Role of the neurotransmitter reuptake-blocking activity of antidepressants in reversing chloroquine resistance in vitro in Plasmodium falciparum.

Since the discovery of the chloroquine (CQ) resistance reversal properties of several different, structurally unrelated classes of compounds, including antidepressants, the way is again open to employ the aminoquinoline drugs to combat malaria effectively. In this study, CQ sensitivity was restored to varying extents in vitro in the CQ-resistant Plasmodium falciparum strain RSA11 by using the antidepressants amitriptyline, citalopram, oxaprotiline, and nomifensine. The 50% inhibitory concentrations (IC(50)) of CQ were reduced from 360 to as low as 11 nM when antidepressants were present. These particular antidepressants are highly specific for blocking the ATP-binding cassette transport protein-mediated reuptake of different neurotransmitters at the synaptic level. This study was aimed at determining the extent to which the neurotransmitter reuptake-blocking properties of these antidepressants play a role in the reversal process. None of the compounds or CQ-antidepressant combinations tested had innate antimalarial activity. No chemosensitizer or combination showed an increased CQ accumulation or significant shift in the IC(50) in the CQ-sensitive clone D10. Of the compounds tested, citalopram, a highly specific serotonin reuptake blocker, produced the largest shift observed in the IC(50) for the resistant isolate RSA11. No particular class of antidepressant was found to be better than any other at restoring CQ sensitivity. We conclude that the resistance-reversing properties of these compounds do not correlate with their activities as reuptake blockers.

An analysis of 17 catatonic patients diagnosed with neuroleptic malignant syndrome.

This study was conducted to show that catatonia is a predisposing factor for neuroleptic malignant syndrome (NMS) and to review the nosological relationship between catatonia and NMS. Seventeen consecutive cases of NMS were analyzed prospectively with reference to clinical and investigative findings before and after exposure to a neuroleptic. The series comprised eight males and nine females, ranging in age from 18 years to 65 years. Prior to neuroleptic exposure, all patients exhibited features compatible with criteria for catatonia (mutism/excitement) according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised, (DSM-III-R). Following neuroleptic administration (single dose in nine cases), patients deteriorated into a febrile, rigid, and obtunded state accompanied by autonomic dysfunction and raised creatine phosphokinase levels. These features were consistent with a diagnosis of NMS. Neuroleptics were discontinued and supportive medical treatment instituted. Benzodiazepines were beneficial in eight cases in relieving stupor, but bromocriptine and dantrolene were generally ineffective. In all patients diagnosed with NMS in the authors' series, catatonia was an invariable prodromal state. It appears that the administration of a neuroleptic intensified the preexisting catatonic state and precipitated a malignant variant of the disorder, which is currently recognized as NMS. The authors, therefore, challenge the separate nosological status of NMS and catatonia and suggest that these syndromes are part of a unitary pathophysiological disorder.

Catatonia: harbinger of the neuroleptic malignant syndrome.

Five consecutive cases of the NMS are presented, in all of which a catatonic state preceded the onset of the condition. Catatonia would appear to represent a highly significant risk factor for the NMS and a possible causal link between the two disorders is suggested.

Attitudes to adverse drug reactions and their reporting among medical practitioners.

The adverse drug reaction (ADR) reporting rate within the medical profession is exceptionally low, and doctors' approaches and attitudes to ADRs were explored through personal structured interviews. The total sample comprised 104 doctors in private practice, divided into three groups: 59 general practitioners, 26 medical specialists and 19 surgical specialists. Certain differences emerged between the groups. The surgical group observed far fewer ADRs than the other groups and not a single member had ever reported an ADR. A significantly larger number of medical specialists considered it necessary to report an ADR to an outside agency, while general practitioners tended to believe that only newly released medicines required ADR reporting. However, few doctors of any specialty regarded ADR reporting as part of the action they would take in their handling of ADRs in practice. The commonest explanation advanced for the marked underreporting of ADRs was that unusual or serious reactions were very infrequent and the common or trivial ones did not warrant reporting. Apathy and indifference were rated as the next most pertinent influence in non-compliance, while such factors as fear of personal consequences (e.g. criticism, medicolegal action) and uncertainty about what to report were deemed to be relatively unimportant.

