Antioxidant and pharmacodynamic effects of pyridoindole stobadine.
1. The review summarizes the most important data known so far on chemistry, pharmacodynamics, toxicology and clinics of the investigational agent, pyridoindole stobadine. 2. Stobadine was shown to be able to scavenge hydroxyl, peroxyl and alkoxyl radicals, to quench singlet oxygen, to repair oxidized amino acids and to preserve oxidation of SH groups by one-electron donation. These effects originated from its ability to form a stable nitrogen-centered radical on indole nitrogen. Consequently, it was able to diminish lipid peroxidation and protein impairment under oxidative stress. 3. In various in vitro and in vivo animal models, stobadine was shown to diminish the impairment of the myocardium induced by mechanisms involving reactive oxygen species (e.g., myocardial infarction, hypoxia/ reoxygenation, catecholamine overexposure). 4. The neuroprotective effect of stobadine was demonstrated in a series of in vivo and in vitro models (brain in situ, brain slices, spinal cord, autonomic ganglia, etc.) during ischemia/reperfusion and hypoxia/ reoxygenation or in the presence of chemical systems generating free oxygen radicals, and so forth. Stobadine improved animal survival rate and synaptic transmission recovery, maintained SH tissue level and diminished lipid peroxidation as well as impairment of Ca-sequestering intracellular systems. 5. Oxidation of low-density lipoproteins (LDLs), which plays a major role in the development of atherosclerosis, was decreased by stobadine in vitro. Both lipid and protein (apo B) components of LDL were protected against Cu(2+)-induced oxidation by this agent. 6. Stobadine proved to be an effective protectant in models of free radical pathology in vivo, such as cyclophosphamide-, MNNG- or 60Co-induced mutagenesis and alloxan-induced hyperglycemia. 7. Besides other remarkable pharmacodynamic effects, stobadine exerts antidysrhythmic, local anesthetic, alpha-adrenolytic, antihistaminic, myorelaxant and antiulcerogenic actions. 8. Pharmacokinetic analyses demonstrated that stobadine was readily absorbed from the gastrointestinal tract. Thanks to its balanced lipo-hydrophilic properties, it was distributed over both water and lipid phases in biological tissues. It was shown to easily penetrate the blood-brain barrier. 9. Acute, subchronic and chronic toxicity studies in several animal species, as well as numerous analyses of embryotoxicity, teratogenicity, mutagenicity and genotoxicity, revealed only a negligible toxic potential of this agent. 10. Phase-one clinical study demonstrated safety of the compound. Only slight side effects--namely, a slight hypotension and a slight sedative effect--were observed subsequent to the highest dose used. In phase-two clinical study, the patients with angina pectoris treated for 4 weeks with stobadine showed a significant decrease in the frequency of anginal attacks, in the number of self-administrations of sublingual nitroglycerine and in plasma lipoprotein, cholesterol and triglyceride levels. A slight decrease in systolic and diastolic blood pressure also was observed. 11. It is suggested that stobadine may be considered a contribution to the search for new effective cardio- and neuroprotectants based on antioxidant or free radical scavenging mechanisms of action.
Horáková
L
L
Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Stolc
S
S
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology; D001711:Biotransformation; D002243:Carbolines / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D006439:Hemodynamics / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D016623:Ion Pumps / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000187:drug effects* / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects; D017202:Myocardial Ischemia; D015428:Myocardial Reperfusion Injury; D010084:Oxidation-Reduction; D010525:Peripheral Nerves / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D014150:Antipsychotic Agents; D002243:Carbolines; D006634:Histamine H1 Antagonists; D007473:Ion Channels; D016623:Ion Pumps; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C100106:dicarbine