Pilot ascending dose tolerance study of parenterally administered 4-(2 hydroxyethyl)-1-piperazine ethane sulfonic acid (TVZ-7) in dogs

We report a pilot toxicity study in healthy beagle dogs which revealed no significant adverse events for TVZ-7 given at i.v. doses up to 520 mg/kg/day. All treated dogs displayed calm behavior and maintained normal clinical laboratory values throughout the study. Increased bone marrow hypercellularity and extramedullary hematopoiesis was also noted in these dogs. Three other dogs with advanced spontaneously occurring tumors have also been dosed. No serious adverse events were reported in any of the dogs. This pilot study suggests that 4-(2 Hydroxyethyl)-1-piperazine ethane sulfonic acid may be used safely in planned human clinical trials.     

The anaesthetist as determinant factor of quality of surgical antimicrobial prophylaxis. A survey in a university hospital.

In actual surgical antimicrobial prophylaxis, the anaesthetist administers the drugs at induction of anaesthesia. In the first phase of our qualityofuse intervention study on antimicrobial drugs in a large university hospital, information on the practice of antimicrobial prophylaxis was needed. The staff of 44 anaesthetists was interviewed by means of a questionnaire. Response rate was 36/44 (82%). The anaesthetists' method of administering surgical prophylaxis was rather uniform and inexpensive: cephalosporins were almost exclusively administered by bolus method. The main reason was that infusion was more cumbersome (range 7785%). Communication between surgeon and anaesthetist was reported to be poor, and in two out of three operating departments, orders of prophylaxis transmitted at or after induction accounted for more than 80%. Seventyseven percent of the responders asked the surgeon if prophylaxis was necessary if they were in doubt; 20% responded that they checked it systematically. The data collected by the inquiry proved useful in the process of optimizing surgical prophylaxis in our hospital.     

Synthesis of bioactive coatings on Ti substrates using glass enamel

Bioactive coatings on titanium can be prepared by dispersing hydroxyapatite particles into a borosilicate glass enamel doped with TiO2. Adhesion of the coating is obtained when the titanium substrate has been preoxidized before enameling in such a way as to form a continuous TiO2-layer. Adhesion results from the diffusion of this TiO2-layer into the liquid glass during enameling. The evolution of the diffusion zone was followed by scanning electron microscopy and electron probe microanalysis. Adhesion disappears after a critical time of firing which corresponds to the completion of the dissolution of the TiO2-layer by the glass. The borosilicate glass wets the hydroxyapatite particles and adheres strongly to them after cooling.     

Signalling through the insulin receptor and the insulin-like growth factor-I receptor

The insulin receptor and the insulin-like growth factor I receptor belong to the family of tyrosine kinase receptors. Both receptors appear as a disulphide-linked dimer; each half of the dimer consisting of a 130 k M_r -subunit linked to a 90 k M_r -subunit. Both halves of the dimer are linked together by disulphide bonds to form an _{2 2} structure. The insulin receptor functions as an allosteric enzyme in which the binding of the hormone to the -subunit leads to a series of conformational changes resulting in activation of the -subunit tyrosine kinase. Upon multisite autophosphorylation the latter becomes competent to phosphorylate cellular substrates resulting in the biological responses of insulin. Recent findings have recognized the mitogen activated protein kinase cascade as a central signalling circuitry linking cell surface receptors, such as the insulin receptor, to the nucleus, and playing a role in regulation of metabolism, growth and differentiation.     

Impact of clinical pharmacokinetics on neuroleptic therapy in patients with schizophrenia.

This review covers some recent work on: 1. The effects of route of administration on the pharmacokinetics of fluphenazine and some of its metabolites; 2. The clinical pharmacokinetics of fluphenazine in acute patients medicated with oral fluphenazine; 3. The clinical pharmacokinetics of haloperidol in acute patients medicated with oral haloperidol; 4. The clinical pharmacokinetics of fluphenazine in the maintenance of individuals with chronic schizophrenia with fluphenazine decanoate; 5. A systematic dose reduction study in maintenance treatment refractory patients with oral haloperidol. A study in which plasma levels of fluphenazine and fluphenazine sulfoxide were measured in a group of DSM-III-R patients with schizophrenia before and after switching from oral fluphenazine to depot fluphenazine, decanoate revealed much higher levels of fluphenazine sulfoxide with oral medication compared with those found with depot fluphenazine. These data illustrate the effect of "first pass" metabolism after oral fluphenazine. Thus in a group of 33 patients randomly assigned to receive 5 mg, 10 mg or 25 mg oral fluphenazine daily, steady state plasma fluphenazine levels at each dose were significantly lower that those of fluphenazine sulfoxide or 7-hydroxy-fluphenazine, although there were no significant differences between the levels of fluphenazine and fluphenazine N4-oxide. On the other hand, plasma levels of the parent drug were significantly higher than those of any metabolite in a corresponding group of patients at steady state on depot medication. These observations underscore the importance of route dependent differences in the pharmacokinetics of fluphenazine which can lead to problems when switching patients from oral to depot neuroleptics. The concept of "disabling side-effects" is an important development in understanding relationships between plasma levels of neuroleptic drugs and clinical response in patients with schizophrenia. Risk-benefit analysis shows clearly that evaluation of relationships between plasma levels and clinical response must take into account the consequences of side-effects which the patient feels have a negating effect on therapy. Emerging data on putative therapeutic plasma level ranges in maintenance therapy are potentially important and may be particularly useful in the maintenance of patients on low dose therapy. It is noteworthy that in a carefully executed dose reduction study in treatment resistant patients under medication with haloperidol, the mean lowest effective dose (8.7 ng/mL) lay within the optimal therapeutic range (5 ng/mL to 12 ng/mL) found in acutely psychotic patients. The study showed that gradual dose reduction of neuroleptic was possible in chronic treatment resistant patients with schizophrenia who were originally thought by ward staff to require high doses of neuroleptic.(ABSTRACT TRUNCATED AT 400 WORDS)     

