Jan Koch‐Weser

The intensity of β-blockade correlated poorly with drug dosage but was linearly related to the logarithm of the plasma concentration, with 8 patients forming a distinct group having a 2.6 times lower ratio of β-blockade to plasma concentration compared to the other 20 subjects.

The Lugano Statements on Controlled Clinical Trials

During a consensus conference in Lugano, Switzerland, 175 statements on controlled clinical trials were drafted by 47 representatives from academia, governmental registration agencies and industry in nine countries. Their opinion on these statements was similar to that of 47 'matched pairs' who did not attend the conference. Thus, the opinion of participants and non-participants appears to reflect the general opinion of those currently involved in designing, conducting and analysing controlled clinical trials. The Lugano statements give answers to the following questions: Is the controlled clinical trial in a crisis? What is the motivation to perform controlled clinical trials? Is it possible for a physician participating in a controlled clinical trial to act in the patient's best interest? Is it possible to obtain truly informed consent in a controlled clinical trial? When is it ethical to withhold active treatment in a controlled clinical trial? What are the controversial issues in the design of a good controlled clinical trial? Is there a double standard with respect to efficacy and adverse drug reactions in controlled clinical trials? What are the alternatives to controlled clinical trials and when should they be performed? How can sponsor bias be minimized? How should an ethics committee decide whether a controlled clinical trial is ethical? Should registration agencies become directly involved in the planning and conduct of controlled clinical trials? Do the declarations of Tokyo and Helsinki facilitate the conduct of ethically valid controlled clinical trials? Is it possible to create an international standard for the conduct and regulation of controlled clinical trials? Why do messages from controlled clinical trials filter into medicine so slowly? Is it possible to bridge the gap between controlled clinical trials and clinical reality? What are the costs of doing and not doing controlled clinical trials? When should drug companies decide to start a trial programme with a specific compound? Is there public hostility against controlled clinical trials? If so, how can it be reduced? The respondents almost unanimously felt that controlled clinical trials are a must: the public must be told that progress in medicine depends on controlled clinical trials, that patients often benefit from participating in them and that the alternative, practising in the face of constant uncertainty, is worse than the possible disadvantages related to the conduct of the trial.

Recent clinical trials demonstrate that orally active β-blockers can reduce the risk of cardiovascular mortality in patients recovering from acute myocardial infarction.

Drug Administration in Hepatic Disease

THE biologic processes that govern the absorption of a drug into the body and its elimination from it are important determinants of its pharmacologic effect and toxicity. Absorption occurs after administration of a drug parenterally or via the gastrointestinal tract, the skin, lung, eye, or other tissues and organs. Each route possesses certain characteristics that control the rate and extent of entry of a drug into the systemic circulation. Drugs are eliminated from the body through the excretion of unchanged drug or through biotransformation to one or more metabolites. Because absorption usually occurs more rapidly than elimination, the processes of . . .

Ranitidine: A New H2-Receptor Antagonist

OVER the past six years the treatment of peptic-ulcer disease has been dramatically altered by the introduction and use of cimetidine. This substituted imidazole compound is an effective H2-receptor antagonist, which acts on the gastric parietal cell to inhibit gastric acid production. Cimetidine is prescribed worldwide, and on the basis of numerous controlled clinical trials, it is considered effective in the healing of both duodenal1 and gastric ulcers.2 Recently, ranitidine, another H2-receptor antagonist, has undergone extensive clinical studies and has been approved by the U.S. Food and Drug Administration for the short-term treatment of duodenal ulcers . . .

Treatment of Herpesvirus Infections

Guidelines for the prophylaxis or therapy of herpesvirus infections are shown in Table 1. Progress is so rapid in this area that frequent revisions of such guidelines will be necessary. Newer drugs or new formulations of older agents are constantly being developed. Combination therapies--e.g., interferon plus acyclovir--appear promising in laboratory models of herpesvirus infections and will undoubtedly receive clinical investigation in the years ahead. The problem of dealing with latent virus infections still eludes us, and major breakthroughs will be necessary before we can discuss cure of recurrent infections. Nevertheless, important strides have been made in the past few years, and further progress is predictable in the years ahead.

Treatment of Herpesvirus Infections

HERPESVIRUS infections remain among the most troublesome afflictions facing patients and clinicians. Although "remedies" for herpes infections have long been with us, until recently none has withstood close scrutiny. Since this subject was last reviewed in the Journal,1 a number of well-controlled clinical trials of anti-herpes agents have been conducted. Moreover, both topical and intravenous preparations of acyclovir have been licensed in the United States, and licensure of oral acyclovir is on the horizon. Other anti-herpes nucleoside derivatives and a multitude of different interferon preparations are under trial. Physicians have gone from a situation in which there was no . . .

