The bisdichloroacetyldiamine WIN 18,446 reversibly inhibits spermatogenesis in many species, including humans; however, the mechanism by which WIN 18,446 functions is unknown. As retinoic acid is essential for spermatogenesis, we hypothesized that WIN 18,446 might inhibit retinoic acid biosynthesis from retinol (vitamin A) within the testes by inhibiting the enzyme aldehyde dehydrogenase 1a2 (ALDH1a2). We studied the effect of WIN 18,446 on ALDH1a2 enzyme activity in vitro, and on spermatogenesis and fertility in vivo, in mature male rabbits for 16 weeks. WIN 18,446 markedly inhibited ALDH1a2 enzyme activity in vitro with an IC50 of 0.3 μM. In vivo, the oral administration of 200 mg/kg WIN 18,446 to male rabbits for 16 weeks significantly reduced intratesticular concentrations of retinoic acid, severely impaired spermatogenesis, and caused infertility. Reduced concentrations of intratesticular retinoic acid were apparent after only 4 weeks of treatment and preceded the decrease in sperm counts and the loss of mature germ cells in tissue samples. Sperm counts and fertility recovered after treatment was discontinued. These findings demonstrate that bisdichloroacetyldiamines such as WIN 18,446 reversibly suppress spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2. These findings suggest that ALDH1a2 is a promising target for the development of a reversible, nonhormonal male contraceptive.
SUMMARY We studied regional blood flow (QR) using radiolabeled microspheres and measured hemodynamic variables in 20 anesthetized dogs in normal sinus rhythm and during ventricular fibrillation treated with cardiopulmonary resuscitation (CPR). Nonsimultaneous compression and ventilation CPR (NSCV-CPR) was performed in seven dogs with a pneumatic piston that gave 50 chest compressions/min with an open airway with 10 ventilations at an airway pressure of 33 mm Hg interposed between each fifth and sixth compression. Simultaneous compression and ventilation (SCV-CPR) was performed in seven dogs with the piston and in six other dogs with a circumferential pneumatic vest. Both devices gave 30 compressions/min simultaneously with 30 ventilations that elevated airway pressure to 80 mm Hg. The abdomen was bound during SCV-CPR. Regional blood flow (mean SD) to the cerebral hemispheres, cardiac ventricles, and kidneys, expressed as ml/min/100 g tissue, was 3.1 + 4.0, 3.4 3.3 and 1.5 1.5, respectively, during NSCV-CPR; 11.5 + 5.9, 4.9 4.7 and 2.7 2.7 during SCV-CPR (vest); and 16.2 + 7.2, 11.0 4.0 and 20.1 20.2 during SCV-CPR (piston) (all p < 0.05 compared with NSCV-CPR). These results indicate that QR to all organs studied is reduced below normal sinus rhythm levels during CPR for ventricular fibrillation, QR to the brain is proportionately greater than QR to the heart and kidneys, and QR to the brain is greater with both forms of SCV-CPR than with NSCV-CPR.BECAUSE cardiopulmonary arrest is one of the greatest stresses the body can suffer, the success of cardiopulmonary resuscitation (CPR) depends upon maintaining vital organ perfusion at a level consistent with full recovery of function after resuscitation. Conventional or nonsimultaneous ventilation and compression CPR (NSCV-CPR) fibrillation (VF) treated with NSCV-CPR and two forms of SCV-CPR. MethodsTwenty adult mongrel dogs, mean weight 23.7 kg, unselected for chest configuration, were studied. Anesthesia was induced with thiopental sodium (1 g) and maintained with ketamine (mean dose 0.6 + 0.3 g; mean time of administration after thiopental 89 + 44 minutes). The dogs were intubated with an endotracheal tube, the proximal end of which extended 2-4 cm outside the mouth. The cuff was inflated to achieve an airtight seal; the exact amount of air inserted was not measured.
Both intranasal midazolam and sufentanil provide rapid, safe, and effective sedation in small children before anesthesia for ambulatory surgery. Sufentanil provided somewhat better conditions for induction and emergence. Midazolam causes more nasal irritation during instillation, and sufentanil causes more postoperative nausea and vomiting. Both drugs enabled patients to be separated from their parents with a minimum of distress. Patients in the midazolam group were discharged approximately 40 minutes earlier (p <0.005).
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