Rest and treadmill exercise first-pass radionuclide ventriculography: Validation of left ventricular ejection fraction measurements

Background

To assess the accuracy of rest and treadmill exercise first-pass radionuclide ventriculographic measurements of left ventricular ejection fraction (LVEF), 40 patients underwent treadmill exercise first-pass and bicycle exercise equilibrium radionuclide ventriculography. To determine the frequency of technically adequate treadmill exercise first-pass studies, an additional 128 consecutive patients undergoing treadmill exercise first-pass procedures during stress^99mTc-labeled sestamibi myocardial perfusion studies were assessed.

Methods and Results

The treadmill exercise first-pass procedure used a multicrystal camera and an²⁴¹Am point source to allow for correction of patient motion. Excellent correlations were observed between resting first-pass and resting equilibrium LVEF (r=0.91; standard error of the estimate=5.6). A high correlation was also observed between treadmill exercise first-pass and bicycle equilibrium exercise LVEF measurements (r=0.85, standard error of the estimate=7.6). Treadmill first-pass LVEF systematically underestimated the bicycle equilibrium LVEF. Intraobserver agreement for rest and exercise first-pass LVEF was high (r values of 0.98 and 0.94, respectively). Of the 168 consecutive treadmill exercise first-pass studies evaluated for technical adequacy, 21 (12.5%) were deemed technically inadequate, with most of the sources of error being avoidable. The frequency of technically adequate studies was as high (87%) in high levels of exercise (Bruce stages 3 and 4) as in lower levels (88%). The findings of this study validate the first-pass treadmill exercise LVEF measurement.

Conclusion

This procedure now provides the option for combining the information of peak treadmill exercise LVEF with measurements of exercise myocardial perfusion from the same injection of radioactivity.     

Decrease of mucosal glutamine concentration in the nutritionally depleted patient

A diminished glutamine delivery by peripheral tissues is suggested to play an important role in the etiology of postoperative complications of nutritionally depleted patients. Decreased glutamine supply to the gut mucosa in these nutritionally depleted patients may have important consequences for the integrity of the gut mucosa barrier. To evaluate whether glutamine concentration in the gut mucosa of depleted patients is altered, patients with either a fat-free mass index below 90% or percentage ideal body weight below 90% as a result of weight loss were studied. 22 patients admitted to the University Hospital Maastricht and 14 controls were studied. After an overnight fast, venous blood was sampled and duodenal biopsies were obtained by endoscopy. Plasma and tissue amino acids were measured. Fat-free mass was determined by bioelectrical impedance measurement. In 10 depleted patients glutamine concentration in the duodenal mucosa was 2883 +/- 250 mumol/kg dry weight. Concentration of alanine was 2570 +/- 263 mumol/kg dry weight. In the non-depleted patients glutamine and alanine concentrations were respectively 3463 +/- 171 mumol/kg dry weight and 3540 +/- 315 mumol/kg dry weight. Concentrations in controls were 3296 +/- 176 mumol/kg dry weight for glutamine and 3682 +/- 372 mumol/kg dry weight for alanine. Concentrations for alanine and glutamine were significantly lower in depleted patients compared to non-depleted patients (p < 0.05). Also, alanine and glutamine concentrations were significantly correlated with percentage ideal body weight (r=0.43, p < 0.005 for glutamine and r=0.62, p < 0.001 for alanine) and fat-free mass index (r=0.42, p < 0.05 for glutamine and r=0.48, p < 0.01 for alanine) This study suggests that in patients depletion appears to be related to decreased plasma and mucosa glutamine and alanine concentrations.