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At least 91 records · Page 5Linked to original sources
PubMed2003

Caspofungin: first approved agent in a new class of antifungals.

Caspofungin (Cancidas, Merck & Co. Inc.) is the first echinocandin antifungal agent to gain FDA-approval for use in the US. It has excellent clinical activity against Candida spp. and Aspergillus spp. but lacks significant activity against Cryptococcus neoformans. Caspofungin may have some activity against dimorphic fungi such as Histoplasma capsulatum and Coccidioides immitis, but no clinical data is available for treatment of these infections. Caspofungin has demonstrated poor activity against most filamentous fungi in vitro. Several clinical trials have demonstrated its efficacy in the treatment of oropharyngeal, oesophageal and invasive candidiasis, as well as invasive aspergillosis. As a result of caspofungin's unique mechanism of action, and the high morbidity and mortality of invasive fungal infections, there is considerable interest in using this new antifungal agent as part of a combination antifungal therapy. In vitro studies and small case series indicate that caspofungin does not appear to be antagonistic when combined with other antifungals, such as itraconazole, voriconazole or amphotericin B against Aspergillus spp. Caspofungin exerts concentration-dependent killing effects in many different in vitro and animal models of disseminated fungal infection. The usual daily dose is 50 mg/day i.v. following a 70 mg i.v. loading dose. However, higher caspofungin doses have been safely administered and up to 70 mg/day can be administered for patients who fail to respond to lower doses. Caspofungin has an excellent safety profile with reduced toxicities, compared to other licensed antifungal agents. Fever, thrombophlebitis, headache and liver enzyme elevations were the most common drug-related side effects reported in clinical trials so far. Additional data are needed to document its safety in long-term use, and with higher doses in patients with invasive fungal infections. Caspofungin is a promising agent as first-line therapy for invasive candidiasis, and as salvage therapy for invasive aspergillosis. However, more clinical data are needed to define its role as primary therapy for invasive aspergillosis, and its role in combination antifungal therapy.

Adult↗
PubMed2003

Pharmacoeconomic aspects of losartan treatment to delay progression of renal disease in patients with Type 2 diabetes.

There is growing evidence from clinical trials that losartan (Cozaar, Merck & Co., Inc.) and other angiotensin (A)-II-receptor antagonists have beneficial effects on the progression of renal disease among Type 2 diabetic patients beyond the benefits derived from the effect of blood-pressure lowering alone [corrected]. Comparators used is the studies were not angiotensin-converting enzyme-inhibitors but typically conventional hypertensive therapy plus placebo, placebo alone and in one case, amlodipine. These trials have reported reductions in progression to end stage renal disease (ESRD) (losartan and irbesartan) and to nephropathy (irbesartan). An important pharmacoeconomic question is whether potential cost-savings on reduced progression to ESRD and nephropathy outweigh the extra costs of A-II-antagonist treatment. This paper will review the published economic studies for A-II-receptor antagonists and their pharmacoeconomic implications. In particular, potential pharmacoeconomic implications and related methodological aspects of the recent RENAAL trial for losartan are considered.

Angiotensin II↗
PubMed2005

Inflammation Research Association: 12th international conference.

The Inflammation Research Association held its 12th international meeting at the Sagamore at Bolton Landing in New York State (3 - 7 October 2004). These meetings were originally intended for scientists from the pharmaceutical industry to get together and discuss the latest developments in inflammation drug discovery, and it remains an industry-dominated affair. The conference covered some highly topical issues such as cyclooxygenase-2 inhibitors (rofecoxib/Vioxx [Merck & Co., Inc.] was withdrawn from the market only a few days before the conference), along with areas of ongoing interest to the pharmaceutical and biotechnology industry, including p38 MAPK inhibitors, nuclear hormone receptor modulators and prostaglandin receptor antagonists. This review will cover the main themes that emerged during the meeting.

Anti-Inflammatory Agents↗
PubMed2001

Disseminated vaccine strain varicella as the acquired immunodeficiency syndrome-defining illness in a previously undiagnosed child.

