Some pharmacological actions of aloe extracts and Cassia abbreviata on rats and mice.

The effects of crude extracts (500 mg/kg IP and 500-1000 mg/kg PO) of three species of aloes and Cassia abbreviata in rats and mice were studied, particularly as regards their abortifacient actions. The LD50 values were as follows: A. globuligemma < 250 mg/kg IP; A.chabaudii 250-500 mg/kg IP; A. cryptopoda > 1500 mg/kg IP and C.abbreviata 500-750 mg/kg IP. Thus the most toxic was A.globuligemma. Their most visibly striking toxic effects in rats were CNS depression, and post mortem investigations showed widespread haemorrhagic lesions. Administration of the aloes and A.abbreviata to pregnant mice and rats did not cause expulsion or resorption of the foetuses. Several rats died within 36 hours of injection of A.chabaudii and A.globuligemma, but even in these rats there was no expulsion or resorption of the foetuses. Rats which survived the treatment delivered normal sized, healthy litters at term. It is suggested that neither the aloe species test nor C.abbreviata possess abortifacient activity at doses which are not toxic to the animals.     

Pre-coital and post-coital anti-implantation and abortifacient activities of <Emphasis Type="Italic">Aristolochia bracteolata Lam</Emphasis>. aerial parts

The ethyl acetate soluble fraction of the ethanolic extract of Aristolochia bracteolata was tested for pre-coital and post-coital anti-implantation and abortifacient activities in female albino rats. In the pre-coital study, the treatment at 20 and 40 mg/kg body weight showed significant and dose-related anti-implantation and abortifacient properties. In the post-coital studies at 20, 30 and 40 mg/kg body weight doses, similar results were observed. The total antifertility activity at 40 mg/kg body weight was found to be comparable to that of standard ethinyl estradiol given for the similar period. The plant merits further investigation to prove the mechanism of action and to isolate its phytoconstituents.     

Influence of aminoglutethimide and spironolactone on the efficacy of carbamazepine and diphenylhydantoin against amygdala-kindled seizures in rats

Antagonists of steroid receptors may interfere with seizure phenomena. The present study deals with effects of aminoglutethimide and spironolactone on the action of carbamazepine and diphenylhydantoin in amygdala-kindled rats of both genders. Co-administration of the antimineralocorticoid with carbamazepine at their ineffective doses (50 and 15 mg/kg, respectively) led to significant reduction of the seizure and afterdischarge durations. No anticonvulsant effect was observed when spironolactone was combined with diphenylhydantoin. The concomitant treatment of aminoglutethimide and carbamazepine (both drugs at their subprotective doses of 5 and 15 mg/kg, respectively) resulted in antiseizure activity in respect of all measured parameters, including the afterdischarge threshold, seizure severity, seizure duration and afterdischarge duration. The similar combination of aminoglutethimide with diphenylhydantoin (2.5 mg/kg) significantly shortened the seizure and afterdischarge durations. The antiseizure effect of tested combinations was not sex-dependent and not reversed by hydrocortisone pretreatment. Pharmacokinetic events may be involved only in the interaction between spironolactone and carbamazepine. Among various chemoconvulsants, bicuculline reversed the action of aminoglutethimide on carbamazepine and diphenylhydantoin. The effect of aminoglutethimide on diphenylhydantoin was also abolished by N-methyl-d-aspartic acid and aminophylline. In conclusion, our results suggest that doses of carbamazepine and diphenylhydantoin should be modified in epileptic patients concomitantly treated with aminoglutethimide or spironolactone.     

Effect of 3,6-dimethylpyrazine-2-thiol on androstenedione-induced increase of uterine weight in female rats

3,6-Dimethylpyrazine-2-thiol administered at 10-70 mg/kg, p.o. was found to suppress androstenedione-induced increase of uterine weight in female rats. This action was weaker than that of aminoglutethimide (3-30 mg/kg, p.o.). After administration of androstenedione, increased plasma estradiol levels were reduced by 3,6-dimethylpyrazine-2-thiol. Moreover, in vitro, production of estradiol in the pregnant mare serum gonadotropin (PMSG)-treated ovary was inhibited by 3,6-dimethylpyrazine-2-thiol. These results suggest that 3,6-dimethylpyrazine-2-thiol has an inhibitory action on aromatase activity.     

