Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Etoricoxib reduced pain and disability and improved quality of life in patients with chronic low back pain: a 3 month, randomized, controlled trial.

BACKGROUND: Chronic low back pain (LBP) is a growing health problem. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat this condition, but have not demonstrated efficacy beyond 2 weeks, and no studies have shown that NSAIDs produce durable improvements in disability. METHODS: To evaluate the efficacy and durability of effect of etoricoxib for chronic LBP, a randomized, double blind, placebo-controlled trial was conducted at 46 centres. Three hundred and twenty-five patients with chronic LBP requiring treatment with an NSAID or paracetamol were randomized 1:1:1 to etoricoxib 60 mg (n=109), 90 mg (n=106), or placebo (n=110), daily for 3 months. Pre-specified endpoints over 3 months included LBP intensity scale (visual analog scale 0-100 mm) time-weighted average change from baseline, the Roland-Morris Disability Questionnaire (RMDQ), the LBP bothersomeness scale, patient and investigator global assessments, and measures of quality of life. RESULTS: Both etoricoxib groups experienced significant reductions in LBP intensity at 4 weeks versus placebo [-15.15 mm and -13.03 mm for 60 and 90 mg, respectively, probability (p)<0.001 for each], which was maintained over 3 months. Treatment resulted in significant improvement from baseline compared to placebo in RMDQ scores (etoricoxib 60 mg, -2.82 and 90 mg, -2.38, p<0.001 for each) over 12 weeks and most other efficacy endpoints. There were no significant differences between treatments in incidence of adverse events (AEs) or discontinuations due to AEs. CONCLUSION: Etoricoxib provided significant relief of symptoms and disability associated with chronic LBP detected at 1 week, confirmed at 4 weeks, and maintained over 3 months. Reductions in chronic LBP severity corresponded to improvements in physical functioning and quality of life. All treatments were generally well tolerated.

Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial.

BACKGROUND: In recent studies of acute pain and primary dysmenorrhea, rofecoxib, a nonsteroidal anti-inflammatory drug that selectively targets the cyclooxygenase-2 enzyme, was found to be similar in efficacy to ibuprofen and naproxen sodium. OBJECTIVE: The purpose of this study was to determine the analgesic efficacy of a single oral dose of rofecoxib 50 mg compared with the combination of codeine 60 mg/acetaminophen 600 mg in a model of postsurgical dental pain. METHODS: In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate or severe pain after the surgical extraction of > or = 2 third molars, at least 1 of which was a mandibular impaction, were randomized to receive placebo, rofecoxib 50 mg, or codeine 60 mg/acetaminophen 600 mg. Patient evaluations of pain intensity, pain relief, and global assessments were recorded throughout the 24-hour period after dosing. The 2-stopwatch method was used to determine time to confirmed perceptible pain relief. The primary end point assessing overall analgesic effect was total pain relief over 6 hours (TOPAR6). Secondary end points were patient global assessment of response to therapy (PGART) at 6 hours, onset of analgesia, peak analgesic effect, and duration of analgesia. RESULTS: A total of 393 patients were enrolled; 182 received rofecoxib, 180 received codeine/acetaminophen, and 31 received placebo. The overall analgesic effect of rofecoxib 50 mg was greater than that of codeine 60 mg/acetaminophen 600 mg for TOPAR6 (12.4 vs 7.0; P < 0.001) and PGART at 6 hours (P < 0.001). The onset of analgesic effect was similar for rofecoxib and codeine/acetaminophen. Peak analgesic effect as measured by peak pain relief scores during the first 6 hours was significantly greater in the rofecoxib group compared with the codeine/acetaminophen group (P < 0.001), as was the duration of analgesic effect measured by the time to rescue analgesia (9.6 hours vs 2.3 hours, P < 0.001). Adverse events were reported in 33.0%, 46.1%, and 32.3% of patients treated with rofecoxib, codeine/acetaminophen, and placebo, respectively. The most common adverse events were nausea (6.0%, 25.0%, and 9.7%, respectively) and vomiting (3.8%, 18.3%, and 6.5%, respectively). Significantly more patients in the codeine/acetaminophen group than in the rofecoxib group experienced adverse events overall (P < 0.050) and nausea in particular (P < 0.001). CONCLUSION: In this study of moderate to severe postoperative dental pain, the analgesic efficacy of rofecoxib 50 mg was greater than that of codeine/acetaminophen, with a lower incidence of adverse events and nausea.

Duration of protection from clinical hepatitis A disease after vaccination with VAQTA.

