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PubMed1999

Antifungal agents.

At this year's ICAAC Meeting, new data on approximately 20 different antifungal agents were presented, while no new agents were disclosed. Drugs in late development include the triazoles, voriconazole (Pfizer Ltd) and Sch-56592 (Schering-Plough Corp), and the echinocandins, caspofungin (Merck & Co Inc) and FK-463 (Fujisawa Pharmaceutical Co Ltd). In contrast to previous years, presentations on these and earlier developmental compounds were relatively modest in scope, with few significant new data. Little new information appeared on the most recent novel class of agents, the sordarins (Glaxo Wellcome plc). Early clinical results were presented for FK-463, showing acceptable tolerability and dose-dependent efficacy in AIDS-associated esophageal candidiasis. A new liposomal formulation of nystatin (Nyotran; Aronex Pharmaceuticals Inc) was shown to be equivalent to conventional amphotericin B in empiric therapy of presumed fungal infection in neutropenic patients, but with reduced toxicity. Intravenous itraconazole (Janssen Pharmaceutica NV) was an effective prophylactic therapy in invasive pulmonary aspergillosis, while oral itraconazole was discussed as a treatment for fungal infection in heart and liver transplant patients. The allylamine compound, terbinafine (Novartis AG), showed good clinical efficacy against fungal mycetoma, a serious tropical infection. A major highlight was the first presentation of inhibitors of fungal efflux pumps as a strategy for overcoming resistance. MC-510027 (milbemycin alpha-9; Microcide Pharmaceuticals Inc) and its derivatives, potentiated the antifungal activity of triazoles and terbinafine in a number of Candida spp. Another pump inhibitor, MC-005172 (Microcide Pharmaceuticals Inc) showed in vivo potentiation of fluconazole in a mouse kidney infection model. Microcide Pharmaceuticals Inc also presented inhibitors of bacterial efflux pumps.

Journal Article↗
PubMed1999

Growth hormone secretagogues.

Growth hormone secretagogues (GHSs) are a class of synthetic compounds that increase growth hormone secretion and serum IGF-1 concentrations. The short-acting GHSs produce transient elevations in GH which lead to little or no changes in IGF-1; the long-acting GHSs stimulate pulsatile GH release due to sustained elevations of IGF-1. GHSs are currently undergoing evaluation as orally active alternatives to the recombinant human proteins, rhGHRH and rhGH. The clinical development of these compounds has been complicated, not by a failure to enhance GH secretion or raise IGF-1 in humans, but by the difficulty of establishing the therapeutic utility of increasing endogenous levels of GH/IGF-1 (as opposed to replacement with exogenous hormone). The phase II/III clinical trials of one GHS, MK0677 (Merck & Co Inc), for the treatment of short-stature in growth hormone-deficient children and frailty in the elderly have been discontinued for lack of sufficient efficacy. This review summarizes recent advances in this new therapeutic area and describes possible future directions.

Journal Article↗
PubMed2006

Evaluation of the comparative efficacy and tolerability of rofecoxib and naproxen in children and adolescents with juvenile rheumatoid arthritis: a 12-week randomized controlled clinical trial with a 52-week open-label extension.