Hypolipidemic Activity of 3-Amino-1-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-1-ones in Rodents

A series of 3-amino-1-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-1-ones were synthesized and shown to be effective in lowering both serum cholesterol and triglyceride levels significantly in CF₁ mice and Sprague-Dawley rats. All analogs showed better activity than the standard drugs, lovastatin and clofibrate, in reducing the serum cholesterol and triglyceride levels in mice at 8 mg/kg/day intraperitoneally. The best active analogs, 3-morpholino-1-(3-nitrophenyl)propan-1-one ( 4 ) and 3-piperidino-1-(3-nitrophenyl)propan-1-one ( 5 ), exhibited 58% and 67% reduction of serum cholesterol levels, respectively, and 42% and 46% reduction of serum triglyceride levels, respectively, after 16 days of administration at 8 mg/kg/day intraperitoneally in CF₁ mice. In Sprague-Dawley rats at 8 mg/kg/day oral administration, both compounds ( 4 and 5 ) significantly decreased the serum cholesterol and triglyceride levels. Rat tissue lipid levels were reduced significantly by compound 4, while less effects resulted from compound 5. The cholesterol and triglyceride levels in chylomicrons, VLDL, and LDL fractions were reduced by both analogs while the HDL cholesterol levels were significantly increased. Compound 5 was also effective in lowering serum cholesterol and triglyceride levels in hyperlipidemic mice, at 8 mg/kg/day intraperitoneally, but not effective in hyperlipidemic rats at 8 mg/kg/day intraperitoneally, but not effective in hyperlipidemic rats at 8 mg/kg/day orally. Cholesterol and triglyceride lowering effects of the agents were correlated with inhibition of the activities of liver acetyl CoA synthetase, HMG CoA reductase, phosphatidylate phosphohydrolase, and lipoprotein lipase, and with elevation of the activity of cholesterol ester hydrolase.     

Antiovulatory and abortifacient effects of Areca catechu (betel nut) in female rats

Objectives:

To study the antiovulatory and abortifacient effects of ethanolic extract of Areca catechu in female rats.

Materials and Methods:

For antiovulatory effect, ethanolic extract of A. catechu at 100 and 300 mg/kg doses was administered orally for 15 days. Vaginal smears were examined daily microscopically for estrus cycle. Rats were sacrificed on 16^th day. Ovarian weight, cholesterol estimation, and histopathological studies were done. Abortifacient activity was studied in rats at 100 and 300 mg/kg doses administered orally from 6^th to 15^th day of pregnancy. Rats were laparotomised on 19^th day. The number of implantation sites and live fetuses were observed in both horns of the uterus.

Results:

The extract of A. catechu showed a significant decrease in the duration of estrus at 100 mg/kg (P = 0.015) and 300 mg/kg doses (P = 0.002) as compared with control. Metestrus phase was also significantly reduced at 100 mg/kg (P = 0.024) and 300 mg/kg doses (P = 0.002). There was a significant increase in proestrus (P < 0.001) phase. However, diestrus phase was unchanged. Histopathological study of the ovaries showed mainly primordial, primary, and secondary follicles in the test groups as compared to control. There was also a significant (P = 0.002) decrease in ovarian weight and a significant (P = 0.021) increase in ovarian cholesterol level at 100 mg/kg dose. In the study to evaluate abortifacient effect, the mean percentage of abortion with 100 and 300 mg/kg doses were 75.5% and 72.22%, respectively, which was significantly (P = 0.008 and P = 0.006, respectively) increased when compared with control.

Conclusion:

The ethanolic extract of A. catechu at doses of 100 and 300 mg/kg has antiovulatory and abortifacient effects.     

Enzymatic sulfation of steroids--XX. Effects of ten drugs on the hepatic glucocorticoid sulfotransferase activity of rats in vitro and in vivo

