaul, Atar, Mahmud, Darawsha, Norberto, Perico, Gaetano La Manna, Giovanni Giorgio Battaglia, Domenico, Santoro, Piermarco, Piatti, Bonora, Enzo, Davide Carlo Maggi, Paolo, Calabrò, Roberto, Cimino, Roberto, Trevisan, Paolo, Fiorina, Antonio, Pisani, Antonello, Pani, Gennaro, Santorelli, Carlo Antonio Bossi, Giancarlo, Tonolo, Enrico, Fiaccadori, Anna Maria Veronelli, Michele, Emdin, Paola, Ponzani, Maria Cristina Gregorini, Franco Luigi Cavalot, Carlo Bruno Giorda, Taro, Shibasaki, Akihiro, Hamasaki, Takashi, Nomiyama, Sunao, Matsubayashi, Junji, Shinoda, Kazunari, Matsumoto, Hideo, Kanehara, Yoshihide, Hirohata, Masayo, Yamada, Jun, Nakazawa, Yoshimitsu, Yamasaki, Mikihiro, Nakayama, Ryuichi, Furuya, Osamu, Ebisui, Satsuki, Kawasaki, Daishiro, Yamada, Masayuki, Noritake, Tamayo, Ishiko, Nobuhiro, Sasaki, Daisuke, Suzuki, Asami, Tanaka, Miyuki, Kubota, Hideo, Araki, Hiroshi, Ohashi, Takeshi, Osonoi, Kazuo, Yamagata, Naruhiro, Fujita, Daisuke, Kanda, Seiichi, Tanaka, Junko, Koide, Masao, Ishii, Takayuki, Ogiwara, Masaaki, Suzuki, Taiji, Sekigami, Takayuki, Higashi, Yuko, Yambe, Yoshiro, Kusano, Hidetoshi, Kikuchi, Hiroaki, Miyaoka, Kiyoe, Kato, Masayuki, 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A, C Bakker, R, Marielle, Krekels, B Brouwer, C, T Luik, P, J N, M Barendregt, Bert-Jan van den Born, Trine, Finnes, Thomas, Karlsson, Hilde, Selsås, Emil, Asprusten, Robert, Hagemeier, Erik, Eriksen, Knut, Risberg, Hans, Høivik, Leidulv, Solnør, Frode, Thorup, Jan, Rocke, Rick, Cutfield, Peter, Dunn, Jeremy, Krebs, Russell, Scott, Kingsley, Nirmalaraj, Nine, Smuts, John, Baker, Veronica, Crawford, Albert, Bautista, Roberto, Mirasol, Elizabeth, Catindig, Glenda, Pamugas, Louie, Tirador, Maribel, Tanque, Janusz, Gumprecht, Piotr, Napora, Edward, Franek, Andrzej, Stankiewicz, Katarzyna, Landa, Agnieszka, Tiuryn-Petrulewicz, Kazimierz, Ciechanowski, Bogna, Wierusz-Wysocka, Barbara, Rewerska, Grazyna, Cieslik, Michal, Hoffmann, Michal, Nowicki, Jolanta, Krzykowska, Stanislaw, Mazur, Katarzyna, Wasilewska, Anna, Ocicka-Kozakiewicz, Ewa, Skokowska, Renata, Wnetrzak-Michalska, Jan, Ruxer, Patrycja, Butrymowicz, Katarzyna, Madziarska, Ilona, Kurnatowska, Teresa, Rusicka, Adam, Madrzejewski, Tomasz, Stompor, Jose, Guia, Amalia, Pereira, Pedro, Melo, Cristina, Roque, Francisco, Rosario, Fernando Teixeira, E Costa, Fernando, Nolasco, Edgar, Almeida, Pedro, Matos, Cesar, Esteves, Rui, Carvalho, Ilidio, Brandao, Susana, Heitor, Ana Vila Lobos, Rosa, Ballesteros, Gil, Silva, Carlos, Barreto, Ana, Silva, Natalya, Vorokhobina, Alexander, Sherenkov, Ivan, Gordeev, Olga, Semenova, Sergey, Levashov, Vyacheslav, Marasaev, Ruslan, Sardinov, Vadim, Klimontov, Vitaliy, Baranov, Nadezhda, Verlan, Albert, Galyavich, Arkadiy, Demko, Zhanna, Kobalava, Elena, Zakharova, Lyudmila, Kvitkova, Oleg, Solovev, Elena, Smolyarchuk, Larisa, Zhukova, Elena, Zhdanova, Andrey, Babkin, Galina, Nechaeva, Olga, Barbarash, Elena, Rechkova, Roman, Libis, Elena, Kosmacheva, Tatyana, Rodionova, Irina, Ipatko, Alexander, Dreval, Nina, Petunina, Elena, Chernyavskaya, Alsu, Zalevskaya, Yuriy, Khalimov, Tatyana, Zykova, Anton, Edin, Ashot, Mkrtumyan, Shamil, Palyutin, Vyacheslav, Mareev, Leonid, Strongin, Olga, Ukhanova, Mikhail, Antsiferov, Davyd, Yakhontov, Leonid, Pimenov, Natalya, Koziolova, Konstantin, Nikolaev, Imad, Merai, Olga, Zanozina, Leyla, Gaysina, Mikhail, Arkhipov, Natalia, Malykh, Oksana, Rymar, Vladimir, Martynenko, Sofya, Malyutina, Polina, Ermakova, Marina, Kalashnikova, Bengt-Olov, Tengmark, Carl-Johan, Lindholm, Dan, Curiac, Ken, Eliasson, Erik, Rein-Hedin, Gregor, Guron, Inga, Soveri, Annette, Bruchfeld, Jonas, Spaak, Malin, Frank, Magnus, Löndahl, Hans, Larnefeldt, Margareta, Hellgren, Olof, Hellberg, Yong Mong Bee, Chee Fang Sum, Ru San Tan, Piyamitr, Sritara, Chaicharn, Deerochanawong, Chatlert, Pongchaiyakul, Natapong, Kosachunhanan, Bancha, Satirapoj, Ahmet, Temizhan, Ibrahim, Gul, Ramazan, Sari, Aytekin, Oguz, Mustafa, Tigen, Huseyin, Yilmaz, Ozer, Badak, Oner, Ozdogan, Talat, Tavli, Necmi, Eren, Murat, Cayli, Sedat, Ustundag, Yavuz, Yenicerioglu, Ismail, Kocyigit, Abdulbaki, Kumbasar, Idris, Sahin, Lee-Ming, Chuang, Ju-Ying, Jiang, Chien-Te, Lee, Der-Cherng, 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Idalia, Acosta, Atoya, Adams, William, Sanchez, Rosa, Suarez, Efrain, Reisin, Carlos, Herrera, Keung, Lee, Csaba, Kovesdy, Adam, Whaley-Connell, Aldo, Peixoto, Ronald, Mayfield, Mahendra, Jain, Earl, Martin, Paul, Norwood, Jonathan, Wise, Hugo, Romeu, Stephen, Halpern, Mustafa, Mandviwala, Thomas, Turk, Anna, Burgner, David, Bleich, Ankur, Doshi, Jose, Carpio, Jorge, Posada, Alexander, Magno, Samer, Nakhle, Gary, Goldstein, Caroline, Mbogua, Dierdre, Mcmullen, Dilawar, Ajani, Wayne, Kotzker, Nelson, Kopyt, Richard, Treger, Yusuf, Ruhullah, Sharon, Adler, Harjeet, Brar, Marc, Rendell, Dennis, Ross, Srinivasan, Beddhu, German, Hernandez, Sylvia, Rosas, M Sue Kirkman, Mohammed, El-Shahawy, Jeffrey, Rothman, Ahmad, Barakzoy, Aparna, Tamirisa, Sabrina, Benjamin, Michael, Bahrami, Prabir, Roy-Chaudhury, Ramprasad, Dandillaya, Gretel, Trullenque, Jose, Birriel, John, Flack, Karen, Johnson, Brenda, Lemus, Guillermo, Umpierrez, Geetha, Maddukuri, Kenneth, Jamerson, Christopher, Case, Patrick, Fluck, Saeed, Kronfli, Violet, Habwe, Bala, Subramanian, Tariq, Shafi, Rupesh, Raina, Roland, Fernando, Sourabh, Kharait, Carlos, Hernandez-Cassis, Raymond, Fink, Jamal, Hammoud, Amer, Al-Karadsheh, Manuel, Montero, Philip, Nicol, Jesus, Navarro, Michael, Shanik, Zia, Din, Francisco, Gonzalez-Abreu, Sam, Lerman, Claude, Galphin, John, Evans, Ashwini, Gore, Radica, Alicic, Mandeep, Sahani, Roberto, Pisoni, Tuan-Huy, Tran, Jeffrey, Ryu, Harvey, Serota, Nilda, Neyra, Richard, O Donovan, Sreedhar, Mandayam, Moustafa, Moustafa, Mark, Smith, Arvind, Krishna, Arjun, Sinha, Anuj, Bhargava, Kodangudi, Ramanathan, Soni, Dhanireddy, Stephen, Thomson, Romanita, Nica, Emaad, Abdel-Rahman, Mark, Barney, Mariana, Markell, Nauman, Shahid, David, Oliver, Tran, Khanh, Pham Nguyen Son, Lam VAN Hoang, Boi Ngoc Nguyen, Nguyen Minh Nui, Lan Phuong Tran, Fayzal, Ahmed, Dorothea, Urbach, Dirkie Jansen van Rensburg, Gracjan, Podgorski, Aslam, Amod, Sindeep, Bhana, Shaifali, Joshi, Essack, Mitha, Deepak, Lakha, Louis van Zyl, Trokis, J, Naresh, Ranjith, Mary, Seeber, Mohamed, Sarvan, Mohammed, Tayob, Brian, Rayner, Larry, Distiller, Heidi, Siebert, Mukesh, Joshi, Paul, Rheeder, Magdalena Madero Rovalo, Gustavo Solache Ortiz, Gustavo Méndez Machado, Rafael Valdez Ortiz, Juan Villagordoa Mesa, Saúl Irizar Santana, Sandro Avila Pardo, Jorge Escobedo de la Peña, Guillermo González Gálvez, Leobardo Sauque Reyna, Miriam Bastidas Adrian, Guillermo Fanghänel Salmón, Ramiro Gutiérrez Ochoa, Luis Nevarez Ruiz, Gabriel Ramos López, Alfredo Chew Wong, Arturo Saldaña Mendoza, Pedro García Hernández, José González González, Melchor Alpizar Salazar, José Lazcano Soto, Amaury, Roman-Miranda, Gregorio, Cortes-Maisonet, Liana, Turcu, Adriana, Dumitrescu, Gabriela, Radulian, Hortensia, Barbonta, Cristina, Mistodie, Georgeta, Vacaru, Alexandrina, Popescu, Adrian, Vlad, Silvia, Paveliu, Nicoleta, Mindrescu, Adrian, Albota, Ella, Pintilei, Lavinia, Pop, Gabriela, Negrisanu, Doina, Catrinoiu, Cornelia, Bala, Amorin, Popa, Iosif, Szilagyi, Ciprian, Constantin, Elena, Caceaune, Adriana, Onaca, Li Yuan Lee, Nor Azizah Aziz, Wan Mohd Izani Wan Mohamed, Wan Hasnul Halimi Bin Wan Hasan, Jeyakantha, Ratnasingam, Nik Nur Fatnoon Nik Ahmad, Rizmy Najme Khir, Norhaliza Mohd Ali, Masni, Mohamad, Chek Loong Loh, Joe, Eustace, John, Holian, Donal, Reddan, Yvonne, O Meara, Mensud, Hatunic, Zuzana, Ochodnicka, Dalibor, Sosovec, Andrej, Dzupina, Ingrid, Buganova, Jana, Babikova, Denisa, Spodniakova, Ruilope, L, Agarwal, R, Anker, S, Bakris, G, Filippatos, G, Nowack, C, Kolkhof, P, Joseph, A, Mentenich, N, Pitt, B, Trevisan, R, Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, and Diabetes Clinic

