Pharmacokinetic drug interactions of vinca alkaloids: summary of case reports

Involvement of the cytochrome P450 (CYP) 3A subfamily in the metabolism of vincristine is well established. However, information is limited regarding vincristine's drug interaction profile. All the substrates and inhibitors of CYP3A4 such as the azole antifungals (itraconazole, ketoconazole), cyclosporine, isoniazid, and nifedipine have very high propensity to interfere with vincristine metabolism. The proposed mechanism is most likely attributed to either inhibition of 3A4 enzymes or blockade of P-glycoprotein pumps. These interactions are clinically significant and can lead to severe vincristine toxicity if not detected. Although case reports discussed here exclusively involve vincristine, it is important to assume that all vinca alkaloids interact in the same manner until proved otherwise, because they share similar metabolism pathways.     

Visual system maldevelopment disrupts extraocular muscle-specific myosin expression

We measured hepatic albumin synthesis in five volunteers (4 men and 1 woman) at 3 and 6 h after recovery from intense exercise. A primed-constant infusion of a stable isotopic tracer of phenylalanine was used to determine hepatic fractional synthetic rate (FSR) and absolute synthetic rate (ASR) of albumin from the enrichment of phenylalanine in albumin. The infusion of the stable isotope tracer began 2 h after upright exercise or upright rest. Albumin FSR and ASR were 6.39 +/- 0.48%/day and 120 +/- 9 mg.kg body wt-1.day-1, respectively, 3-6 h after recovery from exercise; the FSR and ASR on the time control study day were 5.94 +/- 0.47%/day and 104 +/- 9 mg.kg body wt-1.day-1, respectively. The 6 and 16% increases (P < 0.05) in FSR and ASR after exercise were associated with an elevated plasma albumin content at 5 and 6 h of recovery (P < 0.05), an increased total protein content throughout recovery (P < 0.05), and a negative free water clearance (P < 0.05) at 2, 3, and 6.5 h of recovery compared with baseline values; these variables were unchanged from their baselines on the time control study day. Increased albumin content and reduced free water clearance contribute to a retention of fluid within the circulation after intense exercise. The measured increase in albumin synthesis could not account for the entire increase in albumin content at 6 h of recovery from exercise. However, we estimate that if the increased activity was maintained for the next 18 h, it could account for the expected increase in albumin content at 24 h of recovery.     

Psychoneuroendocrinology of anxiety disorders

This article focuses on neuroendocrine measures in anxiety disorders and their relationships to neurotransmitter and neuroendocrine function. In particular, the hypothalamic-pituitary-somatotropin and the hypothalamic-pituitary-adrenal (HPA) axes are emphasized, and a role for extrahypothalamic corticotropin releasing factor is proposed. Additional neuroactive hormones are also considered. A nonhuman primate model of anxiety is discussed in terms of its neuroendocrine relevance. And, throughout, a hypothetical functional-anatomic model for anxiety and panic is proposed using the findings of cognitive neuroscience fear research. Finally, an effort is made to synthesize existing psychoneuroendocrinologic data into a current conceptualization of the pathophysiology of anxiety disorders.     

Thrombolysis for stroke

The fate of 89 patients with meningomyelocele operated at the Institute of Orthopedics and Rehabilitation in Poznań between 1970 and 1989 due to paretic deformities of lower extremities has been traced by the authors. Deformities prevented nursing, standing or ambulating; their type and results of treatment have been related to the level of neurosegmental lesion. Modified Sharrard's classification served to group the patients. The level of lesion established during lower extremities muscles testing has been verified after neurological examination supplemented with electrophysiological tests: sensory response within L3-S2 dermatomes, afferent conduction velocity of the peroneal nerve and selected muscles of lower extremity electromyogram. Deformities due to inadequate nursing (hip and knee contractures and equinus foot) were the main obstacle in the rehabilitation in patients with spinal Th12-L2 lesion. In patients with L3-L5 lesion hip contractures were accompanied by dislocation or subluxation of the hip due to muscular imbalance. Knee contracture was less frequent in this group and foot deformities were diverse. Surgical correction of paretic deformity of the hip was the last stage of management designed to promote rehabilitation, following previous foot and knee surgery. In patients with Th12-L2 lesion recurrence of contractures made standing and walking impossible. In patients with L3-L5 neurosegmental lesion surgery for paretic dislocation or subluxation of the hip inclusive of open reduction, varus-derotation osteotomy of the proximal femur, transiliac osteotomy and iliopsoas transfer to the greater trochanter according to Mustard resulted in stable hip. Seventy percent of patients with L3-L4 lesion and all patients with L5 lesion profited from hip surgery with reduced orthotic use and effective gait.     

