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STUDY QUESTION What is the safety and efficacy profile during long-term (12–24 months) uninterrupted treatment with the selective progesterone receptor modulator asoprisnil, 10 and 25 mg in women with heavy menstrual bleeding (HMB) associated with uterine fibroids? SUMMARY ANSWER Uninterrupted treatment with asoprisnil should be avoided due to endometrial safety concerns and unknown potential long-term consequences. WHAT IS KNOWN ALREADY Asoprisnil was well tolerated in shorter-term studies and effectively suppressed HMB and reduced fibroid volume. STUDY DESIGN, SIZE, DURATION Women with uterine fibroids who had previously received placebo (n = 87) or asoprisnil 10 mg (n = 221) or 25 mg (n = 215) for 12 months in two double-blind studies entered this randomized uncontrolled extension study and received up to 12 additional months of treatment followed by 6 months of post-treatment follow-up. Women who previously received placebo were re-randomized to either asoprisnil 10 or 25 mg for the extension study. This report focuses on the 436 women who received asoprisnil in the double-blind studies and this extension study. Results for women who previously received placebo in the double-blind studies are not described. PARTICIPANTS/MATERIALS, SETTING, METHODS Women ≥18 years of age who completed a 12-month, double-blind, placebo-controlled study, had estradiol levels indicating that they were not menopausal and had no endometrial hyperplasia or other significant endometrial pathology were eligible. The safety endpoints were focused on endometrial assessments. The composite primary efficacy endpoint was the proportion of women who demonstrated a response to treatment by meeting all three of the following criteria at the final month for participants who prematurely discontinued or at month 12 for those who completed the study: a reduction from initial baseline to final visit of ≥50% in the menstrual pictogram score, hemoglobin concentration ≥11 g/dl or an increase of ≥1 g/dl from initial baseline at the final visit, and no surgical or invasive intervention for uterine fibroids. Other efficacy endpoints included rates for amenorrhea and suppression of bleeding, changes in fibroid and uterine volume and changes in hematologic parameters. No statistical tests were planned or performed for this uncontrolled study. MAIN RESULTS AND ROLE OF CHANCE Imaging studies revealed a progressive increase in endometrial thickness and cystic changes that frequently prompted invasive diagnostic procedures. Endometrial biopsy results were consistent with antiproliferative effects of asoprisnil. Two cases of endometrial cancer were diagnosed. At the final month of this extension study (total duration of uninterrupted treatment up to 24 months), the primary efficacy endpoint was achieved in 86 and 92% of women in the asoprisnil 10- and 25-mg groups, respectively. During each month of treatment, amenorrhea was observed in the majority of women (up to 77 and 94% at 10 and 25 mg, respectively). There was a progressive, dose-dependent decrease in the volume of the primary fibroid with asoprisnil 10 and 25 mg (−55.7 and −75.2% median decrease, respectively, from baseline [i.e. the beginning of the placebo-controlled study] to month 12 [cumulative months 12–24] of this extension study). These effects were associated with improvements in quality of life measures. LIMITATIONS, REASONS FOR CAUTION This study was uncontrolled, which limits the interpretation of safety and efficacy findings. The study also had multiple protocol amendments with the addition of diagnostic procedures and, because no active comparator was included, the potential place of asoprisnil in comparison to therapies such as GnRH agonists and surgery cannot be determined. WIDER IMPLICATIONS OF THE FINDINGS Long-term, uninterrupted treatment with asoprisnil leads to prominent cystic endometrial changes that are consistent with the ‘late progesterone receptor modulator’ effects, which prompted invasive diagnostic procedures, although treatment efficacy is maintained. Although endometrial cancers were uncommon during both treatment and follow-up, these findings raise concerns regarding endometrial safety during uninterrupted long-term treatment with asoprisnil. This study shows that uninterrupted treatment with asoprisnil should be avoided due to safety concerns and unknown potential long-term consequences. STUDY FUNDING/COMPETING INTEREST(S) AbbVie Inc. (prior sponsor, TAP Pharmaceutical Products Inc.) sponsored the study and contributed to the design and conduct of the study, data management, data analysis, interpretation of the data and the preparation and approval of the manuscript. Financial support for medical writing and editorial assistance was provided by AbbVie Inc. M. P. Diamond received research funding for the conduct of the study paid to the institution and is a consultant to AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution for Bayer and ObsEva. E. A. Stewart participated as a site investigator in the phase 2 study of asoprisnil and served as a consultant to TAP Pharmaceuticals during the time of design and conduct of the studies while on the faculty of Harvard Medical School and Brigham and Women’s Hospital, Boston, MA. In the last 3 years, she has received support from National Institutes of Health grants HD063312, HS023418 and HD074711. She has served as a consultant for AbbVie Inc., Allergan, Bayer HealthCare AG and Myovant for consulting related to uterine leiomyoma and to Welltwigs for consulting related to infertility. She has received royalties from UpToDate and the Med Learning Group. A.R.W. Williams has acted as a consultant for TAP Pharmaceutical Products Inc. and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr has served as consultant and received research funding from AbbVie Inc. and Synteract (Medicines360). E.R. Myers has served as consultant for AbbVie Inc., Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was a co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie Inc. and owns AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie Inc. and own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER NCT00156195 at clinicaltrials.gov.