Current Status of Benzodiazepines

Clinical Use of BenzodiazepinesAnxietySince 1977, several new benzodiazepines have been marketed in the United States for the treatment of anxiety syndromes67 68 69 70 71 (Table 1). These drugs may offer some subtle clinical options. Prazepam, for example, may cause less drowsiness after single doses than do comparable doses of other benzodiazepines because of the slow appearance of desmethyldiazepam in the blood.72 Some clinical studies suggest a reduced incidence of sedation during treatment with lorazepam and alprazolam — benzodiazepines that have an intermediate half-life — possibly because the extent of drug accumulation is reduced; however, this is not a consistent finding.69 , 70 In . . .

Current Status of Benzodiazepines

When the pharmacologic and clinical properties of the benzodiazepine sedative–anxioly tics were last reviewed comprehensively in 1973 and 1974,1 2 3 their use in clinical practice was very extensive and increasing.4 5 6 It was pointed out that a continuation of the yearly rate of increase would lead to the total tranquilization of America by the turn of the century.7 During the mid-1970s, however, concern emerged among both prescribers and users of these medications about this continuously increasing use. Articles in scientific publications and the lay press suggested some apparently dramatic consequences and hazards of tranquilizer use.8 9 10 11 12 Although the validity of most such reports . . .

Pindolol: A New β-Adrenoceptor Antagonist with Partial Agonist Activity

Psychotropic Drug Use in the Elderly

Antidepressant AgentsIt is important to detect depression in the elderly, since it is often responsive to treatment and since suicide is common in this age group, especially among depressed white widowers.3, 76 Other risk factors for suicide that are found frequently in the elderly include living alone, chronic medical illnesses (which may cause dementia or predispose to delirium), recent loss or bereavement, alcohol or sedative abuse, a sense of hopelessness about problems, and a covert wish by others that the elderly person would die.Clinically important depression is present at any given time in at least 10 per cent of . . .

Concentration Gradients of Free and Total γ‐Aminobutyric Acid and Homocarnosine in Human CSF: Comparison of Suboccipital and Lumbar Sampling

Concentrations of free and total gamma-aminobutyric acid (GABA) and homocarnosine were determined in sequential aliquots of the first 30 ml of CSF obtained by lumbar puncture in five patients. Rostrocaudal gradients were calculated and compared to gradients estimated by determining concentrations of these substances in CSF obtained by simultaneous suboccipital and lumbar punctures in four more patients. In the lumbar fractions study, rostrocaudal mean gradients of 0.36, 36, and 21 pmol/ml for free GABA, total GABA, and homocarnosine, respectively, were calculated. In the suboccipital/lumbar study, gradients of 0.33, 30, and 24 pmol/ml for free GABA, total GABA, and homocarnosine, respectively, were estimated. These results indicate that valid comparison of CSF concentrations of these substances is restricted to similar fractions and suggest that in CSF the substances originate largely from brain rather than from peripheral sources.

Artifactual Increases in the Concentration of Free GABA in Samples of Human Cerebrospinal Fluid Are Due to Degradation of Homocarnosine

Samples of untreated human cerebrospinal fluid (CSF) were kept at room temperature (20 +/- 1 degree C) up to 72 h, and changes in gamma-aminobutyric acid (GABA) and homocarnosine contents were measured. The concentration of free GABA increased with time, and concomitantly a similar decrease occurred in the concentration of homocarnosine. Total GABA after hydrolysis (present in human CSF at concentrations of 40-100 times that of free GABA) did not change. After 2 h the increase in CSF GABA for seven subjects ranged from 42 to 244 pmol/ml. The rate of increase in CSF GABA was positively correlated with the initial homocarnosine concentration. Approximately 5% per h of the initial homocarnosine content was degraded during the first 7 h at room temperature; thereafter the rate gradually decreased. No free GABA was formed in CSF frozen at -70 degrees C for 10 days. When this CSF was restored to room temperature, the formation of free GABA from homocarnosine occurred at essentially the same rate as that observed in fresh CSF. These results demonstrate that the well-known artifactual increase in GABA concentration of untreated human CSF depends on the concentration of homocarnosine. The rapidity of this increase (up to 2 pmol/ml/min) could account for disparities among CSF free GABA concentrations previously reported from normal subjects. It is suggested that measurement of concentrations of total GABA in the CSF would provide a better index of human brain GABA concentration than determination of CSF free GABA.

