Metabolism and excretion of atorvastatin in rats and dogs.

Atorvastatin (AT) is a second-generation potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, clinically approved for lowering plasma cholesterol. Using a mixture of [D(5)/D(0)] AT and/or [(14)C]AT, the metabolic fate and excretion of AT were examined in rats and dogs following single and multiple oral doses. Limited biliary recycling was examined in one dog after a single dose of AT. AT-derived metabolites in bile samples were identified by metabolite screening of the [D(5)/D(0)] AT molecular clusters using tandem mass spectrometry. Bile was a major route of [(14)C] drug-derived excretion, accounting for 73 and 33% of the oral dose in the rat and dog, respectively. The remaining radioactivity was recovered in the feces; only trace amounts were excreted in urine. Radioactive components identified in rat and dog bile were the para- and ortho-hydroxy metabolites, a glucuronide conjugate of ortho-hydroxy AT, and unchanged AT. Two minor radioactive components were identified as beta-oxidation products of AT with one confirmed as a beta-oxidized AT derivative. The reappearance of AT and major metabolites in bile from a dog administered a sample of its previously excreted bile indicated biliary recycling is an important component in AT metabolism. Multiple dose administration in rats did not alter biliary metabolic profiles. Rat and dog plasma profiles after multiple dose administration were similar and showed no additional metabolites not found in bile. Examination of rat and dog bile and plasma indicates that AT primarily undergoes oxidative metabolism.     

Analysis of the action of idazoxan calls into question the reliability of the rat isolated small mesenteric artery assay as a predictor for α1-adrenoceptor-mediated pressor activity

We have studied the effects of idazoxan in rat aorta and small mesenteric artery. In the aorta, idazoxan behaved as a partial agonist (pK_A=6.30). Prazosin produced rightward shift (pA₂=9.88) and steepening of the idazoxan curve. In contrast, idazoxan had no effect of basal tension in the mesenteric artery, but shifted the noradrenaline curve to the right in a parallel manner (pA₂=6.12). The selective al-adrenoceptor agonist, indanidine, also behaved as a partial agonist in the aorta and produced no significant contractions of the small mesenteric artery. Since idazoxan and indanidine have been reported to raise blood pressure in the pithed rat via an action at vascular ₁-adrenoceptors, these results call into question the reliability of the small mesenteric artery assay as a predictor for ₁-adrenoceptor-mediated pressor activity in vivo.     

Cerebral blood flow velocity after mannitol infusion in children

Purpose

There is conflicting evidence as to whether the effect of mannitol on brain bulk arises from haemodynamic, rheologic, or osmotic mechanisms. If mannitol alters cerebral haemodynamics by inducing vasoconstriction, this change should be reflected in cerebral blood flow velocity (CBFV) in the middle cerebral artery (MCA). The purpose of this study was to evaluate the effect of mannitol on CBFV in children.

Methods

Children scheduled for intracranial surgery were enrolled. After a loading dose of 10 μg · kg^?1 of fentanyl, general anaesthesia was maintained with fentanyl (3 μg · kg^?1 · hr^?1), 66% nitrous oxide, and isoflurane (0.2–0.5% inspired). Mean and systolic CBFV (Vm and Vs) and pulsatility index (PI) were recorded with a transcranial Doppler (TCD) directed at the M1 segment of the MCA. Mannitol was administered, 1 gm · kg^?1 iv over 15 min. The osmolality (Osm), haematocrit (Hct), mean arterial pressure (MAP), heart rate (HR), and TCD variables were recorded before and 15, 30, 45, and 60 min after the mannitol infusion.

Results

Mannitol infusion resulted in an increase in Osm and decrease in Hct (P < 0.05). Heart rate, MAP and arterial carbon dioxide tensions did not change (P > 0.05) during the measuring period. The Vm did not vary from baseline. The Vs and P1 both increased briefly (P < 0.01 at 15 min and P < 0.05 at 30 min) after the mannitol, suggesting an increase in resistance distal to the MCA.

Conclusion

The time course of CBFV changes produced by mannitol corresponds with previous animal data concerning cerebrovascular tone. Our results suggest that mannitol briefly increases cerebrovascular resistance and thereby diminishes cerebral blood volume.     