DNA expression vectors have the potential to be useful therapeutics for a wide variety of applications. However, development has been hindered by the lack of systems that provide protection from nuclease-based attack, enable cell or tissue localisation, promote adequate gene expression or provide for controlled release. At least one synthetic polymer, poly(lactide-co-glycolide) (PLG), may provide benefit in this regard. This polymer has a history of safe use in humans, has been demonstrated effective as a delivery system, its use is not hindered by composition patents, and Good Manufacturing Practices grade material is readily available from commercial sources. Safety and applicability to clinical medicine have been proven by use of the polymer as a microparticle delivery vehicle for peptides (luteinizing hormone releasing hormone agonist peptides; Lupron Depot [TAP Pharmaceuticals]; Zoladex [AstraZeneca]) and proteins (human growth hormone recombinant protein, Nutropin Depot [Genentech]). This report focuses on the expanding field of PLG-based DNA delivery and provides a review on research and clinical experience with PLG-plasmid formulations.

Lansoprazole (Prevacid, TAP Pharmaceuticals, Inc.) is a substituted benzimidazole that inhibits gastric acid secretion. This agent is approved for the short-term treatment of erosive reflux oesophagitis, active gastric ulcer, active duodenal ulcer and the treatment of non-steroidal anti-inflammatory drug (NSAID)-induced gastric and duodenal ulcers. It is also approved for the long-term treatment of healed reflux oesophagitis, healed duodenal ulcer, the treatment of hypersecretory conditions such as Zollinger-Ellison syndrome and the eradication of Helicobacter pylori as a component of triple therapy with lansoprazole, clarithromycin and amoxicillin, or dual therapy with lansoprazole and amoxicillin. Its mechanism of action is to selectively inhibit the membrane enzyme H+/K+ ATPase in gastric parietal cells. In clinical trials, lansoprazole is more effective than placebo or histamine (H2)-receptor antagonists in the treatment of reflux oesophagitis. Lansoprazole administered at a dose of 30 mg daily produced faster relief of symptoms and superior healing rates in patients with gastric or duodenal ulcers or reflux oesophagitis than H2-receptor antagonists. A daily dose of 30 mg lansoprazole reduced epigastric pain faster than omeprazole 20 mg daily in patients with peptic ulcer disease but healing rates at 4 and 8 weeks were similar with both agents at these dosages. Lansoprazole was more effective than H2-receptor antagonists in patients with Zollinger-Ellison syndrome and produced similar treatment outcome to omeprazole. Lansoprazole in combination with clarithromycin and amoxicillin produced similar rates of eradication of H. pylori. In clinical trials, lansoprazole is well-tolerated and has a low frequency of side effects similar to that of H2-receptor antagonists or omeprazole.

The central nervous system has the capacity to enhance the activity of dysfunctional penile tissue in men with erectile dysfunction (ED). Phase III clinical trials have been conducted using Apomorphine SL (TAP Pharmaceuticals, Deerfield, IL) as a centrally acting treatment for ED. Apomorphine SL has been administered to over 3000 men in over 75,000 doses. In three phase III crossover double blind studies 854 patients were given a total of 8263 tablets of apomorphine SL in 2 and 4 mg doses. The patients were between 18 and 70 years old and had multiple co-morbid conditions. Outcome measures included intercourse rates and erection rates on a per attempt basis as well as psychometric instruments and partner response evaluations. The results show that 74.1% of patients had moderate or severe grades of ED on inclusion into the studies, 31% had hypertension, 16% had documented coronary artery disease, 16% had dyslipidemia, and 16% had diabetes. Erections occurred rapidly (10–25 min). In 54.4% of attempts at 4 mg (vs 33.8% placebo, P

Background and Procedure High-risk neuroblastoma disease features are correlated with tumor vascularity, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. We therefore examined the efficacy of TNP-470 (TAP Pharmaceuticals, Deerfield, IL) in human neuroblastoma xenograft models. Results Tumor growth rate was markedly inhibited in mice receiving TNP-470 administered alone with a treatment to control ratio (T/C) at day 21 = 0.4 (P < .001). TNP-470 also significantly inhibited tumorigenicity when administered shortly after xenograft inoculation (T/C at day 30 = 0.1, P < .001) and when administered following cyclophosphamide (T/C at day 35 = 0.1, P < .001). Conclusions These data show that TNP-470 is a potent inhibitor of human neuroblastoma growth both alone and when given with conventional chemotherapy, suggesting that it may be a useful adjunctive therapy for high-risk neuroblastoma patients. Med. Pediatr. Oncol. 35:673–676, 2000. © 2000 Wiley-Liss, Inc.