Subjects
Male, Endocrinology, Diabetes and Metabolism, Enfermedad cardiovascular, 030232 urology & nephrology, BAY 94-8862, Type 2 diabetes, 030204 cardiovascular system & hematology, Diabete, Kidney, Aparato circulatorio, Azúcar, chemistry.chemical_compound, Mineralocorticoid Receptor Antagonists/therapeutic use, 0302 clinical medicine, Medicine and Health Sciences, Diabetic Nephropathies, Myocardial infarction, Renal Insufficiency, Chronic, Aldosterone, Outcome, Mineralocorticoid Receptor Antagonists, RISK, COMPLICATIONS, Diabetes, Middle Aged, SPIRONOLACTONE, CHRONIC HEART-FAILURE, Treatment Outcome, Mineralocorticoid, Nephrology, Cardiovascular Diseases, Research Design, Disease Progression, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, Type 2, Glomerular Filtration Rate, medicine.medical_specialty, Finerenone, Naphthyridines/therapeutic use, Renal function, Outcomes, 03 medical and health sciences, Clinical, Double-Blind Method, Diabetes mellitus, Internal medicine, medicine, Diabetes Mellitus, Humans, Naphthyridines, Renal Insufficiency, Chronic, ANTAGONIST, Sistema cardiovascular, Aged, Patient-Oriented, Translational Research: Research Article, Diabetic Nephropathies/complications, Renal Insufficiency, Chronic/drug therapy, RECEPTOR, Aldosterone, Clinical, Diabetes, Kidney, Mineralocorticoid, Outcomes, business.industry, Cardiovascular Diseases/epidemiology, Diabetes Mellitus, Type 2/complications, MILD, WORSENING RENAL-FUNCTION, EFFICACY, medicine.disease, chemistry, Diabetes Mellitus, Type 2, Spironolactone, Albuminuria, business, Kidney disease, Follow-Up Studies
Abstract

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Published
2019
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7. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