Inhibition of in vitro replication of the oyster parasite Perkinsus marinus by the natural iron chelators transferrin, lactoferrin, and desferrioxamine

The mammalian iron-binding proteins transferrin and lactoferrin, the bactericidal peptide lactoferricin B, and the bacterial siderophore desferrioxamine were tested for their ability to inhibit the in vitro replication of the oyster parasite Perkinsus marinus. All three chelators were effective in reducing the parasite proliferation in a dose-dependent manner. Lactoferricin B, a peptide of lactoferrin that exhibits bactericidal properties unrelated to iron chelation, had no inhibitory activity on the parasite. When the chelators were partially or completely saturated with the appropriate iron equivalents, their inhibitory effects on the parasite proliferation were diminished or abolished accordingly, confirming that this activity was related to the chelator's capacity for iron sequestration. Our results indicate that the parasite has a strong requirement for soluble iron and its growth rates are correlated with iron availability. We propose that excess iron accumulation in the host Crassostrea virginica promotes parasite proliferation. P. marinus may avoid oxidative damage that would compromise its intracellular survival by exhaustion the host's intracellular selected iron pools required for superoxide and hydroxyl radical production.     

Enhanced T-cell immunogenicity and protective efficacy of a human immunodeficiency virus type 1 vaccine regimen consisting of consecutive priming with DNA and boosting with recombinant fowlpox virus

The induction of human immunodeficiency virus (HIV)-specific T-cell responses is widely seen as critical to the development of effective immunity to HIV type 1 (HIV-1). Plasmid DNA and recombinant fowlpox virus (rFPV) vaccines are among the most promising safe HIV-1 vaccine candidates. However, the immunity induced by either vaccine alone may be insufficient to provide durable protection against HIV-1 infection. We evaluated a consecutive immunization strategy involving priming with DNA and boosting with rFPV vaccines encoding common HIV-1 antigens. In mice, this approach induced greater HIV-1-specific immunity than either vector alone and protected mice from challenge with a recombinant vaccinia virus expressing HIV-1 antigens. In macaques, a dramatic boosting effect on DNA vaccine-primed HIV-1-specific helper and cytotoxic T-lymphocyte responses, but a decline in HIV-1 antibody titers, was observed following rFPV immunization. The vaccine regimen protected macaques from an intravenous HIV-1 challenge, with the resistance most likely mediated by T-cell responses. These studies suggest a safe strategy for the enhanced generation of T-cell-mediated protective immunity to HIV-1.     

Cytotoxicity of bile in human Hep G2 cells and in primary cultures of rat hepatocytes

There has been increasing interest in the development of a hepatocyte bioreactor for the treatment of acute hepatic failure; however, little is known about the effect of hepatocyte byproducts on the viability of the cells in the bioreactor environment. We investigated the effects of increasing concentrations of bile on the growth and viability of the human hepatoma cell line Hep G2 and on the cytochrome P-450 content and dependent mixed function oxidase (MFO) activities, reduced glutathione (GSH) content, and glutathione S-transferase (GST) activity of primary cultures of rat hepatocytes. Our purpose was to determine whether or not it would be necessary to pretreat the plasma from patients with acute liver failure to remove elevated bile concentrations which might be toxic to the hepatocytes in an artificial liver device. Bile was found to inhibit Hep G2 cell growth at concentrations as low as 0.1% and to decrease viability at concentrations above 0.5%. The cytochrome P-450 and GSH contents and the activities of the MFO system and of GST were decreased in the primary cultures of hepatocytes following 24 h treatment with concentrations of bile at and above 0.5%. The MFO activities associated with different cytochrome P-450 isoenzymes decreased to different extents in the presence of bile with the O-dealkylation of pentoxyresorufin being more labile than that of ethoxyresorufin. Our data indicate that elevated bile concentrations are cytotoxic to liver cells, and it may be necessary to pretreat patient plasma to decrease its bile content to protect the cells during the clinical operation of a hepatocyte bioreactor device.