The effect of cimetidine on anesthetic metabolism and toxicity

Because the H2-receptor antagonist cimetidine has been shown to inhibit drug metabolism, the effects of cimetidine on anesthetic metabolism and toxicity were investigated in a rat model. Cimetidine decreased inorganic plasma fluoride production after methoxyflurane administration both in 21% oxygen (P less than 0.001) and in 100% oxygen (P less than 0.001). Phenobarbital produces an increased fluoride formation after methoxyflurane anesthesia, and this fluoride formation is also reduced by cimetidine (P less than 0.005). There was no significant difference between the plasma fluoride levels in rats anesthetized with halothane or enflurane. Although cimetidine inhibited the in vivo defluorination of methoxyflurane, fluoride levels were still within the nephrotoxic range, and cimetidine is not likely to play a role as part of a preanesthetic regimen that would permit the increased clinical use of methoxyflurane. Cimetidine also inhibited the oxidative metabolism of halothane; cimetidine decreased (P less than 0.05) trifluoroacetic acid concentrations after halothane anesthesia in 21% oxygen and in 100% oxygen and decreased (P less than 0.05) bromide concentrations after halothane anesthesia in 100% oxygen. Trifluoroacetic acid levels were less (P less than 0.02) after halothane anesthesia in 14% oxygen as compared with 100% oxygen, indicating a reduction in oxidative metabolism under hypoxic conditions. However, bromide concentrations were maximal after halothane anesthesia in 21% oxygen, and significantly (P less than 0.001) less after halothane anesthesia in 14% and 100% oxygen. Bromide production, therefore, seems to be inhibited by both hypoxia and hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Onchocerca gutturosa and O. volvulus: studies on the viability and drug responses of cryopreserved adult worms in vitro

The viability and drug responses of cryopreserved adult Onchocerca have been examined in vitro. Male worms were cryopreserved in liquid nitrogen (-196 degrees C) using ethanediol as a cryoprotectant in a 2-step incubation procedure. After thawing, 85-90% of O. gutturosa males were normally motile. These motile worms were evaluated for viability using 4 measurements (long-term motility/survival in culture; [U-14C]adenine uptake and leakage; glucose utilization; MTT-formazan colorimetry) and were no different from unfrozen controls. Subsequent experiments demonstrated that the motility responses of cryopreserved worms exposed to the antifilarial drugs ivermectin, CGP 6140 and levamisole were virtually identical to unfrozen controls. Some success was also obtained with this technique in cryopreserving O. volvulus males, with 2 thawed specimens surviving in culture for 93 and 106 d respectively. Following collagenase isolation, female worms were cryopreserved in medium +10% serum without protectant at -79 degrees C. A batch of 8 female O. gutturosa were all motile when thawed 14 d later, with a mean survival time (based on 5 specimens) of 71 d (range 60-90). However, a batch of worms transferred from -79 degrees C to -196 degrees C were badly damaged when thawed. Female O. volvulus were cryopreserved at -79 degrees C in Guatemala and sent by air freight on solid CO2 to the UK. Most specimens were active when thawed. Survival of motile specimens ranged from 7 to 272 d in culture. It is concluded that these techniques are of practical value for the storage and transportation of adult Onchocerca.     

Transplantation for adults with congenital heart disease.

Heart transplantation is a recognised treatment for end-stage heart failure of any cause including congenital heart disease. Congenital heart disease has contributed relatively little to the adult heart transplant activities in the past two decades. However, this is likely to change as an increasing number of children with congenital heart disease reach adulthood because of the advances in paediatric cardiology and surgery. Some of these grown-ups with congenital heart disease (GUCH patients) will need transplantation for late myocardial dysfunction either secondary to uncorrected lesions, or despite previous repair or palliative surgery. These patients are managed along the same clinical principles as those with cardiac failure of other aetiologies, despite the lack of any evidence to support this approach. Nevertheless, they introduce new challenges. First, some may have pulmonary vascular disease and require heart-lung transplantation, or lung transplantation combined with repair of their cardiac defects. Second, those with failing Fontan circulation are usually much sicker than other transplant candidates, with protein-losing enteropathy along with renal and hepatic dysfunction. Third, a suitable donor organ may not be found due to elevated levels of antibodies in response to previous blood transfusions and possibly the previous implantation of homografts. Fourth, the operation may be technically difficult because of the presence of adhesions secondary to previous operations, collaterals, and unusual anatomy. Fifth, postoperative care may be complicated because of predisposition to bleeding, infection and pulmonary hypertension, and the presence of residual aortopulmonary collaterals resulting in a significant left-to-right shunt. Despite a higher early mortality, the overall results of heart transplantation so far have been encouraging with survivals similar to that of adults with acquired heart disease and that of the paediatric population. However, this may change as the proportion of high-risk patients (failing Fontans) increases. GUCH patients with Eisenmenger's syndrome may be offered lung transplantation with repair of the cardiac defect or heart-lung transplantation. However, because of the limited success of these approaches, and improved management of pulmonary hypertension, patient selection remains difficult.