OBJECTIVE: To compare the safety and efficacy of rofecoxib* to naproxen for the treatment of juvenile rheumatoid arthritis (JRA). METHODS: This was a 12-week, multicenter, randomized, double-blind, double-dummy, active comparator-controlled, non-inferiority study with a prespecified 52-week open-label active comparator-controlled extension. Children (ages 2-11 yrs) and adolescents (ages 12-17 yrs) received lower-dose (LD)-rofecoxib [0.3 mg/kg/day up to 12.5 mg/day (base study only)]; or higher-dose (HD)-rofecoxib (0.6 mg/kg/day up to 25 mg/day) or naproxen 15 mg/kg/day as oral suspensions. Adolescents received daily rofecoxib (LD) 12.5 (base study only) or (HD) 25 mg, or naproxen 15 mg/kg/day (maximum 1,000 mg/day) as tablets. The primary endpoint was the time-weighted average proportion of patients meeting the American College of Rheumatology Pediatric-30 (ACR Pedi 30) response criteria. A prespecified bound for the 95% confidence interval for the ratio of the percentage of ACR Pedi 30 responders was used to assess non-inferiority of treatment response between groups. Safety was assessed throughout the study. RESULTS: A total of 310 patients ages 2-17 years (181 (3/4) age 11) were randomized to receive LD-rofecoxib (N=109), HD-rofecoxib (N=100), or naproxen (N=101). The ACR Pedi 30 response rates following 12 weeks of treatment were 46.2%, 54.5%, and 55.1%, respectively. The relative rates of response compared to naproxen were 0.81 (95% CI 0.61, 1.07) and 0.98 (95% CI 0.76, 1.26) for LD- and HD-rofecoxib, respectively. Both rofecoxib doses were not inferior to naproxen. Patients (N=227) entering the extension received HD-rofecoxib or naproxen with efficacy maintained during the extension. All treatments were generally well tolerated throughout the study. CONCLUSION: Daily treatment of JRA patients with rofecoxib up to 12.5 or 25 mg was well tolerated, providing sustained clinical effectiveness comparable to naproxen 15 mg/kg. *On September 30, 2004, Merck & Co., Inc. announced the voluntary worldwide withdrawal of rofecoxib from the market.

Adolescent↗
PubMedDate not supplied

[Problems of cardiovascular toxicity of coxibs and non-selective NSA].

Non-steroidal antirheumatics (NSA) belong to the most often prescribed drugs. Certain observation studies indicate that they are used by 20 to 30% of population of developed countries. The most common NSA's adverse effects are gastrointestinal complications. Coxibs have been developed as an alternative to conventional non-selective NSA; with similar efficacy, they should reduce the risk of development of gastrointestinal complications. In the few last years, possible toxicity of coxibs and other non-steroidal antirheumatics has been widely discussed. The VIGOR study, which was performed 6 years ago, showed five times higher incidence of nonfatal myocardial infarction in patients with rofecoxib therapy as compared with naproxen. Afterwards, there was much debate about rofecoxib, and coxibs in general, whose cardiotoxicity was supported and confuted at the same time. Possible cardioprotective effect of naproxen was discussed too. Later on, results of the APPROVE study (Adenoma Polyp Prevention on Vioxx) made Merck & Co., Inc. withdraw rofecoxib from all markets voluntarily. In the end of 2004, three controversial studies on celecoxib were published. Although the first study (Adenoma Prevention with Celecoxib study, APC) showed higher cardiovascular risk of celecoxib, the second study (Prevention of Adenomatosus Polyps, PreSAP) did not verify these results. Surprisingly, the third study (Alzheimer Disease and Prevention Trial, ADAPT) proved 50% increase of the risk of cardiovascular (CV) toxicity of naproxen. In the last year, researchers have tried to decide whether CV toxicity is a class effect of coxib group or a class effect of all NSA. Many observation studies proved higher CV risk both of coxibs (particularly rofecoxib) and non-selective NSA including naproxen. These new findings moved the American FDA (Food and Drug Administration) to publish guidance concerning higher CV risk of all coxibs and NSA. For the time being, the EMEA (European Agency for Evaluation of Medicinal Products) does not change its attitude to NSA; coxibs are contraindicated in patients with ischemic heart disease, cerebrovascular disease and peripheral artery disease; they should be used with caution in high-risk patients. Final assessment of the problems of CV toxicity of NSA and coxibs will be a case of a long-term randomized study focused on the incidence of cardiovascular adverse effects.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

The efficacy of ivermectin against Strongyloides papillosus in cattle.

The efficacy of ivermectin was evaluated against Strongyloides papillosus in four controlled trials in cattle. Thirty-four animals were inoculated subcutaneously with S. papillosus 3rd stage larvae 14-24 days before treatment. At 7-14 days after treatment, calves were slaughtered and the number of adult S. papillosus present in the small intestine counted. Faecal egg counts were carried out before and after treatment. Seventeen control animals received a single subcutaneous injection of vehicle solution at a dose volume of 1 ml/50 kg body weight, and 17 calves were treated once with ivermectin at 200 mcg/kg b.w. using a 1% injectable solution (IVOMEC Injection Merck & Co., Inc.), subcutaneously. The control animals had a mean burden of 5,913 worms, while ivermectin significantly (p less than 0.01) reduced the number of adults S. papillosus by more than 99%. There was a greater than 99% reduction in the faecal egg count of treated animals at the last faecal examination compared with that pre-treatment.

