Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques.

The reverse transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) was previously found to offer strong prophylactic and therapeutic benefits in an infant macaque model of pediatric human immunodeficiency virus (HIV) infection. We now summarize the toxicity and safety of PMPA in these studies. When a range of PMPA doses (4 to 30 mg/kg of body weight administered subcutaneously once daily) was administered to 39 infant macaques for a short period of time (range, 1 day to 12 weeks), no adverse effects on their health or growth were observed; this included a subset of 12 animals which were monitored for more than 2 years. In contrast, daily administration of a high dose of PMPA (30 mg/kg subcutaneously) for prolonged periods of time (>8 to 21 months) to 13 animals resulted in a Fanconi-like syndrome (proximal renal tubular disorder) with glucosuria, aminoaciduria, hypophosphatemia, growth restriction, bone pathology (osteomalacia), and reduced clearance of PMPA. The adverse effects were reversible or were alleviated following either complete withdrawal of PMPA treatment or reduction of the daily regimen from 30 mg/kg to 2.5 to 10 mg/kg subcutaneously. Finally, to evaluate the safety of a prolonged low-dose treatment regimen, two newborn macaques were started on a 10-mg/kg/day subcutaneous regimen; these animals are healthy and have normal bone density and growth after 5 years of daily treatment. In conclusion, our findings suggest that chronic daily administration of a high dose of PMPA results in adverse effects on kidney and bone, while short-term administration of relatively high doses and prolonged low-dose administration are safe.

Anesthetic management in feline renal transplantation.

OBJECTIVE: To document perioperative and anesthetic management of 30 feline renal transplant recipients (1996-1998). STUDY DESIGN: Retrospective clinical study. ANIMALS: Thirty adult cats in end-stage renal failure that underwent heterotopic renal transplantation. MATERIALS AND METHODS: The medical records were reviewed from 30 feline heterotopic renal transplant recipients. Cases were included only if they had been treated for hypertension using a beta-adrenergic antagonist, a calcium channel blocker or hemodialysis. Data regarding signalment, preoperative management, surgical technique, type and doses of anesthetics administered, perioperative hemodynamics and intra- and postoperative complications, postoperative analgesia, morbidity and early mortality were recorded. Data were expressed as mean ± SD. RESULTS: Preanesthetic medication included a combination of an anticholinergic and an opioid (oxymorphone). Anesthesia induction was performed mostly with isoflurane and oxygen delivered by mask. Anesthesia maintenance was primarily achieved with isoflurane in 100% oxygen. Nitrous oxide was often used as part of the anesthetic technique. The mean duration of anesthesia was 4.6 hours ± 27 minutes. The mean renal allograft ischemic time was 60 minutes. During the anesthetic period, the majority of the recipient cats received either fresh whole blood (FWB) (N = 25, 83%), cross-matched packed red blood cells (PRBC) (N = 3, 10%) or fresh frozen plasma (FFP) (N = 2, 7%) combined with a balanced electrolyte solution. Blood products administered averaged 63 ± 34 mL and crystalloid 94 ± 62 mL. The most common treated intraoperative complications were hypotension (N = 14, 47%), hypothermia (N = 13, 43%), metabolic acidosis (N = 11, 37%), hypocalcemia (N = 5, 17%), hypoglycemia (N = 4, 13%), hypertension (N = 2, 7%), bradycardia (N = 1, 3%), and ventricular premature contractions (N = 1, 3%). All cats received opioid analgesics postoperatively. Complications observed in the first 24 hours postoperatively were hypertension (N = 20, 67%), hematuria (N = 14, 47%), electrolyte disturbances (N = 9, 30%), temperature imbalances (N = 5, 17%), decreased PCV requiring blood transfusion (N = 5, 17%), decreased perfusion of a foot associated with external iliac anastomosis technique (N = 5, 17%), seizures associated with hypertension (N = 3, 10%), uroabdomen (N = 2, 7%), acute graft rejection (N = 1, 3%) and, corneal ulceration (N = 1, 3%). Survival rates in the perioperative period were 100, 96.7, and 93.4% intraoperatively, at 24 hours, and 7 days following surgery. CONCLUSION: Successful anesthesia can be performed in critically ill renal transplant recipients. However, for optimal graft function and patient survival, normothermia, normovolemia, normotension, and normal acid-base and electrolyte balance should be carefully maintained. Successful anesthetic management requires understanding of the pathophysiology of end-stage renal disease and the maintenance of homeostasis during the different stages of the perioperative period.