The effects of ten drugs on hepatic glucocorticoid sulfotransferase activity (HGSTA) were examined in male rats. The enzyme activity per 100 g body weight was elevated 152, 94.9, 140, 140, 73.1, 63.9, 76.9, and 140% after administration of daily i.p. doses of 111 mg spironolactone/kg (6-10 days), 66.7 mg WIN-24540/kg (6-10 days), 150 mg metyrapone/kg (19-31 days), 33.3 mg pentachlorophenol/kg (9-16 days), 16.5 mg aspirin/kg (10-16 days), 90.5 mg alloxan/kg (23.27 days), 104 mg aminoglutethimide/kg (12-20 days), and 16.8 mg propranolol/kg (21-27 days). Shorter experimental periods or lower drug doses caused smaller effects on HGSTA. Most notably, spironolactone (111 mg/kg) and WIN-24540 (66.7 mg/kg) caused 50-75% elevation of HGSTA in 2 days. Effects of WIN-24540, aspirin and pentachlorophenol were due mostly to elevation of hepatic levels of sulfotransferase III (STIII), the glucocorticoid-preferring sulfotransferase of rat liver. Effects of the other test drugs were due to elevation of hepatic levels of sulfotransferases I and II (STI and STII), which much prefer dehydroepiandrosterone as substrate, but also catalyze glucocorticoid sulfation. Enzyme inhibition studies showed that the test drugs interacted with the HGSTA in vitro in a fashion that appeared to be related to the in vivo effects already described. None of the drugs interacted exclusively with STI, STII or STIII in vitro. However, some differences of the strengths of individual drug-sulfotransferase interactions were observed. The drug effects are discussed in relation to drug and glucocorticoid actions.     

FURTHER STUDIES ON THE EFFECTS OF ADRENAL STEROIDS IN THE ACTIVE TRANSPORT OF SEROTONIN INTO RAT PLATELETS

Male rats were treated with a fixed dose of aminoglutethimide (50 mg/kg s.c.) or with progressively increasing doses (50-100 mg/kg s.c.) for 3 days. Corticosterone levels were found to be decreased in the latter group. Platelet uptake of serotonin as well as the apparent Vmax were decreased, whereas the Km of uptake were increased when compared with that of the control group. Addition of ACTH (10 iu/dl) to control rat platelet and corticosterone (10-80 micrograms/dl) or triamcinolone (0.5-5.0 micrograms/dl) to adrenalectomized rat platelet suspension in vitro did not increase the serotonin uptake of the preparation. Administration of exogenous dexamethasone (0.05-0.2 mg/kg i.m.) or triamcinolone (0.05-5.0 mg/kg i.m.) to adrenalectomized rats, caused a dose related increase in active uptake of serotonin by the platelets. Deoxycorticosterone (0.1-1.0 mg/kg i.m.) did not have this effect. The time course of response to, and the maximum percentage increase in platelet serotonin uptake by, exogenous corticosteroids are related to their glucocorticoid potency. The possible role of glucocorticoids on platelet serotonin uptake process is discussed.     

Novel diallyldisulfide analogs ameliorate cardiovascular remodeling in rats with L-NAME-induced hypertension

Diallyldisulfide (DADS), an active principle of garlic (Allium sativum) is known for its antihypertensive properties. The present study was designed to evaluate the effect of novel DADS analogs, against L-NAME induced hypertension in Wistar rats. The daily administration of L-NAME (50mg/kg) for six weeks along with DADS analogs (20mg/kg) significantly decreased the elevated systolic blood pressure (SBP) and the activity of angiotensin converting enzyme (ACE) and also inhibited the decline in nitrite/nitrate (NO(x)) concentrations and cyclic guanosine monophosphate (cGMP) levels. Adverse changes such as lipid peroxidation, protein damage and a decrease in the levels of antioxidant enzymes, were rectified after the administration of DADS analogs. Oral administration of DADS analogs preserved the expression of endothelial nitric oxide synthase (eNOS). The ability of the DADS analogs to inhibit L-NAME induced hypertension was compared with Enalapril (15mg/kg), which was taken as a standard. The DADS analogs prevented L-NAME-induced cardio toxicity, which was also reflected at the microscopic level indicative of its cardio protective effects. DADS analogs induced vasorelaxation was completely abolished by the removal of the endothelium or by pre-treatment with L-NAME, an inhibitor of nitric oxide synthase. DADS analogs inhibited the calcium influx induced by phenylephrine (0.3μM) and high K(+) (60mM) and this effect was completely abolished by pretreatment of L-NAME. Taken together, our results show that the DADS analogs induce vasorelaxation and have antihypertensive properties, which may be mediated through activation of eNOS.     