Triple therapy with a proton pump inhibitor (PPI), amoxicillin, and clarithromycin is widely accepted for Helicobacter pylori eradication. The choice of PPI for triple therapy in Israel is arbitrary, with no preference for any one PPI except for economic considerations. Direct comparison between omeprazole and lansoprazole for efficacy of H. pylori eradication has never been performed in an Israeli poplulation. Based on the pharmacokinetic data, lansoprazole-based therapy may be a better alternative than omeprazole-based therapy. The aim of this study was to compare the effectiveness of triple therapy regimens with omeprazole (Losec, AstraZeneca; or Omeradex, Dexxon) or lansoprazole (TAP Pharmaceuticals) in eradicating H. pylori infection. The database of the biggest health insurance provider in Israel was reviewed for all patients who received 1 week of treatment with omeprazole (n = 1293) or lansoprazole (n = 85) with additional amoxicillin and clarithromycin for H. pylori eradication in 2002. All patients underwent the 13C-urea breath test (13CUBT) for validation of eradication. A negative 13CUBT result was noted in 1026 of the patients treated with omeprazole (79.4%) and 61 treated with lansoprazole (71.8%). On logistic regression analysis, none of the confounding factors (sex, age, indication, chronic use of PPI, eradication protocol) were found to contribute to the discrimination between a negative (successful eradication) and a positive (failed eradication) 13CUBT. There is no statistically significant difference between omeprazole and lansoprazole as part of a PPI-based triple therapy for eradication of H. pylori.

GnRH analogs (GnRH-a) have proven to be efficacious and have become the standard treatment for central precocious puberty (CPP). To confirm the diagnosis of CPP and to monitor the adequacy of hvpothalamic-pituitary-gonadal (HPG) axis suppression, GnRH stimulation testing has been essential. To determine whether 24-h urinary gonadotropin excretion could adequately assess HPG axis suppression, we compared the results of simultaneous GnRH stimulation tests and 24-h urinary gonadotropin determinations in 18 girls with CPP who were receiving GnRH-a therapy (leuprolide acetate, Depot-Lupron, TAP Pharmaceuticals). HPG axis suppression was defined as the absence of significant LH and FSH responses to GnRH stimulation. Simultaneous GnRH stimulation tests and urinary gonadotropin determinations had a concordance rate of 68% (42 of 62). The sensitivity and specificity of urinary LH determinations to detect inadequate HPG suppression were 75% and 64%, respectively. For urinary FSH determinations, the sensitivity and specificity were 90% and 28%, respectively. Hence, single timed urine collections lacked the sensitivity and specificity to assess HPG axis suppression and, thus, cannot replace GnRH stimulation tests for monitoring the adequacy of the GnRH-a dose.

Pelvic lymphadenectomy unquestionably is still the most accurate method to identify the presence or absence of lymphatic extension of prostate cancer. Lymphatic spread follows the lymph channels that leave the prostate posteriorly and then spread primarily to a lymphatic field of drainage that includes the perivesical, hypogastric, obturator, presacral, and presciatic lymph nodes. The obturator nodes are commonly the first site of meta~tasis.~' The risk of nodal involvement is increased with larger tumor volume and local periprostatic spreadlo; however, when only the histopathologic grade of the tumor is used, no method is precise in detecting positive pelvic lymph nodes with increasing Gleason score.2,18,22,28 At present, no imaging modality can identify accurately lymphatic involvement with prostate cancer. The role of CT scan in evaluating lymph node involvement is limited, with an accuracy rate of only 65%.3 In addition, microscopic nodal metastases cannot be demonstrated by CT scan in patients with advanced disease of the prostate (stages B,, C, or D).15,32 Unless the nodes are grossly enlarged, CT scan imaging of the prostate is limited as a staging tool for prostate cancer. The value of ultrasonography and magnetic resonance imaging for pelvic lymph node involvement is similar to that of CT scan, with a reported accuracy of 84% to 89%:~~~ Pedal lymphangiography, Color reproduction in this article courtesy of a grant by Tap Pharmaceuticals, Inc.

Objective To compare the efficacy of a 3-month trial of leuprolide acetate (LA; Lupron; TAP Pharmaceuticals, Deerfield, IL) versus danazol (Danocrine; Scenofi Winthrup Pharmaceuticals, New York, NY) therapy on laparoscopically proven endometriosis. Design Endometriosis severity was assessed at the time of laparoscopy and patients were randomized to receive 0.1mg SC LA (n=22) or 800mg danazol orally (n=18) daily for 3 months. A second laparoscopy and/or laparotomy was performed to assess the change in the extent of endometriosis and for surgical therapy. Setting Private practice at a university-affiliated hospital. Patients Forty patients with mild, moderate, or severe endometriosis. Ten patients were excluded. Intervention Three-month treatment randomly assigned to either LA or danazol. Main Outcome Measures Prospective measurement of American Fertility Society endometriosis scores and size of ovarian endometriomata before and after therapy via laparoscopy. Results The mean endometriosis score including adhesions decreased significantly from 36±4.9 to 29±5.0 (mean±SEM) with LA and from 34±6.4 to 29±6.5 with danazol. The mean laparoscopic endometriosis score not including adhesions decreased from 27±3.5 to 22±3.4 with LA and 22±3.5 to 19±3.1 with danazol. Seven of 18 (39%) endometriomata responded to LA and 6 of 15 (40%) endometriomata responded to danazol. Conclusion We conclude that both danazol and LA will reduce endometriosis scores after a 3-month course of therapy. Larger clinical trials are needed to compare short courses of therapy with the more established 6-month trials. A 3-month versus a 6-month course of therapy offers obvious benefits including decreased cost and decreased side effects.