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Hiddo J L Heerspink, Hans-Henrik Parving, Dennis L Andress, George Bakris, Ricardo Correa-Rotter, Fan-Fan Hou, Dalane W Kitzman, Donald Kohan, Hirofumi Makino, John J V McMurray, Joel Z Melnick, Michael G Miller, Pablo E Pergola, Vlado Perkovic, Sheldon Tobe, Tingting Yi, Melissa Wigderson, Dick de Zeeuw, Alicia Elbert, Augusto Vallejos, Andres Alvarisqueta, Laura Maffei, Luis Juncos, Javier de Arteaga, Gustavo Greloni, Eduardo Farias, Alfredo Zucchini, Daniel Vogel, Ana Cusumano, Juan Santos, Margaret Fraenkel, Martin Gallagher, Tim Davis, Shamasunder Acharya, Duncan Cooke, Michael Suranyi, Simon Roger, Nigel Toussaint, Carol Pollock, Doris Chan, Stephen Stranks, Richard MacIsaac, Zoltan Endre, Alice Schmidt, Rudolf Prager, Gert Mayer, Xavier Warling, Michel Jadoul, Jean Hougardy, Chris Vercammen, Bruno Van Vlem, Pieter Gillard, Adriana Costa e Forti, Joao Lindolfo Borges, Luis Santos Canani, Freddy Eliaschewitz, Silmara Leite, Fadlo Fraige Filho, Raphael Paschoalin, Jose Andrade Moura Neto, Luciane Deboni, Irene de Lourdes Noronha, Cintia Cercato, Carlos Alberto Prompt, Maria Zanella, Nelson Rassi, Domingos D'Avila, Rosangela Milagres, Joao Felicio, Roberto Pecoits Filho, Miguel Carlos Riella, Joao Salles, Elizete Keitel, Sergio Draibe, Celso Amodeo, Joseph Youmbissi, Louise Roy, Serge Cournoyer, Shivinder Jolly, Vincent Pichette, Gihad Nesrallah, Harpreet Singh Bajaj, Hasnain Khandwala, Ronnie Aronson, Richard Goluch, Paul Tam, Christian Rabbat, Gordon Bailey, Stephen Chow, Alvaro Castillo, Alfredo Danin Vargas, Fernando Gonzalez, Rodrigo Munoz, Vicente Gutierrez, Gonzalo Godoy, Hongwen Zhao, Zhangsuo Liu, Minghui Zhao, Xiaohui Guo, Benli Su, Shuxia Fu, Yan Xu, Jinkui Yang, Bingyin Shi, Guanqing Xiao, Wei Shi, Chuanming Hao, Changying Xing, Fanfan Hou, Qun Luo, Yuxiu Li, Linong Ji, Li Zuo, Song Wang, Zhaohui Ni, Guohua Ding, Nan Chen, Jiajun Zhao, Weiping Jia, Shengqiang Yu, Jian Weng, Gang Xu, Ping Fu, Shiren Sun, Bicheng Liu, Xiaoqiang Ding, Ivan Rychlik, Alexandra Oplustilova, Dagmar Bartaskova, Vaclava Honova, Hana Chmelickova, Martin Petr, Petr Bucek, Vladimir Tesar, Emil Zahumensky, Johan Povlsen, Kenneth Egstrup, Anna Oczachowska-Kulik, Peter Rossing, Jorma Lahtela, Jorma Strand, Ilkka Kantola, Catherine Petit, Christian Combe, Philippe Zaoui, Vincent Esnault, Pablo Urena Torres, Jean-Michel Halimi, Bertrand Dussol, Tasso Bieler, Klemens Budde, Frank Dellanna, Thomas Segiet, Christine Kosch, Hans Schmidt-Guertler, Isabelle Schenkenberger, Volker Vielhauer, Frank Pistrosch, Mark Alscher, Christoph Hasslacher, Christian Hugo, Anja Muehlfeld, Christoph Wanner, Ploumis Passadakis, Theofanis Apostolou, Nikolaos Tentolouris, Ioannis Stefanidis, Konstantinos Mavromatidis, Vasilios Liakopoulos, Dimitrios Goumenos, Konstantinos Siamopoulos, Vincent Yeung, Risa Ozaki, Samuel Fung, Kathryn Tan, Sydney Tang, Sing Leung Lui, Siu Fai Cheung, Seamus Sreenan, Joseph Eustace, Donal O'Shea, Peter Lavin, Austin Stack, Yoram Yagil, Julio Wainstein, Hilla Knobler, Josef Cohen, Irina Kenis, Deeb Daoud, Yosefa Bar-Dayan, Victor Frajewicki, Faiad Adawi, Loreto Gesualdo, Domenico Santoro, Francesco Marino, Andrea Galfre, Chiara Brunati, Piero Ruggenenti, Giuseppe Rombola, Giuseppe Pugliese, Maura Ravera, Fabio Malberti, Giuseppe Pontoriero, Teresa Rampino, Salvatore De Cosmo, Ciro Esposito, Felice Nappi, Cataldo Abaterusso, Giuseppe Conte, Vincenzo Panichi, Davide Lauro, Giovambattista Capasso, Domenico Russo, Jiichi Anzai, Motoji Naka, Keita Ato, Tetsuro Tsujimoto, Toshinori Nimura, Eitaro Nakashima, Tetsuro Takeda, Shinya Fujii, Kunihisa Kobayashi, Hideaki Iwaoka, Koji Nagayama, Hiroyuki Harada, Hajime Maeda, Rui Kishimoto, Tadashi Iitsuka, Naoki Itabashi, Ryuichi Furuya, Yoshitaka Maeda, Daishiro Yamada, Nobuhiro Sasaki, Hiromitsu Sasaki, Shinichiro Ueda, Naoki Kashihara, Shuichi Watanabe, Takehiro Nakamura, Hidetoshi Kanai, Yuichiro Makita, Keiko Ono, Noriyuki Iehara, Daisuke Goto, Keiichiro Kosuge, Kenichi Tsuchida, Toshiaki Sato, Takashi Sekikawa, Hideki Okamoto, Tsuyoshi Tanaka, Naoko Ikeda, Takenobu Tadika, Koji Mukasa, Takeshi Osonoi, Fuminori Hirano, Motonobu Nishimura, Yuko Yambe, Yukio Tanaka, Makoto Ujihara, Takashi Sakai, Mitsuo Imura, Yutaka Umayahara, Shinya Makino, Jun Nakazawa, Yukinari Yamaguchi, Susumu Kashine, Hiroaki Miyaoka, Katsunori Suzuki, Toshihiko Inoue, Sou Nagai, Nobuyuki Sato, Masahiro Yamamoto, Noriyasu Taya, Akira Fujita, Akira Matsutani, Yugo Shibagaki, Yuichi Sato, Akira Yamauchi, Masahiro Tsutsui, Tamayo Ishiko, Shizuka Kaneko, Nobuyuki Azuma, Hirofumi Matsuda, Yasuhiro Hashiguchi, Yukiko Onishi, Mikiya Tokui, Munehide Matsuhisa, Arihiro Kiyosue, Junji Shinoda, Kazuo Ishikawa, Ghazali Ahmad, Shalini Vijayasingham, Nor Azizah Aziz, Zanariah Hussein, Yin Khet Fung, Wan Hasnul Halimi Wan Hassan, Hin Seng Wong, Bak Leong Goh, Norhaliza Mohd Ali, Nor Shaffinaz Yusuf Azmi Merican, Indralingam Vaithilingam, Nik Nur Fatnoon Nik Ahmad, Noor Adam, Norlela Sukor, V Paranthaman P Vengadasalam, Khalid Abdul Kadir, Mafauzy Mohamed, Karina Renoirte Lopez, Aniceto Leguizamo-Dimas, Alfredo Chew Wong, Jose Chevaile-Ramos, Jose Gonzalez Gonzalez, Raul Rico Hernandez, Jose Nino-Cruz, Leobardo Sauque Reyna, Guillermo Gonzalez-Galvez, Magdalena Madero Rovalo, Tomasso Bochicchio-Ricardelli, Jorge Aldrete, Jaime Carranza-Madrigal, Liffert Vogt, Peter Smak Gregoor, JNM Barendregt, Peter Luik, Ronald Gansevoort, Gozewijn Laverman, Helen Pilmore, Helen Lunt, John Baker, Steven Miller, Kannaiyan Rabindranath, Luis Zapata-Rincon, Rolando Vargas-Gonzales, Jorge Calderon Ticona, Augusto Dextre Espinoza, Jose Burga Nunez, Carlos Antonio Zea-Nunez, Benjamin Herrada Orue, Boris Medina-Santander, Cesar Delgado-Butron, Julio Farfan-Aspilcueta, Stanislaw Mazur, Miroslaw Necki, Michal Wruk, Katarzyna Klodawska, Grazyna Popenda, Ewa Skokowska, Malgorzata Arciszewska, Andrzej Wiecek, Kazimierz Ciechanowski, Michal Nowicki, Rita Birne, Antonio Cabrita, Aura Ramos, Manuel Anibal Antunes Ferreira, Evelyn Matta Fontanet, Altagracia Aurora Alcantara-Gonzalez, Angel Comulada-Rivera, Eugenia Galindo Ramos, Jose Cangiano, Luis Quesada-Suarez, Ricardo Calderon Ortiz, Jose Vazquez-Tanus, Rafael Burgos-Calderon, Carlos Rosado, Nicolae Hancu, Ella Pintilei, Cristina Mistodie, Gabriel Bako, Lavinia Ionutiu, Ligia Petrica, Romulus Timar, Liliana Tuta, Livia Duma, Adriana Tutescu, Svetlana Ivanova, Ashot Essaian, Konstantin Zrazhevskiy, Natalia Tomilina, Elena Smolyarchuk, Anatoly Kuzin, Olga Lantseva, Irina Karpova, Minara Shamkhalova, Natalia Liberanskaya, Andrey Yavdosyuk, Yuri Shvarts, Tatiana Bardymova, Olga Blagoveshchenskaya, Oleg Solovev, Elena Rechkova, Natalia Pikalova, Maria Pavlova, Elena Kolmakova, Rustam Sayfutdinov, Svetlana Villevalde, Natalya Koziolova, Vladimir Martynenko, Vyacheslav Marasaev, Adelya Maksudova, Olga Sigitova, Viktor Mordovin, Vadim Klimontov, Yulia Samoylova, Tatiana Karonova, Lee Ying Yeoh, Boon Wee Teo, Marjorie Wai Yin Foo, Adrian Liew, Ivan Tkac, Aniko Oroszova, Jozef Fekete, Jaroslav Rosenberger, Ida Obetkova, Alla Fulopova, Eva Kolesarova, Katarina Raslova, Peter Smolko, Adrian Oksa, Larry Distiller, Julien Trokis, Luthando Adams, Hemant Makan, Padaruth Ramlachan, Essack Mitha, Kathleen Coetzee, Zelda Punt, Qasim Bhorat, Puvenesvari Naiker, Graham Ellis, Louis Van Zyl, Kwan Woo Lee, Min Seon Kim, Soon-Jib Yoo, Kun Ho Yoon, Yong-Wook Cho, Tae-Sun Park, Sang Yong Kim, Moon-Gi Choi, Tae Keun Oh, Kang-Wook Lee, Ho Sang Shon, Sung Hwan Suh, Byung-Joon Kim, Kim Doo-Man, Joo Hark Yi, Sang Ah Lee, Ho Chan Cho, Sin-Gon Kim, Dae-Ryong Cha, Ji A Seo, Kyung Mook Choi, Jeong-Taek Woo, Kyu Jeung Ahn, Jae Hyuk Lee, In-Joo Kim, Moon-Kyu Lee, Hak Chul Jang, Kyong-Soo Park, Beom Seok Kim, Ji Oh Mok, Mijung Shin, Sun Ae Yoon, Il-Seong Nam-Goong, Choon Hee Chung, Tae Yang Yu, Hyoung Woo Lee, Alfonso Soto Gonzalez, Jaume Almirall, Jesus Egido, Francesca Calero Gonzalez, Gema Fernandez Fresnedo, Ildefonso Valera Cortes, Manuel Praga Terente, Isabel Garcia Mendez, Juan Navarro Gonzalez, Jose Herrero Calvo, Secundino Cigarran Guldris, Mario Prieto Velasco, Jose Ignacio Minguela Pesquera, Antonio Galan, Julio Pascual, Maria Marques Vidas, Judith Martins Munoz, Jose Rodriguez-Perez, Cristina Castro-Alonso, Josep Bonet Sol, Daniel Seron, Elvira Fernandez Giraldez, Javier Arrieta Lezama, Nuria Montero, Julio Hernandez-Jaras, Rafael Santamaria Olmo, Jose Ramon Molas Coten, Olof Hellberg, Bengt Fellstrom, Andreas Bock, Dee Pei, Ching-Ling Lin, Kai-Jen Tien, Ching-Chu Chen, Chien-Ning Huang, Ju-Ying Jiang, Du-An Wu, Chih-Hsun Chu, Shih-Ting Tseng, Jung-Fu Chen, Cho-Tsan Bau, Wayne Sheu, Mai-Szu Wu, Ramazan Sari, Siren Sezer, Alaattin Yildiz, Ilhan Satman, Betul Kalender, Borys Mankovskyy, Ivan Fushtey, Mykola Stanislavchuk, Mykola Kolenyk, Iryna Dudar, Viktoriia Zolotaikina, Orest Abrahamovych, Tetyana Kostynenko, Olena Petrosyan, Petro Kuskalo, Olga Galushchak, Oleg Legun, Ivan Topchii, Liliya Martynyuk, Vasyl Stryzhak, Svitlana Panina, Sergii Tkach, Vadym Korpachev, Peter Maxwell, Luigi Gnudi, Sui Phin Kon, Hilary Tindall, Phillip Kalra, Patrick Mark, Dipesh Patel, Mohamed El-Shahawy, Liqun Bai, Romanita Nica, Yeong-Hau Lien, Judson Menefee, Robert Busch, Alan Miller, Azazuddin Ahmed, Ahmed Arif, Joseph Lee, Sachin Desai, Shweta Bansal, Marie Bentsianov, Mario Belledonne, Charles Jere, Raul Gaona, Gregory Greenwood, Osvaldo Brusco, Mark Boiskin, Diogo Belo, Raffi Minasian, Naveen Atray, Mary Lawrence, John Taliercio, Pablo Pergola, David Scott, German Alvarez, Bradley Marder, Thomas Powell, Wa'el Bakdash, George Stoica, Christopher McFadden, Marc Rendell, Jonathan Wise, Audrey Jones, Michael Jardula, Ivy-Joan Madu, Freemu Varghese, Brian Tulloch, Ziauddin Ahmed, Melanie Hames, Imran Nazeer, Newman Shahid, Rekha John, Manuel Montero, David Fitz-Patrick, Lawrence Phillips, Antonio Guasch, Elena Christofides, Aijaz Gundroo, Mohammad Amin, Cynthia Bowman-Stroud, Michael Link, Laura Mulloy, Michael Nammour, Tarik Lalwani, Lenita Hanson, Adam Whaley-Connell, Lee Herman, Rupi Chatha, Sayed Osama, Kenneth Liss, Zeid Kayali, Anuj Bhargava, Ezra Israel, Alfredo Peguero-Rivera, Michael Fang, Judith Slover, Elena Barengolts, Jose Flores, Rosemary Muoneke, Virginia Savin, Stella Awua-Larbi, Andrew Levine, George Newman, Laden Golestaneh, Guillermo Bohm, Efrain Reisin, Lucita Cruz, Robert Weiss, Franklin Zieve, Edward Horwitz, Peale Chuang, James Mersey, John Manley, Ronald Graf, Fadi Bedros, Sudhir Joshi, Juan Frias, Ali Assefi, Andrew O'Shaughnessy, Roman Brantley, Todd Minga, David Tietjen, Samuel Kantor, Aamir Jamal, Ramon Guadiz, Kenneth Hershon, Peter Bressler, Nelson Kopyt, Harold Cathcart, Scott Bloom, Ronald Reichel, Samer Nakhle, Emily Dulude, Joshua Tarkan, Penelope Baker, Steven Zeig, Jaynier Moya Hechevarria, Armando Ropero-Cartier, Gilda De la Calle, Ankur Doshi, Fadi Saba, Teresa Sligh, Sylvia Shaw, Jayant Kumar, Harold Szerlip, George Bayliss, Alan Perlman, Lakhi Sakhrani, Steven Gouge, Georges Argoud, Idalia Acosta, John Elder, Sucharit Joshi, John Sensenbrenner, Steven Vicks, Roberto Mangoo-Karim, Claude Galphin, Carlos Leon-Forero, John Gilbert, Eric Brown, Adeel Ijaz, Salman Butt, Mariana Markell, Carlos Arauz-Pacheco, Lance Sloan, Odilon Alvarado, Serge Jabbour, Eric Simon, Anjay Rastogi, Sam James, Karen Hall, John Melish, Brad Dixon, Allen Adolphe, Csaba Kovesdy, Srinivasan Beddhu, Richard Solomon, Ronald Fernando, Ellis Levin, Charuhas Thakar, Brooks Robey, David Goldfarb, Linda Fried, Geetha Maddukuri, Stephen Thomson, Andrew Annand, Saeed Kronfli, Paramjit Kalirao, Rebecca Schmidt, Neera Dahl, Samuel Blumenthal, Debra Weinstein, Ove Ostergaard, Talia Weinstein, Yasuhiro Ono, Murat Yalcin, Shahana Karim, APH - Health Behaviors & Chronic Diseases, Nephrology, ACS - Amsterdam Cardiovascular Sciences, ACS - Microcirculation, Biomedical Signals and Systems, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Groningen Kidney Center (GKC), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Heerspink, H. J. L., Parving, H. -H., Andress, D. L., Bakris, G., Correa-Rotter, R., Hou, F. -F., Kitzman, D. W., Kohan, D., Makino, H., Mcmurray, J. J. V., Melnick, J. Z., Miller, M. G., Pergola, P. E., Perkovic, V., Tobe, S., Yi, T., Wigderson, M., de Zeeuw, D., Elbert, A., Vallejos, A., Alvarisqueta, A., Maffei, L., Juncos, L., de Arteaga, J., Greloni, G., Farias, E., Zucchini, A., Vogel, D., Cusumano, A., Santos, J., Fraenkel, M., Gallagher, M., Davis, T., Acharya, S., Cooke, D., Suranyi, M., Roger, S., Toussaint, N., Pollock, C., Chan, D., Stranks, S., Macisaac, R., Endre, Z., Schmidt, A., Prager, R., Mayer, G., Warling, X., Jadoul, M., Hougardy, J., Vercammen, C., Van Vlem, B., Gillard, P., Costa e Forti, A., Borges, J. L., Santos Canani, L., Eliaschewitz, F., Leite, S., Fraige Filho, F., Paschoalin, R., Moura Neto, J. A., Deboni, L., de Lourdes Noronha, I., Cercato, C., Prompt, C. A., Zanella, M., Rassi, N., D'Avila, D., Milagres, R., Felicio, J., Pecoits Filho, R., Riella, M. C., Salles, J., Keitel, E., Draibe, S., Amodeo, C., Youmbissi, J., Roy, L., Cournoyer, S., Jolly, S., Pichette, V., Nesrallah, G., Bajaj, H. S., Khandwala, H., Aronson, R., Goluch, R., Tam, P., Rabbat, C., Bailey, G., Chow, S., Castillo, A., Danin Vargas, A., Gonzalez, F., Munoz, R., Gutierrez, V., Godoy, G., Zhao, H., Liu, Z., Zhao, M., Guo, X., Su, B., Fu, S., Xu, Y., Yang, J., Shi, B., Xiao, G., Shi, W., Hao, C., Xing, C., Hou, F., Luo, Q., Li, Y., Ji, L., Zuo, L., Wang, S., Ni, Z., Ding, G., Chen, N., Zhao, J., Jia, W., Yu, S., Weng, J., Xu, G., Fu, P., Sun, S., Liu, B., Ding, X., Rychlik, I., Oplustilova, A., Bartaskova, D., Honova, V., Chmelickova, H., Petr, M., Bucek, P., Tesar, V., Zahumensky, E., Povlsen, J., Egstrup, K., Oczachowska-Kulik, A., Rossing, P., Lahtela, J., Strand, J., Kantola, I., Petit, C., Combe, C., Zaoui, P., Esnault, V., Urena Torres, P., Halimi, J. -M., Dussol, B., Bieler, T., Budde, K., Dellanna, F., Segiet, T., Kosch, C., Schmidt-Guertler, H., Schenkenberger, I., Vielhauer, V., Pistrosch, F., Alscher, M., Hasslacher, C., Hugo, C., Muehlfeld, A., Wanner, C., Passadakis, P., Apostolou, T., Tentolouris, N., Stefanidis, I., Mavromatidis, K., Liakopoulos, V., Goumenos, D., Siamopoulos, K., Yeung, V., Ozaki, R., Fung, S., Tan, K., Tang, S., Lui, S. L., Cheung, S. F., Sreenan, S., Eustace, J., O'Shea, D., Lavin, P., Stack, A., Yagil, Y., Wainstein, J., Knobler, H., Cohen, J., Kenis, I., Daoud, D., Bar-Dayan, Y., Frajewicki, V., Adawi, F., Gesualdo, L., Santoro, D., Marino, F., Galfre, A., Brunati, C., Ruggenenti, P., Rombola, G., Pugliese, G., Ravera, M., Malberti, F., Pontoriero, G., Rampino, T., De Cosmo, S., Esposito, C., Nappi, F., Abaterusso, C., Conte, G., Panichi, V., Lauro, D., Capasso, G., Russo, D., Anzai, J., Naka, M., Ato, K., Tsujimoto, T., Nimura, T., Nakashima, E., Takeda, T., Fujii, S., Kobayashi, K., Iwaoka, H., Nagayama, K., Harada, H., Maeda, H., Kishimoto, R., Iitsuka, T., Itabashi, N., Furuya, R., Maeda, Y., Yamada, D., Sasaki, N., Sasaki, H., Ueda, S., Kashihara, N., Watanabe, S., Nakamura, T., Kanai, H., Makita, Y., Ono, K., Iehara, N., Goto, D., Kosuge, K., Tsuchida, K., Sato, T., Sekikawa, T., Okamoto, H., Tanaka, T., Ikeda, N., Tadika, T., Mukasa, K., Osonoi, T., Hirano, F., Nishimura, M., Yambe, Y., Tanaka, Y., Ujihara, M., Sakai, T., Imura, M., Umayahara, Y., Makino, S., Nakazawa, J., Yamaguchi, Y., Kashine, S., Miyaoka, H., Suzuki, K., Inoue, T., Nagai, S., Sato, N., Yamamoto, M., Taya, N., Fujita, A., Matsutani, A., Shibagaki, Y., Sato, Y., Yamauchi, A., Tsutsui, M., Ishiko, T., Kaneko, S., Azuma, N., Matsuda, H., Hashiguchi, Y., Onishi, Y., Tokui, M., Matsuhisa, M., Kiyosue, A., Shinoda, J., Ishikawa, K., Ahmad, G., Vijayasingham, S., Aziz, N. A., Hussein, Z., Fung, Y. K., Hassan, W. H. H. W., Wong, H. S., Goh, B. L., Ali, N. M., Merican, N. S. Y. A., Vaithilingam, I., Nik Ahmad, N. N. F., Adam, N., Sukor, N., Vengadasalam, V. P. P., Abdul Kadir, K., Mohamed, M., Renoirte Lopez, K., Leguizamo-Dimas, A., Chew Wong, A., Chevaile-Ramos, J., Gonzalez Gonzalez, J., Rico Hernandez, R., Nino-Cruz, J., Sauque Reyna, L., Gonzalez-Galvez, G., Madero Rovalo, M., Bochicchio-Ricardelli, T., Aldrete, J., Carranza-Madrigal, J., Vogt, L., Smak Gregoor, P., Barendregt, J. N. M., Luik, P., Gansevoort, R., Laverman, G., Pilmore, H., Lunt, H., Baker, J., Miller, S., Rabindranath, K., Zapata-Rincon, L., Vargas-Gonzales, R., Calderon Ticona, J., Dextre Espinoza, A., Burga Nunez, J., Zea-Nunez, C. A., Herrada Orue, B., Medina-Santander, B., Delgado-Butron, C., Farfan-Aspilcueta, J., Mazur, S., Necki, M., Wruk, M., Klodawska, K., Popenda, G., Skokowska, E., Arciszewska, M., Wiecek, A., Ciechanowski, K., Nowicki, M., Birne, R., Cabrita, A., Ramos, A., Antunes Ferreira, M. A., Matta Fontanet, E., Alcantara-Gonzalez, A. A., Comulada-Rivera, A., Galindo Ramos, E., Cangiano, J., Quesada-Suarez, L., Calderon Ortiz, R., Vazquez-Tanus, J., Burgos-Calderon, R., Rosado, C., Hancu, N., Pintilei, E., Mistodie, C., Bako, G., Ionutiu, L., Petrica, L., Timar, R., Tuta, L., Duma, L., Tutescu, A., Ivanova, S., Essaian, A., Zrazhevskiy, K., Tomilina, N., Smolyarchuk, E., Kuzin, A., Lantseva, O., Karpova, I., Shamkhalova, M., Liberanskaya, N., Yavdosyuk, A., Shvarts, Y., Bardymova, T., Blagoveshchenskaya, O., Solovev, O., Rechkova, E., Pikalova, N., Pavlova, M., Kolmakova, E., Sayfutdinov, R., Villevalde, S., Koziolova, N., Martynenko, V., Marasaev, V., Maksudova, A., Sigitova, O., Mordovin, V., Klimontov, V., Samoylova, Y., Karonova, T., Yeoh, L. Y., Teo, B. W., Foo, M. W. Y., Liew, A., Tkac, I., Oroszova, A., Fekete, J., Rosenberger, J., Obetkova, I., Fulopova, A., Kolesarova, E., Raslova, K., Smolko, P., Oksa, A., Distiller, L., Trokis, J., Adams, L., Makan, H., Ramlachan, P., Mitha, E., Coetzee, K., Punt, Z., Bhorat, Q., Naiker, P., Ellis, G., Van Zyl, L., Lee, K. W., Kim, M. S., Yoo, S. -J., Yoon, K. H., Cho, Y. -W., Park, T. -S., Kim, S. Y., Choi, M. -G., Oh, T. K., Lee, K. -W., Shon, H. S., Suh, S. H., Kim, B. -J., Doo-Man, K., Yi, J. H., Lee, S. A., Cho, H. C., Kim, S. -G., Cha, D. -R., Seo, J. A., Choi, K. M., Woo, J. -T., Ahn, K. J., Lee, J. H., Kim, I. -J., Lee, M. -K., Jang, H. C., Park, K. -S., Kim, B. S., Mok, J. O., Shin, M., Yoon, S. A., Nam-Goong, I. -S., Chung, C. H., Yu, T. Y., Lee, H. W., Soto Gonzalez, A., Almirall, J., Egido, J., Calero Gonzalez, F., Fernandez Fresnedo, G., Valera Cortes, I., Praga Terente, M., Garcia Mendez, I., Navarro Gonzalez, J., Herrero Calvo, J., Cigarran Guldris, S., Prieto Velasco, M., Minguela Pesquera, J. I., Galan, A., Pascual, J., Marques Vidas, M., Martins Munoz, J., Rodriguez-Perez, J., Castro-Alonso, C., Bonet Sol, J., Seron, D., Fernandez Giraldez, E., Arrieta Lezama, J., Montero, N., Hernandez-Jaras, J., Santamaria Olmo, R., Molas Coten, J. R., Hellberg, O., Fellstrom, B., Bock, A., Pei, D., Lin, C. -L., Tien, K. -J., Chen, C. -C., Huang, C. -N., Jiang, J. -Y., Wu, D. -A., Chu, C. -H., Tseng, S. -T., Chen, J. -F., Bau, C. -T., Sheu, W., Wu, M. -S., Sari, R., Sezer, S., Yildiz, A., Satman, I., Kalender, B., Mankovskyy, B., Fushtey, I., Stanislavchuk, M., Kolenyk, M., Dudar, I., Zolotaikina, V., Abrahamovych, O., Kostynenko, T., Petrosyan, O., Kuskalo, P., Galushchak, O., Legun, O., Topchii, I., Martynyuk, L., Stryzhak, V., Panina, S., Tkach, S., Korpachev, V., Maxwell, P., Gnudi, L., Kon, S. P., Tindall, H., Kalra, P., Mark, P., Patel, D., El-Shahawy, M., Bai, L., Nica, R., Lien, Y. -H., Menefee, J., Busch, R., Miller, A., Ahmed, A., Arif, A., Lee, J., Desai, S., Bansal, S., Bentsianov, M., Belledonne, M., Jere, C., Gaona, R., Greenwood, G., Brusco, O., Boiskin, M., Belo, D., Minasian, R., Atray, N., Lawrence, M., Taliercio, J., Pergola, P., Scott, D., Alvarez, G., Marder, B., Powell, T., Bakdash, W., Stoica, G., Mcfadden, C., Rendell, M., Wise, J., Jones, A., Jardula, M., Madu, I. -J., Varghese, F., Tulloch, B., Ahmed, Z., Hames, M., Nazeer, I., Shahid, N., John, R., Montero, M., Fitz-Patrick, D., Phillips, L., Guasch, A., Christofides, E., Gundroo, A., Amin, M., Bowman-Stroud, C., Link, M., Mulloy, L., Nammour, M., Lalwani, T., Hanson, L., Whaley-Connell, A., Herman, L., Chatha, R., Osama, S., Liss, K., Kayali, Z., Bhargava, A., Israel, E., Peguero-Rivera, A., Fang, M., Slover, J., Barengolts, E., Flores, J., Muoneke, R., Savin, V., Awua-Larbi, S., Levine, A., Newman, G., Golestaneh, L., Bohm, G., Reisin, E., Cruz, L., Weiss, R., Zieve, F., Horwitz, E., Chuang, P., Mersey, J., Manley, J., Graf, R., Bedros, F., Joshi, S., Frias, J., Assefi, A., O'Shaughnessy, A., Brantley, R., Minga, T., Tietjen, D., Kantor, S., Jamal, A., Guadiz, R., Hershon, K., Bressler, P., Kopyt, N., Cathcart, H., Bloom, S., Reichel, R., Nakhle, S., Dulude, E., Tarkan, J., Baker, P., Zeig, S., Moya Hechevarria, J., Ropero-Cartier, A., De la Calle, G., Doshi, A., Saba, F., Sligh, T., Shaw, S., Kumar, J., Szerlip, H., Bayliss, G., Perlman, A., Sakhrani, L., Gouge, S., Argoud, G., Acosta, I., Elder, J., Sensenbrenner, J., Vicks, S., Mangoo-Karim, R., Galphin, C., Leon-Forero, C., Gilbert, J., Brown, E., Ijaz, A., Butt, S., Markell, M., Arauz-Pacheco, C., Sloan, L., Alvarado, O., Jabbour, S., Simon, E., Rastogi, A., James, S., Hall, K., Melish, J., Dixon, B., Adolphe, A., Kovesdy, C., Beddhu, S., Solomon, R., Fernando, R., Levin, E., Thakar, C., Robey, B., Goldfarb, D., Fried, L., Maddukuri, G., Thomson, S., Annand, A., Kronfli, S., Kalirao, P., Schmidt, R., Dahl, N., Blumenthal, S., Weinstein, D., Ostergaard, O., Weinstein, T., Ono, Y., Yalcin, M., Karim, S., Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, and Diabetes Clinic