Sequence analysis of herpes simplex virusgB gene homologs of two platyrrhine monkey α-herpesviruses

Summary Homologs of the herpes simplex virusgB gene were identified in two -herpesviruses of platyrrhine monkeys, Herpesvirus saimiri 1 (HVS 1) and H. ateles 1 (HVA 1). These genes were cloned and sequenced in their entirety. Analysis of the predicted amino acid sequences indicated that the gB glycoproteins of these two viruses are of similar size, have 10 Cys residues and 5 potential N-linked glycosylation sites which align exactly with those in other primate -herpesvirus gB polypeptides, and have a similar distribution of predicted secondary structural features, all of which indicate a conserved structure of the gB polypeptide. Alignment of these two gB sequences with those of four other primate -herpesviruses (SA 8, B virus, HSV 1 and HSV 2) revealed localized regions of extensive sequence divergence as well as highly conserved regions. On comparison of the six primate virus gB sequences, the gBs of the two platyrrhine monkey viruses form a subgroup separate from that of the four catarrhine virus gBs. The degree of relatedness of the HVA 1 and HVS 1 gB sequences to each other was equivalent to the degree of relatedness between the human and the cercopithecine monkey virus gB sequences.     

Digit repetition performance in patients with focal brain damage

Digit span forward and backward was investigated in well-matched samples of patients with discrete quadrant brain lesions. The incidence of significantly impaired digit repetition performance and the incidence of large forward and backward digit span discrepancies were also studied. Correlational data of digit span performance and various intellectual, memory, and constructional measures was examined. Approximately 60% of all brain-damaged patients showed an impairment of digit span forward, while only 5% showed a similar impairment on the digit span backward task. These data indicate that digit span forward is a more sensitive measure of brain dysfunction from focal brain lesions. No difference was found in the performance of patients with right or left hemisphere lesions; however, the low incidence of aphasia (8%) in this sample may account in part for the relatively adequate performance by the left hemisphere patients. Although the current data regarding visual constructive deficits and impaired ability to repeat digits backward is inconclusive, there did not appear to be a strong relationship between these two functions for these patients. Digit repetition performance does appear to be related to both general intellectual ability and to performance on the Wechsler Memory Scale.     

Tissue cultures from cerebrospinal fluid specimens in the study of human brain tumors.

The authors report a study in which 109 cerebrospinal fluid (CSF) specimens from patients with varying neurological disorders were incubated in tissue culture medium for 1, 3, and sometimes 7 days. Strict criteria for malignancy were applied to cells found at these intervals. In 35 patients with verified central nervous system neoplasms, eight cases had malignant cells and 11 others had "doubtful" cells by tissue-culture analysis. Thirty-three of these cases were also examined with standard millipore cytological techniques: six had malignant cells and four had "doubtful" cells. Of 50 cases with inflammatory or other non-neoplastic conditions, cells were cultured in 13. None was considered malignant by our criteria. Tissue culture of CSF has several potential benefits. Even with stringent criteria, it is possible to demonstrate the presence of unequivocally malignant cells in CSF by tissue culture. The systemic application of such criteria may eventually increase the positive identification of malignancies. Further, since these cells are growing, the degree of malignancy may be more accurately determined by a study of growth in culture. Such a study could not be done by conventional methods. Finally, tissue culture can help to guide therapy in certain instances in which a surgical biopsy cannot be obtained.     

Response to rubella immunisation education in health authority family planning clinics: a controlled clinical trial

The response of women attending family planning clinics run by the Area Health Authority providing health education on protection against rubella (cases), was compared with those attending clinics with no specific educational provision (controls). The effectiveness of the intervention was determined by studying the number of women approaching their General Practitioner in the ensuing four months for serological testing to determine their immune-status. Of 174 cases and 170 controls registered with a General Practitioner, follow-up information was obtained on 164 (94%) cases and 155 (91%) controls. General Practitioners' records revealed pre-existing knowledge of serologically confirmed immunity or previous rubella immunisation in only 35 (21%) cases and 29 (19%) controls. In response to health education, 12 (7%) cases approached their GP on the subject compared with 3 (2%) controls - a small but significant difference (P less than 0.05) which was confined to women aged 25-29 years. This suggests that such a programme would fail to make a significant contribution to the prevention of congenital rubella.