Pooled analysis of three large clinical trials to determine the optimal dose of dolasetron mesylate needed to prevent postoperative nausea and vomiting. The Dolasetron Prophylaxis Study Group.

STUDY OBJECTIVE: To identify the maximally effective dolasetron dose (i.e., maximum efficacy with minimum adverse events) for prevention of postoperative nausea and vomiting (PONV) using the statistical power generated in a pooled patient sample from three large, nearly identical clinical trials. DESIGN: Three randomized, multicenter, placebo-controlled, double-blinded trials. SETTING: Trials 1, 2, and 3 enrolled patients at 10, 25, and 17 hospitals and/or surgical centers, respectively. PATIENTS: A total of 1,946 ASA physical status, I, II, and III patients. Trials 1 and 2 enrolled only female patients (n = 916) undergoing gynecologic surgery. Trial three enrolled 722 females (approximately 70% gynecologic surgeries) and 308 males (approximately 46% orthopedic surgeries) undergoing a variety of surgical procedures. INTERVENTIONS: All surgical procedures used balanced general anesthesia. Patients received 12.5, 25, 50, or 100 mg of the antiemetic, dolasetron, near the end of anesthesia. MEASUREMENTS AND MAIN RESULTS: Efficacy endpoints were identical and measured for 24 hours: complete response (no vomiting or rescue medication) and maximum nausea, reported using a 100-mm visual analog scale (VAS). Safety was assessed using adverse event reports, laboratory and electrocardiographic data, and vital signs. All four dolasetron doses produced significant increases in complete response and decreases in maximum VAS nausea compared with placebo (p < 0.01). No increased efficacy was observed with dolasetron doses higher than 12.5 mg. Safety was similar between each dolasetron dose and placebo. CONCLUSION: Dolasetron 12.5 mg, given near the end of anesthesia, is the maximally effective dose studied for preventing postoperative nausea and vomiting.

Rationale for the use of a single fixed intravenous dolasetron dose for the prevention of cisplatin-induced nausea and vomiting. Pooled analysis of 14 clinical trials.

Dolasetron mesilate is a selective 5-HT3 receptor antagonist that prevents chemotherapy-induced and postoperative nausea and vomiting. For the majority of patients in intravenous dolasetron trials for chemotherapy-induced nausea and vomiting, dosing has been based on body weight (mg/kg). The approved weight-based dose is 1.8 mg/kg based on results of controlled clinical trials. However, trials of dolasetron evaluating oral doses for prevention of chemotherapy-induced emesis, and intravenous doses for prevention and treatment of postoperative emesis have used a fixed milligram dose. To identify an appropriate intravenous fixed milligram dose for the prevention of chemotherapy-induced nausea and vomiting, this analysis was performed to derive efficacy results for fixed milligram doses from pooled results obtained with dosing based on body weight. Intravenous dolasetron doses for 1,598 patients treated on a mg/kg basis (0.3, 0.6, 1.2, 1.8, 2.4, 3.0 and 5.0 mg/kg) in 14 clinical trials were converted to fixed milligram doses based on weight. Fixed-dose groups were established at doses of 50, 75, 100, 125, 150, and 200 mg. Doses less than or equal to the midpoint between two dose groups were included in the lower dose group. Pooled results showed that the 100 mg intravenous dolasetron dose group (who received actual doses of 88-112 mg) produced the highest rate (53%) of complete response (0 emetic episodes and no rescue medication in the 24-h period following initiation of chemotherapy).

Generation of fractals from incursive automata, digital diffusion and wave equation systems.

This paper describes modelling tools for formal systems design in the fields of information and physical systems. The concept and method of incursion and hyperincursion are first applied to the fractal machine, an hyperincursive cellular automata with sequential computations with exclusive or where time plays a central role. Simulations show the generation of fractal patterns. The computation is incursive, for inclusive recursion, in the sense that an automaton is computed at future time t + 1 as a function of its neighbouring automata at the present and/or past time steps but also at future time t + 1. The hyperincursion is an incursion when several values can be generated for each time step. External incursive inputs cannot be transformed to recursion. This is really a practical example of the final cause of Aristotle. Internal incursive inputs defined at the future time can be transformed to recursive inputs by self-reference defining then a self-referential system. A particular case of self-reference with the fractal machine shows a non deterministic hyperincursive field. The concepts of incursion and hyperincursion can be related to the theory of hypersets where a set includes itself. Secondly, the incursion is applied to generate fractals with different scaling symmetries. This is used to generate the same fractal at different scales like the box counting method for computing a fractal dimension. The simulation of fractals with an initial condition given by pictures is shown to be a process similar to a hologram. Interference of the pictures with some symmetry gives rise to complex patterns. This method is also used to generate fractal interlacing. Thirdly, it is shown that fractals can also be generated from digital diffusion and wave equations, that is to say from the modulo N of their finite difference equations with integer coefficients.

Pharmacokinetics of tinidazole in chronic renal failure and in patients on haemodialysis.

The pharmacokinetics of tinidazole after infusion (800 mg in 15 min) were studied in 12 patients with chronic renal failure (RI) and in five patients undergoing regular dialysis treatment (RD). Tinidazole elimination plasma half-life was 15.09 +/- 0.68 h (mean +/- s.e. mean) (RI) and 12.9 +/- 1.0 h after dialysis (RD), but there was a significant decrease in half-life during dialysis (4.25 +/- 0.43 h) P less than 0.001). The apparent volume of distribution (0.64 +/- 0.03 l/kg) was equal to extra and intracellular water volume and tinidazole was little bound to plasma protein (8%). There was a slight sex difference in apparent volume of distribution between male patients (0.70 +/- 0.09 l/kg) and female patients (0.59 +/- 0.10 l/kg) (P = 0.07), but as body clearance decreases in the same order, there was no modification of plasma half-life. In renal failure, pharmacokinetics of tinidazole were not disturbed because no correlation between half-life, body clearance and creatinine clearance occurred; urine elimination was about 7% of administered dose. Plasma clearance during dialysis was 49.9 +/- 3.2 ml/min and about 43% of the available drug was eliminated during the 6 h dialysis procedure. These results suggest that an additional half-dose infusion should be given after the end of dialysis in patients undergoing regular dialysis treatment.

Molecular model of postsynaptic potential.

A molecular model of the excitatory postsynaptic membrane is given in terms of two biochemical cycles intimately associated: an acetylcholine cycle and a calcium cycle. The acetylcholine controls the Na ionophores while calcium ions control the tk ionophore. The two ionophores are spatially separated but interact in such a way that the variation in K conductance precedes that in Na conductance. Digital simulation shows that our model accounts quantitatively for both the evolution of excitatory postsynaptic potential and current in a variety of experimental conditions.

A molecular model of action potentials.

A QUANTITATIVELY CONSISTENT MODEL OF NERVE ACTIVITY IS GIVEN IN TERMS OF TWO MAIN BIOCHEMICAL CYCLES NARROWLY INTERLOCKED: an acetylcholine cycle and a calcium cycle. The activity of both cycles is controlled among other things by the electric field and various allosteric effectors. As shown by digital simulations our model accounts for the basic properties of an action potential as described by the electrophysiologists. Thus the shape, time course, and behavior under voltage clamping conditions of both sodium and potassium permeability variations are adequately reproduced.