Separation of the locomotor stimulant and discriminative stimulus effects of cocaine by its C-2 phenyl ester analog,RTI-15

During a routine evaluation of several analogs of cocaine, we observed that the C-2 phenyl ester, RTI-15, appeared to suppress motor activity in rats. We subsequently examined RTI-15 for its cocaine-like stimulus effects as well as for its locomotor activity effects. RTI-15 dose-dependently generalized from the cocaine stimulus in rats trained to discriminate 10 mg/kg cocaine from saline with complete substitution (⩾80% cocaine-lever responding) occurring at 24 mg/kg. During automated locomotor activity tests in mice, cocaine (3–60 mg/kg) dose-dependently increased activity counts and movement time across the entire 1 h test session. RTI-15, however, had little affect on activity counts and movement time from 10–30 mg/kg, and decreased these measures at 60 mg/kg, the highest dose tested. These results indicate that while changing the C-2 methyl ester of cocaine to a C-2 phenyl ester increases dopamine-transporter selectivity, it dissociates its locomotor activity effects from its discriminative stimulus effects suggesting that the underlying mechanisms mediating these effects are not identical.     

The stereotypy-inducing effects of N-substituted benztropine analogs alone and in combination with cocaine do not account for their blockade of cocaine self-administration

Rationale

Previous studies have demonstrated that several N-substituted 4′, 4″-diF-benztropine (BZT) analogs with high dopamine transporter affinity selectively decreased cocaine self-administration without affecting food-maintained behavior in rats.

Objectives

The present study examined if the decreases in cocaine self-administration are due to competition from excess behavioral activity (hyperlocomotion or stereotypy) induced by the BZT analogs alone or in combination with cocaine.

Results

Pretreatments with the typical dopamine uptake inhibitor methylphenidate [1.0, 3.2, and 10 mg/kg, intraperitoneally (i.p.)] dose-dependently shifted the cocaine self-administration dose–effect curve (0, 0.032, 0.1, 0.32, and 1.0 mg/kg/injection) leftward. The shift in the dose–effect curve was obtained at doses of methylphenidate that, when administered alone, also decreased food-maintained behavior and increased locomotor activity and stereotypy. In contrast, the N-substituted BZT analogs, JHW 007 (1.0, 3.2, and 10 mg/kg, i.p.), AHN 1-055 (10 mg/kg), and, AHN 2-005 (10 mg/kg), as previously reported, decreased the maximum for the cocaine self-administration dose–effect curve, and did so at doses that were virtually without effects on food-maintained behavior. Further, the BZT analogs alone had minimal effects on locomotor activity and stereotypies and did not appreciably change the effects of cocaine on these measures when administered in combination with cocaine.

Conclusions

The present results suggest that the decrease in cocaine self-administration produced by the N-substituted BZT analogs is due to an antagonism of the reinforcing effects of cocaine rather than due to interference from competing behavioral overstimulation, and further supports the development of N-substituted BZT analogs as medications to treat cocaine abuse.     

The alpha 2-adrenoceptor antagonist activity of ipsapirone and gepirone is mediated by their common metabolite 1-(2-pyrimidinyl)-piperazine (PmP)

Ipsapirone and gepirone, analogs of buspirone, a newly developed antianxiety agent, form 1-(2-pyrimidinyl)-piperazine (PmP) during their biotransformation in rats. After oral administration (10 mg/kg) of a parent drug, e.g. ipsapirone or gepirone, the metabolite appears in significant amounts in plasma, with maximal concentrations of 0.9 and 1.4 nmol/ml respectively. The metabolite half-life ranged from about 140 to 200 min. Ipsapirone is eliminated more slowly than gepirone, with a half-life of about 100 and 30 min, respectively. The metabolite to parent drug ratios for the areas under the plasma concentration-time curve (AUC) were 1 for ipsapirone and 14 for gepirone. PmP (0.5-2 mg/kg p.o), ipsapirone, gepirone and buspirone (5-20 mg/kg p.o.) dose dependently antagonized the slowing of gastrointestinal transit induced by clonidine 0.1 mg/kg s.c. The doses inhibiting the antitransit effect of clonidine by 50% were 0.8 mg/kg for PmP, 14 mg/kg for ipsapirone and 9 mg/kg for both gepirone and buspirone. Analysis of small intestinal longitudinal muscle of rats given the ED50 of PmP, ipsapirone, gepirone, buspirone showed that PmP concentrations in the longitudinal muscle (with attached myenteric plexus) fell within a relatively narrow range and were consistent with the appropriate transit scores. The plasma was also tested for anticlonidine activity. These data indicate that PmP formation is a pharmacologically significant metabolic process for the buspirone-related drugs, ipsapirone and gepirone, and that this metabolite is responsible for the alpha 2-adrenoceptor blocking activity exerted by these drugs in vivo in the rat.     

