Clofibrate and gemfibrozil induce an embryonic malabsorption syndrome in zebrafish.

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 Cu2+-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, α-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.

Antioxidant and Pharmacodynamic Effects of Pyridoindole Stobadine

For patients with relapsing—remitting multiple sclerosis (RRMS), there are currently six approved medications that have been shown to alter the natural course of the disease. The approved medications include three beta interferon formulations, glatiramer acetate, natalizumab and mitoxantrone. Treating aggressive forms of RRMS and progressive disease forms of MS still presents a great challenge to neurologists. Intense immunosuppression has long been thought to be the only feasible therapeutic option. In patients with progressive forms of MS, lymphoid tissues have been detected in the central nervous system (CNS) that may play a critical role in perpetuating local inflammation. Agents that are currently approved for patients with MS have no or very limited bioavailability in the brain and spinal cord. In contrast, cyclophosphamide (CYC), an alkylating agent, penetrates the blood—brain barrier and CNS parenchyma well. However, while CYC has been used in clinical trials and off-label in clinical practice in patients with MS for over three decades, data on its efficacy in very heterogeneous groups of study patients have been conflicting. New myeloablative treatment paradigms with CYC may provide a therapeutic option in patients that do not respond to other agents. In this article we review the scientific rationale that led to the initial clinical trials with CYC. We will also outline the safety, tolerability and efficacy of CYC and provide neurologists with guidelines for its use in patients with MS and other inflammatory disorders of the CNS, including neuromyelitis optica (NMO). Finally, an outlook into relatively novel treatment approaches is provided.

https://journals.sagepub.com/doi/pdf/10.1177/1756285609344375

Cyclophosphamide in Multiple Sclerosis: Scientific Rationale, History and Novel Treatment Paradigms

Green tea extract increases cyclophosphamide-induced teratogenesis by modulating the expression of cytochrome P-450 mRNA.

Both selenium (Se) and polysaccharides from Pyracantha fortuneana (Maxim.) Li (PFPs) (P. fortuneana) have been reported to possess antioxidative and immuno-protective activities. Whether or not Se-containing polysaccharides (Se-PFPs) have synergistic effect of Se and polysaccharides on enhancing the antioxidant and immune activities remains to be determined. We previously reported that polysaccharides isolated from Se-enriched P. fortuneana (Se-PFPs) possessed hepatoprotective effects. However, it is not clear whether or not they have anti-mutagenic effects. In the present study, we compared and evaluated anti-mutagenic effects of Se-PFPs at three concentrations (1.35, 2.7 and 5.4 g/kg body weight) with those of PFPs, Se alone or Se + PFPs in mice using micronucleus assay in bone marrow and peripheral blood as well as mitomycin C-induced chromosomal aberrations in mouse testicular cells. We also elucidated the underlying mechanism. Our results demonstrated that Se-PFPs inhibited cyclophosphamide (CP)-induced micronucleus formation in both bone marrow and peripheral blood, enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in mouse liver, and reduced the activity and expression of cytochrome P450 1A (CYP4501A) in mouse liver in a dose-dependent manner. In addition, we found that the anti-mutagenic potential of Se-PFPs was higher than those of PFPs, Se alone or Se + PFPs at the same level. These results suggest that the anti-mutagenic potential of Se-PFPs may be mediated through the inhibition of the activity and expression of CYP4501A. This study indicates that application of Se-PFPs may provide an alternative strategy for cancer therapy by targeting CYP1A family.

https://www.mdpi.com/1420-3049/21/12/1731/pdf

Antimutagenic Effects of Selenium-Enriched Polysaccharides from Pyracantha fortuneana through Suppression of Cytochrome P450 1A Subfamily in the Mouse Liver.

Pregnant rabbit does received daily oral doses of 62 or 186 mg/kg cyclophosphamide (CP) on days 6-20 of gestation On day 29, shortly before term, the uterine content was removed by Caesarean section At the dose of 62 mg/kg CP maternal mortality was 2/9 does and at 186 mg/kg CP one abortion was recorded Body weight gain of pregnant females was essentially unaffected by CP treatment Both doses of CP elicited significant dose-dependent decrease of fetal body, organ (heart, lung, liver, kidney) as well as placental weight After treatment with 186 mg/kg CP, gross examination of fetuses revealed significantly increased incidence of exophthalmos, cleft palate/lip, syndactyly, and brachycardia Skeletal anomalies and malformations, significantly increased after the higher CP dose, included sternebrae, back-bone and limb defects Oral administration of CP to rabbits in the dose of 186 mg/kg during organogenesis resulted in pronounced embryotoxic and teratogenic changes

Teratogenicity of cyclophosphamide in New Zealand white rabbits.

