Clinical implications of imipramine plasma levels for depressive illness.

Sixty depressed nonschizophrenic patients were admitted to a research unit. Following one drug-free week and one week of placebo, patients received 3.5 mg/kg of imipramine hydrochloride for 28 days. Plasma levels of imipramine and its metabolite desipramine hydrochloride (desmethylimipramine) were measured three times weekly and the relationship between plasma steady-state levels and clinical outcome was examined. Steady-state levels ranged from 50 to 1,050 ng/ml. There was a statistically and clinically significant relationship between plasma levels and response. The relationship existed across the entire sample, and was accentuated when the bipolar and unipolar nondelusional populations were examined. Because a strong relationship between sex and outcome was observed, the unipolar nondelusional patients were stratified by sex and a significant relationship still persisted. Only the unipolar delusional patients failed to demonstrate an association between blood level and clinical response.

Depression, Delusions, and Drug Response.

Depressed patients with delusions were found to be markedly unresponsive to tricyclic drug therapy during an ongoing study of depressed patients. After four weeks of administration of imipramine hydrochloride, only 3 of 13 delusional depressed patients had responded to the drug, but 14 of 21 nondelusional depressed patients had responded. The authors conclude on the basis of these data and those of other researchers that delusional depressed patients should not be treated with tricyclic antidepressants and that current research with depressed patients should be reevaluated in the light of this finding.

Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective.

From a genetic standpoint, humans living today are Stone Age hunter-gatherers displaced through time to a world that differs from that for which our genetic constitution was selected. Unlike evolutionary maladaptation, our current discordance has little effect on reproductive success; rather it acts as a potent promoter of chronic illnesses: atherosclerosis, essential hypertension, many cancers, diabetes mellitus, and obesity among others. These diseases are the results of interaction between genetically controlled biochemical processes and a myriad of biocultural influences--lifestyle factors--that include nutrition, exercise, and exposure to noxious substances. Although our genes have hardly changed, our culture has been transformed almost beyond recognition during the past 10,000 years, especially since the Industrial Revolution. There is increasing evidence that the resulting mismatch fosters "diseases of civilization" that together cause 75 percent of all deaths in Western nations, but that are rare among persons whose lifeways reflect those of our preagricultural ancestors.

[The use of nebivolol for the treatment of hypertension in patients with osteoarthrosis]. / Vozmozhnosti terapii nebivololom éssentsial'noi arterial'noi gipertenzii u bol'nykh s soputstvuiushchim osteoartrozom.

Nebivolol (5 mg/day) was given for 3 months to 20 patients with essential hypertension and osteoarthrosis treated with diclofenac and to 20 other patients with essential hypertension. After 3 months lowering of blood pressure, decreases of components of 24-hour blood pressure profile, improvements of signs of left ventricular hypertrophy occurred in both groups. There were no significant differences between changes of parameters studied between 2 groups. Thus diclofenac (nonselective cyclooxygenase inhibitor) did not attenuate antihypertensive effect of nebivolol and its action on left ventricular hypertrophy.

Improved method for determination of light filth in chocolate products.

The recovery of rodent hairs from chocolate has been significantly improved by the introduction of an additional defatting step, substitution of 40% isopropanol for water, and substitution of mineral oil-heptane (85+15) for heptane in the trapping-off step. These changes have no adverse effect on insect fragment recovery. An average recovery of 95% was obtained for rodent hairs, coefficient of variation 7.9%. Insect fragment recoveries were 100%.

Rhabdomyolysis complicating rapid intramuscular neuroleptization.

A case of rhabdomyolysis is described, with onset following three intramuscular injections of loxapine and one injection of benztropine over a 7-hour period. The possible additive effects of intramuscular drug administration and psychotic episode-associated increased muscle membrane permeability are discussed. Because of the risk of acute renal failure following rhabdomyolysis, monitoring of creatine phosphokinase levels and urine tests for myoglobin are recommended for patients who develop muscular discomfort, nausea, or confusion while receiving frequent intramuscular injections of neuroleptics.

Plasma haloperidol and clinical response: a role for reduced haloperidol in antipsychotic activity?

Seventeen hospitalized psychotic patients were treated with a fixed oral dose of haloperidol, 5 mg twice daily for 28 days. Most were chronic schizophrenics with an acute exacerbation of their illness. All patients also received benztropine 3 mg twice daily during the last 11 days of the study, regardless of the presence or absence of extrapyramidal side effects. No significant linear or curvilinear relationship was found between steady state plasma levels of haloperidol and clinical response measured by total Brief Psychiatric Rating Scale score. At 28 days, the correlations between plasma levels and percent improvement were rs = 0.187 (not significant) for haloperidol and rs = 0.582 (p = 0.04) for the hydroxymetabolite, reduced haloperidol. The correlation for the sum was rs = 0.511 (p = 0.078). Metabolite levels were substantially higher than plasma haloperidol, on the average 2.7 times greater. Eleven days of benztropine treatment had no significant effect on haloperidol or metabolite plasma levels or on clinical status. At the end of the study, nine of 17 patients (53%) had recovered as judged by discharge readiness. Within the limitations implied by the small number of patients, these data suggest that reduced haloperidol is an important component of plasma antipsychotic activity and cannot be neglected in correlative studies, and that a substantial proportion of patients--about half--can be successfully treated with only 10 mg of haloperidol. The routine use of large doses is thus not necessary for many patients.

Plasma levels of imipramine in depression. Environmental and genetic factors.

On the basis of tentative evidence obtained with 26 patients with unipolar affective illness, the variability in the response to imipramine is mostly due to interindividual differences in hydroxylating microsomal enzymes which are genetically controlled but whose activities are subject to modification by environmental factors such as overall pharmacological exposure and tobacco smoking. Additional significant pharmacodynamic variability (twofold) was found in the range of the volumes of distribution of imipramine in the patients. Clinical outcome was unequivocally related to plasma level. Unipolar nondelusional patients with levels less than 180 ng/ml had a low probability of recovery, while levels above 180 ng/ml were assoicated with a high probability of recovery. Unlike the findings of investigators working with nortriptyline, our data do not suggest an upper limit on plasma levels beyond which clinical response deteriorates. It appears that, on the basis of family studies, similar genetic characteristics are related to the ones controlling the pharmacodynamics will be the subject of further examination in our continuing studies.