Gestagenic and contraceptive activity of new synthetic progesterone analogs in experimental animals

The gestagenic activity of new 17alpha-hydroxyprogesterone analogs was studied in experiments on infantile female rabbits (Clauberg-McPhail assay) and ovariectomized animals (Comer-Allen assay). The new steroidal preparations produced significant secretory transformations in immature rabbit endometrium. The maximum gestagenic activity was observed for butagest, while the minimum effect was produced by duhydrogesterone (dufaston). Butagest, megestrol capronate, and AMOL isopropyl ester showed the ability to maintain pregnancy in ovariectomized female rabbits. The compositions of gestagens (0.8 mg/kg) with ethinylestradiol (0.04 mg/kg) produced high contraceptive effect in rats.     

Evaluation of antiinflammatory and analgesic activities of alcoholic extract of Kaempferia galanga in rats

Alcoholic extract of Kaempferia galanga was tested for analgesic and antiinflammatory activities in animal models. Three doses, 300 mg/kg, 600 mg/kg and 1200 mg/kg of the plant extract prepared as a suspension in 2 ml of 2% gum acacia were used. Acute and sub acute inflammatory activities were studied in rats by carrageenan induced paw edema and cotton pellet induced granuloma models respectively. In both models, the standard drug used was aspirin 100 mg/kg. Two doses 600 mg/kg and 1200 mg/kg of plant extract exhibited significant (P<0.001) antiinflammatory activity in carrageenan model and cotton pellet granuloma model in comparison to control. Analgesic activity was studied in rats using hot plate and tail-flick models. Codeine 5 mg/kg and vehicle served as standard and control respectively. The two doses of plant extract exhibited significant analgesic activity in tail flick model (P<0.001) and hot plate model (P<0.001) in comparison to control. In conclusion K. galanga possesses antiinflammatory and analgesic activities.     

Locomotor activity in morphine-treated rats: Effects of and comparisons between cocaine,procaine, and lidocaine

The effects of cocaine, procaine, and lidocaine on open field and spontaneous (actophotometer) locomotor activities were assessed and compared in rats (1) treated acutely with morphine (single injection), (2) made dependent on morphine (SC pellets), (3) implanted with morphine and withdrawn at the time of peak dependence, and (4) implanted SC with lactose-containing pellets (sham). Cocaine-induced (10 or 30 mg/kg) open field and spontaneous locomotor activities were significantly greater in each of the four groups than those of the corresponding groups administered saline. Procaine (50 or 100 mg/kg) significantly reduced open field locomotor activity in all morphine-treated rats and spontaneous locomotor activity in acute rats. Lidocaine (30 mg/kg) significantly depressed spontaneous locomotor activity in acute rats. Upon comparison of the activities induced by the three local anesthetics, open field locomotor activity of sham-implanted rats was greater following cocaine (10 or 30 mg/kg) than following procaine (50 or 100 mg/kg). Only morphine withdrawn rats manifested greater activity following cocaine (10 mg/kg) than following either procaine (50 mg/kg) or lidocaine (10 mg/kg); activities were equivalent in dependent and acute rats. In contrast, cocaine-induced (30 mg/kg) open field locomotor activity of all morphine-treated rats was greater than either procaine- (100 mg/kg) or lidocaine- (30 mg/kg) induced activities. Spontaneous locomotor activity of all groups except acute morphine was greater following both doses of cocaine than following both doses of either procaine or lidocaine. In acute rats, only cocaine (10 mg/kg) induced greater activity than the other local anesthetics. Thus, stimulation of locomotor activity following cocaine treatment is a pharmacological property unique to cocaine and not shared by either procaine or lidocaine. Further, the data indicate that the methods selected for assessing locomotor activity may not give comparable results.     

Investigation of MDMA-related agents in rats trained to discriminate MDMA from saline.