Objective To evaluate the effects of two different doses (3.75mg versus 7.5mg) of leuprolide acetate (LA, Lupron; Tap Pharmaceuticals, Deerfleld, IL) on myoma size, blood loss during myomectomy, on magnetic resonance imaging (MRI) signal quality, and histopathologic changes in women requiring myomectomy. Design Prospective, nonrandomized, sequential study. Setting Urban center teaching hospital. Patients Twenty-eight women with uterine leiomyomata requiring myomectomy. Interventions Nine women were entered as controls (group 1), 10 women received 3.75mg IM (group 2), and 9 women received 7.5mg IM of LA (group 3) each for 3months before myomectomy. Results The uterine size and hematocrit among the three groups of patients before treatment was not significantly different. A significant reduction of 34.5% and 34.6% in myomata size was seen in groups 2 and 3. The estimated average blood loss at myomectomy was 745±101mL, 615±177mL, and 722±192mL in groups 1, 2, and 3, respectively. The postoperative hematocrit was not different among the three groups (29.8%±0.9%, 30.4%±1.6%, and 29.8%±1.2%). There was no evidence of cytologic atypia, increased mitosis, or change in fibrosis in LA-treated women. There were no characteristic MRI or histologic changes seen after LA treatment as compared with controls. Conclusions The results of this study have demonstrated that both doses of LA (3.75 and 7.5mg) can induce a significant and similar degree of size reduction in myomas and that neither dose of LA aided in the reduction of blood loss at myomectomy and therefore should not be used routinely.

Leuprolide acetate acts as a superactive gonadotropin-releasing hormone (GnRH) agonist in mammals. Its administration to humans in a depot formulation (Lupron Depot 3.75 mg; TAP Pharmaceuticals, Deerfield, IL) consisting of microspheres suspended in a diluent of carboxymethylcellulose and other elements leads to an initial increase in serum gonadotropin levels followed by a prolonged suppression of ∼ 1 month's duration. To test whether it might act in cockatiels to prevent egg laying, we administered Lupron Depot to groups of pairs (at least 6 pairs/group) stimulated to reproduce by provision of nest boxes and exposure to sexually stimulatory daylengths (15:9 L:D). A single intramuscular injection of Lupron Depot, calculated to achieve a daily release rate of 0 (control; diluent only), 17, 52, or 156 μg/kg/day of leuprolide acetate, was administered on day 0, when birds received nest boxes and after daylength had been stepwise increased. Egg production began on day 12 in the 0 and 17 μg dose groups, and on day 31 in the groups receiving the higher doses. Number of eggs per clutch, candled fertility, and percent hatchability were not significantly different among the groups. In a separate experiment in which leuprolide was administered prior to photostimulation and nest box presentation, nest-inspection behavior was not prevented. We conclude that a single injection of Lupron Depot is effective in reversibly preventing egg laying in cockatiels. © 1994 Wiley-Liss, Inc.

We treated a patient with Huntington's disease and exhibitionism using leuprolide acetate (Lupron Depot, TAP Pharmaceuticals), a gonadotropin-releasing hormone agonist. The result was elimination of his deviant sexual behavior with few side effects. This regimen may be a safe and effective pharmacological treatment of the paraphilias. The occurrence of paraphilias in basal ganglia disorders is reviewed.

Objective To examine if changes in insulin sensitivity and glucose effectiveness in women with polycystic ovarian disease (PCOD) occurred after ovarian androgen suppression with a GnRH agonist, leuprolide acetate (LA, Lupron; TAP Pharmaceuticals, Deerfield, IL) using the minimal model method. Design Twelve patients with PCOD were tested in the untreated state (baseline) and after 6 weeks of LA treatment. Subjects were divided into two groups based on the degree of impairment of their baseline insulin sensitivity index (S I ; (min –1 )( μ U/mL –1 ): mild insulin resistance (S I > 1) or severe insulin resistance (S I Results In all patients, serum T was significantly decreased from elevated baseline levels to normal female concentrations after 6 weeks of LA therapy. Insulin sensitivity in PCOD patients with mild insulin resistance significantly improved from baseline after 6 weeks of LA therapy, whereas no change in S I on LA therapy was seen in PCOD women with severe insulin resistance. Glucose utilization independent of increased insulin secretion did not change as a function of LA treatment in either group. Conclusion These findings indicate a significant improvement in S I in mildly insulin-resistant women with PCOD after suppression of ovarian function with LA treatment.

