Hershel Jick

DRUG RASH WITH AMPICILLIN AND OTHER PENICILLINS

Abstract In a comprehensive drug surveillance system which monitored 3985 consecutive medical inpatients, rash attributed to any drug was recorded in 9.5% of 422 patients treated with ampicillin and in 4.5% of 622 patients treated with other penicillins (P=0.002). The frequency of rash in 2941 patients not given these drugs was 1.8%. The estimates of attributable risk for ampicillin and other penicillins were thus 7.7% and 2.7% respectively. With ampicillin the route of administration does not appear to affect the risk substantially; with other penicillins there is some evidence that drug rash occurs less frequently after oral than after parenteral administration. The excess frequency with ampicillin is accounted for by a group of patients whose onset of rash is delayed. This suggests that additional antigenic impurities may be present in ampicillin.

CADMIUM CONTENT OF CIGARETTES

Abstract Analysis of the cadmium content of whole cigarettes and cigarette ash and filters (after smoking) of six brands of cigarettes shows that about 70% of the cadmium content of cigarette tobacco passes into the smoke.

The epidemiology of digoxin: A study in three boston hospitals☆

Two thousand and ninety-eight consecutive patients have been studied in context of a comprehensive surveillance program which monitored all the drugs which they received. The results with digoxin given to 441 consecutive patients have been reported. The drug was judged to have been effective in 91.7 per cent and poor in 2.8 per cent of all patients in whom a consistent evaluation was made. Adverse reactions were reported in 18.4 per cent of all patients receiving the drug, and these were confirmed in 82.8 per cent of all cases investigated. The major reaction rate was 3.7 per cent. Increased admission weight (p < 0.05), potassium depletion due to diuretics (p < 0.01), and increased admission BUN levels (p < 0.05) were significantly associated with toxicity attributed to digoxin. Within the dosage ranges employed in this study, adverse reactions were not related to mean daily dosage, age, sex, or race. The same held true for efficacy which in addition was unrelated to weight. No deaths were attributed to digoxin. On scanning all drugs given in association with digoxin, toxicity attributed to the drug was found to be significantly associated with the following: meperidine, morphine, heparin, hydrochlorothiazide (all p < 0.05), furosemide, aminophyllin (all p < 0.01), and prochlorperazine (p < 0.001). The findings with meperidine, morphine, and heparin were unexpected, and for the present, are reported without comment. It is suggested that aminophyllin might have an irritative effect on the myocardium and thus potentiate digoxin toxicity. It is emphasized that associations do not necessarily imply cause and effect relationships and that in the context of the drug surveillance program, they could be due to chance, or to the effects of hidden variables. The interaction between digoxin toxicity and the diuretics, hydrochlorothiazide and furosemide, quantitatively supports current clinical and pharmacological knowledge. Prochlorperazine was found to be associated with toxicity because of its use in the treatment of nausea and vomiting caused by digoxin. Given the methodology employed by the surveillance system, this was logical and expected.

On the Concentrating Defect in Cirrhosis of the Liver

The capacity of patients with cirrhosis of the liver to produce a dilute urine after a water load has been extensively investigated (1, 2). The concentrating ability of these patients has not been carefully studied, although the assumption has been made that a defect exists (1, 3). The present studies describe the characteristics-of the concentrating system in patients with cir-rhosis and attempt to clarify the mechanisms involved in any existing defect. Methods Twenty-seven patients with cirrhosis of the liver of varying severity associated with chronic alcoholism and 17 patients with other chronic diseases were studied. Each patient was receiving at least 75 g of dietary protein and at least 1 g of dietary sodium per day. None gave a history of renal disease, and all had normal uri-nalysis, nonprotein nitrogen, and serum creatinine. No patients above the age of 65 were included. Except for the absence of azotemia or intrinsic renal disease, the cirrhotics represented a wide range of patients with this disease. The mean age of cirrhotics was 50 and ranged from 35 to 62 years. The degree of ascites ranged from no apparent ascites (seven patients) to massive ascites (three patients) and included varying degrees of protein depletion as estimated by degree of muscle wasting. The mean age of the 17 chronically ill patients without cirrhosis was 49 and ranged from 38 to 58 years, and they represented the only noncirrhotic patients in the medical service (180 beds) at a given time who satisfied the above criteria for inclusion in the study. The degree of ascites and degree of muscle wasting were estimated in each cirrhotic by a scale of 0 to ++++. Age and sex were recorded. 1) Special studies were carried out in nine patients with cirrhosis to evaluate and characterize the maximal * t This investigation was carried out during tenure as a Clinical Pharmacology Trainee and was supported by grants from the U. measurement of urine osmolality (Ucam) starting at 14 hours after the last oral intake and 10 hours after 5 U of vasopressin in oil intramuscularly. Urine samples were obtained intermittently until a last sample was obtained after 21 to 25 hours of dehydration. 2) Volume and urea, ammonia, sodium, and potassium concentrations of Uma. urines were measured in 11 cir-rhotics. In other patients urine sodium excretion was recorded as 0 to ++++ based on the approximate percentage of the oral sodium …