The Food and Drug Administration licensed a live-virus varicella vaccine (Varivax; Merck & Co Inc, West Point, PA) in March 1995. Prelicensure adverse events were minimal; however, since licensure and increased vaccine use, rare previously undetected risks have arisen. Presented here is the clinical course of a previously undiagnosed, human immunodeficiency virus-infected boy who developed dissemination of the vaccine strain of varicella zoster after immunization. chickenpox, human immunodeficiency virus, pneumonia, encephalopathy, varicella vaccine, adverse events, dissemination.

Chickenpox↗
PubMed2007

Prevention of rotavirus disease: guidelines for use of rotavirus vaccine.

On February 3, 2006, a bovine-based pentavalent rotavirus vaccine (RotaTeq, Merck & Co Inc, Whitehouse Station, NJ) was licensed by the US Food and Drug Administration for use in infants in the United States. The American Academy of Pediatrics recommends routine immunization of infants with 3 doses of pentavalent rotavirus vaccine administered orally at 2, 4, and 6 months of age. The first dose should be administered between 6 and 12 weeks of age; immunization should not be initiated for infants older than 12 weeks of age. Subsequent doses should be administered at 4- to 10-week intervals, and all 3 doses of vaccine should be administered by 32 weeks of age. Pentavalent rotavirus vaccine can be coadministered with other childhood vaccines. Pentavalent rotavirus vaccine is contraindicated for infants with a serious allergic reaction to any vaccine component or to a previous dose of vaccine.

Administration, Oral↗
PubMed2004

Cardiovascular effects of selective cyclooxygenase-2 inhibitors.

Selective cyclooxygenase-2 inhibitors represent a significant advance in the management of inflammatory disorders. They have similar efficacy to nonselective 'conventional' nonsteroidal anti-inflammatory drugs, but a superior gastrointestinal safety profile. However, a significant caveat is the perceived potential of cyclooxygenase-2 inhibitors to cause adverse cardiovascular effects, an issue first raised by the Vioxx Gastrointestinal Outcomes Research (VIGOR) study of rofecoxib (Vioxx, Merck & Co. Inc.). Mechanisms by which cyclooxygenase-2 inhibitors may increase cardiovascular risk are selective inhibition of prostaglandin I2 over thromboxane A2 within the eicosanoid pathway, which promotes thrombosis, and inhibition of prostaglandins E2 and I2 within the kidney, which leads to sodium and water retention and blood pressure elevation. In spite of this, the cardiovascular findings from VIGOR are not firmly supported by observations from large cohort studies and other clinical trials of selective cyclooxygenase-2 inhibitors, including the Celecoxib Long-term Arthritis Safety Study. The two main theories that explain the VIGOR findings are that the comparator used (naproxen; Naprosyn, Roche) is cardioprotective and that very high doses of rofecoxib were used, but at present neither is backed by firm evidence. Indeed, there is now early evidence that selective cyclooxygenase-2 inhibition with celecoxib may even protect against the progression of cardiovascular disease, on the basis that cyclooxygenase-2 mediates key processes in atherothrombosis. Currently, it is not clear what the net cardiovascular effects of cyclooxygenase-2 inhibitors are. The data are inconsistent and at best, speculative. It may be also that celecoxib and rofecoxib differ in their cardiovascular effects. Clarification of these issues is of vital importance given the vast number of patients presently taking both types of cyclooxygenase-2 inhibitors. Therefore, what is clear in this situation is the urgent need for randomized clinical trials designed specifically to examine the impact of selective cyclooxygenase-2 inhibitors on cardiovascular risk.

Cardiotonic Agents↗
PubMed2005

Rhabdomyosarcoma: new windows of opportunity.