Objective To examine the relationship between serum T levels and sexual function when T levels are varied in the normal male range by pharmacological means. Two groups of healthy men were treated with a depot form of GnRH agonist leuprolide acetate (Lupron depot; TAP Pharmaceuticals, Chicago, IL) on days 1 and 31 to suppress endogenous T production and either 4 (n=6) or 8 (n=5) mg/d T replacement by a sustained release, long-acting T microcapsule formulation on day 1. Outcome Measures Sexual function was evaluated by daily logs of sexual activity and electroencephalogram-coupled nocturnal penile tumescence recording before and after 9weeks of treatment. Results Serum T levels in 4 and 8mg/d groups were at low and high ends of the normal male range, respectively (10.5±1.7 versus 26.5±3.4nmol/L). The number and duration of rapid eye movement (REM) periods, latency to REM sleep, erections/REM period, magnitude, and duration of tumescence were not significantly different between the 4 and 8mg groups. Sexual logs also did not show significant differences in overall scores or in subcategories of intensity of sexual feelings (libido) and sexual activity between the two doses. Conclusions These data indicate that erectile function and sexual activity and feelings are restored by relatively low T levels. These data may help explain why some partially hypogonadal men continue to have normal sexual function and the absence of good correlation between serum T levels in the normal range and sexual function.

Study Objective To evaluate the prognostic and therapeutic value of a Lupron (leuprolide acetate; Tap Pharmaceuticals, North Chicago, IL) screening test before ovarian stimulation for in vitro fertilization (IVF). Design Prospective. Setting Outpatient IVF program. Patients Eighty patients exhibited four early estradiol (E 2 ) patterns. Patients with pattern A and B remained on a flare-up ovarian stimulation protocol. Patients with pattern C were randomized to three ovarian stimulation protocols. Patients with pattern D were treated with the flare-up protocol using a high pure follicle-stimulating hormone (FSH) dose. Results Patterns A, B, C, and D occured in 44%, 16%, 25%, and 15% of the patients, respectively. The E 2 pattern recurred in 77% of subsequent IVF cycles. Pattern A and B patients achieved a 41% (23/56) and 22% (5/23) ongoing pregnancy rate (PR) per stimulated cycle. An early luteal phase Lupron protocol had the best ongoing PR per stimulated cycle (10/27, 37%) in patients with a pattern C response. Pattern D patients had a 20% (5/25) ongoing PR per stimulated cycle. Conclusion The Lupron screening test allows prospective selection of stimulation protocols in ovulatory patients undergoing IVF. Early E 2 patterns A and B should be treated with the flare-up protocol. Pattern C patients benefit from the luteal phase Lupron protocol and pattern D patients benefit from a high pure FSH flare-up protocol.

The safety and efficacy of leuprolide acetate (LA) for depot suspension (Lupron depot; TAP Pharmaceuticals, North Chicago, IL), 3.75 mg versus placebo, in the treatment of pain associated with endometriosis was assessed in a randomized, double-blind, multicenter study involving 52 patients. Dysmenorrhea, pelvic pain, and pelvic tenderness all responded significantly to LA treatment in comparison with placebo. Menses were suppressed in all of the LA patients. Estradiol decreased significantly to menopausal levels in the LA group. There were small to moderate changes in a variety of laboratory parameters, but these were not clinically significant. The most common adverse event was vasodilatation, occurring significantly more frequently in the LA group. Lupron depot was shown to be safe and effective in inducing a hormonal and menstrual suppression in patients with endometriosis, resulting in alleviation of pain symptoms.

Three treatment protocols were used in 156 in vitro fertilization cycles. Leuprolide acetate was begun on day 1 of the cycle in one group (n = 20), on day 3 in another (n = 48), and the third control group (n = 88) did not receive the gonadotropin-releasing hormone analog. Human menopausal gonadotropin was initiated on day 3 in all groups. Peak estradiol (E2) levels and the mean numbers of mature oocytes and embryos transferred per cycle were significantly greater in the day 3 group than in either the day 1 or control groups. Patients who received the day 3 protocol had significantly fewer cancelled cycles. A decline in E2 was observed on the third day of analog administration in certain patients, particularly those on the day 1 protocol. Follicle-stimulating hormone and luteinizing hormone (LH) levels increased two- to fivefold 24 hours after initiation of the analog. Thereafter the gonadotropin levels fell, but nevertheless remained above those of controls for most of the cycle. Hence, it appears that enhanced follicular growth attributed to the early transient rises in gonadotropins can be coupled to a suppression of endogenous LH surges in leuprolide-treated women. These beneficial effects seem to be more likely to occur if leuprolide is initiated on cycle day 3 rather than day 1.