Recent papers examining the expected persistence of anti-hepatitis A virus antibody following vaccination with inactivated hepatitis A vaccine have estimated that geometric mean antibody levels will remain above cut-off levels for 10-30 years. However, the methodology used in these papers did not take into account any estimates of variability between subjects. In this paper data from the persistence of antibody after the administration of another vaccine, VAQTA (hepatitis A vaccine, inactivated; MSD), were used to develop further models of antibody decay. Using individual subject estimates instead of group means allowed the estimation of time to negativity for various percentiles of the population (including the median), and the construction of confidence intervals on estimates of time to negativity. Data from studies of subjects who seroreverted to negativity, and subsequently received a booster dose, were also considered to show that subjects who lose detectable antibody are likely to remain protected from hepatitis A disease by persistent immune memory and rapid anamnestic response soon after exposure to hepatitis A virus. The estimates of duration of protection suggest that VAQTA will provide protection for many years, first through presence of antibody and further through an anamnestic response based on persistent immune memory.

Medicament release from suppository bases I: Physicochemical characteristics and bioavailability of indomethacin in rabbits.

This investigation was designed to determine the in vitro release of indomethacin from suppository bases and the in vivo bioavailability in rabbits. Suppositories containing 25 mg of indomethacin were made by the fusion method with theobroma oil, esterified fatty acids (C10-C18), and polyethylene glycol 1000. To produce an exact dosage form, a formula for the determination of the displacement value was derived, and it was found that theobroma oil greater than esterified fatty acids (C10-C18) greater than polyethylene glycol 1000. The suppository hardness was determined by using appropriate apparatus and it was found that the esterified fatty acids (C10-C18) allowed the formation of more brittle suppositories. The release rates were determined with the USP dissolution apparatus, with or without cellophane membrane, and it was found that polyethylene glycol 1000 greater than esterified fatty acids (C10-C18) greater than theobroma oil. The bioavailability of indomethacin after rectal administration was greater with polyethylene glycol base. Significant correlation was obtained during the first 45 min between the in vitro release (dialyzing tubing) and the in vivo bioavailability.

Studies on interaction of timolol, hydrochlorothiazide and amiloride in the rat.

1. The acute effects of hydrochlorothiazide, amiloride, timolol and their combinations on diuresis and arterial pressure were studied in rats. 2. Timolol did not modify the diuretic and saluretic effects of hydrochlorothiazide and/or amiloride and had no diuretic or antidiuretic effects alone. 3. At a single dose of 1.25 mg/kg, p.o., timolol alone had no antihypertensive effect in spontaneously hypertensive rats. 4. The antihypertensive effect of hydrochlorothiazide + amiloride + timolol was significantly greater than with any of the drugs alone.

Cardiotonic effects of anthopleurin-A, a polypeptide from a sea anemone.

The positive inotropic effect of anthopleurin-A (AP-A) was studied in vitro on isolated cat heart papillary muscles and in vivo in anesthetized and conscious dogs. In vitro, in low Ca2+ solution (1.27 mM), AP-A increased the force of contractions of isolated cat heart papillary muscles at concentrations from 0.2 x 10(-8) M and higher; on a molar basis, AP-A was more than 200 times as potent as digoxin and on a weight basis, 33 times as potent. In vivo in anesthetized dogs, AP-A at 0.2 microgram/kg/min i.v. increased myocardial contractile force; the geometric mean dose of AP-A required to increase the contractile force by 25% was 2.6 micrograms/kg; the corresponding dose of digoxin (infused at 2.8 micrograms/kg/min) was 107.4 micrograms/kg. The geometric mean lethal dose of AP-A for 8 dogs was 19.3 and that of digoxin 263.2 micrograms/kg i.v. The therapeutic index of AP-A was significantly higher than that of digoxin. All animals that received either AP-A or digoxin died in ventricular fibrillation. The reversal of t-wave was typical for AP-A. As measured by left ventricular pressure telemetry, AP-A, 2 micrograms/kg i.v. single dose, increased LV dp/dt max in conscious dogs for longer than 2 hr.

Diuretic and antihypertensive effects of 2-aminoethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK-447).

2-Aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride or MK-447, is a chemically novel diuretic agent which produced diuretic and saluretic effects in rats, dogs and chimpanzees. At doses ranging from 0.1 to 10 mg/kg p.o. (0.32-32 mumol/kg) MK-447 was more effective then furosemide at the same or higher doses in increasing the excretion of Na+, K+ and Cl- in rats and dogs. At single oral doses, MK-447 had antihypertensive activity in spontaneously hypertensive rats and renal hypertensive dogs. Other diuretics are known to lower arterial pressure in these models only by repeated administration. The antihypertensive and diuretic effects of MK-447 in spontaneously hypertensive rats were reduced by indomethacin.

Mantel-Haenszel analyses of litter-matched time-to-response data, with modifications for recovery of interlitter information.

The Mantel-Haenszel procedure for comparing sets of time-to-response data is adaptable to data that can be stratified on other variables. A particular adaptation, which we have used, is one in which animals from the same litter have been assigned to different treatment groups, e.g., some to a control group and some to a drug treatment group. The time to response used was that of tumor appearance; death from other causes was considered a loss to observation. The initial litter-adjusted analysis seemed to have only limited advantages compared to analysis that ignored litters and could be interpreted as suggesting that litter matchihg was not advantageous. Contributing to the difficulty was the fact that in the litter-matched analysis no further information was forthcoming from the remaining similarly treated animals in a litter when there were no remaining contrastingly treated littermates. Several devices for recovering interlitter information from such remnants and for combining it with intralitter information are examined and applied.