Rate-Controlled Drug Delivery

THE goal of pharmaceutical research is to find drugs with desirable therapeutic properties and low risks of undesirable side effects. Drugs with such high therapeutic ratios are usually sought as new chemical entities — molecules designed to produce the desirable effects without the undesirable ones. However, another method of achieving the goal of pharmaceutical research is through the development of drug-delivery systems that achieve pharmacologic selectivity not solely on the basis of chemical structure but also on the basis of pharmacokinetic principles. Drug products achieving controlled rates of delivery offer one such approach. A few of these are already available . . .

Atenolol is a beta-1 selective blocker with a long half-life allowing once-daily dosing, while timolol is a nonselective beta-blocker lacking membrane-stabilizing activity.

Thrombolytic Therapy

IN the continuing search for new and improved methods of treating thromboembolic diseases, the concept of an agent to dissolve clots has always been attractive. After the efficacy of heparin in venous thromboembolism was established by Barritt and Jordan,1 many physicians regarded its use as definitive, but in reality its action was only preventive. What was needed was an agent that would act on the morbid event directly — i.e., that would dissolve thromboemboli in pulmonary embolism. By restoring pulmonary vascular space, relieving pulmonary hypertension, and recompensating right ventricular function, such therapy could minimize morbidity and perhaps decrease mortality, particularly . . .

Drug Disposition in Old Age

THE appropriate and rational use of drugs by the elderly is a matter of growing medical and social concern. Life expectancy in the Western world currently stands at 69 years for men and 77 years for women and is increasing.1 , 2 In 1980 an estimated 11 per cent of the total population was over 65 years old; the proportion is expected to exceed 15 per cent by the year 2040. As compared with the young, elderly persons on the average spend more money and a greater fraction of their income on health care. Old people have more illnesses and hospitalizations than . . .

GreenblattThe Journal of Clinical Pharmacology

Importance of Protein Binding for the Interpretation of Serum or Plasma Drug Concentrations

The extent of drug binding to plasma protein does not influence the concentration of unbound drug in plasma at steady state but does influence the interpretation of total drug concentrations. An increase in free fraction (reduction in the extent of binding) decreases the therapeutic and toxic ranges for total drug concentrations. Conversely, a reduction in free fraction (increase in the extent of binding) increases these ranges. Laboratories generally measure total rather than unbound drug concentrations, and clinicians must use caution in interpreting these total drug concentrations in clinical situations where the extent of binding of extensively bound drugs may be altered. Free drug serum or plasma concentrations are inherently more reliable indices of the intensity of drug action than are total concentrations. Methodology for routine measurement of free concentration is becoming available and should ultimately be utilized for therapeutic monitoring of drugs that are highly bound to protein.

Captopril

Captopril (D-3-mercapto-2-methylpropranoyl-L-proline [SQ 14,225, Capoten]) is the first orally active inhibitor of angiotensin-converting enzyme, the enzyme responsible for conversion of inactive angiotensin I to the potent pressor peptide angiotensin II. It is a potent, relatively specific competitive inhibitor of angiotensin-converting enzyme (kininase II), as well as an effective antihypertensive agent. Prior experience with the nonapeptide inhibitor of angiotensin-converting enzyme, teprotide (SQ 20,881), demonstrated that this parenterally administered agent was effective in the treatment of most patients with hypertension.1 , 2 The search for an orally effective inhibitor led to the development of captopril (Fig. 1),3 which has since undergone intensive clinical investigation . . .

Effect on prostatic growth of 2-difluoromethylornithine, an effective inhibitor of ornithine decarboxylase

2-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, causes marked changes in the polyamine metabolism of ventral prostate when given to adult rats in drinking water (20 g/l) for 3 consecutive days. A 90% inhibition of ornithine decarboxylase activity is accompanied by approx. 80% decreases of the concentrations of putrescine and spermidine and by a 36% decrease in spermine. Concomitantly, S-adenosylmethionine decarboxylase activity increases 7-fold and the concentration of decarboxylated S-adenosylmethionine 450-fold. When DFMO is given to immature rats for 12 consecutive days the above described changes are accompanied by a marked reduction in the age-dependent increases of the wet weight and RNA and DNA contents of the ventral prostate. In adult rats DFMO decreases the weight and RNA content of the ventral prostate within 4 days by 32% and 24% respectively and maintains them constant for the next 19 days. After 23 days of treatment, the prostatic weight is 46% of that of control animals of the same age, whereas the weights of other organs are only slightly decreased. Cytological studies carried out at this time show that DFMO reduces the size of both prostatic acini and the epithelial cells lining the acini.