4 results on '"Reddy, Padmalatha S."'
Search Results
2. Oral Ritlecitinib and Brepocitinib for Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2b Study.
- Author
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Sandborn, William J., Danese, Silvio, Leszczyszyn, Jaroslaw, Romatowski, Jacek, Altintas, Engin, Peeva, Elena, Hassan-Zahraee, Mina, Vincent, Michael S., Reddy, Padmalatha S., Banfield, Christopher, Salganik, Mikhail, Banerjee, Anindita, Gale, Jeremy D., and Hung, Kenneth E.
- Abstract
The efficacy and safety of ritlecitinib (oral JAK3/TEC family kinase inhibitor) and brepocitinib (oral TYK2/JAK1 inhibitor) as induction therapy were assessed in patients with active, moderate-to-severe ulcerative colitis. This phase 2b, parallel-arm, double-blind umbrella study randomized patients with moderate-to-severe ulcerative colitis to receive 8-week induction therapy with ritlecitinib (20, 70, 200 mg), brepocitinib (10, 30, 60 mg), or placebo once daily. The primary endpoint was total Mayo Score (TMS) at week 8. Of 319 randomized patients, 317 received ritlecitinib (n = 150), brepocitinib (n = 142), or placebo (n = 25). The placebo-adjusted mean TMSs (90% confidence interval) at week 8 were −2.0 (−3.2 to −0.9), −3.9 (−5.0 to −2.7), and −4.6 (−5.8 to −3.5) for ritlecitinib 20, 70, and 200 mg, respectively (P =.003, P <.001, P <.001), and −1.8 (−2.9 to −0.7), −2.3 (−3.4 to −1.1), and −3.2 (−4.3 to −2.1) for brepocitinib 10, 30, and 60 mg, respectively (P =.009, P =.001, P <.001). Estimates (90% confidence interval) for placebo-adjusted proportions of patients with modified clinical remission at week 8 were 13.7% (0.5%–24.2%), 32.7% (20.2%–45.3%), and 36.0% (23.6%–48.6%) for ritlecitinib 20, 70, and 200 mg, respectively, and 14.6% (1.9%–25.7%), 25.5% (11.0%–38.1%), and 25.5% (11.0%–38.1%) for brepocitinib 10, 30, and 60 mg, respectively. Adverse events were mostly mild, and there were no serious cases of herpes zoster infection. Infections were observed with brepocitinib (16.9% [12.5%–23.7%]), ritlecitinib (8.7% [5.2%–13.4%]), and placebo (4.0% [0.2%–17.6%]). One death due to myocardial infarction (ritlecitinib) and 1 thromboembolic event (brepocitinib) occurred; both were considered unrelated to study drug. Ritlecitinib and brepocitinib induction therapies were more effective than placebo for the treatment of moderate-to-severe active ulcerative colitis, with an acceptable short-term safety profile. ClinicalTrials.gov number: NCT02958865. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2023
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3. Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study.
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Krueger, James, Clark, James D., Suárez-Fariñas, Mayte, Fuentes-Duculan, Judilyn, Cueto, Inna, Wang, Claire Q., Tan, Huaming, Wolk, Robert, Rottinghaus, Scott T., Whitley, Maryann Z., Valdez, Hernan, von Schack, David, O'Neil, Shawn P., Reddy, Padmalatha S., and Tatulych, Svitlana
- Abstract
Background Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. Objective We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis. Methods Twelve patients with plaque psoriasis were randomized (3:1) to receive 10 mg of tofacitinib or placebo twice daily for 12 weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67 + keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT] + nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray. Results In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1 day of tofacitinib (baseline, median of 1290 pSTAT1 + cells/μm 2 ; day 1, median of 332 pSTAT1 + cells/μm 2 ; and nonlesional, median of 155 pSTAT1 + cells/μm 2 ). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P = .016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/T H 17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression. Conclusions Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC and T-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/T H 17 pathway. [ABSTRACT FROM AUTHOR]
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- 2016
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4. Evolutionary and biochemical differences between human and monkey acidic mammalian chitinases
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Krykbaev, Rustem, Fitz, Lori J., Reddy, Padmalatha S., Winkler, Aaron, Xuan, Dejun, Yang, Xiaoke, Fleming, Margaret, and Wolf, Stanley F.
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CHITINASE , *ASTHMA , *MACAQUES , *HOMOLOGY (Biology) , *GENE expression , *CHITIN , *KRA , *GENOMES , *PHYSIOLOGY - Abstract
Abstract: Acidic mammalian chitinase (AMCase), an enzyme implicated in the pathology of asthma, is capable of chitin cleavage at a low pH optimum. The corresponding gene (CHIA) can be found in genome databases of a variety of mammals, but the enzyme properties of only the human and mouse proteins were extensively studied. We wanted to compare enzymes of closely related species, such as humans and macaques. In our attempt to study macaque AMCase, we searched for CHIA-like genes in human and macaque genomes. We found that both genomes contain several additional CHIA-like sequences. In humans, CHIA-L1 (hCHIA-L1) is an apparent pseudogene and has the highest homology to CHIA. To determine which of the two genes is functional in monkeys, we assessed their tissue expression levels. In our experiments, CHIA-L1 expression was not detected in human stomach tissue, while CHIA was expressed at high levels. However, in the cynomolgus macaque stomach tissue, the expression pattern of these two genes was reversed: CHIA-L1 was expressed at high levels and CHIA was undetectable. We hypothesized that in macaques CHIA-L1 (mCHIA-L1), and not CHIA, is a gene encoding an acidic chitinase, and cloned it, using the sequence of human CHIA-L1 as a guide for the primer design. We named the new enzyme MACase (Macaca Acidic Chitinase) to emphasize its differences from AMCase. MACase shares a similar tissue expression pattern and pH optimum with human AMCase, but is 50 times more active in our enzymatic activity assay. DNA sequence of the mCHIA-L1 has higher percentage identity to the human pseudogene hCHIA-L1 (91.7%) than to hCHIA (84%). Our results suggest alternate evolutionary paths for human and monkey acidic chitinases. [Copyright &y& Elsevier]
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- 2010
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