Subjects
Male, endothelin, albuminuria, nephropathy, inhibition, Diabetes Mellitus, Type 2/drug therapy, Endocrinology, Diabetes and Metabolism, Placebo-controlled study, Administration, Oral, 030204 cardiovascular system & hematology, Settore MED/13 - Endocrinologia, chemistry.chemical_compound, 0302 clinical medicine, ENDOTHELIN, 80 and over, Diabetic Nephropathies, 030212 general & internal medicine, Renal Insufficiency, Chronic, Aged, 80 and over, Diabetic Nephropathies/blood, General Medicine, Middle Aged, Atrasentan/administration & dosage, Editorial Commentary, Treatment Outcome, Nephrology, Creatinine, Administration, young adult, Female, medicine.symptom, Glomerular filtration rate, Type 2, Endothelin A Receptor Antagonists/administration & dosage, medicine.drug, Glomerular Filtration Rate, Human, Oral, Adult, medicine.medical_specialty, ALBUMINURIA, Endothelin A Receptor Antagonists, NEPHROPATHY, Urology, INHIBITION, Renal function, Serum Albumin, Human, Placebo, Nephropathy, 03 medical and health sciences, Young Adult, Double-Blind Method, Atresentan, diabetes, chronic kidney disease, medicine, Diabetes Mellitus, Aged, Atrasentan, Diabetes Mellitus, Type 2, Humans, Renal Insufficiency, Chronic, Serum Albumin, business.industry, Creatinine/blood, medicine.disease, Serum Albumin, Human/urine, n/a OA procedure, chemistry, Albuminuria, Renal Insufficiency, Chronic/blood, business, aged, 80 and over, Kidney disease
Abstract

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Published
2019
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8. Efficacy of low-dose rosuvastatin in patients with type 2 diabetes and hypo high-density lipoprotein cholesterolaemia

Author

Mariko Murakami, Makoto Ujihara, Sachiko Takagi, Yasushi Tanaka, Akio Ohta, Takuyuki Katabami, Tomoya Matsui, Mariko Higa, Suzuko Kobayashi, and Takamasa Ichijo

Subjects
Male, Type 2 diabetes, Biochemistry, Gastroenterology, chemistry.chemical_compound, High-density lipoprotein, Prospective Studies, Rosuvastatin Calcium, Creatine Kinase, Hypolipidemic Agents, Aged, 80 and over, Sulfonamides, biology, Anticholesteremic Agents, General Medicine, Middle Aged, Female, lipids (amino acids, peptides, and proteins), Lipoproteins, HDL, medicine.drug, Adult, medicine.medical_specialty, Renal function, Carbohydrate metabolism, Young Adult, Internal medicine, medicine, Humans, Rosuvastatin, Triglycerides, Aged, Dyslipidemias, business.industry, Cholesterol, HDL, Biochemistry (medical), nutritional and metabolic diseases, Type 2 Diabetes Mellitus, Cholesterol, LDL, Cell Biology, medicine.disease, Fluorobenzenes, Glucose, Pyrimidines, Endocrinology, Diabetes Mellitus, Type 2, chemistry, biology.protein, Creatine kinase, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Lipoprotein
Abstract

Objective To analyse the efficacy of low-dose rosuvastatin for treating hypo high-density lipoprotein (HDL) cholesterolaemia in patients with type 2 diabetes and dyslipidaemia. Methods Patients with HDL-cholesterol (C) Results Out of 49 patients, all lipid parameters other than TG were significantly improved at 3 and 6 months. At 3 months, 83.3% of patients had achieved the target LDL-C level. Among nonlipid parameters, no changes were observed except for estimated glomerular filtration rate, which was improved by + 5.2% and + 9.6% at 3 and 6 months, respectively. Conclusions Low-dose rosuvastatin was effective in improving hypo-HDL cholesterolaemia and may have renoprotective effects.