Animals↗
PubMed1980

Multiclinic evaluation of the antihypertensive effect of a methyldopa, hydrochlorothiazine, and amiloride combination.

A multiclinic, double-blind, randomized study in 361 patients with essential hypertension compared Aldoretic, (Merck & Co., Inc., New Jersey), a combination of methyldopa, hydrochlorothiazide, and amiloride with the combination of hydrochlorothiazide and amiloride and with methyldopa alone. At the end of week 12, the proportion of patients who were classified as normotensive (diastolic less than or equal to 90 mm Hg) was 61% in the group treated with Aldoretic, which was statistically significantly greater than the 48% in the hydrochlorothiazide/amiloride group and the 35% in the methyldopa group.

Adult↗
PubMed1996

Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP)

This report provides recommendations for use of the newly licensed hepatitis A vaccines (HAVRIX, manufactured by SmithKline Beecham Biologicals, and VAQTA, manufactured by Merck & Company, Inc.) in persons > or = 2 years of age and updates previous recommendations for use of immune globulin (IG) for protection against hepatitis A (superseding MMWR 1990;39[No. RR-2]:1-5). For preexposure protection, hepatitis A vaccine can now be used instead of IG in many circumstances; for postexposure prophylaxis, the recommendations for IG use are unchanged.

Adolescent↗
PubMed1996

Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. 5. Physical activity as therapy for osteoporosis.

OBJECTIVE: To examine exercise as a therapy for people with osteoporosis. OPTIONS: Immobilization, standing low-load and high-load physical activities. OUTCOMES: Risk of injury, quality of life, risk of falls and fractures, strength and posture and pain management. EVIDENCE: Relevant epidemiologic studies, clinical trials and reviews were examined, including the large-scale FICSIT trial in the United States, a prospective 4-year study of women enrolled in an exercise program in Toronto and the large-scale Study of Osteoporotic Fractures. VALUES: Minimizing risk of injury and increasing quality of life were given a high value. BENEFITS, HARMS, AND COSTS: Moderate physical activity in people with osteoporosis can reduce the risk of falls and fractures, decrease pain and improve fitness and overall quality of life. It may also stimulate bone gain and decrease bone loss. Its positive effects are an adjunct to other interventions, such as hormonal therapy. It may give patients the confidence to resume regular activity and can provide social interaction and support. During exercise programs, proper nutrition is necessary to prevent excessive weight loss and impaired immune function resulting from inadequate protein, vitamin and mineral intake. RECOMMENDATIONS: Immobilization should be avoided if possible in anyone with osteoporosis or at increased risk for osteoporosis. Regular, moderate physical activity is recommended for those with osteoporosis. Elderly people should be assessed for risk of falling to identify those in greatest need of an exercise program. Community group exercise programs are beneficial. Younger people with osteoporosis also need exercise that will preserve or improve bone mass, muscular strength, endurance and cardiovascular fitness. Weight loss as a result of physical activity should be avoided and adequate intake of protein, vitamins and minerals assured. Because the benefits of physical activity are independent of the effect of other therapies, physical activity is an essential adjunct to appropriate nutrition and other therapies. VALIDATION: These recommendations were developed by the Scientific Advisory Board of the Osteoporosis Society of Canada at its 1995 Consensus Conference. They are in agreement with the position taken on osteoporosis and exercise by the United States Center for Disease Control and Prevention and the American College of Sports Medicine. SPONSORS: Sponsors of the 1995 conference included the Dairy Farmers of Canada, Eli Lilly Canada, Inc., Hoffmann-La Roche Canada Ltd., Merck Frosst Canada Inc. and Procter & Gamble Pharmaceuticals Canada Inc.

Accidental Falls↗
PubMed1999

Antifungal drug discovery and development--fourth international summit. 10-11 March 1999, Princeton, New Jersey, USA.

