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PubMed2005

Hepatic uptake of the novel antifungal agent caspofungin.

Caspofungin (CANCIDAS, a registered trademark of Merck & Co., Inc.) is a novel echinocandin antifungal agent used in the treatment of esophageal and invasive candidiases, invasive aspergillosis, and neutropenia. Available data suggest that the liver is a key organ responsible for caspofungin elimination in rodents and humans. Caspofungin is primarily eliminated by metabolic transformation; however, the rate of metabolism is slow. Accordingly, it was hypothesized that drug uptake transporters expressed on the basolateral domain of hepatocytes could significantly influence the extent of caspofungin uptake and subsequent elimination. In this study, experiments ranging from perfused rat livers to heterologous expression of individual hepatic uptake transporters were utilized to identify the transporter(s) responsible for the observed liver-specific uptake of this compound. Data from perfused rat liver studies were consistent with the presence of carrier-mediated caspofungin hepatic uptake, although this process appeared to be slow. To identify a relevant hepatic uptake transporter, we developed novel Tet-on HeLa cells expressing OATP1B1 (OATP-C, SLC21A6) and OATP1B3 (OATP8, SLC21A8), whose target gene can be overexpressed by the addition of doxycycline. A modest but statistically significant uptake of caspofungin was observed in cells overexpressing OATP1B1, but not OATP1B3. Taken together, these findings suggest that OATP1B1-mediated hepatic uptake may contribute to the overall elimination of this drug from the body.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Disposition of caspofungin, a novel antifungal agent, in mice, rats, rabbits, and monkeys.

The metabolism, excretion, and pharmacokinetics of caspofungin (Cancidas; Merck & Co., Inc.) were investigated after administration of a single intravenous dose to mice, rats, rabbits, and monkeys. Caspofungin had a low plasma clearance (0.29 to 1.05 ml/min/kg) and a long terminal elimination half-life (11.7 h to 59.7 h) in all preclinical species. The elimination kinetics of caspofungin were multiphasic and displayed an initial distribution phase followed by a dominant beta-elimination phase. The presence of low levels of prolonged radioactivity in plasma was observed and was partially attributable to the chemical degradation product M0. Excretion studies with [(3)H]caspofungin indicated that the hepatic and renal routes play an important role in the elimination of caspofungin, as a large percentage of the radiolabeled dose was recovered in urine and feces. Excretion of radioactivity in all species studied was slow, and low levels of radioactivity were detected in daily urine and fecal samples throughout a prolonged collection period. Although urinary profiles indicated the presence of several metabolites (M0, M1, M2, M3, M4, M5, and M6), the majority of the total radioactivity was associated with the polar metabolites M1 [4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine] and M2 [N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine]. Caspofungin was thus primarily eliminated by metabolic transformation; however, the rate of metabolism was slow. These results suggest that distribution plays a prominent role in determining the plasma pharmacokinetics and disposition of caspofungin, as very little excretion or biotransformation occurred during the early days after dose administration, a period during which concentrations in plasma fell substantially. The disposition of caspofungin in preclinical species was similar to that reported previously in humans.

Animals↗
PubMed1964

NUTRITION OF "ADENINELESS" AUXOTROPHS OF YEASTS.

Demain, Arnold L. (Merck Sharp & Dohme Research Laboratories, Division of Merck & Co., Inc., Rahway, N.J.). Nutrition of "adenineless" auxotrophs of yeasts. J. Bacteriol. 88:339-345. 1964.-Nutritional studies on 29 "adenineless" yeast strains were carried out. In no case could guanine, xanthine, or their ribonucleosides or ribonucleotides be used to satisfy the purine requirement. The cultures fell into three nutritional groups: group A, absolute purine requirement satisfied by adenine or hypoxanthine; group B, stimulatory purine requirement (leaky) satisfied by adenine or hypoxanthine; group C, absolute purine requirement satisfied only by adenine. Although adenosine, adenylic acid (AMP), inosine, and inosinic acid (IMP) could not be used by the absolute mutants, the leaky mutants were stimulated by these compounds. The rapid growth on adenine observed with members of all three nutritional groups was delayed by guanine. No inhibition was observed with guanosine or guanylic acid (GMP). Guanine and its derivatives did not inhibit growth of wild-type Saccharomyces cerevisiae. The slow growth of the leaky mutants in unsupplemented medium was inhibited by guanine, guanosine, and GMP. The results were interpreted as follows. (i) Yeasts lack GMP-reductase. (ii) Group A and B yeasts are blocked before IMP; group C yeasts lack one of the enzymes leading from IMP to AMP. (iii) The absolute mutants cannot take ribonucleotides or ribonucleosides into the cell and cannot break down these compounds extracellularly to the free base; the leaky mutants can slowly use extracellular nucleosides and nucleotides. (iv) Guanine competes with adenine for entry into the cell. (v) Guanine inhibits de novo synthesis of AMP. The inhibition is probably a weak feedback effect which can only be demonstrated with leaky strains which synthesize purines at suboptimal rates.