Published
2014
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10. Prevalence of metabolic syndrome in stroke patients: a prospective multicenter study in Japan

Author

Yasuhiro Manabe, Eiichi Araki, Makoto Ujihara, Shozo Kobori, Hayato Takayama, Takaaki Kikuno, Takeshi Takahashi, Masahiro Yasaka, Masahiro Harada, and Daikai Sadamitsu

Subjects
medicine.medical_specialty, Waist, business.industry, General Engineering, Infarction, medicine.disease, Obesity, Internal medicine, Diabetes mellitus, medicine, Physical therapy, Metabolic syndrome, business, Prospective cohort study, Stroke, Dyslipidemia
Abstract

Aims The fact that Metabolic Syndrome (MetS) increases the risk of atherosclerosis has been epidemiologically studied and proven; however, a prospective study on the prevalence of MetS in stroke patients has never been conducted because of the difficulty in diagnosis under critical illness in the acute phase. Therefore, we conducted a prospective multicenter study to investigate the prevalence of MetS in stroke patients with modified diagnostic criteria for MetS. Methods Stroke patients admitted in the seven participating Emergency and Critical Care Centers within the two years from April 2007 were registered in this study as a prospective multicenter study. Inclusion criteria were 50 to 89 year-old stroke patients who presented within three days from the onset of symptoms. A total of 992 subjects were classified according to the stroke type and the prevalence of MetS and the associated risk factors were investigated. The participants in a medical checkup without any history of a stroke were enrolled as the control group, and compared between the two groups. Results The prevalence of MetS as well as hyperglycemia and dyslipidemia in the infarction group was significantly higher than that in the non-stroke group. While the hemorrhage group showed no significant difference in the prevalence of MetS, only hypertension was significantly high. According to a subtype analysis, there is a significant correlation between waist circumference increment of the stroke patients and the prevalence of the risk factors of hypertension, hyperglycemia and dyslipidemia. Conclusions Different risk factors are significantly related to the type of stroke.

Published
2013
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11. Granulocyte-macrophage colony-stimulating factor ensures macrophage survival and generation of the superoxide anion: a study using a monocytic-differentiated HL60 subline

Author

Osamu Yamada, Kazue Takano, Makio Kobayashi, Makoto Ujihara, Kaoru Nomura, and Noriyuki Shibata

Subjects
Necrosis, Arteriosclerosis, Cell Survival, Cellular differentiation, Apoptosis, HL-60 Cells, DNA Fragmentation, Biology, Biochemistry, Monocytes, Paracrine signalling, Calcitriol, Superoxides, Physiology (medical), medicine, Humans, Macrophage, Interleukin 8, Autocrine signalling, Aorta, Cells, Cultured, Macrophages, Granulocyte-Macrophage Colony-Stimulating Factor, Cell Differentiation, Immunohistochemistry, Molecular biology, Granulocyte macrophage colony-stimulating factor, Microscopy, Fluorescence, Tetradecanoylphorbol Acetate, medicine.symptom, medicine.drug
Abstract

A large number of constituents, such as growth factors, cytokines, and vasoregulatory molecules, contribute a network of cellular interactions to atherosclerotic lesions, and current evidence suggests that granulocyte-macrophage colony-stimulating factor (GM-CSF) is one of these constituents. We conducted this study to determine whether GM-CSF has an effect on the fate and function of macrophages. We examined the effect of GM-CSF on macrophages in vitro with a highly inducible HL60 subclone (HL60/DU-1) that we recently established. HL60 cells have been reported to preserve functional GM-CSF receptors, but a GM-CSF allele was rearranged and partially deleted. HL60/DU-1 cells were devoid of GM-CSF immunoreactivity and of autocrine stimulation of GM-CSF. HL60/DU-1 cells fated to die soon after terminal differentiation of macrophages by 1, 25-dihydroxy vitamin D(3) treatment. We found cell death to be mediated mainly by necrosis, not apoptosis, as confirmed by DNA fragmentation in agarose gel electrophoresis, morphological observation under a fluorescence microscope, and assay of lactate dehydrogenase release. Exogeneously administered GM-CSF rescued cells from necrotic death and caused them to survive and generate superoxide anions. We also conducted immunohistochemical analysis on an atherosclerotic human artery. Macrophages, endothelial cells, and smooth muscle cells were found to be GM-CSF positive in an atherosclerotic lesion. In summary, GM-CSF, which is produced by macrophages, endothelial cells, and smooth muscle cells, is thought to act in an autocrine and a paracrine fashion as a necrosis-inhibiting factor against arterial macrophages. This unique function may play an important role in ensuring survival and promoting function in atherosclerotic lesions.

Published
2001
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12. Down-regulation of telomerase activity is an early event of cellular differentiation without apparent telomeric DNA change

Author

Minoko Takanashi, Osamu Yamada, Hideaki Mizoguchi, and Makoto Ujihara

Subjects
Cancer Research, Telomerase, Cellular differentiation, Down-Regulation, Tretinoin, Biology, chemistry.chemical_compound, Calcitriol, Downregulation and upregulation, Tumor Cells, Cultured, Humans, Telomerase reverse transcriptase, DNA Primers, Base Sequence, Cell Differentiation, DNA, Hematology, Telomere, Molecular biology, Kinetics, Oncology, chemistry, Cell culture, Luminescent Measurements, Hemin, K562 cells
Abstract

With the use of three different hematopoietic cell lineages, the downregulation of telomerase activity was found to be a general response to the induction of differentiation. The decrease in telomerase activity occurred as early as 24 h when HL-60 and K562 cells were cultured in the presence of 1alpha, 25 dihydroxyvitamin D3 (VD3), all-trans-retinoic acid (ATRA) and hemin, and completely disappeared after 3 days. On the other hand, MEG-01 cells showed a marked inhibition of telomerase activity after 6 days of culture with 12-0-tetradecanoylphorbal 13-acetate (TPA). The analysis of telomeric DNA in the HL-60 cells and K562 cells demonstrated no detectable loss of telomeric DNA with cellular differentiation, with a loss of telomerase activity. The repression of telomerase is a common molecular event during leukemic cell differentiation.

Published
1998
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13. Establishment of a stable HL60 subline having the potential for monocytic differentiation using granulocyte-macrophage colony-stimulating factor: possible use for the study of monocytic differentiation and oxidative stress

Author

Hiroshi Demura, Osamu Yamada, Makoto Ujihara, and Kaoru Nomura

Subjects
HL60, Cellular differentiation, CD14, Population, Carbazoles, Tretinoin, Biology, Monocytes, Propanolamines, chemistry.chemical_compound, Calcitriol, Superoxides, Tumor Cells, Cultured, medicine, Humans, education, education.field_of_study, Monocyte, Granulocyte-Macrophage Colony-Stimulating Factor, Cell Differentiation, Free Radical Scavengers, Molecular biology, Oxidative Stress, Probucol, medicine.anatomical_structure, Granulocyte macrophage colony-stimulating factor, chemistry, Integrin alpha M, Cell culture, Immunology, biology.protein, Carvedilol, Cardiology and Cardiovascular Medicine, medicine.drug
Abstract

A stable HL60 subline having the potential for monocytic differentiation was established by use of GM-CSF. HL60, a human promyelocytic cell line, has frequently been employed for research in the fields of monocytic differentiation and atherosclerosis because of its potential to differentiate into either granulocytes or monocytes. However, HL60 are frequently seen to change their phenotype during long-term culture. To date, many sublines or variants of HL60 cells have been established. However, most of them display diminished or complete loss of activities that characterize parental cells. The present study was conducted to establish a stable HL60 subline with the potential for monocytic differentiation. Firstly, a single HL60 cell was isolated by limiting dilution, and was successfully proliferated by incubation with GM-CSF. Secondly, from this population, cells were selected that had the ability to generate superoxide after VD-induced monocytic differentiation. Cells obtained in this manner (designated HL60/DU-1) exhibited expression of CD14 and CD11b and suppression of CD3 expression after monocytic differentiation. NBT positivity showed a consistent level of over 971% after a 6-day challenge with VD throughout the experimental period of 12 months. HL60/DU-1 cells, which were cryopreserved in liquid nitrogen for 6 months, thawed and re-cultured, exhibited over 97% NBT positivity. Carvedilol and probucol, which exhibit antioxidative activity, inhibited superoxide release from the differentiated HL60/DU-1 cells. HL60/DU-1 cell line is a promising model for the study of monocytic differentiation and the effects of oxygen radicals.

Published
1998
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14. Prevalence of metabolic syndrome in stroke patients: a prospective multicenter study in Japan

Author

Takeshi, Takahashi, Masahiro, Harada, Takaaki, Kikuno, Makoto, Ujihara, Daikai, Sadamitsu, Yasuhiro, Manabe, Masahiro, Yasaka, Hayato, Takayama, Shozo, Kobori, and Eiichi, Araki

Subjects
Original Articles
Abstract

The fact that Metabolic Syndrome (MetS) increases the risk of atherosclerosis has been epidemiologically studied and proven; however, a prospective study on the prevalence of MetS in stroke patients has never been conducted because of the difficulty in diagnosis under critical illness in the acute phase. Therefore, we conducted a prospective multicenter study to investigate the prevalence of MetS in stroke patients with modified diagnostic criteria for MetS.Stroke patients admitted in the seven participating Emergency and Critical Care Centers within the two years from April 2007 were registered in this study as a prospective multicenter study. Inclusion criteria were 50 to 89 year-old stroke patients who presented within three days from the onset of symptoms. A total of 992 subjects were classified according to the stroke type and the prevalence of MetS and the associated risk factors were investigated. The participants in a medical checkup without any history of a stroke were enrolled as the control group, and compared between the two groups.The prevalence of MetS as well as hyperglycemia and dyslipidemia in the infarction group was significantly higher than that in the non-stroke group. While the hemorrhage group showed no significant difference in the prevalence of MetS, only hypertension was significantly high. According to a subtype analysis, there is a significant correlation between waist circumference increment of the stroke patients and the prevalence of the risk factors of hypertension, hyperglycemia and dyslipidemia.Different risk factors are significantly related to the type of stroke.

Published
2013

15. LH and testosterone modulate mercuric chloride-induced acute renal failure in male rats: the implication of stress-induced hypogonadism

Author

Makoto Ujihara, M Ogasawara, K Nomura, S Toraya, C Kikuchi, M Katayama, and Hiroshi Demura

Subjects
Male, Testosterone propionate, medicine.medical_specialty, Metabolic Clearance Rate, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Renal function, Kidney, Nephrotoxicity, Gonadotropin-Releasing Hormone, chemistry.chemical_compound, Endocrinology, Internal medicine, medicine, Animals, Testosterone, Orchiectomy, Rats, Wistar, business.industry, Hypogonadism, Acute Kidney Injury, Luteinizing Hormone, Androgen, Adaptation, Physiological, Rats, Castration, chemistry, Creatinine, Mercuric Chloride, Leuprolide, Gonadotropin, business, Stress, Psychological
Abstract

The significance of stress-induced hypogonadism remains unclear. Since plasma testosterone and LH have renotropic activity that is other than reproductive, we hypothesize that stress-induced hypogonadism is an adaptive response to protect the kidney. To examine this hypothesis, we prepared hypogonadal male rats with different levels of LH and testosterone through orchiectomy (castration), through chronic treatment with a slowly secreted form of gonadotropin-releasing hormone agonist (GnRHA; GnRHA pretreatment), or through both treatments concomitantly (castration with GnRHA pretreatment). Castrated rats had undetectable plasma testosterone and high plasma LH. GnRHA-pretreated rats had low plasma testosterone and normal plasma LH. Castrated rats with GnRHA pretreatment had undetectable plasma testosterone and normal plasma LH. We compared their sensitivity to HgCl2 nephrotoxicity and found that, when a low dose of HgCl2 (1·5 mg/kg body weight (BW)) was injected s.c. to induce acute renal failure, endogenous creatinine clearance (Ccr) decreased from 390 ± 30 to 94 ± 17 ml/h per kg BW in intact (unpretreated) rats. Such a decrease in Ccr was completely prevented in castrated rats (388 ± 30 ml/h per kg BW) and partially prevented in GnRHA-pretreated rats (216 ± 40 ml/h per kg BW). When a high dose of HgCl2 (2·25 mg/kg BW) was injected, half of the eight intact rats died but castrated rats and GnRHA-pretreated rats survived (PA pretreatment, but was restored by additional pretreatment with ovine LH (40 μg/day), as evidenced by changes in Ccr. Elevated resistance in castrated rats was also reduced by the administration of testosterone propionate. In conclusion, hypogonadism activated the preventive and defensive mechanisms that protect the kidney through both decreased plasma testosterone and high or even normal plasma LH. Journal of Endocrinology (1996) 148, 553–559

Published
1996
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16. Plasma aldosterone response to upright posture and angiotensin II infusion in aldosterone-producing adenoma

Author

S Toraya, Nobuo Horiba, Makoto Ujihara, Hiroshi Demura, Kaoru Nomura, and M Aiba

Subjects
Adenoma, medicine.medical_specialty, Pituitary gland, Neoplasms, Hormone-Dependent, endocrine system diseases, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Posture, education, Clinical Biochemistry, Adrenal Gland Neoplasms, Biochemistry, chemistry.chemical_compound, Endocrinology, Primary aldosteronism, Infusion Procedure, Internal medicine, Adrenal Glands, medicine, Humans, Infusions, Intravenous, Aldosterone, business.industry, Angiotensin II, Biochemistry (medical), medicine.disease, Hyperaldosteronism, medicine.anatomical_structure, chemistry, Mineralocorticoid, business
Abstract

Nineteen patients with primary aldosteronism due to surgically confirmed aldosterone-producing adenoma (APA) were examined to evaluate the response of aldosterone to upright posture and angiotensin II infusion. Upright posture reportedly decreases the plasma aldosterone concentration (PAC) in APA but raises it in idiopathic hyperaldosteronism. However, our findings showed the opposite result, in that the upright posture did not change or raised PAC in 15 of 19 cases (79%). Angiotensin II was infused i.v. at doses from 0.5-2 ng/min.kg body weight in six patients in whom the upright posture raised PAC, but did not raise PAC in all cases. This result supports the assumption that APA is functionally insensitive to angiotensin II. A concomitant rise of ACTH, pretreatment with calcium channel blockade, and other modulating factors may be involved in this PAC rise. Whatever the reason, such a high frequency of patients with increased PAC in APA raises some question about the clinical value of the upright posture test. We believe, then, there is reason to check any interpretation concerning increased PAC in the case of the upright posture test in distinguishing between APA and idiopathic hyperaldosteronism.