Some cardiovascular effects of ST-91 and clonidine.

St-91, 2(2,6-diethylphenylamino)-2-imidazoline, is a clonidine derivative which does not penetrate the blood-brain barrier. In spontaneously hypertensive (SH) rats is acutely increased arterial pressure and reduced heart rate while at 8 to 12 h after oral administration, it slightly lowered arterial pressure. In contrast, clonidine had acute antihypertensive activity at all doses used. By intracerebroventricular administration to SH rats, both drugs (St-91 and clonidine) reduced arterial pressure and heart rate; in this respect, clonidine was more potent then St-91. Cardiac acceleration induced by low frequency electrical stimulation of right cardiac sympathetic nerves in anesthetized and vagotomized dogs was reduced by St-91 at the same doses by clonidine. Phenoxybenzamine, phentolamine and desipramine antagonized the inhibitory effects of St-91 on electrically induced cardiac acceleration. It was concluded that St-91, like clonidine, stimulates inhibitory alpha-adrenergic receptors at the sympathetic nerve endings but, unlike clonidine, is substantially devoid of acute antihypertensive activity. This suggests that stimulation of peripheral presynaptic inhibitory alpha-adrenergic receptors is not likely to represent the sole mechanism of antihypertensive action of clonidine.

Effect of cage size on patterns of activity and health of beagle dogs.

Thirty-two male beagle dogs were assigned at random, 16 to standard size cages (30 X 30 X 30 inches) and 16 to large cages (90 X 30 X 30 inches) for a period of 13 weeks, and then were "crossed-over" for an additional period of 13 weeks. The dogs were observed daily and weighed weekly. Electrocardiographic and ophthalmologic examinations were made once and hematologic and biochemical measurements were made twice during the control period and at monthly intervals during the study. Photographs were taken of each dog every 60 seconds, 7 days a week, for about 8.5 hours each day. The film was processed and analyzed for the acf standing sitting, lying, or sleeping. In addition, dogs in the large cages were scored for the region (front, middle, or back) occupied. No statistically significant differences were found between dogs in the standard or large cages with respect to weight gain, percent of time standing, and percent of time sleeping. Statistically significant (p less than 0.05) differences were found for percent of time sitting (standard cages 12.7%; large cages 9.4%) and percent of time lying (standard cages 6.6%; large cages 8.3%); however, the differences were not large enough to be of any practical concern. Transient patterns of response over 13-week periods of the study were essentially the same (statistically verified) for dogs in either size cage. Also statistical results showed that there was no significant carryover (residual) effect associated with any of the parameters measured. No beneficial or adverse effects were noted that could be related to the size of the two cages. The size of the standard cage appeared adequate for laboratory beagle dogs and no advantage was found when the dogs were in larger cages with respect to behavior, patterns of activity, or health.

Selecting key parameters in pharmaceutical formulations by principal component analysis.

The role of principal component analysis in the selection of pharmaceutical formulations is presented. The objective and the procedure of the analysis are discussed in detail. The technique was successfully applied to a system consisting of 10 response variables (tablet properties). Analysis of the results showed that the first component (dissolution) and components one and two together (dissolution and disintegration) contributed 95.4 and 99.3%, respectively, to the overall information about the formulations and that eight of 10 response parameters contributed nothing further to the overall information. The results obtained from this method of analysis may be found useful for achieving economy in both cost and time of measuring response. Principal component analysis also provides a basis for understanding the underlying mechanism of the system under consideration.

An improved Mantel-Bryan procedure for "safety" testing of carcinogens.

A published method by Mantel and Bryan for calculating "safe" doses of carcinogens is updated by incorporating several improvements. These improvements include more effective procedures for taking into account any spontaneous tumor rate and for combining data at several dose levels. An added feature is that it permits the combining of data from several experiments by postulating that it is only the spontaneous rate that differs between experiments. The improved method is illustrated with data from five hypothetical experiments, using a risk level of 10-8, a conservative slope of one probit or normal deviate per tenfold dose increase, and a nominal assurance level of 99%. The hypothetical experiments were geared to bring out particular pointsas, for example, the applicability of the model in the absence of control data. A large variety of issues involved in the determination of "safe" doses are discussed, including questions of experiment design and extrapolitan between species. A statistical appendix is provided, laying the framework for the calculating procedure and detailing complications therein. The "safe" dose approach helps resolve certain dilemmas in questions relating to food additives. A "no-detectable-level" prescription for chemical residues may be dangerous to the public where detection techniques are insufficiently sensitive, but it can become far too restrictive as exquisitely sensitive detection techniquesare developed. Only levels in excess of the "safe" dose would require detection. Calculated values for the "safe" dose could be updated and increased as more clear evidence of safety becomes available.