Activity of 6-methyl-8-substituted ergolines against the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma.

The ability of a series of 8-beta-carboxamido ergolines, 8-formamido ergolines, and 8-methyl ergolines to cause regressions of established dimethylbenz[a]anthracene-induced mammary carcinomas was compared to some ergot alkaloids. Although most of the ergoline derivatives depressed serum prolactin concentrations in rats, only a few had pronounced effects against the dimethylbenz[a]anthracene-induced mammary carcinoma in rats. Some derivatives from each of the three groups of substituted ergolines gave comparable activities against the dimethylbenz[a]anthracene-induced mammary carcinoma.

Structure-activity relationships of dimeric Catharanthus alkaloids. 1. Deacetylvinblastine amide (vindesine) sulfate.

Exploration of the effects of "minor" structural differences on the antitumor activity and toxicity of dimeric Catharanthus alkaloids resulted in the preparation of deacetylvinblastine amide (vindesine, VDS) from either vinblastine (VLB) or deacetylvinblastine. Adequate amounts of vindesine for biological testing were prepared by preferential hydrazinolysis of the C23-ester in the vindoline moiety of VLB, followed by hydrogenolysis of the resulting deacetylvinblastine hydrazide. Vindesine in its activity spectrum against rodent tumor systems resembles vincristine (VCR) rather than its parent VLB, while its neurotoxic potential appears to be less than that of VCR. The experimental models developed to estimate this potential include in vitro measurements of axoplasmic transport effects in the cat sciatic nerve and the estimation of neuromuscular disturbances in chickens and monkeys by vindesine in comparison with VCR. A radioimmunoassay for VLB, VCR, and VDS, developed by means of deacetylvinblastine acid azide, has been used to study the pharmacokinetics of vindesine in man. The clinical investigation of vindesine is in progress. Deacetylvinblastine, in contrast to earlier reports, showed activity against several murine tumor systems.

Molecular biology of mycotoxin biosynthesis.

Mycotoxins are secondary metabolites produced by many important phytopathogenic and food spoilage fungi including Aspergillus, Fusarium and Penicillium species. The toxicity of four of the most agriculturally important mycotoxins (the trichothecenes, and the polyketide-derived mycotoxins; aflatoxins, fumonisins and sterigmatocystin) are discussed and their chemical structure described. The steps involved in the biosynthesis of aflatoxin and sterigmatocystin and the experimental techniques used in the cloning and molecular characterisation of the genes involved in the pathway are described in detail. The biosynthetic genes involved in the fumonisin and trichothecene biosynthetic pathways are also outlined. The potential benefits gained from an increased knowledge of the molecular organisation of these pathways together with the mechanisms involved in their regulation are also discussed.

The use of reverse transcription-polymerase chain reaction (RT-PCR) for monitoring aflatoxin production in Aspergillus parasiticus 439.

A detection system based on reverse transcription PCR (RT-PCR) has been developed to monitor aflatoxin gene expression in Aspergillus parasiticus. Total RNAs of aflatoxigenic A. parasiticus 439 grown in aflatoxin permissive and non-permissive media were amplified and monitored over time by RT-PCR with specific primers designed from two genes of the aflatoxin biosynthetic pathway. Gene transcription in both media was assessed by monitoring the house keeping beta-tubulin gene and aflatoxin production was correlated with transcription by thin layer chromatography. This RT-PCR technique has the potential to be employed as a tool to investigate the effects of a variety of physiological factors on the transcription of the aflatoxin genes.

Dopaminergic properties of nomifensine.

Nomifensine and a proposed dihydroxy metabolite produced stimulation of motor behavior in mice with nomifensine being more potent. Weak cage-climbing behavior (stereotypy) was also produced. The stimulatory effects were greater in mice in which dopamine receptor sensitivity was increased by long-term haloperidol. Both of the analogs were potent inhibitors of dopamine and norepinephrine uptake in vitro with nomifensine approximately 3 times more potent than the metabolite. In contrast, the two analogs had weak affinity for the post-synaptic dopamine receptor (as measured by displacement of ligand binding in vitro) with dihydroxynomifensine approximately 6 times more potent than nomifensine. These results suggest that the behavioral effects of nomifensine are largely dependent on presynaptic catecholamine mechanisms but that weak direct dopamine agonist properties do exist, particularly in vivo where the drug may be metabolized to a more active form.

Progress in the development of a transcutaneously powered axial flow blood pump ventricular assist system.

Development of the Jarvik 2000 intraventricular assist system for long-term support is ongoing. The system integrates the Jarvik 2000 axial flow blood pump with a microprocessor based automatic motor controller to provide response to physiologic demands. Nine devices have been evaluated in vivo (six completed, three ongoing) with durations in excess of 26 weeks. Instrumented experiments include implanted transit-time ultrasonic flow probes and dual micromanometer LV/AoP catheters. Treadmill exercise and heart pacing studies are performed to evaluate control system response to increased heart rates. Pharmacologically induced cardiac dysfunction studies are performed in awake and anesthetized calves to demonstrate control response to simulated heart failure conditions. No deleterious effects or events were encountered during any physiologic studies. No hematologic, renal, hepatic, or pulmonary complications have been encountered in any study. Plasma free hemoglobin levels of 7.0 +/- 5.1 mg/dl demonstrate no device related hemolysis throughout the duration of all studies. Pathologic analysis at explant showed no evidence of thromboembolic events. All pump surfaces were free of thrombus except for a minimal ring of fibrin, (approximately 1 mm) on the inflow bearing. Future developments for permanent implantation will include implanted physiologic control systems, implanted batteries, and transcutaneous energy and data transmission systems.

A rapid batch method for the production of specific fluorescein isothiocyanate-labeled globulins to Dirofilaria immitis microfilaria.

A rapid, reproducible method for the production of specifically labeled anti-Dirofilaria immitis microfilaria (MFF) globulins (MAG) has been devised. These labeled antibodies have made the detection of D immitis in serum possible by a fluorescent-antibody technique.

Mycophenolic acid and its mechanism of action in cancer and psoriasis.

Mycophenolic acid is active against fungi, bacteria, and viruses in vitro and is active against some viruses and tumors in experimental animals. Mycophenolic acid is not effective in the treatment of cancer in man, but it is effective in treating psoriasis. In all of the various diseases MA presumably inhibits the synthesis of GMP resulting in decreased synthesis of RNA and DNA. The direct inhibition of GMP synthesis is the result of MA activity against the IMPDHase and GMP synthetase as determined in experimental tumors. The inhibition of GMP synthesis can be circumvented by the guanine salvage pathway which is controlled by PRTase activity. PRTase may be the sole factor in preventing the inhibition caused by MA in the biosynthesis of GMP (Fig. 3). However, before MA can stop GMP synthesis, MA must enter the cell. The current data show that MA is almost completely detoxified in man and circulates in the plasma as the glucuronide, MAG, Glucuronides are normally inactive forms of active drugs. Due to their bivalent and non-lipophilic nature, glucuronides do not normally cross the cell membranes. Therefore, MAG is extracellular and beta-Gase intracellular, and this prevents hydrolysis of MAG to the active MA in cancer patients.