Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep

Abstract— Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0·45 ± 0·05 L h^?1 kg^?1), distribution volume (4·4 ± 2·0 L kg^?1), mean residence time (9·6 ± 4·1 h) and half-life (12·1 ± 3·1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26·3 mg kg^?1, but was curvilinear above this dose. Abomasal bioavailability at 6·4 mg kg^?1 was 0·26 ± 0·09, and mean absorption time was 4·7 ± 11·1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.     

Circulating endothelial cell/leucocyte adhesion molecules in ischaemic heart disease

Increased levels of the endothelial markers soluble E-selectin ( P  = 0.011), soluble thrombomodulin ( P  = 0.0001) and von Willebrand factor (VWF, P  < 0.0001) were found in 116 patients with ischaemic heart disease compared to an equal number of age- and sex-matched asymptomatic controls. In a multivariate analysis of the markers versus the major risk factors for atherosclerosis, VWF correlated with total cholesterol ( P  = 0.002) and E-selectin with sex (lower in women, P  = 0.004) and triglycerides ( P  = 0.007). The data point to profound differences in the release mechanisms of these three endothelial cell products and suggests that further studies into the roles of these molecules in coronary artery disease are warranted.     

Silent pulmonary embolism in patients with deep venous thrombosis. Incidence and fate in a randomized,controlled trial of anticoagulation versus no anticoagulation

Abstract. Objectives . A high frequency of asymptomatic pulmonary embolism (PE) in patients with deep venous thrombosis (DVT) has been reported, but information about the outcome of the patients with PE remains sparse. The aims of the present study were to assess the prevalence of silent PE in patients with symptomatic, venographically proven DVT, and to evaluate the natural history of silent PE. Design . Consecutive patients from one centre of primary care were included in a randomized, open study with blinded control. All patients gave written, informed consent. Subjects . Eighty-seven consecutive patients with venographically proven DVT and with a perfusionventilation lung scintigraphy performed within 48 h of the DVT diagnosis were included. On the 10th and 60th days the lung scintigraphy was repeated in 80 and 60 patients, respectively. All the patients were followed for 3 months in the out-patient clinic. Interventions . All patients were ambulated from the first day and were allocated randomly to no anticoagulant (non-AC) therapy or to AC therapy with intravenous heparin infusion for at least 6 days and oral AC therapy for 3 months. Results . Forty-three of these patients had a high probability lung scintigraphy for PE. Distal vein and femoral vein thrombosis embolized in 33 and 53% of patients, respectively. The progression rate after 60 days was 3% in both the AC and the non-AC group and after 10 days the rates were 13 and 8%, respectively. Conclusions . A high frequency of silent PE in patients with DVT both above and below the knee is demonstrated. AC treatment did not influence the resolution rate of PE or the rate of clinical PE in a 3-month follow-up period.     

A New Pacemaker Algorithm for Continuous Capture Verification and Automatic Threshold Determination: Elimination of Pacemaker Afterpotential Utilizing a Triphasic Charge Balancing System

A new pacemaker algorithm designed to automatically verify pacemaker capture and determine pacing threshold by detection of a stimulus evoked potential was studied in 20 patients undergoing permanent pacemaker implantation. To eliminate pacing stimulus afterpotential and detect an evoked response, a hardware feedback circuit and a software template matching algorithm were used to produce a triphasic charge-balanced pacing pulse. After charge balancing the pacing lead, a residual artifact is measured. A capture window is defined as the area integral of the first 24 msec of the evoked depolarization, and a capture threshold as one third the amplitude of the capture window. The maximum allowable residual artifact is one eighth the amplitude of the capture window. Once the stimulus afterpotential is eliminated and the evoked response detected, capture threshold is automatically and continuously determined and the algorithm adds a 0.8-V safety margin to the pacemaker output. This algorithm was run automatically and after simulated loss of capture, produced by manually decreasing pacer output below threshold, in the bipolar (13 patients) and unipolar (20 patients) pacing modes. In each patient loss of capture was immediately detected. The data were consistent (P = NS) between algorithm runs. During unipolar pacing the area integral of the first 24 msec of the evoked response was 412 +/- 137 versus 413 +/- 144 and the residual artifact 5.8 +/- 4.8 versus 8.1 +/- 7.5. The resulting ratio (signal/noise) of the two parameters was 150 +/- 141 versus 145 +/- 181. Automatically determined threshold was 0.69 +/- 0.43 V versus 0.69 +/- 0.42.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sodium Nitroprusside Enhances Contractions of the Guinea-pig Isolated Vas Deferens

The effects of sodium nitroprusside on the electrical and mechanical properties of the smooth muscle of the guinea-pig vas deferens, and its responses to transmitter substances, have been investigated by use of the sucrose-gap technique. Isolated longitudinal segments of guinea-pig vas deferens contracted in response to electrical field stimulation (100 V, 0.04–0.1 ms, 1–5 Hz, 10 s train every 60 s) and application of ATP (1 mM) or noradrenaline (10 μM). Sodium nitroprusside (0.1 mM) did not affect resting tension but did enhance contractions evoked by electric-field stimulation but not by ATP or noradrenaline. The sodium nitroprusside-induced enhancement was unaffected by the nitric oxide synthase inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) (0.1 mM). Conversely, electrically evoked contractions were unaffected by the nitric oxide precursor L-arginine (1 mM) or the nitric oxide donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) (0.1 mM). The amplitudes of electrically evoked excitatory junction potentials (EJPs) were not affected by application of sodium nitroprusside, although it caused a small depolarization of 0.7 ± 0.3 mV. Similarly, the depolarization caused by exogenous application of ATP or noradrenaline was unaffected by the presence of sodium nitroprusside. L-NAME, L-arginine and SNAP did not affect EJP amplitude or baseline membrane potential. It is concluded that sodium nitroprusside enhances electrically evoked contractions of the guinea-pig vas deferens by reducing the threshold voltage for action potential firing in smooth-muscle cells.