To the Editor. —Leuprolide acetate (Lupron Depo, Lupron Injection, TAP Pharmaceuticals Inc, Deerfield, Ill) is a gonadotropin-releasing hormone used to control endometriosis or advanced prostatic cancer. To our knowledge, this is the first overview of possible adverse ocular events occurring in patients receiving this drug. Cases were received from TAP Pharmaceuticals Inc, the World Health Organization Collaborating Center for International Drug Monitoring, Uppsala, Sweden (which instigated this review), and the National Registry of Drug-Induced Ocular Side Effects, Casey Eye Institute, Portland, Ore. The most common adverse ocular event possibly associated with leuprolide acetate is blurred vision, with or without headaches and/or dizziness (Table). This may occur after each injection or as late as the sixth injection, as in one patient. Transitory blurred vision may occur shortly after the injection, usually lasting 1 to 2 hours, but in rare instances may continue for 2 to 3 weeks. This may be a

Lansoprazole is a proton pump inhibitor widely prescribed for gastroesophageal reflux and benign peptic ulcer disease. According to the manufacturer's package insert (TAP Pharmaceuticals, Lake Forest, IL, USA), the most common side-effects are diarrhea, headache and abdominal pain, which occur in approximately 3% of patients and are reversible with drug discontinuation. An unusual case of microscopic colitis is reported in a previously asymptomatic patient who developed new-onset diarrhea after initiation of lansoprazole. The case is reviewed and possible mechanisms of diarrhea secondary to proton pump inhibitors are discussed.

Anti-CTLA-4 is a monoclonal antibody (Ipilimumab or Yervoy, Bristol-Myers Squibb) that was recently FDA-approved for the treatment of patients with metastatic melanoma. Since anti-CTLA-4 targets a T cell specific molecule, as opposed to a tumor-specific molecule, it is being tested for therapeutic efficacy in multiple malignancies, including prostate cancer. In addition, since anti-CTLA-4 enhances anti-tumor T cell responses by blocking an inhibitory signal on activated T cells, it has been postulated that traditional therapies that lead to tumor cell death, thereby releasing tumor antigens to prime and potentially activate T cell responses, can be used in combination with CTLA-4 blockade to sustain activated T cell responses and enhance anti-tumor immune responses. Pre-clinical mouse models have shown this to be true. To determine the impact of combination therapy on human immune responses, we designed a pre-surgical clinical trial with a hormonal agent consisting of leuprolide acetate, a standard agent that has therapeutic efficacy against prostate cancer, plus anti-CTLA-4 (ipilimumab), in the setting of patients with regional, high-risk prostate cancer. As of October 2011, we have treated 4 out of a planned 20 patients on trial. Patients receive one injection of leuprolide acetate (Lupron, Tap Pharmaceuticals) at a dose of 22.5 mg on week 0 and ipilimumab at 10 mg/kg/dose on weeks 1 and 4. Patients then undergo surgery at week 8. Tumor tissues are collected prior to any therapy and then at the time of surgery. Blood is collected throughout the study prior to each therapeutic intervention and after surgery. Immunologic analyses are ongoing on all collected patients’ samples. These data will be compared to those obtained from previously completed trials consisting of a trial whereby patients were treated with ipilimumab monotherapy and a trial whereby patients were treated with hormonal therapy prior to surgery. Our preliminary data indicate that combination therapy impacts T cell responses including a measurable increase in the frequency of T cells expressing the inducible costimulator (ICOS) molecule. In addition, four patients have completed the trial, including surgery, without any serious adverse events related to the combination therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4388. doi:1538-7445.AM2012-4388

The effects of follicular phase clomiphene citrate (CC) and two regimens of leuprolide acetate on estrogen-progesterone-induced hyperprolactinemia in nonhuman primates were studied. All groups received estradiol (E2) benzoate (12.5 micrograms intramuscularly on cycle days 2 to 33) and progesterone (P) (silastic implant for cycle days 14 to 33). A gonadotropin-releasing hormone agonist (GnRH-a) (Lupron 0.5 mg daily, TAP Pharmaceuticals, Chicago, IL) was administered from cycle day 2 to 14 in group II and from day 20 of the previous cycle until cycle day 14 in group III. Oral CC was given on cycle days 3 through 7 in group IV. No significant differences of mean E2 and P concentrations were noted between groups. Neither GnRH-a nor CC had an overall effect on E2/P-induced hyperprolactinemia. However, for the 5-day interval at the onset of the P treatment there was a significant increase in prolactin (PRL) secretion for group II (130.4 +/- 30.6) versus group I (53.9 +/- 3.3), group III (64.4 +/- 11.1), and group IV (68.8 +/- 14.3). This suggests that leuprolide may exert a delayed stimulatory effect on PRL secretion, or that complete suppression of the putative paracrine regulation of PRL stimulation may require more than 13 days of GnRH-a administration.