Published
1992
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17. A Case of Hypocalciuric Hypercalcemia without Family History

Author

Makoto Ujihara, Hiroshi Demura, Kanji Sato, Keizo Kasono, Takashi Ohashi, Naoki Tomori, and Toshio Tsushima

Subjects
Male, musculoskeletal diseases, medicine.medical_specialty, endocrine system diseases, Pulmonary Fibrosis, Asymptomatic, Gastroenterology, Hypocalciuria, Phosphates, Diagnosis, Differential, Endocrinology, Internal medicine, Pulmonary fibrosis, medicine, Humans, Magnesium, Family history, Aged, Family Health, Familial hypocalciuric hypercalcemia, business.industry, General Engineering, nutritional and metabolic diseases, medicine.disease, Urinary calcium, Pedigree, Parathyroid Hormone, Hypercalcemia, Calcium, Female, Hypermagnesemia, medicine.symptom, business, hormones, hormone substitutes, and hormone antagonists, Hypophosphatemia
Abstract

Familial hypocalciuric hypercalcemia (FHH) is usually characterized by asymptomatic hypercalcemia, mild hypermagnesemia, and low urinary calcium excretion, and is occasionally associated with pulmonary fibrosis. It is inherited as an autosomal-dominant, and no sporadic case of hypocalciuric hypercalcemia has been heretofore reported. This report describes a patient with hypocalciuric hypercalcemia completely compatible with FHH but with no family history, suggesting that the most likely diagnosis is "nonfamilial" hypocalciuric hypercalcemia. We propose that the urinary excretion of calcium be examined in all patients with hypercalcemia, hypophosphatemia, and increased PTH before neck surgery, even if patients have no family history of hypercalcemia.

Published
1991
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18. Downward Regulation of Plasma LH by LHRH Agonist, Leuprolide Acetate, Resulting in Inhibited Renal Growth and Function in the Castrated Male Rat

Author

Hiroshi Demura, Yuko Sato, Shohzou Toraya, Makoto Ujihara, Nobuo Horiba, Makoto Watanabe, and Kaoru Nomura

Subjects
Male, Agonist, medicine.medical_specialty, Hypophysectomy, Fractional excretion of sodium, medicine.drug_class, medicine.medical_treatment, Down-Regulation, Capsules, Gonadotropin-releasing hormone, Biology, Gonadotropin-Releasing Hormone, Kidney Tubules, Proximal, chemistry.chemical_compound, Endocrinology, Internal medicine, Renin, Renin–angiotensin system, medicine, Animals, Kidney, Sodium, General Engineering, Rats, Inbred Strains, DNA, Organ Size, Luteinizing Hormone, Creatine, Rats, medicine.anatomical_structure, Castration, chemistry, Leuprolide, Luteinizing hormone, Orchiectomy
Abstract

We previously reported that ovine and porcine luteinizing hormone (LH) stimulated kidney growth in castrated hypophysectomized rats. Our present study focuses on the physiological role of the renotropic activity of LH isoforms. Plasma LH levels were decreased to 10% of that of castrated control rats by injections of a slow-releasing LHRH agonist, leuprolide acetate, from microcapsules. Compared to controls, which were injected with microcapsules only, the kidney weight in leuprolide-treated castrated rats decreased 12%. Renal protein and DNA contents decreased significantly. Body, liver and spleen weights were not changed by the treatment, however. This effect on the kidney was not observed in castrated hypophysectomized rats, suggesting that leuprolide affected the kidneys indirectly, rather than directly, by suppressing LH secretion. In leuprolide-treated castrated rats, urinary fractional excretion of sodium (FENa) increased, indicating suppressed renal function at the proximal tubules. We concluded that the secretion of renotropically active LH isoforms was regulated at least partially by LHRH and played a physiological role in growth and the function of the proximal tubules.

Published
1991
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19. Uninephrectomy inducing quantitative and qualitative changes in LH isoforms in the male rat

Author

Shohzoh Toraya, Kaoru Nomura, Hiroshi Demura, and Makoto Ujihara

Subjects
Male, Gene isoform, medicine.medical_specialty, Surgical stress, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Biology, Kidney, Nephrectomy, Endocrinology, Prostate, Internal medicine, medicine, Animals, Regeneration, Testosterone, Chromatofocusing, Rats, Inbred Strains, Organ Size, General Medicine, Luteinizing Hormone, Pathophysiology, Rats, medicine.anatomical_structure, Pituitary Gland, sense organs, Follicle Stimulating Hormone, Gonadotropin
Abstract

Recent findings that LH stimulates renal growth have prompted us to examine whether LH exercises renotropic effects on the growing kidney following uninephrectomy. Intact (not castrated) male rats were used for sham uninephrectomy to induce surgical stress suppressing plasma LH and testosterone levels. Compared to sham surgery, uninephrectomy caused a transient 240% increase in plasma LH with a transient increase in plasma testosterone (80%) and in prostate weight on day 2. Although pituitary LH content did not change, chromatofocusing of pituitary extract revealed changed distribution patterns among seven LH isoforms, suggesting selective synthesis or secretion of LH isoforms. Castrated rats were then used so that surgical stress did not affect LH. Uninephrectomy caused sustained increases in plasma LH levels (60-110% increase) for up to six days. Three days after uninephrectomy, pituitary LH content increased significantly (30% increase) with a change in chromatofocusing profiles of LH isoforms. Plasma and pituitary FSH levels did not change. In summary, uninephrectomy changed LH isoforms quantitatively and qualitatively. These changes imply a change in gonadotropic and renotropic activities of LH after uninephrectomy.

Published
1990
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20. [Congenital hypogonadotropic hypogonadism]

Author

Makoto, Ujihara

Subjects
Homeodomain Proteins, Male, Genotype, DAX-1 Orphan Nuclear Receptor, Receptors, Retinoic Acid, Hypogonadism, Luteinizing Hormone, beta Subunit, Prognosis, Chorionic Gonadotropin, Receptors, G-Protein-Coupled, DNA-Binding Proteins, Diagnosis, Differential, Gonadotropin-Releasing Hormone, Repressor Proteins, Phenotype, Follicle Stimulating Hormone, beta Subunit, Mutation, Humans, Female, Testosterone, Receptors, LHRH, Receptors, Kisspeptin-1
Published
2006

21. Performance of the basal aldosterone to renin ratio and of the renin stimulation test by furosemide and upright posture in screening for aldosterone-producing adenoma in low renin hypertensives

Author

Kaoru Nomura, Kazue Takano, Dai Hirohara, Makoto Ujihara, and Takahiro Okamoto

Subjects
Adenoma, Adult, Male, medicine.medical_specialty, animal structures, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Population, Posture, Adrenal Gland Neoplasms, urologic and male genital diseases, Biochemistry, chemistry.chemical_compound, Endocrinology, Furosemide, Internal medicine, Renin–angiotensin system, Renin, medicine, Humans, False Positive Reactions, education, Diuretics, Aldosterone, Retrospective Studies, education.field_of_study, Aldosterone-to-renin ratio, business.industry, Biochemistry (medical), Middle Aged, medicine.disease, Hyperaldosteronism, female genital diseases and pregnancy complications, chemistry, Mineralocorticoid, Area Under Curve, Case-Control Studies, Hypertension, Female, business, Tomography, X-Ray Computed, hormones, hormone substitutes, and hormone antagonists, circulatory and respiratory physiology, medicine.drug
Abstract

An aldosterone-producing adenoma causes surgically correctable hypertension. Screening tests should be assessed for their accuracy and ability to detect aldosterone-producing adenoma in an appropriate population. This study aims to validate the accuracy and efficacy of the basal plasma aldosterone concentration (picomoles per liter) to PRA (nanograms per liter/sec) ratio and of combined stimulation of PRA by the furosemide and upright posture test in screening for aldosterone-producing adenoma in hypertensives with PRA less than 0.28 ng/liter.sec (1 ng/ml.h). Thirty-five aldosterone-producing adenoma and 79 nonaldosterone-producing adenoma patients were retrospectively selected from among 159 patients examined with the furosemide and upright posture test between 1989 and 1999. Selection criteria were based on blood pressure, PRA, and plasma aldosterone concentration. Diagnosis was based on surgical outcome, computed tomography scans with adrenal scintigraphy, or venous sampling. The accuracy and efficacy of basal (aldosterone/PRA ratio) and dynamic (postfurosemide and upright posture PRA) screening tests were assessed based on test sensitivity, specificity, likelihood ratio, and receiver operating characteristics. At a cut-off value of 3,200, the aldosterone/PRA ratio had a high sensitivity of 1.0 and a low specificity of 0.61. The importance was strengthened by using a multilevel likelihood ratio, i.e. positive (aldosterone/PRA ratio >10,000), negative (aldosterone/PRA ratio

Published
2001

22. Ectopic adrenocorticotropin syndrome exhibiting paradoxical adrenocorticotropin responsiveness to gonadotropin-releasing hormone

Author

Reika Cho, Toshihiro Imaki, Kaoru Nomura, Kazue Takano, Makoto Ujihara, Toshio Nishikawa, Takanobu Yoshimoto, and Yasuo Totsuka

Subjects
Adult, Male, endocrine system, medicine.medical_specialty, Corticotropin-Releasing Hormone, Endocrinology, Diabetes and Metabolism, Thyrotropin-releasing hormone, Adrenocorticotropic hormone, Gonadotropin-releasing hormone, Carcinoid Tumor, Dexamethasone, Gonadotropin-Releasing Hormone, Corticotropin-releasing hormone, Endocrinology, Adrenocorticotropic Hormone, Internal medicine, medicine, Humans, Deamino Arginine Vasopressin, Desmopressin, Glucocorticoids, Thyrotropin-Releasing Hormone, business.industry, Histocytochemistry, Mediastinum, Magnetic Resonance Imaging, Inferior petrosal sinus sampling, ACTH Syndrome, Ectopic, Dexamethasone suppression test, business, Tomography, X-Ray Computed, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Hormone
Abstract

In a 37-year-old man who had Cushing's syndrome, investigations, including overnight dexamethasone suppression test, corticotropin-releasing hormone (CRH) test, pituitary MRI and inferior petrosal sinus sampling suggested the presence of ectopic adrenocorticotropin (ACTH) production. Interestingly, gonadotropin-releasing hormone (GnRH) increased plasma ACTH from 73 pg/ml to 708 pg/ml at 15 min. Furthermore, desmopressin also increased plasma ACTH whereas CRH and thyrotropin-releasing hormone (TRH) had no effect. Such paradoxical responses of plasma ACTH were observed repeatedly. A thoracic CT scan revealed a right anterior mediastinal mass, which was surgically resected. Histological and immunohistochemical examination confirmed that the tumor was an ACTH-producing carcinoid. ACTH and cortisol decreased immediately following surgery. Neither desmopressin nor GnRH administration resulted in elevation of plasma ACTH while ACTH-responsiveness to dexamethasone and CRH was restored. To our knowledge, this is the first report documenting GnRH responsiveness in ectopic ACTH syndrome.