Rhabdomyosarcoma is a highly malignant, small blue cell tumor characterized by muscle differentiation. With modern treatment, more than 70% of children and adolescents with this disease are cured. Adequate biopsy to obtain sufficient tissue for accurate diagnosis and molecular characterization is critical. Patients must be assessed for tumor extent; the Intergroup Rhabdomyosarcoma Study (IRS) clinical group and Staging system is universally applied in North America. Multidisciplinary therapy is necessary to maximize cure rates. Local control relies on complete surgical excision when possible; those whose tumors are not completely excised and those with alveolar histology tumors require local irradiation to maximize local control. In North America, vincristine (Oncovin); Eli Lilly and Company, Indianapolis, http://www.lilly.com), dactinomycin (Cosmegen); Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com), and cyclophosphamide are the standard chemotherapy agents. The IRS has used therapeutic window studies to confirm the predictive nature of preclinical xenograft models and to identify several new single agents and combinations of agents with activity in high-risk patient groups. Despite these efforts, the outcome for these high-risk patients remains poor. The next generation of Children's Oncology Group studies will evaluate the efficacy of topoisomerase-I inhibitors and dose-compression therapy approaches. New advances in molecular characterization of tumors, including gene-expression analysis, may identify new therapeutic targets that can be exploited by expanded preclinical drug discovery efforts, and hold the promise of revolutionizing risk-based therapies.

Combined Modality Therapy↗
PubMed2005

Combined therapy with weekly irinotecan, infusional 5-fluorouracil and the selective COX-2 inhibitor rofecoxib is a safe and effective second-line treatment in metastatic colorectal cancer.

The purpose of this study was to determine the tolerability and activity of rofecoxib (Vioxx; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com) combined with weekly irinotecan (Camptosar; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) and infusional 5-fluorouracil (5-FU) as second-line therapy in metastatic colorectal cancer (MCRC). Enrolled patients had previously treated metastatic disease, were aged > or =18 to < or =75 years, and had adequate performance status. A cycle of treatment consisted of i.v. irinotecan on days 1, 8, 15, and 22, rofecoxib at an oral dose of 50 mg/day, and infusional 5-FU at a fixed dose of 200 mg/m(2) per day for 5 weeks followed by 3 weeks of therapy with rofecoxib alone. In the dose-finding study, the starting dose of irinotecan was 87.5 mg/m(2) and further dose escalations were planned by increments of 12.5 mg/m(2) up to 125 mg/m(2). Forty-eight consecutive patients were enrolled in the study. Among the 15 cases enrolled in the dose-finding study, one patient experienced grade 3 reversible diarrhea as the dose-limiting toxicity, at the fourth dose level tested. Therefore, the dose of irinotecan for the phase II study was 125 mg/m(2), and 33 patients were enrolled and received a total of 75 cycles. Hematological side effects were moderate, with grade 4 neutropenia recorded in only two patients. The most common nonhematological toxicity was diarrhea, occurring in 25 patients (75.8%) and considered to be of grade 3 in 12 patients (36.4%). Sixteen patients achieved partial responses (48.5%; 95% confidence interval [CI], 30.8%-66.5%), and another 10 patients (30.3%) had stable disease. The median time to progression was 7 months (95% CI, 5-12) and the median overall survival (OS) was 18 months; the 1-year estimated OS rate was 69.4%. The unique schedule tested in this study is feasible, is well-tolerated, and has promising activity in patients with MCRC after progression on oxaliplatin (Eloxatin; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us)-based chemotherapy.

Adult↗
PubMed2006

Evaluation of the thermal stability of Gardasil.

The thermostability of GARDASIL (Merck & Co., Inc, Whitehouse Station, NJ, USA), a developmental vaccine against human papillomavirus (HPV), was evaluated using an enzyme immunoassay, referred to as the in vitro relative potency (IVRP) assay and differential scanning calorimetry (DSC). Gardasil samples were stored at temperatures ranging from 4 to 42 degrees C and tested for IVRP at various time points. Extrapolation of the IVRP results indicates GARDASIL is extremely stable. The half-life of the vaccine is estimated to be 130 months or longer at temperatures up to 25 degrees C. At 37 degrees C, the half-life is predicted to be 18 months and at 42 degrees C, the half-life is predicted to be approximately three months. Differential scanning calorimetry (DSC) analysis was used to evaluate the process of protein denaturation during a rapid temperature increase (as opposed to long-term storage at a specific temperature). Differences were seen among the DSC profiles of the four HPV types tested. This indicates that small differences in the amino acid structure can have a significant effect on the intermolecular contacts that stabilize the L1 proteins and the VLP assembly. For the Gardasil samples evaluated here, DSC results demonstrated the relative overall structural stability of the VLPs, but were not predictive of the excellent long-term stability observed with the IVRP assay.