There is an alarming trend in the field of medicine, whose portents are ominous but do not seem to shake the complacency and merry making doing the rounds. The wants of the medical man have multiplied beyond imagination. The cost of organizing conferences is no longer possible on delegate fees. The bottom-line is: Crores for a Conference Millions for a Mid-Term. However, the problem is that sponsors keep a discreet but careful tab on docs. All in all, costs of medicines escalate, and quality medical care becomes a luxury. The whole brunt of this movement is borne by the patient. Companies like GlaxoSmithKline, Bayer, Pfizer, Bristol-Myers Squibb, AstraZeneca, Schering-Plough, Abbott Labs, TAP Pharmaceuticals, Wyeth and Merck have paid millions of dollars each as compensation in the last few years. The financial condition of many pharmaceutical majors is not buoyant either. Price deflation, increased Rand D spending, and litigation costs are the main reasons. In the future, the messy lawsuits situation would no longer be restricted to industry. It would involve academia and practising doctors as well. Indian pharma industry captains, who were busy raking in the profits at present, would also come under the scanner. If nothing else, it means industry and docs will have to sit down and do some soul searching. Both short and long-term measures will have to be put into place. Short-term measures involve reduction in i) pharma spending over junkets and trinkets; ii) hype over ‘me too’ drugs; iii) manipulation of drug trials; iv) getting pliant researchers into drug trials; iv) manipulation of Journal Editors to publish positive findings about their drug trials and launches; v) and for Indian Pharma, to conduct their own unbiased clinical trial of the latest drug projected as a blockbuster in the West, before pumping in their millions. The long-term measures are related to the way biomedical advance is to be charted. We have to decide whether medicine is to become a corporate enterprise or remain a patient welfare centered profession. A third approach involves an eclectic resolution of the two. Such amount of patient welfare as also ensures profit, and such amount of profit as also ensures patient welfare is to be forwarded. For, profit, without patient welfare, is blind. And patient welfare, without profit, is lame. According to this approach, medicine becomes a patient welfare centered professional enterprise. The various ramifications of each of these approaches are discussed in this monograph.

TAP Pharmaceuticals, a joint venture between Abbott Laboratories and Takeda Pharmaceuticals, agreed to pay a $875 million fine and plead guilty to one count of criminal conspiracy to violate the Prescription Drug Marketing Act. The indictment described a scheme in which TAP salespeople provided doctors with free samples of Lupron (leuprolide acetate), a prostate cancer drug, which were fraudulently billed to Medicare. According to the indictment, the company offered physicians generous ‘freebies’ to convince them to switch to Lupron. Six TAP employees and five physicians have been indicted. The US Government says Medicare rip-offs amount to as much as $100 billion per year, and has announced its intention to investigate other cases of alleged drug-pricing fraud. AB

New details about the way a key anticancer drug interacts with its human target protein have been revealed though independent studies by two research groups. The studies could aid the structure-based design of agents with improved activity and lower toxicity and could lead to a better fundamental understanding of the drug's effects in the body. The drug, TNP-470, is an analog of the fungal natural product fumagillin. Both compounds fight cancer by curbing angiogenesis, the growth of the new blood vessels that tumors need to sustain themselves and spread. The agents act by inhibiting methionine aminopeptidase-2 (MetAP-2), an enzyme that plays a key role in protein synthesis. In 1992, TNP-470 became the first anti-angiogenesis drug to enter the clinic as an anticancer agent. It is currendy in Phase II trials sponsored by TAP Pharmaceuticals, Deerfield, Ill. However, it is toxic to some degree and breaks down quickly in the body, so drug researchers are interested ...

Q LARGE TRIAL COMPARES LANSOPRAZOLE TO OMEPRAZOLE DO Castell, JE Richter, M Robinson, S Sontag. The Graduate Hospital, Philadelphia, PA; University of Alabama, Birmingham, AL; Oklahoma Foundation for Digestive Research, Oklahoma City, OK; Hines VA Hospital, Hines, IL. Lansoprazole (LAN) 30 mg and l5 mg QD were compared to omeprazole (OME) 20 mg QD and placebo (PBO) in patients with endoscopically proven erosive reflux esophagitis (RE) in a randomized, double-blind, multicenter clinical trial. Forty-four (44) investigators enrolled 1284 patients (836 males/448 females): LAN 30 rag: 422 patients, LAN 15 mg: 218 patients, OME 20 rag: 431 patients, PBO: 213 patients. Study medication was taken each day for eight weeks. Endoscopies were performed at baseline, weeks 2, 4 and 8 (and week 6 if not healed at week 2 and week 4). Results: LAN 30 mg was as effective as r~nt~ e of Ni hts with a e ~ m OME 20 mg and both were more effective ~w,,.~L ~,~,,,o~ (p 2% occurrence) were headache, diarrhea, and nausea. As expected, fasting serum gastrin levels increased significantly from baseline in all active-treatment groups; however, median fasting serum gastrin levels remained within normal limits for all treatment groups. Conclusion: LAN 30 mg QD provided faster heartburn reliefthan OME 20 mg QD and is as safe and effective as OME 20 mg QD in healing erosive RE. This research was funded by TAP Pharmaceuticals Inc., Deerfield, IL. • HP POSITIVE FUNCTIONAL DYSPEPSIA IN ELDERLY PATIENTS: COMPARISON OF TWO TREATMENTS. F. catalano, °R. Terranova, A. Brogna, G. Branciforte, R. Catanzaro, A. Liberti, C. Bentivegna, *S. Luca. Dept of Internal Medicine. Gastroenterology Unit. *Geriatric Dept. University of Catania. Italy.