Adenine↗
PubMed1965

EXCRETION AND DEGRADATION OF RIBONUCLEIC ACID BY BACILLUS SUBTILIS.

Demain, A. L. (Merck & Co., Inc., Rahway, N.J.), R. W. Burg, and D. Hendlin. Excretion and degradation of ribonucleic acid by Bacillus subtilis. J. Bacteriol. 89:640-646. 1965.-Bacillus subtilis MB-1480 was found to produce several 5'-ribonucleotides in the extracellular medium, in addition to the previously found 5'-guanosine monophosphate and guanosine diphosphate. The nucleotides accumulated after excretion of high-molecular-weight ribonucleic acid (RNA) and subsequent extracellular breakdown. Excretion of RNA paralleled growth closely, and was accompanied by deoxyribonucleic acid (DNA) and protein excretion. The process occurred in the absence of visible lysis. Whereas extracellular DNA was stable, the other macromolecules were degraded after excretion. With extracellular DNA as a measure of maximal lysis, it was calculated that the major part of the extracellular RNA must have been excreted by cells which had not undergone lysis.

Bacillus subtilis↗
PubMed1982

Superoxol(catalase)test for identification of Neisseria gonorrhoeae.

The Superoxol (Merck & Co., Inc., Rahway, N.J.) test (catalase test using 30% H2O2) was used to differentiate Neisseria gonorrhoeae from other Neisseria species. A positive test was defined as immediate, brisk bubbling upon dropping 30% H2O2 onto a bacterial colony. One hundred percent of the gonococci were Superoxol positive. Only 1% of Superoxol-positive isolates on Thayer-Martin agar were organisms other than gonococci (99% specificity). The test was more reliable than the coagglutination test. Individual strains of a wide variety of Neisseria and Branhamella species were Superoxol positive. They could usually be differentiated from N. gonorrhoeae by their poor growth on selective media, colonial morphology on nonselective media, and simple biochemical tests. The Superoxol test is an excellent screening test for N. gonorrhoeae. A positive result on a clinical isolate growing on Thayer-Martin agar is strongly suggestive of the presence of gonococci.

Catalase↗
PubMed1986

Gellan gum as a substitute for agar in leptospiral media.

An albumin polysorbate semisolid medium (Ellinghausen McCullough Johnson Harris medium) gelled with gellan gum (Gelrite; Kelco Div., Merck & Co., Inc.) compared favorably with conventional agar media for the cultivation of both pathogenic and saprophytic leptospires. The gellan gum medium supported the growth of all 18 leptospiral strains studied which included an array of serovars with various fastidious growth characteristics. Gellan gum medium was also used advantageously as a long-term maintenance medium; 9- to 12-month-old cultures still contained viable organisms. The colonial growth in gellan gum plating medium of six representative strains was consistent with previously described colonial growth on agar plating media. In addition, gellan gum medium appeared to be an excellent medium for the recovery of leptospires from the blood, liver, and kidneys of hamsters experimentally infected with a virulent Leptospira interrogans serovar bataviae strain. As few as 1 to 10 organisms in the infective tissue could be recovered in semisolid Ellinghausen McCullough Johnson Harris-gellan gum medium. The antigenicity did not appear to be affected by growth in gellan gum medium. The hamster-virulent strain of L. interrogans serovar bataviae isolated from a moribund hamster maintained its virulence after 10 sequential passages in gellan gum medium. Gellan gum medium can be a valuable adjunct to currently used cultural procedures.

Agar↗
PubMed1999

Comparison of rizatriptan 10 mg vs. naratriptan 2.5 mg in migraine.