Alprazolam--a new triazolobenzodiazepine.

The advent of another benzodiazepine, alprazolam (Xanor; Upjohn), is of interest because of the antidepressant properties which this agent seems to possess. A short résumé of the pharmacology of alprazolam is presented in an attempt to provide an early perspective on its place in therapeutics.

Effect of the H2-receptor antagonist ranitidine on depression and anxiety in duodenal ulcer patients.

Depression and anxiety were measured during the course of a double-blind, placebo-controlled trial of the histamine H2-receptor antagonist, ranitidine (150 mg twice daily), in patients suffering from duodenal ulcer but free of systemic disease. There were 25 patients in the ranitidine group (mean age: 33.2 years) and 28 in the placebo group (mean age: 37.2 years). In both groups there was a highly significant and progressive decrease in depression and anxiety scores over the 4 weeks of treatment. There were no instances of mental confusion. In our group of otherwise physically healthy patients, ranitidine appeared to be free of neuropsychiatric complications.

Apparent half-life of excretion of cannabinoids in man.

The apparent half-life of excretion of cannabinoids was calculated from their concentration in the urine of 27 psychotic patients. The best estimate was about 4 days but the range was too wide to be of use in predicting time to total clearance from the body of any randomly chosen patient.

The effect of disulfiram on the urinary excretion of catecholamine metabolites in alcoholic males.

The urinary excretion of vanillylmandelic acid (VMA), homovanillic acid (HVA) and total metanephrines (TMNs) was studied in a group of White male alcoholic patients under three experimental conditions--on admission and prior to treatment, after 7 days of administration of a placebo, and after 9 days of administration of disulfiram 400 mg/d Disulfiram caused a significant decrease in VMA levels compared with the pretreatment (P less than 0,01) and placebo (P less than 0,05) levels. The output of HVA and TMNs was unchanged. It is suggested that disulfiram may produce false-negative results in cases of suspected phaeochromocytoma if VMA levels only are assayed. TMNs would appear to be the measurement of choice in such a situation.

Cannabis-associated psychosis with hypomanic features.

The mental state of 20 psychotic men with high urinary cannabinoid levels on admission to a psychiatric hospital was compared with that of 20 matched cannabis-free controls. All patients underwent toxicological analysis to exclude the presence of alcohol and other exogenous agents. Cannabis levels were measured by a semiquantitative enzyme immunological technique and mental state was assessed by the use of the Present State Examination (PSE), once shortly after admission and again 7 days later. The cannabis group showed significantly more hypomania and agitation and significantly less affective flattening, auditory hallucinations, incoherence of speech, and hysteria than did the controls. Clouding of consciousness was absent in most cannabis patients. After 1 week the cannabis group showed marked improvement (particularly in the psychotic syndromes), whereas the controls remained virtually unchanged. There was no significant difference in amount of medication received between the two groups. Our data suggest that a high intake of cannabis may be related to a rapidly resolving psychosis manifesting with marked hypomanic features, though often presenting as a schizophrenia-like illness.

First-pass effect and intrinsic clearance of propranolol and pindolol in the isolated perfused rat liver.

This study investigated the first-pass effect (E) and total hepatic intrinsic clearance (Clint) of propranolol and pindolol by means of an isolated rat liver perfusion model. It was shown that propranolol has a highly significantly greater E and Clint than pindolol. These marked differences between the drugs may be accounted for by the strong initial binding of propranolol to liver sites, a phenomenon possibly related to the greater lipid solubility of propranolol compared with pindolol.

An unusual case of the Capgras syndrome.

A variant of the Capgras syndrome is described in a 43-year-old woman who had vitiligo and multinodular goitre. The unusual feature of the case was that the patient not only misidentified members of her own family but also claimed that she herself had been replaced by a double.