GnRH analogs are now preferred therapy for central precocious puberty (CPP). Although short term trials of the depot preparation of leuprolide acetate (TAP Pharmaceuticals, Inc.) have been reported, results from large series of patients are unavailable. We report the results of GnRH stimulation tests in 127 patients in screening for CPP at 9 centers over a 20 month period. Fifty-three patients (49 F, mean age 7.0 yr) with peak stimulated LH >10 IU/L (DELFIA) and bone age (BA) advancement >1 yr were enrolled in a protocol initiating 300 ug/kg IM q4wk (7.5-15 mg) before age 9 yr in females and 10 yr in males. Follow-up GnRH stimulation tests were performed at 4, 12, 24, 36, 48, and every 24 weeks thereafter; BA was evaluated q24wk. Comparing baseline and 24wk serum levels (mean±SE), estradiol fell from 19.5±4.9 to 5 pg/ml) during therapy, but 3/4 males had transient delectable testosterone (>10 ng/dl). 86% of subjects showed regression or no change in Tanner breast (or genital) stage. Height velocity diminished from 11.5±0.8 to 6.5±0.7 cm/yr, but BA/CA was unchanged in the first 6 mo. There were no local injection reactions. We conclude that depot leuprolide is immediately effective in suppression of pubertal progression and gonadotropin and sex steroid production, but bone age advancement continues in the initial treatment period. Further data will assess the effect of long term therapy upon predicted and final heights.

EARLY this year, an East Coast obstetrician-gynecologist sent documentation to the general counsel's office at the American Medical Association (AMA) of a promotion by TAP Pharmaceuticals, a joint venture of Abbott Laboratories, Abbott Park, Ill.The promotion, called "The Road to ACOG 1991 Sweepstakes," was intended to send 700 physicians to the American College of Obstetricians and Gynecologists (ACOG) meeting now in progress in New Orleans, La (May 5 through May 8).The trip was to include round-trip airfare, 4 nights' lodging, and the conference registration fee, all of which appear to violate basic provisions of the AMA—Pharmaceutical Manufacturers Association (PMA) guidelines that went into effect during the course of the promotion.Winners of the trip were selected in random drawings held monthly starting August 1, 1990, and ending February 1, 1991,2 months after the guidelines went into effect. Physicians could register repeatedly for the drawings through the mail or

Leuprolide (Lupron, TAP Pharmaceuticals), a potent agonist analogue of GnRH, has been shown to suppress testicular androgen production in animals. In order to determine the potential of leuprolide as an alternative to surgical castration in human males with prostatic cancer, this agent was administered to castrate and noncastrate males with carcinoma of the prostate. Baseline and treatment levels of LH, FSH, testosterone and dihydrotestosterone were determined serially. Leuprolide suppressed pituitary production of LH and FSH and, consequently, testicular production of testosterone and dihydrotestosterone. This agent simulates the results achieved with surgical castration.

Leuprolide (Lupron, TAP Pharmaceuticals, North Chicago), a gonadotropin-releasing hormone analogue, was administered to 26 premenopausal women with metastatic breast cancer. Of 25 evaluable patients, 11 (44%) had a partial response with a median duration of 39 weeks and five (20%) remained stable. Six patients showed early rapid progression of their disease. Toxicity was mild and included hot flashes, nausea, vomiting, and headache. Leuprolide induced amenorrhea in all patients who received treatment for ten weeks or longer. We conclude that this GnRH analogue provides a safe and effective means of producing medical castration in premenopausal patients with metastatic breast carcinoma.

Leuprolide acetate (Lupron, TAP Pharmaceuticals, North Chicago), a gonadotropin-releasing hormone analogue, was administered subcutaneously at a 1-mg dose for a minimum of 8 weeks to 23 patients with refractory epithelial ovarian cancer. Eighteen of these patients were evaluable. There were no complete responses. Four patients (17%) had a partial response, with a median duration of 52 weeks. Three of six patients with grade 1 carcinomas had a partial response and two had stabilized disease. There was only one response among 15 patients with grade 2 or 3 disease. Therapy was well tolerated, with three patients complaining of hot flashes and two of mild pedal edema. Leuprolide acetate thus shows evidence of antitumor activity against refractory grade 1 epithelial adenocarcinoma of the ovary. Further trials with larger numbers of patients should be conducted.

A randomized, double-blind study was performed on 16 women to compare the efficacy of daily subcutaneous (SC) injections of leuprolide acetate (LA; TAP Pharmaceuticals, North Chicago, IL) plus oral placebo tablets (group A, n = 7) with SC LA plus oral medroxyprogesterone acetate (The Upjohn Company, Kalamazoo, MI; group B, n = 9) in the treatment of leiomyomata uteri. Patients in group A had a significant reduction in uterine size from a pretreatment volume of 601 +/- 62 cm3 (mean +/- standard error) to a mean uterine volume of 294 +/- 46 cm3 at 24 weeks of therapy (P less than 0.01). Group B patients had a reduction in uterine volume from 811 +/- 174 cm3 to 688 +/- 154 cm3, which was not statistically significant. However, only one patient in group B experienced hot flashes, whereas six patients in group A had this symptom (P less than 0.01). Both groups demonstrated significant increases in mean hemoglobin concentrations, hematocrits, and serum iron levels at 24 weeks of therapy compared with pretreatment levels.