Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors.

BACKGROUND: Many patients with congestive heart failure do not receive the benefits of angiotensin-converting enzyme (ACE) inhibitors because of intolerance. We sought to determine the tolerability of an angiotensin II receptor blocker, candesartan cilexetil, among patients considered intolerant of ACE inhibitors. METHODS: Patients with CHF, left ventricular ejection fraction less than 35%, and history of discontinuing an ACE inhibitor because of intolerance underwent double-blind randomization in a 2:1 ratio to receive candesartan (n = 179) or a placebo (n = 91). The initial dosage of candesartan was 4 mg/d; the dosage was increased to 16 mg/d if the drug was tolerated. A history of intolerance of ACE inhibitor was attributed to cough (67% of patients), hypotension (15%), or renal dysfunction (11%). RESULTS: The study drug was continued for 12 weeks by 82.7% of patients who received candesartan versus 86.8% of patients who received the placebo. This 4.1% greater discontinuation rate with active therapy was not significant; the 95% confidence interval ranged from 4.8% more discontinuation with placebo to 13% more with candesartan. Titration to the 16-mg target dose was possible for 69% of patients who received candesartan versus 84% of those who received the placebo. Frequencies of death and morbidity were not significantly different between the candesartan and placebo groups (death 3.4% and 3.3%, worsening heart failure 8.4% and 13.2%, myocardial infarction 2.8% and 5.5%, all-cause hospitalization 12.8% and 18.7%, and death or hospitalization for heart failure 11.7% and 14.3%). CONCLUSIONS: Candesartan was well tolerated by this population. The effect of candesartan on major clinical end points, including death, remains to be determined.

Candesartan in heart failure--assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators.

BACKGROUND: Chronic heart failure (CHF) is an increasing burden to health care. Pharmacological treatment with angiotensin-converting enzyme (ACE) inhibitors and beta blockers improve survival and reduce hospitalizations in patients with low left ventricular ejection fraction (LVEF). Despite these therapies, morbidity and mortality remains problematic. Furthermore, 30% to 50% of patients with CHF have a preserved LVEF. It is not known if treatments are of benefit in this group. DESIGN: Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) is a program designed to investigate the clinical usefulness of the long-acting angiotensin II type 1 receptor blocker, candesartan cilexetil, in a broad spectrum of patients with symptomatic heart failure. Patients with systolic dysfunction, tolerant or intolerant to an ACE-inhibitor, and patients with preserved systolic function are included. Specifically, the CHARM program consists of 3 independent, parallel, placebo-controlled studies in patients with (1) LVEF less than or equal to 40%, ACE-inhibitor treated (n = 2,300); (2) LVEF less than or equal to 40%, ACE-inhibitor intolerant (n = 1,700); (3) LVEF greater than 40%, not treated with ACE inhibitors (n = 2,500). The 3 studies will be combined to evaluate the effect of candesartan cilexetil on all-cause mortality in the broad spectrum of symptomatic heart failure. The primary objective in each trial is to evaluate the effects on the combined endpoint of cardiovascular mortality or CHF hospitalization. Other endpoints include the effects on myocardial infarction, all-cause hospitalization, and resource utilization. CHARM is intended to randomize 6,500 patients with symptomatic heart failure from 26 countries in Europe, the United States, Canada, South Africa, and Australia. The CHARM program started to enroll patients in March 1999. The follow-up period is a minimum of 2 years. The study is expected to end in the third quarter of 2002.

Stimulus effects of delta(9)-THC and its interaction with naltrexone and catecholamine blockers in rats.

Rats trained in a T-shaped maze to discriminate the effects of i.p. injections of delta(9)-tetrahydrocannabinol (delta(9)-THC, 4 mg/kg) and the effects of the vehicle were tested for antagonism and generalization to the delta(9)-THC stimulus by naltrexone (4 mg/kg), haloperidol (0.32 mg/kg), propranolol (20 mg/kg), and phenoxybenzamine (10 mg/kg). None of these drugs blocked the delta(9)-THC stimulus, nor were they found to generalize to delta(9)-THC.

Delta9-THC as a discriminative cue in pigeons: effects of delta8-THC, CBD, and CBN.

Pigeons, trained to discriminate the effects of i.m. injections of delta9-tetrahydrocannabinol (delta9-THC, 0.25 mg/kg) from the effects of the vehicle in a drug discrimination paradigm, were tested for generalization with the isomeric delta8-THC, cannabidiol (CBD) and cannabinol (CBN). When given in sufficient doses, delta8-THC and CBN were found to substitute for delta9-THC whereas CBD did not. CBD and CBN did not antagonize the stimulus effect of delta9-THC. The combination of CBN and delta9-THC rather appeared to accentuate the drug response.

Interactions between alcohol and other drugs on open-field and temperature measurements in gerbils.

Open-field activity and rectal temperature were measured in mongolian gerbils treated with alcholol (1 and 2 g/kg) only and when alcohol was combined with bemegride (20 and 40 mg/kg), DH-524 (20 mg/kg), or d-amphetamine (8 mg/kg). None of the purported antagonists normalized the alcholol-produced changes in the open-field test, nor did they reverse the alcohol-induced hypothermia. However, alcohol offered protection against bemegride-induced convulsion and death. When compared with pervious data (1) it is suggested that alcohol is differentiated from pentobarbital and diazepam on the basis of their interactional effects with bemegride.

The new breed of Malthusians.

PIP: Neo-Malthusians, publishing in popular rather than scientific journals, are predicting dire results from rampant population growth and recommending coercive remedies, e.g., mass sterilizations, child rationing, and controlled extermination. The hysteria is unwarranted. The fertility transition is already under way in many developing countries and will probably happen everywhere. Population growth slowdowns take time even if governmental policies are directed toward them. The arguments for future massive crises due to population pressure (war, famine, and pestilence) are unconvincing. Coercive measures to control population growth are unnecessary so long as the problem of unwanted births remains. Efforts to change motivation in the direction of lowering fertility may help. Governmental policies which reduce the benefits of large families, raise the status of women, and lower the necessity for many children will be effective.^ieng