Calorimetry, Differential Scanning↗
PubMedDate not supplied

Safety and immunogenicity of a combination measles, mumps, rubella and varicella vaccine (ProQuad).

BACKGROUND: A combination measles, mumps, rubella, and varicella vaccine (ProQuad, Merck & Co., Inc, West Point, PA) was evaluated in five clinical trials. Use of ProQuad would result in fewer injections for children and would facilitate universal immunization against all four diseases. OBJECTIVE: To describe the combined results obtained from the studies conducted during the clinical development program for ProQuad. METHODS: A total of 5833 healthy children, 12-23 months of age, and 399 healthy children, 4-6 years of age, received 1 or 2 doses of ProQuad in five controlled clinical trials. M-M-R II and VARIVAX were used as the control for most studies. Safety was evaluated for six weeks postvaccination and immunogenicity was assessed six weeks after each dose by a sensitive assay (ELISA or gpELISA). RESULTS: A single dose of ProQuad in 12- to 23-month-old children was shown to be as immunogenic as a single dose of M-M-R II and VARIVAX and was generally well tolerated. ProQuad can be used concomitantly with other vaccines (hepatitis B and Hoemophilus influenzoe b). A higher rate of fever was reported after 1 dose of ProQuad compared to M-M-R II and VARIVAX, but fever episodes were transient without long-term sequelae. Both a 2-dose regimen of ProQuad in 12- to 23-month-olds and use of ProQuad in place of M-M-R II at 4-6 years were shown to be immunogenic and well tolerated. The incidence of adverse experiences following a second dose of ProQuad was lower than that following the initial dose. CONCLUSIONS: A single dose of ProQuad is as immunogenic as M-M-R II and VARIVAX and is well tolerated in a 1- or 2-dose schedule. ProQuad should easily fit into the routine immunization schedule.

Antibodies, Viral↗
PubMed2000

Dexanabinol Pharmos.

Dexanabinol is a non-psychotropic cannabinoid NMDA receptor antagonist under development by Pharmos Corp for the potential treatment of cerebral ischemia, glaucoma, Alzheimer's disease, cardiac failure, head injury and multiple sclerosis (MS) [311522]; it is in phase III trials for traumatic brain injury (TBI) [388709]. Dexanabinol was licensed to Pharmos for development from its originator, the Hebrew University of Jerusalem [180441]. Pharmos is seeking to enter into a strategic agreement with another company to develop and commercialize dexanabinol [317369]. Unlike its enantiomer, HU-210 (Yissum Research Development Co), dexanabinol does not interact with cannabinoid receptors [223330]. It has also exhibited more effective antioxidant and anti-inflammatory properties than MK-801 (dizocilpine; Merck & Co Inc) [167980], [168212]. In addition, dexanabinol is generally well tolerated and appears toxicologically safe [170116]. Pharmos has been awarded a Small Business Innovation Research grant from the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke, Division of Stroke and Trauma. The grant covers the development of new prodrugs and novel formulations of dexanabinol and will support additional study of dexanabinol compounds for various indications. The prodrugs being studied are part of the group of compounds that include dexanabinol [247958]. A Notice of Allowance was received in March 1999 on a patent covering the use of the drug in the treatment of MS [324163]. The use of dexanabinol and its derivatives to treat MS is described in US-05932610 [358503]. An oral formulation of dexanabinol is claimed in US-05891468. Dexanabinol analogs with special utility in acute and chronic pain are claimed in US-04876276, while dexanabinol analogs for neuroprotection are claimed in US-06096740. Pharmos estimates that the worldwide market for dexanabinol in the treatment of severe head trauma may reach $1 billion per year [319244].