Rizatriptan (MAXALT(TM), Merck & Co., Inc.) is a selective 5-HT(1B/1D) receptor agonist with rapid oral absorption and early onset of action for the acute treatment of migraine. This randomized, double-masked, double-dummy, placebo-controlled study compared rizatriptan 10 mg to naratriptan (NARAMIG(TM), AMERGE(TM), both Glaxo Wellcome plc) 2.5 mg in 522 patients treating a single migraine attack. Rizatriptan was more effective than naratriptan. Rizatriptan provided earlier headache relief than naratriptan (hazard ratio 1.62, p < 0.001), acting as early as 30 min. More patients were pain free at 2 h on rizatriptan than on naratriptan (44.8 vs. 20.7%, p < 0.001). Rizatriptan also provided earlier relief of associated migraine symptoms within 2 h than naratriptan and more patients had normal function at 2 h (39.3 vs. 22.6%, p < 0. 001). Both active treatments were effective compared to placebo. Both active treatments were well tolerated. The most common side effects with rizatriptan were dizziness, asthenia/fatigue, nausea and somnolence, while the most common side effects with naratriptan were dizziness and asthenia/fatigue.

Adult↗
PubMed2001

Comparison of preference for rizatriptan 10-mg wafer versus sumatriptan 50-mg tablet in migraine.

Rizatriptan (MAXALT, a registered trademark of Merck & Co. Inc.) is a selective 5-HT(1B/1D) receptor agonist with rapid oral absorption and early onset of action in the acute treatment of migraine. This randomized, open-label, crossover outpatient study assessed the preference of 481 patients for rizatriptan 10-mg rapidly disintegrating tablets versus sumatriptan (IMIGRAN, a registered trademark of GlaxoWellcome PLC) 50-mg tablets in the treatment of a single migraine attack with each therapy. Almost twice as many patients preferred rizatriptan 10-mg rapidly disintegrating tablet to sumatriptan 50-mg tablet (64.3 vs. 35.7%, p < or = 0.001). Faster relief of headache pain was the most important reason for the preference, cited by 46.9% of patients preferring rizatriptan and 43.4% of patients who preferred sumatriptan. Headache relief at 2 h was 75.9% with rizatriptan and 66.6% with sumatriptan (p < or = 0.001), with rizatriptan being superior to sumatriptan within 30 min of dosing. Fifty-five percent of patients were pain free 2 h after rizatriptan, compared with 42.1% treated with sumatriptan (p < or = 0.001), rizatriptan being superior within 1 h of treatment. Forty-one percent of patients taking rizatriptan were pain free at 2 h and had no recurrence or need for additional medication, compared to 32.3% of patients on sumatriptan. Rizatriptan was also superior to sumatriptan in terms of the proportions of patients with no nausea, phonophobia or photophobia, and patients with normal function 2 h after treatment intake (p < 0.05). More patients were (completely, very or somewhat) satisfied 2 h after treatment with rizatriptan (73.3%) than 2 h after treatment with sumatriptan (59.0%) (p < or = 0.001). Additionally, 2 h after the dose, more patients found rizatriptan to be very convenient, convenient or somewhat convenient (87.2%) than they did sumatriptan (76.3%) (p < or = 0.001). Both active treatments were well tolerated. The most common side effects with rizatriptan and sumatriptan were nausea (6.6 and 6.9% of patients, respectively), dizziness (6.1 and 5.8%) and somnolence (7.4 and 6.7%).

Administration, Oral↗
PubMedDate not supplied

Prevention of coronary heart disease in clinical practice: a commentary on current treatment patterns in six European countries in relation to published recommendations.

Market research surveys can be a source of up-to-date information about current clinical practices. Data from one such survey, Cholesterol Monitor (made available by Merck & Co., Inc., Whitehouse Station, N.J., USA) was examined to ascertain to what extent management of cholesterol in six European countries conforms with the advice of the joint Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension for prevention of coronary heart disease (CHD). Rates of cholesterol testing in patients with CHD varied from less than 50% in the UK to more than 80% in France and Italy. Across Europe, the average cholesterol levels in surveyed patients was 6 mmol/l, and the average intervention level was 7.5 mmol/l. In all countries, there was evidence of a substantial treatment gap, even among high-risk patients with established CHD. This gap took the form of non-treatment of a proportion of patients whose risk status merited intervention on the basis of expert recommendations and the results of the Scandinavian Simvastatin Survival Study (in which sustained lowering of total and low-density lipoprotein cholesterol reduced total and coronary mortality in patients with baseline total cholesterol as low as 5.5 mmol/l). The findings indicate that a concerted programme of physician education is required if the recommendations of the joint Task Force are to be put into effect, and if the present nontreatment/undertreatment of cholesterol in high-risk patients is to be corrected.