Published
2001

23. Surgical stress increases renal glutathione content via increased glucocorticoid, and resistance to subsequent oxidative injury in the rat: significant link between endocrine response and cell defense system under the stress

Author

Makoto Ujihara, Makiko Ogasawara, Noriyuki Shibata, Hiroshi Demura, Makiko Kobayashi, and Kaoru Nomura

Subjects
Male, medicine.medical_specialty, Surgical stress, Kidney Cortex, Swine, Endocrinology, Diabetes and Metabolism, Biology, Antioxidants, Dexamethasone, Cell Line, chemistry.chemical_compound, Endocrinology, Adrenocorticotropic Hormone, Corticosterone, Stress, Physiological, Internal medicine, medicine, Animals, Rats, Wistar, Aldosterone, Glucocorticoids, Creatinine, Kidney, Laparotomy, Glutathione, Rats, medicine.anatomical_structure, Kidney Tubules, chemistry, Mercuric Chloride, Glucocorticoid, medicine.drug
Abstract

Systemic and nonspecific stress response effects on the cellular defense mechanism were studied in the male rat kidney. Two days after laparotomy-induced surgical stress, rats showed increased serum corticosterone and renal cortical reduced glutathione (GSH). Rats were then injected s.c. with mercuric chloride (HgCl2) to oxidatively injure renal tubuli. Increased serum creatinine levels indicated that laparotomy pretreatment lessened renal damage. To study the effects of the activated pituitary-adrenal axis on renal cortical GSH content and vulnerability to subsequent oxidative injury, rats were injected s.c. with ACTH on two consecutive days. ACTH administration increased both corticosterone and aldosterone. These rats showed increased, dose-dependent renal cortical GSH content, i.e., controls (n=7): 1.25 +/- 0.23 micromol/g tissue, daily dose of 10 microg/100 gBW (n=7): 1.53 +/- 0.24 micromol/g tissue, and daily dose of 40 microg/100 gBW (n=7): 2.31 +/- 0.23 micromol/g tissue. Rats receiving daily doses of 40 microg of ACTH/100 gBW acquired resistance to oxidative injury, indicated by serum creatinine levels: controls (n=6), 22 +/- 4 micromol/L; HgCl2 (n=6), 145 +/- 88 micromol/L; ACTH and HgCl2 (n=6), 37 +/- 11 micromol/L. Morphological evidence indicated that ACTH pretreatment in HgCl2-injected rats prevented renal tissue from inflammatory cell infiltration but not from tubular degeneration. Cellular GSH content of LLC-PK1 cells, porcine renal-tubule-derived culture cells, increased significantly in incubation with dexamethasone or aldosterone, suggesting that adrenal steroids directly stimulate renal cell GSH. We demonstrated that stress or ACTH administration activates the defense mechanism in the kidney via increased GSH. This stress-activatable defense system may therefore indicate a connection between endocrine stress response and the cellular defense mechanism.

Published
1999

24. An additional exon of stress-inducible heat shock protein 70 gene (HSP70-1)

Author

Kaoru Nomura, Hiroshi Demura, Shoichi Shimizu, and Makoto Ujihara

Subjects
Transcription, Genetic, Molecular Sequence Data, Biophysics, Codon, Initiator, Biology, Exon shuffling, Response Elements, Biochemistry, Polymerase Chain Reaction, Exon, Exon trapping, Stress, Physiological, Humans, HSP70 Heat-Shock Proteins, RNA, Messenger, Cloning, Molecular, Promoter Regions, Genetic, Molecular Biology, Gene, Cells, Cultured, Sequence Deletion, Genetics, Splice site mutation, Base Sequence, Models, Genetic, Depression, Genome, Human, Alternative splicing, Intron, Cell Biology, Exons, Molecular biology, Introns, Alternative Splicing, Gene Expression Regulation, Leukocytes, Mononuclear, Tandem exon duplication
Abstract

The HSP70-1 gene, reportedly a single exon, encodes a major stress-inducible 72-kDa heat shock protein (HSP70). We recently demonstrated that patients with major depression had a 162-base pair (bp)-deletion in the 5′-flanking sequence of HSP70-1 mRNA in their peripheral blood mononuclear cells. Present study has been conducted to clarify how this short mRNA is generated, and demonstrated that a novel 385 bp sequence is located 1.1 kb upstream from the HSP70-1 gene of normal subjects. Except for the 162 bp deletion, it is compatible with part of the 5′-flanking sequence of the HSP70-1 gene, and contains another exon of 358 bp (exon 1) that may be connected to the 3′-terminus (exon 3) of the conventional HSP70-1 gene. Alternative transcription of exons 1 and 3 may cause the short mRNA. It is concluded that HSP70-1 gene is constituted of three exons and may cause alternative splicing.

Published
1999

25. Clinical implications of renal cyst in primary aldosteronism

Author

Mayumi Katayama, Atsushi K. Kono, Makoto Ujihara, Hiroshi Demura, Makiko Ogasawara, Shozo Toraya, Chizu Kikuchi, and Kaoru Nomura

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Adrenal Gland Neoplasms, Renal function, Pheochromocytoma, Gastroenterology, Cohort Studies, chemistry.chemical_compound, Endocrinology, Primary aldosteronism, Internal medicine, parasitic diseases, Hyperaldosteronism, medicine, Humans, Cyst, Aged, Creatinine, Analysis of Variance, business.industry, Calcinosis, Adrenalectomy, Kidney Diseases, Cystic, Middle Aged, medicine.disease, Hypokalemia, Blood pressure, chemistry, Hypertension, Female, Kidney Diseases, medicine.symptom, Nephrocalcinosis, business, Tomography, X-Ray Computed
Abstract

The present study surveyed 69 patients with aldosteronoma to study the clinical implications of renal cysts demonstrated in computed tomography. Patients who had cysts (n = 16, 23.2%) were older and had a longer duration of hypertension and more severe hypokalemia than those without cysts (n = 53). Patients with cysts therefore had longer-term, more severe hypokalemia than those without cysts. Endogeneous creatinine clearance (Ccr), measured in 61 patients, was significantly lower in patients with cysts (58.4 +/- 7.1 ml/min, n = 16) than in those without cysts (77.3 +/- 7.1 ml/min, n = 45, P = 0.0039). This significant difference was observed even after adjusting for covariables (age, duration of hypertension, and serum potassium) between the two groups by analysis of covariance (ANCOVA). No significant difference was observed in gender, blood pressure, serum creatinine, plasma aldosterone, or PRA. Age, serum potassium levels, and systolic and diastolic blood pressure were the significant determinants in predicting Ccr in a backward stepwise multiple regression analysis (r = 0.505, n = 61, P = 0.0025). Cysts were graded into four classes on the basis of number and size. Cyst grading correlated negatively with Ccr at a Spearman rank correlation (rho = -0.33, n = 61, P = 0.0103). The incidence of chronic renal failure was significantly higher in patients with cysts (18.8%) than in patients without (0%) in a Fischer's exact probability test (P = 0.0107). Thus, both renal cysts and dysfunction arose and/or developed from common roots, i.e., the duration and severity of hypokalemia, in primary aldosteronism. In addition, we surveyed 27 patients with pheochromocytoma. Patients with renal cysts (n = 8) had a significantly longer duration of hypertension than those without cysts. No significant difference was observed in Ccr between patients with and those without cysts. Thus, a significant link between renal cysts and Ccr was a specific feature of primary aldosteronism, but not of pheochromocytoma. In summary, the renal cysts in primary aldosteronism should be recognized as a significant complication representing the extent of renal injury and dysfunction.

Published
1996

26. An allel-specific abnormal transcript of the heat shock protein 70 gene in patients with major depression

Author

Kaoru Nomura, Takashiro Suzuki, Makoto Ujihara, Hiroshi Demura, Hiroo Shibata, Kaoru Sakamoto, and Shoichi Shimizu

Subjects
Male, DNA, Complementary, Transcription, Genetic, Blotting, Western, Molecular Sequence Data, Biophysics, Gene Expression, Biology, Biochemistry, Peripheral blood mononuclear cell, Polymerase Chain Reaction, law.invention, Arthritis, Rheumatoid, Open Reading Frames, law, Reference Values, Heat shock protein, Humans, HSP70 Heat-Shock Proteins, Amino Acid Sequence, RNA, Messenger, Cloning, Molecular, Molecular Biology, Gene, Polymerase chain reaction, Alleles, DNA Primers, Gene Library, Messenger RNA, Depressive Disorder, Genomic Library, Base Sequence, Chromosome, Chromosome Mapping, Cell Biology, Molecular biology, Graves Disease, Hsp70, genomic DNA, Hypertension, Schizophrenia, Chromosomes, Human, Pair 6, Female
Abstract

Stress-inducible 72-kDa heat shock proteins (HSP70) were encoded on genes in multiple chromosomes. The expression of mRNA transcribed from the gene (HSP70-1) on chromosome 6 was studied using reverse-transcript polymerase chain reaction in peripheral blood mononuclear cells of patients with different diseases. The deletion of 29 bp occurred in 5′ noncoding and subsequent 133 bp in coding sequences of HSP70 mRNA in patients with major depression (n=18), while normal subjects (n=10) and patients with schizophrenia (n =5), essential hypertension (n=3), rheumatoid arthritis (n=7), and Graves' disease (n=3) had normal mRNA. No such deletion occurred in genomic DNA and no protein was translated from deleted mRNA. The allel-specific abnormal transcript of the HSP70 gene on chromosome 6 thus may underlie the altered stress and/or immune response in major depression.

Published
1996

27. Mutagenesis of the 'determinant loop' region of human choriogonadotropin beta

Author

Fang Chen, Hiroaki Yoshida, David Puett, Jianing Huang, Haiying Xia, and Makoto Ujihara

Subjects
Protein Conformation, Protein subunit, Mutant, Molecular Sequence Data, Mutagenesis (molecular biology technique), Gene Expression, Biology, Transfection, Biochemistry, Binding, Competitive, Chorionic Gonadotropin, Endocrinology, Receptors, Gonadotropin, Cricetinae, Animals, Humans, Point Mutation, Chorionic Gonadotropin, beta Subunit, Human, Amino Acid Sequence, Site-directed mutagenesis, Molecular Biology, Peptide sequence, Progesterone, Expression vector, Base Sequence, Sequence Homology, Amino Acid, Ligand binding assay, Chinese hamster ovary cell, Peptide Fragments, Mutagenesis, Mutagenesis, Site-Directed, Biological Assay
Abstract

The hormone-specific β subunits of the four human glycoprotein hormones are homologous, and mapping studies are underway in many laboratories to delineate the amino acid residues responsible for receptor binding and activation. Results on the human choriogonadotropin β (hCGβ) subunit, obtained using synthetic peptides, chemically modified derivatives, and mutant forms prepared via site-directed mutagenesis, have suggested that amino acid residues enclosed by the purported disulfide loop between Cys-93 and Cys-100 may contribute to receptor binding and perhaps specificity. Indeed, the 93–100 amino acid sequence is referred to as a determinant loop. We have used site-directed mutagenesis to prepare single amino acid residue replacements at positions not previously investigated in full length β subunits; these include Arg-95, Ser-96, Thr-97, and Thr-98. In addition, Leu-92 was studied in an effort to determine whether changes immediately adjacent to the determinant loop alter receptor binding. The wild-type and mutant cDNAs for hCGβ were subcloned into a Prsv expression vector and transiently transfected into Chinese hamster ovary cells containing a stably integrated gene for bovine α. The concentrations of total expressed hCGβ in heterodimer form with the bovine α subunit were determined by radioimmunoassays. The mutant gonadotropins were assayed in vitro using a competitive binding assay with [125I]hCG and progesterone production, both in the transformed murine Leydig cell line, MA-10. Mutant β subunits containing the replacements Lys-92, Ser-95, Asp-96, and Tyr-97 exhibited normal α subunit binding. The resulting heterodimers with β replacements at positions 92 and 97 gave comparable potency to control gonadotropin containing hCGβ wild-type, and mutant gonadotropins containing replacements at positions 95 and 96 yielded reduced potency in the binding assay. Interestingly, the potencies of these latter two mutant gonadotropins were comparable to the wild-type gonadotropin in the steroidogenic assay, although the maximal Steroidogenesis was less in the hormone with the Arg-95 → Ser replacement. Substitution of Thr-98 with Asp and with Arg resulted in mutant β subunits with reduced subunit assembly; however, both heterodimers were active in the in vitro bioassays. Accurate potencies could not be obtained with the gonadotropin containing hCGβ(Arg-98), but the activity associated with hCGβ(Asp-98) appeared less than with wild-type gonadotropin. A comparison of these results with other data obtained on the determinant loop region leads to the following conclusions. Arg-94, Arg-95, Ser-96, Thr-98, and Asp-99 contribute to CG/lutropin receptor binding, although neither is absolutely critical since certain substitutions can be tolerated without a total loss of activity. The determinant loop region also appears to participate in some manner to α subunit binding, perhaps involving Thr-98. It remains to be determined if this region serves as a crucial determinant for β chain folding or represents a direct contact site for the α subunit. The question of whether the determinant loop region is important in receptor specificity is still open, but available data argue strongly that several residues in this disulfide loop contribute to CG/lutropin receptor binding.