Animals↗
PubMed2002

Elucidating the antidepressant actions of substance P (NK1 receptor) antagonists.

Substance P (NK1 receptor) antagonists (SPAs) are currently the best validated and clinically most advanced novel approach to treating major depressive disorder (MDD), and several compounds are in advanced clinical development. Three years since the discovery of the antidepressant efficacy of MK-869 (Merck & Co Inc), the first in a new class of drugs that act by selectively blocking the actions of substance P, the principle that blocking the NK1 receptor can alleviate major depression has recently been replicated in a placebo-controlled, blinded study. SPAs are active in a range of preclinical assays that detect clinically used antidepressant drugs, but they have a pharmacological profile that is distinct from established drugs. There is preliminary evidence that substance P and NK1 receptor density may be altered in MDD, suggesting a possible link between substance P and depressive pathophysiology. Studies in animals indicate that the psychotherapeutic effects of SPAs may be mediated at least partly through stimulation of hippocampal neurogenesis, by direct blockade of NK1 receptors in the amygdala and its associated output projections, and also via interactions with monoamines. Additional studies are needed to explore these hypothesesfurther.

Animals↗
PubMed2003

Antagonists at the neurokinin receptors--recent patent literature.

This review describes the patent applications and relevant scientific literature published during 2002 in the field of novel neurokinin receptor antagonists, with an emphasis on the medicinal chemistry of recent patent publications. A brief update on the development status of compounds including: the neurokinin-1 receptor antagonists aprepitant (Merck & Co Inc), vofopitant, ezlopitant (Pfizer Inc), R-673 (F Hoffmann-La Roche Ltd); the neurokinin-2 receptor antagonists nepadutant (Menarini Ricerche SpA), saredutant (Sanofi-Synthelabo), SR-144190 (Sanofi-Synthelabo) and UK-290795 (Pfizer Inc); and the neurokinin-3 receptor antagonists osanetant (Sanofi-Synthelabo) and talnetant (GlaxoSmithKline plc) will be given. The review also reports the recent published patent literature in the area of novel therapeutic uses and novel formulations and combinations claimed for neurokinin receptor antagonists.

Animals↗
PubMed2004

Gaboxadol. Lundbeck/Merck.

H Lundbeck A/S, in collaboration with Merck & Co Inc, is developing gaboxadol, a GABAA agonist, for the potential treatment of sleep disorders. The compound is currently undergoing phase III clinical trials.

Animals↗
PubMed2004

Etoricoxib.

Etoricoxib (Arcoxia, Merck & Co., Inc.) is a selective inhibitor of cyclooxygenase-2 (COX-2), an enzyme involved in pain and inflammation. It is a member of the COX-2-selective (coxib) class of nonsteroidal antiinflammatory drugs (NSAIDs). Extensive clinical trials have confirmed its analgesic and antiinflammatory efficacy to be at least as good as and in some cases superior to nonselective NSAIDs in a number of disease and patient treatment settings. Etoricoxib displays improved gastrointestinal safety compared with nonselective NSAIDs and has a favorable overall safety and tolerability profile. It is rapidly and completely absorbed following oral administration providing a rapid onset of action. Its long plasma half-life allows for once-daily dosing. Etoricoxib is currently approved in a number of countries for various indications including the treatment of acute pain, acute gouty arthritis, chronic low back pain, primary dysmenorrhea, and chronic treatment for the signs and symptoms of osteoarthritis and rheumatoid arthritis. In countries where it is approved, the highest recommended daily dose for chronic use is 90 mg for rheumatoid arthritis and 60 mg for osteoarthritis and chronic low back pain. The recommended daily dose for acute pain relief treatment from primary dysmenorrhea and acute gouty arthritis is 120 mg. This review summarizes the published preclinical and clinical data relevant to the use of etoricoxib in clinical practice.

Arthritis↗