Evaluation of BTS 67 582, a novel antidiabetic agent, in normal and diabetic rats

1. The effect of BTS 67 582, a novel antidiabetic agent, has been evaluated on plasma glucose and plasma insulin in normal and streptozotocin-induced diabetic rats. 2. BTS 67 582 (3 to 300 mg kg-1, p.o.) caused a dose- and time-dependent reduction in plasma glucose and an increase in plasma insulin in both fasted and glucose-loaded normal rats. The ED50 for the glucose lowering effect of BTS 67 582 in fasted rats was 37.6, 18.4 and 18.5 mg kg-1 at 1, 2 and 4 h after administration respectively. 3. In streptozotocin-induced (50 mg kg-1, i.v.) diabetic rats, BTS 67 582 (37-147 mg kg-1, p.o.) caused significant reductions of plasma glucose following a glucose load, whereas glibenclamide (100 mg kg-1, p.o.) was ineffective. BTS 67 582 significantly increased plasma insulin compared to controls whereas glibenclamide did not. 4. BTS 67 582 did not displace [3H]-glibenclamide from its binding sites in rat brain, guinea-pig ventricle or the HIT-T15 insulinoma beta-cell line. BTS 67 582 does not therefore appear to modulate its action via an effect on the 'sulphonylurea' receptor. 5. In fasted rats, the glucose lowering effect of BTS 67 582 (100 mg kg-1 p.o.) and glibenclamide (1 mg kg-1, p.o.) were antagonized by diazoxide (30 mg kg-1, i.p.). In addition BTS 67 582, like glibenclamide, caused a dose-dependent rightward shift of cromakalim-induced relaxation of noradrenaline precontracted rat aortic strips, suggesting the involvement of KATP channels. 6. In summary, BTS 67 582 produces a blood glucose-lowering effect in normal and streptozotocin-induced diabetic rats associated with increased insulin concentrations. This effect appears to be due to a blockade of ATP-sensitive potassium channel activity via a different binding site to that of glibenclamide.     

Toxoplasma gondii alters eicosanoid release by human mononuclear phagocytes: role of leukotrienes in interferon gamma-induced antitoxoplasma activity

Toxoplasma gondii tachyzoites markedly alter the profile of eicosanoids released by human mononuclear phagocytes. Freshly isolated, 2-h adherent human monocytes release both cyclooxygenase (e.g., thromboxane [TX] B2, prostaglandin [PG] E2) and 5-lipoxygenase (e.g., leukotriene [LT] B4, LTC4) products of arachidonic acid metabolism after stimulation by the calcium ionophore A23187 or ingestion of opsonized zymosan particles or heat-killed T. gondii. However, after incubation with viable T. gondii, normal and chronic granulomatous disease monocytes release only the cyclooxygenase products TXB2 and PGE2 and fail to form LTB4, LTC4, or other 5-lipoxygenase products. Monocytes maintained in culture for 5 d lose this capacity to release TXB2 and PGE2 after incubation with T. gondii. T. gondii significantly inhibit calcium ionophore A23187-induced LTB4 release by monocyte-derived macrophages; heat-killed organisms do not affect this calcium ionophore A23187-induced release of LTB4. T. gondii-induced inhibition of LTB4 release by calcium ionophore A23187-stimulated monocyte-derived macrophage is reversed by interferon (IFN)-gamma treatment of the monolayers. LTB4 induced extensive damage to the cellular membranes and cytoplasmic contents of the organisms as observed by transmission electron microscopy. Exogenous LTB4 (10(-6) M) induced intracellular killing of ingested T. gondii by non-IFN-gamma-treated monocyte-derived macrophages. IFN-gamma-induced antitoxoplasma activity in monocyte-derived macrophages was inhibited by the selective 5-lipoxygenase inhibitor zileuton but not by the cyclooxygenase inhibitor indomethacin. These findings suggest a novel role for 5-lipoxygenase arachidonic acid products in human macrophage IFN-gamma-induced antitoxoplasma activity.     

Pentazocine fibrous myopathy: report of two cases and literature review

Two patients are described in whom the analgesic, pentazocine (Talwin), injected intramuscularly over long periods of time, resulted in a fibrous myopathy of the injected muscles. Although early testing of pentazocine indicated a low abuse potential and no skin or muscle complications, reports of such abuse and complications have since appeared in the literature, a review of which is included.     

Parathyroid hormone as a possible causal factor in osteopetrosis of the tl rat

The possibility of parathyroid dysfunction as a causal factor in the osteopetrosis of the tl rats was explored by evaluating serum calcium (Ca) and immunoreactive parathyroid hormone (iPTH) concentrations in this strain of rats, as compared with those of phenotypically normal littermate (LM) and non-littermate (NLM) control groups. The mean serum Ca concentration in the tl rat was not significantly different from that of the NLM group, although it was less than that of the LM group. However, all Ca values were within the normal range. The mean serum iPTH concentration in the tl rats was not significantly different from those of either control group. The data indicate that the adult tl rat has adequate but not excessive PTH secretion. Therefore, osteopetrosis and its manifestations in the adult tl are not caused by an abnormality of parathyroid function.     

Infrared spectrophotometric analysis of medicinal gases for trace impurities

The feasibility of examining medical gases for trace impurities, using an infrared spectrophotometer in conjunction with a 10 m gas cell, was investigated. Many of the impurities for which the USP includes limits were detected and measured at concentrations at or below those permitted by the USP; these include sulfur dioxide, carbon dioxide, carbon monoxide, and water. However, others (hydrogen sulfide, nitric oxide, and nitrogen dioxide) were not detected at these levels by this technique. Methane was found at low levels in some samples.     

Arterial prosthesis of microporous expanded polytetrafluoroethylene for construction of aorta-pulmonary shunts

A new arterial prosthesis made of polytetrafluoroethylene (OTFE) was evaluated in 10 infants with complex cyanotic congenital heart disease. All grafts used were 4 mm. in diameter and varied in length from 0.8 to 6 cm. The grafts were anastomosed to the main pulmonary artery or its bifurcation in 8 infants and to the right and left pulmonary arteries in one each. There were two early deaths, one of which was related to shunt failure. The advantages of a shunt to the main pulmonary artery are obvious, and the intraoperative procedure is facilitated with the prosthesis. Follow-up averages 9 months in the 8 survivors, and the patients have nearly doubled their preoperative weight. A shunt murmur is present in each case and the children have mild-to-moderate cyanosis at rest. Repeat aortograms in 2 patients, 8 and 10 months postoperatively, show a smooth graft without luminal narrowing. The aortic oxygen saturations were 73 per cent. The PTFE graft and/or anastomoses will not grow with the growth of the child and therefore may not accommodate growth by increased flow. This may prove to be a limiting factor in its long-term use in fants. We reserve the use of these grafts for infants with complex cyanotic defects undergoing emergency surgery or in older children in whom a conventional shunt is not possible or a previous shunt has failed.