Evaluation of amphotericin B-cyclosporine interaction in the rat

Although a significant interaction between cyclosporine and amphotericin-B (AmpB) has been observed clinically, these findings have not been duplicated in animal studies. A total of 64 male albino rats were used in single- and multiple-dose experiments with AmpB and CsA in the absence or presence of systemic Candida infection. No significant differences in glomerular filtration rate were found in rats given single i.v. doses of AmpB 1 mg/kg compared with AmpB and CsA. Furthermore, rats given i.p. AmpB 1 mg/kg and CsA 10 mg/kg daily for 10 days showed no significant differences in GFR compared with animals given CsA alone. Morphology and CsA whole-blood pharmacokinetics were not different between groups administered single-dose CsA, AmpB, or the combination; similarities also existed with multiple-dose studies. In an attempt to mimic the clinical setting, 2 groups of rats were administered i.p. CsA 10 mg/kg/day for 10 days followed by inoculation of Candida albicans. After 48 hr, a single i.v. dose of AmpB 1.0 mg/kg was associated with a 33% decline in GFR compared with those given sterile water (P less than 0.05). Systemic clearance of CsA was markedly reduced in candidiasis rats administered AmpB compared with controls given sterile water. A significant reduction in renal Candida colony-forming units was found in rats given CsA and AmpB compared with those administered CsA alone. These data suggest that the presence of systemic Candida highlights the interaction of CsA and AmpB in the rat model.     

The search for a physiologic marker of Machado-Joseph disease

Machado-Joseph disease is a dominantly inherited, multisystem, degenerative disorder that lacks a proven genetic marker. Peripheral nerve conduction-refractory period, sensory evoked potentials, and quantified oculomotor recordings were studied in nine patients affected with this disease to look for a potential physiologic marker. Only the oculomotor measurements of saccade and smooth pursuit gain were consistently abnormal in all patients. Identical eye movement recordings in 12 asymptomatic individuals at risk for Machado-Joseph disease revealed findings typical of affected patients in only 1 individual. Quantified oculomotor studies may contribute to the early confirmation of the disease, primarily in individuals at risk with minor or equivocal neurologic signs.     

The effect of naloxone on the preoperative gastric volume and pH

The effect of 4 mg oral naloxone on preoperative gastric volume and pH of gastric aspirate was studied in a double-blind, randomized study. Twenty patients received 10 ml of naloxone (4 mg) mixed with 10 ml of orange juice, and 20 patients received 10 ml of isotonic saline mixed with 10 ml of orange juice, 2 h before surgery. Gastric content was obtained immediately after intubation of the trachea. No significant difference in gastric volume and pH of gastric aspirate was found between the two groups. It is concluded that naloxone does not affect gastric emptying and gastric acid secretion to a degree great enough to protect against aspiration of gastric contents into the lungs.     

Modulating role of dopamine on anesthetic requirements

The influence of dopamine on halothane anesthetic requirements was determined in mice. Halothane anesthetic requirement was defined as the minimum anesthetic concentration (MAC) that prevented 50% animals from moving in response to a supramaximal stimulus. Levodopa (L-DOPA) dose-dependently decreased halothane MAC to a maximum of 49% of control; over the same dose range L-DOPA increased striatal dopamine nearly 4-fold. The MAC-reducing effect of L-DOPA was attenuated by selective antagonism of the D2 dopamine receptor with YM-09151-2 while selective blockade of the D1 dopamine receptor with SCH-23390 did not alter L-DOPA's effect on the MAC for halothane. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreased striatal dopamine by 82% and increased the MAC for halothane by 27%. Repletion of striatal dopamine with L-DOPA, in MPTP-treated mice, restored the MAC for halothane back to the control state. The regression line derived from the plot of halothane MAC versus striatal dopamine content shows a highly significant correlation between the two variables (r2 = 0.94). These are the first results to suggest that anesthetic requirements can be modulated directly and precisely by increasing or decreasing the content of a single neurotransmitter in the central nervous system.     

Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B

Clinical studies suggest that deprenyl may retard the progression of Parkinson's disease, an effect that may be related to its monoamine oxidase (MAO) inhibiting properties. Deprenyl also protects against the neurodegenerative effects of the noradrenergic toxin DSP-4. In this study we investigated the role of MAO B inhibition in this protection. C57BL/6 mice were given DSP-4 (50 mg/kg i.p.) 1 h. 24 h or 4 days after the administration of deprenyl (10 mg/kg i.p.) or the selective MAO B inhibitor MDL 72974 (1.25 mg/kg), and then killed 1 week later for assay of hippocampal norepinephrine. The MAO B inhibiting effects of deprenyl or MDL 72974 were also determined after these same intervals of time. Deprenyl and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (greater than 95%), 24 h (greater than 90%) or 4 days (greater than 70%) after their administration. Given 1 h before, deprenyl totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between deprenyl and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, we detected no activity using DSP-4 as a substrate for MAO. These findings suggest that the ability of deprenyl to protect against DSP-4-induced neuronal degeneration may not depend on its MAO B inhibiting properties.     

Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys

Systemic administration of the recently discovered neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces severe clinical parkinsonism and degeneration of the substantia nigra in humans and monkeys. In previous studies, no convincing structural damage to nerve cells outside the substantia nigra could be demonstrated in subhuman primates. Using a protracted MPTP regimen and older animals, we now report locus ceruleus lesions and eosinophilic inclusion bodies in squirrel monkeys. The inclusions were seen only in areas where Lewy bodies are found in human Parkinson's disease. No such abnormalities were seen in control animals. These findings suggest that similarities between the neuropathology of MPTP-induced parkinsonism in the monkey and human Parkinson's disease are greater than first thought and increase the usefulness of the MPTP monkey model for research in Parkinson's disease.     

Pulmonary vascular changes associated with prolonged prostaglandin E1 treatment

Prostaglandin E's (PGEs) are used therapeutically in newborn infants to maintain an open ductus arteriosus when there is obstruction to systemic or pulmonary arterial blood flow. These prostaglandins have been shown to have other systemic physiologic effects, such as vasodilation, inhibition of platelet aggregation, and enhancement of chemotactic-factor-mediated polymorphonuclear leukocyte infiltration, with resultant loss of lysosomal granules and possibly the generation of free radicals. We have recently seen previously unreported vascular lesions in 3 infants with hypoplastic left heart syndrome treated with usual therapeutic doses of PGE1 for prolonged periods. At autopsy, pulmonary vascular changes reflecting increased flow were present in each infant. One infant had a necrotizing vasculitis, sometimes associated with infarcts, in the lungs and in small muscular arteries in other organs. The form and severity of the vascular changes appear to be related to the duration of PGE1 administration.     

Malignant Melanoma of Soft Parts Involving the Head and Neck Region: Review of Literature and Case Report

Malignant melanoma of soft parts (MMSP) was originally described as a distinct entity by Enzinger in 1965 and was termed “clear cell sarcoma of tendons and aponeuroses” because of its association with tenosynovial structures. It has been shown immunophenotypically and ultrastructurally that this tumor is derived from neuroectoderm and shares a number of features with cutaneous melanoma. Over 95% of MMSPs present in the extremities, with the head and neck region (1.9%) being an unusual site. This study presents an additional case of MMSP of the head and neck region involving the posterior cervical region in a 15-year-old Hispanic male and reviews the literature on MMSP. Ultrastructural examination showed rudimentary cell attachments, smooth cell membranes, discontinuous basal lamina, scanty glycogen, and occasional premelanosomes in some tumor cells. Cytogenetic analysis showed a reciprocal translocation between the long arms of chromosomes 12 and 22 [t(12:22)(q13;q12.2)], characteristic for MMSP and not seen in cutaneous melanoma. Survival in MMSP has been correlated with tumor size, tumor necrosis, and ploidy status. Overall reported clinical outcome for this tumor is as follows: died of disease, 45%; alive with disease, 23%; no evidence of disease, 30%; and died of other causes, 2%. MMSP represents a distinct entity with a characteristic ultrastructural appearance and a tumor defining cytogenetic translocation.