Control of persistent ventricular ectopic beats by alprenolol, a new beta-adrenergic blocking agent

Abstract A new β-adrenergic blocking agent, alprenolol, was found to be effective in thirteen patients in a double-blind cross-over study comparing its effect in reducing persistent ventricular ectopic beats with that of a placebo. The dose employed (20 mg. every 6 hours orally) did not affect systolic, diastolic, or mean blood pressure but did tend to lower the heart rate. No side effect or change in blood count, urinalysis, kidney, or liver function tests could be seen with the low dose used. It is concluded that 1-(o-allylphenoxy)-3-isopropylamino-2-propanol-hydrochloride (alprenolol) is an effective drug in the short-term oral dose employed in the management of persistent ventricular ectopic beats.

THE ROLE OF GENETIC FACTORS AND SERUM PROTEIN BINDING IN DETERMINING DRUG RESPONSE AS REVEALED BY COMPREHENSIVE DRUG SURVEILLANCE

Individual variation in response to drugs has long been recognized at the clinical level. Such variation results from a combination of numerous genetic and acquired factors of which relatively few have as yet been precisely defined. The specialty of pharmacogenetics emerged when a number of distinct examples of variation in response to specific drug challenges were explicable on a genetic basis.’ Careful metabolic and pharmacokinetic studies of many such phenomena revealed the existence of distinct enzyme or metabolic differences sufficient to explain the observed variation in drug response.2 Additional valuable information concerning the influence of hereditable factors on drug response can be obtained by approaching the problem from the opposite direction. Such an approach has already been utilized to define subpopulations showing an increased propensity to the development of certain disease states, e.g. the finding of unusual ABO blood type distributions in patients with diseases such as gastric carcinoma, duodenal ulcer, rheumatic heart disease, pernicious anemia, diabetes mellitus, and ~ t h e r s . ~ A unique opportunity allowing the study of genetic characterization and variation in response to drugs arose when a comprehensive drug surveillance program was started in Boston in 1966. Initially it involved all patients admitted into two 30 bed wards at the Lemuel Shattuck Hospital, B o ~ t o n . ~ Since this time, the program has gradually expanded so that currently 12 medical and two psychiatric wards involving eight hospitals in three countries are under surveillance: To each ward is attached a specially trained nurse (nurse monitor) who, using self-coding forms, collects all required data. In addition to obtaining precise details as to each patient’s vital statistics, past drug experience, and definitive diagnoses, she tests patients for certain genetically determined traits such as color blindness and phenylthiourea tasting, and draws blood, (which she sends to a laboratory operating within the program) for the defining of a genetic profile. Included in this profile is measurement of the total serum protein and albumin fraction.

Drug combinations‐uses, dangers, and fallacies

The use of many drugs for the treatment of a single disease or symptom complex has been a prevalent practice throughout history. Indeed, William Witherings clinical description of “dropsy” published in 1785 advocated treatment which included “medicines of the de‐obstruent tonic, antispasmodic, diuretic and evacuate kinds.” In the best tradition of multiple component therapy, he advised the use of “pills of Myrrh and white vitriol; and if costive, a pill with calomel and sloes.” Now as then, the psychological appeal of prescribing “not just one but a combination of medically proven ingredients” is apparently hard to resist, presumably on the basis of “more” being necessarily better than “less.”

A new method for assessing the clinical effects of oral analgesic drugs

A randomized double‐blind trial comparing aspirin and a placebo in the treatment of mild to moderate pain was introduced into a comprehensive drug surveillance program. The programs standard methods of data collection were judgments of attending physicians on the efficacy and adverse effects of drugs. The napsylate and hydrochloride salts of propoxyphene were also compared. The already established effectiveness of aspirin was demonstrated. No evidence of a difference in efficacy between the two salts of propoxyphene was found. A randomized, double‐blind, large‐scale evaluation of certain marketed and unmarketed drugs within a comprehensive drug surveillance program is feasible and can be of considerable value in their clinical assessment.