Pharmacology of N-desmethylclozapine

Currently available treatments for schizophrenia have limited efficacy and are generally poorly tolerated. However, among these antipsychotic agents, clozapine stands apart in having generally superior motoric tolerability and efficacy. One intriguing possibility, based on clinical correlations, receptor activity profiles and studies with animal models predictive of antipsychotic or cognitive action is that the activity of N-desmethylclozapine (NDMC), a major metabolite of clozapine, may, at least in part, underlie the unique efficacy of clozapine. In this review we compare the pharmacological properties of NDMC to those of clozapine and consider how they may contribute to the overall clinical properties of clozapine. We also consider whether NDMC, in its own right, might be a superior antipsychotic drug.     

Differential regulation of muscarinic M1 receptors by orthosteric and allosteric ligands

Allosteric modulation of membrane receptors is a widespread mechanism by which endogenous and exogenous agents regulate receptor function. For example, several members of the nicotinic receptor family are modulated by physiological concentrations of extracellular calcium ions. In this paper, we examined conformational changes underlying this modulation and compare these with changes evoked by ACh. Two sets of residues in the α7 acetylcholine receptor extracellular domain were mutated to cysteine and analyzed by measuring the rates of modification by the thiol-specific reagent 2-aminoethylmethane thiosulfonate. Using Ba²⁺ as a surrogate for Ca²⁺, we found a divalent-dependent decrease the modification rates of cysteine substitutions at M³⁷ and M⁴⁰, residues at which rates were also slowed by ACh. In contrast, Ba²⁺ had no significant effect at N⁵²C, a residue where ACh increased the rate of modification. Thus divalent modulators cause some but not all of the conformational effects elicited by agonist. Cysteine substitution of either of two glutamates (E⁴⁴ or E¹⁷²), thought to participate in the divalent cation binding site, caused a loss of allosteric modulation, yet Ba²⁺ still had a significant effect on modification rates of these residues. In addition, the effect of Ba²⁺ at these residues did not appear to be due to direct occlusion. Our data demonstrate that modulation by divalent cations involves substantial conformational changes in the receptor extracellular domain. Our evidence also suggests the modulation occurs via a binding site distinct from one which includes either (or both) of the conserved glutamates at E⁴⁴ or E¹⁷².     

Dual use of Veterans Affairs services and use of recommended ambulatory care

BACKGROUND: Use of more than one health care system to obtain care is common among adults receiving care within the Veterans Affairs (VA) medical system. It is not known what effect using care from multiple sources has on the quality of care patients receive. OBJECTIVES: To examine whether use of recommended ambulatory care services differs between exclusive and dual VA users. METHODS: Cross-sectional analysis of the 2004 Behavior Risk Factor Surveillance System, a nationally-representative survey of community-dwelling adults aged 18 years or older. Our outcome measures were self-reported use of 18 recommended services for cancer prevention, cardiovascular risk reduction, diabetes management, and infectious disease prevention. We used multivariable logistic regression to examine the association between exclusive and dual VA use and use of recommended ambulatory services. RESULTS: There were 3470 exclusive VA users and 4523 dual VA users. Dual users were significantly more likely to be older and white, have higher incomes, have graduated from college, and be insured when compared with exclusive VA users. In unadjusted analyses, dual users received higher rates of recommended services. After adjustment for patient characteristics, use of recommended services was largely similar among exclusive and dual VA users. Exclusive VA users reported 14% greater use of breast cancer screening and 10% greater use of cholesterol monitoring among patients with hypercholesterolemia, and 6% lower use of prostate cancer screening and 7% lower use of influenza vaccination. CONCLUSIONS: After adjustment for patient characteristics, exclusive and dual VA users reported similar rates of recommended ambulatory service use.     

Pericardial effusion diagnosed by echocardiography. Clinical and electrocardiographic findings in 171 patients

Clinical and electrocardiographic findings in 171 patients with pericardial effusion diagnosed by echocardiographic studies were reviewed. In 70 patients the effusion was unsuspected. There were 87 small, 50 moderate, and 31 large effusions. Cardiac tamponade was present in three patients. Congestive heart failure was the most common cause of pericardial effusion and occurred in 37 patients. Other frequently noted conditions included cardiac disease without congestive heart failure, neoplasms, acute nonspecific pericarditis, renal failure, and acute myocardial infarction. A pericardial friction rub was present in 23 patients, two-thirds of whom had moderate or large effusions. Atrial arrhythmias were common. Low voltage occurred in 31 of 136 patients and was more common with large effusions. The ability to distinguish between a small effusion and the quantity of pericardial fluid present normally is a problem requiring further clarification.