Teratological studies of the hypolipidaemic drugs etofylline clofibrate (VULM) and fenofibrate were carried out in mice. Pregnant mice were given etofylline clofibrate and fenofibrate in doses 11.7, 117.1, and 585.5 mg/kg orally from day 7 to 16 of gestation. Terminal maternal body weight was significantly decreased after all doses of etofylline clofibrate in a non-dose-related fashion compared to the control group. The foetuses were examined on day 19 of gestation. They were weighed and inspected for external, skeletal and visceral abnormalities. The low and middle doses of etofylline clofibrate and fenofibrate had no adverse effects on embryofoetal development. The highest etofylline clofibrate dose induced a significant decrease of foetal weight at term, likewise postimplantation loss was significantly increased after the highest dose of fenofibrate. The incidence of external, skeletal and visceral anomalies was not dose-dependent. In this study no teratogenic effects were detected, yet with the highest etofylline clofibrate and fenofibrate doses some foetotoxic effects were observed.

Teratological study of the hypolipidaemic drugs etofylline clofibrate (VULM) and fenofibrate in Swiss mice.

cis-(-)-2,3,4,4a,5,9b-Hexahydro-2,8-dimethyl-1H-pyrido-[4,3-b]indole dipalmitate (stobadin dipalmitate; in the following briefly called STB) a new prospective cardioprotective drug, was evaluated for effects on fertility, general reproductive performance, prenatal and peri-postnatal development in the rat. Doses of 5, 15 and 50 mg/kg/d were administered orally in aqueous suspension to rats in all studies. Daily treatment of male rats for 70 days before mating and female rats for 14 days before mating and during gestation and lactation had no adverse effects on fertility, survival rate and weight gains of parental animals or on prenatal and postnatal development of pups. There was only evidence of slight adult toxicity late in the experiment, significant increase of anomalous foetuses in both the 15 and 50 mg/kg/d doses and decreased body weight of the young at 50 mg/kg/d on day 21 post partum. Daily oral treatment of pregnant rats with STB throughout organogenesis (day 4 to 16) had no overt effects on dams or on embryo-foetal development, except of increased incidence of some skeletal variations in all treated groups. In the peri-postnatal toxicity study treatment of pregnant dams with STB continuously from day 15 of gestation through parturition and lactation had no adverse effects on reproductive parameters of dams or on survival and development of F1 offspring at any dose used. There were only signs of slight maternal toxicity at 50 mg/kg/d, which consisted of sedated behaviour, reduced liver weight and reversible histopathological changes in kidney tissue. The results of these studies did not reveal serious developmental hazard potentials of STB administered to rats in doses up to 50 mg/kg/d.

Reproductive toxicity studies with cis-(-)-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido-[4,3-b]indole dipalmitate in rats.

The pyridoindole derivative (DH 1011), a new antiarrhythmic agent, and quinidine were examined for teratogenic and embryotoxic activity in chick embryos. The tested substance was injected into egg albumen on incubation days 5, 6 or 7 in doses of 0.4, 0.8 or 1.6 mg per egg. All embryos were examined on day 19. A significantly decreased survival rate of embryos was recorded only after the dose of 1.6 mg DH 1011 per egg administered on incubation day 5. Correlation between body and heart weight was found in all surviving embryos after administration of each agent on incubation days 5 and 6. Chondrodystrophy was the major deformity in chick embryos treated on incubation day 5. The results of this investigation suggest that neither quinidine nor DH 1011 have adverse effects on the late embryonal development of chickens.

Effect of pyridoindole derivative (DH 1011) on late chick embryo-genesis.

The cardioprotective drug stobadine in the form of dipalmitate salt DP 1031 was evaluated for its effects on perinatal and postnatal development in the rat. Doses of 5, 15 and 50 mg/kg/day representing approximately 1, 3, and 10 times the anticipated maximum daily human therapeutic dose were administered to rats orally in aqueous suspension. Treatment of pregnant rats with stobadine continuously from day 15 of gestation through parturition and lactation had no adverse effects on reproductive parameters of dams or on survival and development of F1 offspring at any dose used. There were only signs of slight maternal toxicity at 50 mg/kg/day, which consisted of sedated behaviour, reduced liver weight and reversible histopathological changes in kidney tissue. (Tab. 3, Fig. 4, Ref. 24).

Effect of the cardioprotective agent stobadine on reproduction in rats.

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