Cholesterol↗
PubMed1983

International prescription drug labeling.

Yesterday's therapeutic compounds were meticulously prepared, elegantly presented, and relatively innocuous (Dunlop). Today's powerful and complex drugs are manufactured with sophisticated technology and require clear, concise, and comprehensive information for the physicians throughout the world in order to provide maximum benefit for the patient. Our company, Merck & Co, Inc, has adhered for many years to strict requirements for full and balanced disclosure in all information disseminated to professionals about our products, including circulars, labeling, and advertising. Our practice is to provide complete information to physicians, pharmacists, and regulatory authorities, both on the recommended uses for our products and on their potential adverse effects. The cornerstone of our international disclosure system, the International Physicians Circular (IPC), is provided for each product and comprises part of the initial submission to each national health authority in connection with application for marketing approval. Each IPC sets forth the company's best scientific judgment with respect to both the positive and negative aspects of our drugs, defining actions, indications, and dosage, as well as all contraindications, precautions, and side effects. These circulars are updated in the process of continuous medical review.

Drug Industry↗
PubMed2006

The Mectizan Donation Program - highlights from 2005.

Through the Mectizan Donation Program, Merck & Co., Inc. has donated Mectizan (ivermectin, MSD) for the treatment of onchocerciasis worldwide since 1987. Mectizan has also been donated for the elimination of lymphatic filariasis (LF) since 1998 in African countries and in Yemen where onchocerciasis and LF are co-endemic; for LF elimination programs, Mectizan is co-administered with albendazole, which is donated by GlaxoSmithKline. The Mectizan Donation Program works in collaboration with the Mectizan Expert Committee/Albendazole Coordination, its scientific advisory committee. In 2005, a total of 62,201,310 treatments of Mectizan for onchocerciasis were approved for delivery via mass treatment programs in Africa, Latin America, and Yemen. Seventy-seven percent and 20% of these treatments for onchocerciasis were for countries included in the African Programme for Onchocerciasis Control (APOC) and the former-Onchocerciasis Control Programme in West Africa (OCP), respectively. The remaining 3% of treatments approved were for the six onchocerciasis endemic countries in Latin America, where mass treatment is carried out twice-yearly with the goal of completely eliminating morbidity and eventually transmission of infection, and for Yemen. All 33 onchocerciasis endemic countries where mass treatment with Mectizan is indicated have ongoing mass treatment programs. In 2005, 42,052,583 treatments of co-administered albendazole and Mectizan were approved for national Programs to Eliminate LF (PELFs) in Africa and Yemen. There are ongoing PELFs using albendazole and Mectizan in nine African countries and Yemen; these represent 35% of the total number of countries expected to require the co-administration of these two chemotherapeutic agents for LF elimination. In Africa, the expansion of existing PELFs and the initiation of new ones have been hampered by lack of resources, technical difficulties with the mapping of LF endemicity, and the co-endemicity of LF and loiasis. Included in this review are recommendations recently put forward for the co-administration of albendazole and Mectizan in areas endemic for LF, loiasis, and onchocerciasis.

Journal Article↗
PubMed2004

Aprepitant for chemotherapy-induced nausea and vomiting.

Although the development of serotonin receptor antagonists has greatly improved treatment for chemotherapy-induced nausea and vomiting, patients receiving chemotherapy continue to experience this troublesome side effect. On March 26, 2003, the U.S. Food and Drug Administration approved aprepitant (Emend, Merck & Co., Inc., Whitehouse Station, NJ) for use in combination with standard antiemetic agents for acute and delayed nausea and vomiting with initial and repeat courses of highly emetogenic therapy. Aprepitant appears to provide superior control of acute and delayed emesis compared to standard antiemetic therapy. Aprepitant was well tolerated in phase III studies, with side effects similar to standard therapy. Healthcare providers need to be aware of potential drug interactions with aprepitant. Oncology nurses continue to play a key role in helping patients adhere to their antiemetic schedules, stressing the importance of prevention of nausea and vomiting.