Published
1993

28. Clinical significance of adrenal computed tomography in Addison's disease

Author

Kaoru Nomura, Zhong Hua Sun, Toshihiro Suda, Nobuo Horiba, Atsushi Kono, Hiroshi Demura, Makoto Ujihara, Shohzoh Toraya, and Toshio Tsushima

Subjects
Adult, Male, endocrine system, Pathology, medicine.medical_specialty, endocrine system diseases, Hydrocortisone, medicine.disease_cause, Autoimmunity, Pathogenesis, Endocrinology, Atrophy, Addison Disease, Adrenal Glands, medicine, Isoniazid, Humans, Adrenal calcification, Clinical significance, Tuberculosis, Pulmonary, Aged, Adrenal gland, business.industry, General Engineering, Middle Aged, medicine.disease, medicine.anatomical_structure, Addison's disease, Etiology, Streptomycin, Female, Rifampin, business, Tomography, X-Ray Computed
Abstract

Adrenal computed tomographic (CT) scanning was conducted in twelve patients with Addison's disease during the clinical course. In tuberculous Addison's disease (n = 8), three of four patients examined during the first two years after disease onset had bilaterally enlarged adrenals, while one of four had a unilaterally enlarged one. At least one adrenal gland was enlarged after onset in all six patients examined during the first four years. Thereafter, the adrenal glands may atrophy bilaterally, in contrast to adrenal glands in idiopathic Addison's disease, which atrophy bilaterally from disease onset (n = 2). Adrenal calcification was a less sensitive clue in tracing pathogenesis, i.e., adrenal calcification was observed in five of eight patients with tuberculous Addison's disease, but not in idiopathic patients. Thus, adrenal CT scanning could show the etiology of Addison's disease (infection or autoimmunity) and the phase of Addison's disease secondary to tuberculosis, which may be clinically important for initiating antituberculous treatment.

Published
1992

29. Subunit-specific sulphation of oligosaccharides relating to charge-heterogeneity in porcine lutrophin isoforms

Author

Hiroshi Demura, Yasunori Nakamura, Makoto Ujihara, Toshiaki Osawa, Kazutaka Ohmura, Kazuo Yamamoto, Kaoru Nomura, and Satoshi Toyoshima

Subjects
Gene isoform, Swine, Protein subunit, Molecular Sequence Data, Oligosaccharides, Biochemistry, Methylation, Chromatography, Affinity, chemistry.chemical_compound, Affinity chromatography, Exoglycosidase, Carbohydrate Conformation, Electrochemistry, Animals, G alpha subunit, biology, Molecular Structure, Isoelectric focusing, Sulfates, Luteinizing Hormone, Chromatography, Ion Exchange, Sialic acid, chemistry, Carbohydrate Sequence, Concanavalin A, biology.protein
Abstract

Lutrophin (LH) consists of an array of isoforms with different charges and bioactivities. This study was undertaken to clarify specifically how oligosaccharides of alpha and beta subunits contribute to LH isoform charges. Porcine LH (pLH) was separated into four isoforms by isoelectric focusing (IEF), followed by subunit isolation. Their oligosaccharides were released by hydrazinolysis, labelled by reduction with NaB3H4, and fractionated by HPLC with a Mono Q column into five populations differing in the number of sulphate (S) and sialic acid (N) residues, designated as Neutral, N-1, S-1, S-N and S-2. Oligosaccharides were predominantly sulphated (S-1 and S-2) and infrequently sialylated (N-1 and S-N). Further analysis, including concanavalin A (Con A) affinity chromatography, desialylation, desulphation, sequential exoglycosidase digestion and methylation, clarified the structures of the acidic oligosaccharides. All were of the biantennary complex type. Their two peripheral branches were SO4-4GalNAc beta 1-4Glc-NAc and GalNAc beta 1-4GlcNAc or GlcNAc in S-1, SO4-4GalNAc beta 1-4GlcNAc and Sia alpha 2-6Gal beta 1-4GlcNAc in S-N, and (SO4-4GalNAc beta 1-4GlcNAc)2 in S-2 (where GalNAc is N-acetylgalactosamine and GlcNAc is N-acetylglucosamine). Ten percent of S-1 and of S-N had a bisecting GlcNAc residue. Sulphate residues occurred in nearly the same amount for both subunits; however, the alpha and beta subunits were sulphated differently. S-1 predominated in the alpha subunit, while S-1 and S-2 were major components in the beta subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1992

30. Renotropic and gonadotropic activity in homologous and heterologous hybrids of ovine luteinizing hormone and human chorionic gonadotropin subunits

Author

Makoto Ujihara, Kaoru Nomura, Hiroshi Demura, Kazutaka Ohmura, Shohzou Toraya, Nobuo Horiba, and Yasunori Nakamura

Subjects
Male, medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Radioimmunoassay, Heterologous, Biology, Gonadotropic cell, Kidney, Tritium, Chorionic Gonadotropin, Human chorionic gonadotropin, Endocrinology, Testicular Neoplasms, Internal medicine, Testis, medicine, Cyclic AMP, Tumor Cells, Cultured, Animals, Cells, Cultured, Hypophysectomy, Kidney metabolism, Leydig Cells, Biological activity, General Medicine, DNA, Luteinizing Hormone, Rats, Gonadotropin, Protein Multimerization, Luteinizing hormone, Leydig Cell Tumor, Thymidine
Abstract

We previously demonstrated the renotropic activity of ovine and porcine LH, i.e. the stimulation of [3H]thymidine incorporation into the renal DNA of castrated hypophysectomized rats. We conducted this study to determine which condition is required to promote renotropic activity. We prepared homologous (oLHα· oLHβ, hCGα·hCGβ) and heterologous (oLHα·hCGβ, hCGα·oLHβ) hybrids from isolated oLH- and/or hCG-derived subunits. Native oLH and all hybrids showed gonadotropic activity when examined for cyclic AMP generation in cultured Leydig tumour cells (MA-10). Native oLH and the hybrids which showed renotropic activity were all found to contain at least one of the oLH subunits. Our findings point out the important, special role of oLH subunits in promoting renotropic activity. The condition required is suggested to be presence of a common structure in the two oLH subunits. Such a structure should consequently not be present in hCG. A carbohydrate moiety of oLH containing a sulphate group is proposed as a candidate, but the assumption remains to be demonstrated.

Published
1991

32. Renotropic activity of lutropin: Direct stimulation of DNA synthesis of cultured rat renal cortical cells

Author

Yuko Sato, Makoto Ujihara, Kazuo Shizume, Hiroshi Demura, Kaoru Nomura, and Nobuo Horiba

Subjects
Male, Fetus, medicine.medical_specialty, Kidney Cortex, DNA synthesis, Biophysics, Rats, Inbred Strains, DNA, Cell Biology, Luteinizing Hormone, Biology, Fetal Blood, Biochemistry, Rats, Thymidine incorporation, Endocrinology, Internal medicine, medicine, Animals, Cattle, Castration, Molecular Biology, Direct stimulation, Hypophysectomy
Abstract

Two differently purified ovine lutropin (LH) preparations were studied to see if they stimulated [3H] thymidine incorporation into cultured rat renal cortical cells. Both preparations showed a dose-dependent (0.11–1 ng/ml), time-dependent (peaking at 18 h), serum-dependent (7.5% of fetal calf serum or 10% castrated-hypo-physectomized rat serum) renotropic effect. Ovine TSH and FSH failed to mimic this specific, renotropic effect. We concluded that LH directly stimulates renal DNA synthesis in cooperation with other serum factor's.

Published
1988
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33. Porcine luteinizing hormone isoform(s): relationship between their molecular structures, and renotropic versus gonadotropic activities

Author

Kaoru Nomura, Kazutaka Ohmura, Yuri Shirakura, Yasunori Nakamura, Koji Ohki, Makoto Ujihara, Kazuo Shizume, Nobuo Horiba, and Yuko Sato

Subjects
Gene isoform, Male, medicine.medical_specialty, Macromolecular Substances, Swine, Molecular Sequence Data, Carbohydrates, Phenylalanine, Biology, Endocrinology, Internal medicine, medicine, Cyclic AMP, Animals, Amino Acid Sequence, Threonine, Amino Acids, Peptide sequence, chemistry.chemical_classification, Leydig Cells, Biological activity, Luteinizing Hormone, In vitro, Amino acid, Rats, Biochemistry, chemistry, Pituitary Gland, Glycine
Abstract

We recently demonstrated the renotropic activity in ovine LH isoform(s). In this study we purified porcine (p) LH isoforms and analyzed their structures and bioactivities. Purified pLH preparation (G-100 fraction 3) was dissociated into alpha- and beta-subunits, followed by isolation with reverse phase HPLC. Six components were isolated and analyzed for their amino acid compositions and amino-terminal amino acid sequences. alpha-Subunits were found to have heterogeneous N-terminal sequences, which started at Phe-1, Gly-4, Phe-6, or Thr-7. This N-terminal heterogeneity and the presence of the initial 6 amino acids has not been reported previously to the best of our knowledge. Moreover, the first 10 residues, Phe-Pro-Asp-Gly-Glu-Phe-Thr-Met-Gln-Gly, were identical with those of the ovine LH alpha subunit. At least 3 different beta-subunits were identified as heterogeneous in their carboxyl-terminal amino acids. The pLH preparation (G-100-fraction 3) was then chromatographed by an isoelectrofocusing (IEF) column. Four IEF fractions were obtained. Their amino acid structures appeared to be identical, as judged by the identical elution profiles on reverse phase HPLC, but their carbohydrate compositions were slightly different, especially in N-acetylgalactosamine in alpha-subunits. Thus, fractionation on IEF depended on the heterogeneity in carbohydrate structures. Each IEF fraction had different potencies in terms of its gonadotropic activity (in vitro) and renotropic activity (in vivo and in vitro). The discrepancy was observed not only between gonadotropic activity and renotropic activity, but also between in vivo and in vitro renotropic activity. This study identified the structural heterogeneity of pLH isoforms and demonstrated their biological heterogeneity. We concluded that the carbohydrate structure of the pLH isoform is important for expressing its biological heterogeneity (gonadotropic and renotropic activity.

Published
1989

34. [A case of pseudotumor cerebri probably due to the withdrawal of adrenal corticosteroid hormone]

Author

Mikio Osawa, Toshiko Takemiya, Makoto Ujihara, Shoichi Maruyama, and Itsuro Kobayashi

Subjects
Adult, Male, Neurologic Examination, medicine.medical_specialty, Pseudotumor Cerebri, medicine.drug_class, business.industry, Pseudotumor cerebri, General Medicine, medicine.disease, Kidney Transplantation, Magnetic Resonance Imaging, Methylprednisolone, Substance Withdrawal Syndrome, Endocrinology, Internal medicine, medicine, Corticosteroid, Humans, business, Tomography, X-Ray Computed, Hormone
Abstract

症例は25才,男性で腎移植後メチルプレドニゾロンの投与を開始. 16mgから12mgに減量された後に光視症,後頭部痛が出現し,眼科で乳頭浮腫を指摘されたため,精査目的で当科に入院した.髄液圧は250mmH2Oと高かったが,他の髄液所見に著明な異常を認めず,また頭部CT, MRIでは頭蓋内に占拠性病変を認めないことから, pseudotumor cerebriと診断した.原因としてメチルプレドニゾロンの減量が最も疑われた.メチルプレドニゾロンを増量せずに経過観察をしたところ,光視症,後頭部痛は軽快し,髄液圧は正常化した.

Published
1988

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