Sigma-Tau Pharmaceuticals (United States)

Highly Active Anti-Retroviral Therapy (HAART) has increased the lifespan of persons with HIV infection. As a result, HIV infection can now be thought of as a “chronic disease”. Though clearly beneficial, the use of HAART in persons with HIV infection or AIDS can result in mitochondrial abnormalities and dysfunction. Because HAART is toxic to the mitochondria, muscle endurance may be impaired in persons on HAART. PURPOSE: To test the hypothesis that muscle endurance is less in persons with HIV infection on HAART compared to those with HIV not on HAART. METHODS: Nine HAART (8 men, 1 woman) and 6 nonHAART (4 men, 2 women) performed regional submaximal isokinetic knee extension of the quadriceps (Biodex, 30 kicks/min, 50% peak torque, 120 degrees/s) and systemic cycle ergometer exercise (55% YMCA predicted max VO2) to task failure. Endurance time (ET) was the time to task failure and muscle fatigue was indicated by post-exercise peak force/pre-exercise peak force. Data were analyzed using unpaired t-tests. RESULTS: Data are mean ± SD. HAART and nonHAART subjects were of similar age (HAART = 43 ± 5 yr, nonHAART = 42 ± 5, p = 0.70). For the isokinetic exercise there was no difference in strength between groups (HAART = 539 ± 200 N, nonHAART = 422 ± 110, p = 0.21). Nevertheless, the group on HAART had a shorter ET compared to those not on HAART, (HAART = 165 ± 110s, nonHAART = 330 ± 164, p= 0.02). All participants fatigued to a similar end point (HAART = 75 ± 16 %, nonHAART = 82 ± 26, p = 0.50). Unlike the isokinetic exercise, cycling ET was similar in both groups (HAART = 8.2 ± 7.8 min, nonHAART = 10.5 ± 11.2, p = 0.66). CONCLUSIONS: HAART in persons with HIV infection results in decreased local muscle endurance consistent with decreased muscle oxidative capacity and mitochondrial impairment.

Adult, male Sprague-Dawley rats were injected with 3-ni-tropropionic acid (3-NPA) at 30 mg/kg or methamphetamine (METH) at 20 mg/kg alone or following pretreatment with L-cartnitine (LC) at 100 mg/kg. Rectal temperature was measured before and 4 h following treatment. Animals were sacrificed at 4 h posttreatment. Monoamine neurotransmitters, dopamine (DA) and serotonin (5-HT), and their metabolites were analyzed in the striatum using high-performance liquid chromatography method coupled with electrochemical detection (HPLC/ED). Transcripts of several genes related to DA metabolism were quantified using real time reverse transciption polymerase chain reaction (RT-PCR). Core temperature decreased significantly after 3-NPA acid and increased in METH-treated rats (P < 0.05). Temperature change at 4 h exhibited a significant LC effect for 3-NPA, preventing hypothermia (P < 0.05) and no effect for METH. Concentration of DA and 5-HT, and their metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), increased significantly in 3-NPA and decreased in METH-treated rats. An increase in DOPAC/DA turnover and serotonin observed after 3-NPA was abolished in LC-/3-NPA-treated rats. In both 3-NPA- and METH-treated rats, LC prevented an increase in DA receptor D(1) gene expression. It appears that carnitine effect preventing hypothermia after 3-NPA treatments may be related not only to its mitochondriotropic actions but also to inhibitory effect on the DA and 5-HT systems activated after the exposure to 3-NPA. The same effect observed at the transcriptional level, at least for the DA receptor D(1), may account for protection against METH toxicity.

Inactivation of CEACAM1 in L-SACC1 mice by a dominant-negative transgene in liver impairs insulin clearance and increases serum free fatty acid (FFA) levels, resulting in insulin resistance. The contribution of elevated FFAs in the pathogenesis of insulin resistance is herein investigated. Treatment of L-SACC1 female mice with carnitine restored plasma FFA content. Concomitantly, it normalized insulin levels without directly regulating receptor-mediated insulin internalization and prevented glucose tolerance in these mice. Similarly, treatment with nicotinic acid, a lipolysis inhibitor, restored insulin-stimulated receptor uptake in L-SACC1 mice. Taken together, these data suggest that chronic elevation in plasma FFAs levels contributes to the regulation of insulin metabolism and action in L-SACC1 mice.