Antiemetics↗
PubMed2006

Gardasil: Introducing the new human papillomavirus vaccine.

In 2006, the U.S. Food and Drug Administration (FDA) approved the first vaccine for prevention of cervical cancer based on the molecular biology of the disease. Gardasil (quadrivalent human papillomavirus [HPV] [types 6, 11, 16, and 18] recombinant vaccine, Merck & Co., Inc., Whitehouse Station, NJ) combats the common types of HPV responsible for cervical cancer precursor lesions. This article provides a simple overview of the (a) epidemiology of HPV, (b) HPV vaccine, (c) dosing and administration, and (d) nursing implications about this possibly life-saving vaccine.

Adolescent↗
PubMed2002

Ertapenem. A review of its microbiologic, pharmacokinetic and clinical aspects.

Ertapenem sodium (trade name Invanz, also designated as MK-0826, MK-826 and L-749345), manufactured by Merck & Co., Inc. is a structurally unique parenteral 1 beta-methyl carbapenem. It has a broad spectrum of antimicrobial activity, including common community-acquired Gram-positive and Gram-negative aerobic and anaerobic pathogens, and restricted activity against nosocomial pathogens such as Pseudomonas aeruginosa, Acinetobacter species, methicillin-resistant staphylococci and enterococci. Ertapenem demonstrates excellent activity against cephalosporin-resistant enteric organisms producing extended spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases and excellent activity against penicillin-resistant Streptococcus pneumoniae. Its high level of protein binding and serum half-life of 4 h allows it to be dosed once daily. Ertapenem may be administered intravenously or intramuscularly and has an excellent adverse reaction and tolerability profile. Invanz was approved by the United States Food and Drug Administration in November 2001 for the treatment of adult patients with moderate to severe infections caused by designated strains of susceptible microorganisms. The infections include complicated intraabdominal infections, complicated skin and skin structure infections, community-acquired pneumonia, complicated urinary tract infections including pyelonephritis and acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecologic infections. Invanz has also been approved in Mexico, Brazil and New Zealand.

Animals↗
PubMed2000

Rofecoxib.

Rofecoxib (Vioxx, Merck & Co., Inc.) is a new orally-effective non-steroidal anti-inflammatory drug (NSAID) approved for treatment of acute pain, fever, primary dysmenorrhea and pain and inflammation in osteoarthritis (OA). It is also being evaluated for treatment of rheumatoid arthritis and adenomatous polyps of the colon. Rofecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), thereby inhibiting prostanoid synthesis in cells that express COX-2, including inflammatory cells. As cells in the gastrointestinal (GI) tract principally express COX-1, a different isoform of cyclooxygenase, it is predicted that rofecoxib will have less GI toxicity than other less selective NSAIDs. In clinical trials, rofecoxib was found to be as effective as other NSAIDs for management of pain and inflammation. In trials that compare rofecoxib with ibuprofen, diclofenac and indomethacin, less GI toxicity has been observed, as assayed by a decrease in lesions visible on endoscopy, by GI blood loss and, in a meta-analysis, by frequency of serious adverse GI events. The presence of COX-2 in cells other than inflammatory cells results in side effects common among NSAIDs, including peripheral oedema and hypertension. These side effects are dose-dependent. Rofecoxib, together with other branded NSAIDs, are relatively expensive, which has led to concern regarding costs versus benefits. There is also concern regarding potential risks associated with the use of rofecoxib by populations that would otherwise not tolerate NSAIDs.

Animals↗
PubMed2003

Aprepitant--a novel NK1-receptor antagonist.

Recently, a new class of agents, the substance P antagonists, has heralded a novel approach for the control of emesis. Aprepitant (Emend, Merck & Co., Inc.), the first of this class, was recently approved by the FDA for the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). Of interest is the vast array of processes in which substance P is involved such as pain, anxiety, depression and inflammation and the potential wide applicability of substance P antagonists to a number of medical conditions outside of the nausea and vomiting realm. The following review provides an overview of aprepitant including pharmacokinetics, pharmacology and clinical evidence for its use in CINV. A brief discussion of other possible indications for aprepitant will also be presented.

Antiemetics↗