Genetic and genomic approaches to discovery, selection and evaluation of antifungal targets were extensively discussed by several speakers at this meeting. Experimental targets with early lead compounds available from screening programs include translation (Ribogene Inc), transcription (SCRIPTGEN Pharmaceuticals Inc), and protein geranylgeranylation (Mitotix Inc). Classes of compounds which are more advanced in preclinical evaluation include the sordarins, inhibitors of fungal elongation factor 2 under development by Glaxo Wellcome plc and Merck and Co Inc, and a series of fungicidal peptides originally derived from a domain of the human neutrophil bactericidal permeability-increasing protein (BPI, Xoma Ltd). Preclinical and early clinical data were presented for two compounds: caspofungin (MK-0991, Merck and Co Inc), an echinocandin with a broad-spectrum of activity for parenteral application, and Sch-56592 (Schering-Plough Corp), an orally active triazole. The oral antimycotic, terbinafine (Novartis AG), primarily used in dermatological infections, shows potent synergy with azoles and has potential applications against several serious and drug-resistant fungal pathogens. Amphotericin B, which has long been the gold standard for therapy of life-threatening infections, is now available in several liposomal formulations, including AmBisome (Fujisawa Pharmaceutical Co Ltd) and Abelcet (The Liposome Company Inc) which show a reduced incidence of adverse events.

Journal Article↗
PubMed2005

Repeated high doses of avermectins cause prolonged sterilisation, but do not kill, Onchocerca ochengi adult worms in African cattle.

BACKGROUND: Ivermectin (Mectizan, Merck and CO. Inc.) is being widely used in the control of human onchocerciasis (Onchoverca volvulus) because of its potent effect on microfilariae. Human studies have suggested that, at the standard dose of 150 microg/kg an annual treatment schedule of ivermectin reversibly interferes with female worm fertility but is not macrofilaricidal. Because of the importance of determining whether ivermectin could be macrofilaricidal, the efficacy of high and prolonged doses of ivermectin and a related avermectin, doramectin, were investigated in cattle infected with O. ochengi. METHODS: Drugs with potential macrofilaricidal activity, were screened for the treatment of human onchocerciasis, using natural infections of O. ochengi in African cattle. Three groups of 3 cows were either treated at monthly intervals (7 treatments) with ivermectin (Ivomec, Merck and Co. Inc.) at 500 microg/kg or doramectin (Dectamax, Pfizer) at 500 microg/kg or not treated as controls. Intradermal nodules were removed at 6 monthly intervals and adult worms were examined for signs of drug activity. RESULTS: There was no significant decline in nodule diameter, the motility of male and female worms, nor in male and female viability as determined by the ability to reduce tetrazolium, compared with controls, at any time up to 24 months from the start of treatments (mpt). Embryogenesis, however, was abrogated by treatment, which was seen as an accumulation of dead and dying intra-uterine microfilariae (mf) persisting for up to 18 mpt. Skin mf densities in treated animals had fallen to zero by <3 mpt, but by 18 mpt small numbers of mf were found in the skin of some treated animals and a few female worms were starting to produce multi-cellular embryonic stages. Follow-up of the doramectin treated group at 36 mpt showed that mf densities had still only regained a small proportion of their pre-treatment levels. CONCLUSION: These results have important implications for onchocerciasis control in the field. They suggest that ivermectin given at repeated high does may sterilise O. volvulus female worms for prolonged periods but is unlikely to kill them. This supports the view that control programmes may need to continue treatments with ivermectin for a period of decades and highlights the need to urgently identify new marcofiliaricidal compounds.

Journal Article↗
PubMed1999

Division of Medicinal Chemistry--general oral session/fellowship awards.

The primary purpose of this session was to recognize the outstanding achievements in the field of medicinal chemistry. The ACS award for Creative Invention went to researchers at Merck and Co Inc, who successfully developed Crixivan (indinavir, L-735524), an HIV-1 protease inhibitor, which received FDA approval in record time and is now used by over 300,000 patients worldwide. A former Merck scientist, John Baldwin (Pharmacopeia Inc, USA), was honored with the EB Hershberg award for Important Discoveries in Medicinally Active Substances. Dr Hershberg has been at the forefront of drug discovery technologies, such as combinatorial chemistry and rational drug design. During his 30-year career at Merck, he was involved with the Pepcid, Crixivan and Trusopt projects, but eventually left in 1993 when he co-founded Pharmacopeia.

Journal Article↗