Fred E. Karch

Toward the operational identification of adverse drug reactions

The evaluation of adverse drug reactions in clinical practice is somewhat arbitrary and is characterized by considerable differences of opinion. This report presents a decision table algorithm approach toward the development of an operational system for the identification of adverse drug reactions. The algorithm incorporates an estimate of the certainty of the link between the untoward clinical event and the suspect drug, and examines the underlying causes of the identified drug reactions. Use of such a system is a first step toward reducing ambiguity in the evaluation of adverse drug reactions.

Adverse drug reactions—a matter of opinion

The accurate identification of adverse drug reactions (ADRs) is difficult because ADRs usually present no unique clinical or laboratory findings that demarcate them from the manifestations of concurrent illnesses. The identification of ADRs depends on the clinical assessments of physicians‐sometimes the clinician treating the patient and at other times a clinical pharmacologist. Considering the complex and subjective nature of clinically identifying ADRs, how accurately are ADRs identified? To answer this question, three clinical pharmacologists each independently evaluated 60 selected cases to determine if medication, alcohol, or “recreational” drugs had caused the hospitalization. The three clinical pharmacologists agreed on only 30 cases (50%), and 27 of these were thought to be unrelated to medications. In 19 of the 30 cases about which the clinical pharmacologists disagreed, they disagreed on whether or not a medication‐ or alcohol‐related event had occurred at all. The clinical pharmacologists disagreed with the physicians treating the patient in 22% to 37% of the cases, but because of the differences among the pharmacologists, the treating physicians agreed with at least one of them in 95% of the cases. Complete agreement between the clinical pharmacologists and the treating physicians occurred in 47% of the cases. This degree of disparity in the clinical identification of ADRs shows that the evaluation of ADRs is subjective and imprecise. The accurate identification of ADRs awaits the development of an objective technique for recognizing ADRs.

Effect of lithium on plasma chlorpromazine levels

The interaction of lithium and chlorpromazine (CPZ) was studied in healthy volunteers in a randomized crossover study. Each subject ingested two doses of CPZ (l00 mg) as the liquid concentrate: (1) without concurrent lithium therapy and (2) after a 7‐day treatment with lithium carbonate (900 mg/day). When CPZ was administered with lithium, peak plasma CPZ levels were 40.3% (mean) lower than those without lithium (p = 0.006), and the area under the CPZ plasma concentration time curve was 26.6% smaller (p = 0.08). The time to reach peak plasma CPZ levels was similar in both groups. All subjects slept for 4 to 6 hr after oral CPZ and had a maximum fall in both systolic (8 to 32 mg Hg) and diastolic (5 to 23 mg Hg) blood pressure at the time of peak plasma CPZ concentration. This lithium‐CPZ interaction may explain the low plasma CPZ levels reported previously in psychiatric patients taking both lithium and CPZ.

Renal infarction due to renal artery dysplasia with dissection: Report of a case in a normotensive patient

A previously healthy 44-year-old man with well-documented normotension had a sudden onset of left flank pain and delayed onset of constitutional symptoms, hematuria, and elevations of lactic dehydrogenase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and creatinine levels. Angiography revealed unilateral renal artery fibromuscular dysplasia with dissection and infarction. In the year since, he has remained well and normotensive without therapy. The literature is reviewed.

Diatrizoate Enemas: Facts and Fallacies of Colonic Toxicity

Rats were given enemas of Gastrografin in two strengths, Renografin--76, and Tween--80 in a 10% dilution. There were no deleterious effects on the colons with these media used in volumes to fill the colon. Severe changes resulted from volumes which produced overdistention.

Comparative efficacy and tolerability of two long-acting calcium antagonists, mibefradil and amlodipine, in essential hypertension

Abstract In a previous forced-titration trial, mibefradil 100 mg QD was as effective as amlodipine 10 mg QD in reducing sitting diastolic blood pressure (SDBP), and it produced significantly less leg edema than did amlodipine 10 mg QD. The present multicenter, double-masked, randomized, parallel-design trial was performed to assess the reproducibility of these results using a flexible-titration design. Following a 4-week, single-masked, placebo run-in period, 296 patients with a trough SDBP of between 95 and 114 mm Hg (21 to 27 hours postdose) were randomized to receive once-daily treatment with mibefradil 50 mg (n = 146) or amlodipine 5 mg (n = 150). In patients whose trough SDBP was greater than 90 mm Hg after 4 or 8 weeks of double-masked therapy, the dosage was titrated upward to mibefradil 100 mg or amlodipine 10 mg for the remainder of the 12-week active treatment period. A greater proportion of amlodipine-treated patients (65%) than of mibefradil-treated patients (54%) required titration to the higher dose. Despite this difference, statistically equivalent reductions in trough SDBP were observed after 12 weeks of treatment with 50 to 100 mg of mibefradil QD (−11.7 ± 6.4 mm Hg) and 5 to 10 mg of amlodipine QD (−11.9 ± 6.9 mm Hg). SDBP was normalized to ≤90 mm Hg at week 12 in 66% of patients treated with mibefradil and 65% of those receiving amlodipine. The tolerability profile of mibefradil was superior to that of amlodipine, with significantly fewer patients ( P = 0.009) reporting leg edema after mibefradil treatment (7%) than after amlodipine treatment (17%). The results of this study confirm those of the previous trial. Once-daily treatment with mibefradil 50 to 100 mg for 12 weeks was as effective as 12 weeks of once-daily treatment with amlodipine 5 to 10 mg in reducing SDBP and was associated with a significantly lower incidence of leg edema.

Evidence for a histamine-component of the heart rate response to stellate ganglion stimulation.

Histamine exerts a positive chronotropic effect on the myocardium mediated by histamine H 2 -receptors. High concentrations of histamine are present in both myocardial tissue and the stellate ganglia which innervate the heart. Stimulation of the right stellate ganglion produces a positive chronotropic myocardial response. These associations suggest a possible neurotransmitter role for histamine. The present study examines the effect of histamine H 1 - and H 2 -receptor blockers on the myocardial chronotropic response to stellate ganglion stimulation and the coronary sinus histamine concentration following right stellate ganglion stimulation in dogs. Neither metiamide alone nor in combination with diphenhydramine diminished the positive chronotropic response to right stellate ganglion stimulation. However, when the animals were pretreated with propranolol to eliminate the β-adrenergic component of the response, metiamide decreased the positive chronotropic response to right stellate ganglion stimulation by 63% (p 2 -receptors, may mediate a portion of the positive chronotropic response to right stellate ganglion stimulation in the dog.