To determine whether metabolite-related analogs of N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) produce stimulus effects similar to those of the parent compound, and to determine the structural requirements associated with the MDMA stimulus, several MDMA analogs were examined in tests of stimulus generalization using rats trained to discriminate 1.5 mg/kg MDMA from saline. Although several of the analogs produced up to 50-60% MDMA-appropriate responding, none [with the exception of N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA)] resulted in stimulus generalization. The partial generalization, coupled with the possible reduced ability of certain of the agents to penetrate the blood-brain barrier relative to MDMA, suggests that these agents are not behaviorally inactive. PMMA, although not a metabolite of MDMA, is closely related in chemical structure to MDMA and its metabolites; PMMA produces > 80% MDMA-appropriate responding and is approximately three times more potent (ED50 = 0.2 mg/kg) than MDMA itself (ED50 = 0.76 mg/kg). PMMA is a newer scheduled substance with an as yet unknown mechanism of action; however, on the basis of the stimulus generalization observed PMMA may share some behavioral and mechanistic similarity with MDMA. These results also indicate that an intact methylenedioxy ring, such as that found in MDMA but absent in PMMA, is not a prerequisite for MDMA-like activity and further support the notion that ring-opened MDMA metabolites may produce effects that contribute to the actions of MDMA.     

Effects of denopamine on rat myocardium in comparison with isoprenaline

The adverse effects of denopamine (TA-064) were investigated on rat myocardium in comparison with those of isoprenaline (isoproterenol). Experiment 1. Rats were treated with isoprenaline (10 mg/kg) or denopamine (10 mg/kg) once by subcutaneous injection. 15 h after drug administration, rat hearts were isolated, and heart mitochondria were prepared. Activities of three portions of electron transport chain (NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase) of mitochondria were measured. In rats treated with isoprenaline, significant decreases in NADH-cytochrome c reductase and cytochrome c oxidase activities were observed. While, in rats treated with denopamine, NADH-cytochrome c reductase activity was not decreased significantly, and decrease in cytochrome c oxidase activity was less than that observed in the isoprenaline group. Experiment 2. Rats were treated with isoprenaline (10 mg/kg) or denopamine (10 mg/kg) by subcutaneous injection once a day for 6 successive days. After the last drug administration, hearts were isolated, and cardiac membranes were prepared. Numbers of beta-adrenergic receptors were measured using 3H-dihydroalprenolol. In rats treated with isoprenaline, a significant decrease in the number of beta-adrenergic receptors was observed. On the contrary, administration of denopamine did not affect significantly the number of beta-adrenergic receptors.     

Tetramethylcyclopropyl analogue of a leading antiepileptic drug, valproic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives

Although valproic acid (VPA) is an extensively used antiepileptic drug for treatment of various kinds of epilepsies, it has been proven to possess two life-threatening side effects: hepatotoxicity and teratogenicity. Amide and urea derivatives of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) were prepared to discover lead compounds with clinical potential. In the amide and alkylamide series of TMCA derivatives, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (21) was one of the most active compounds, having the subcutaneous metrazol test (scMet) ED50 values of 35 mg/kg in rats and 74 mg/kg in mice. In the maximal electroshock-induced seizure test (MES), this compound had ED50 values of 108 mg/kg in rats and 115 mg/kg in mice. Compound 21 was 18.5 and 4.5 times more potent than VPA in the corresponding rat tests. The most active compound in the series of urea derivatives was 2,2,3,3-tetramethylcyclopropanecarbonylurea (25), possessing MES ED50 values of 29 mg/kg in rats and 90 mg/kg in mice. In the scMet test this compound had ED50 values of 92 mg/kg in rats and 125 mg/kg in mice. The median toxic dose (TD50) in rats was 538 mg/kg, providing compound 25 with a wide safety margin and a protective index (TD50/ED50) of 18.5 in the MES test, which is about 12 times greater than that of VPA. Compounds 21 and 25 have the potential for development as novel potent and safe central nervous system active drugs with a broad spectrum of antiepileptic activity.     

Antidepressant-like effects of a novel pentapeptide,nemifitide, in an animal model of depression

Background Nemifitide is a novel peptide analog of melanocyte-inhibiting factor (MIF) that has been reported to relieve depressive symptoms in a very short period.Objectives The Flinders Sensitive Line (FSL) rat, a genetic animal model of depression with innate exaggerated immobility in the forced swim test, was used to obtain more detailed information about the antidepressant-like effects of nemifitide.Methods The FSL rats were treated chronically with various doses of nemifitide or reference antidepressants desipramine and fluoxetine for 5 or 14 days and the forced swim test was conducted 22–24 h after the last treatment.Results Nemifitide significantly increased swimming in the FSL rats at both low (0.025–0.3 mg/kg) and high (3.0–15.0 mg/kg) doses but not at intermediate (0.4–2.4 mg/kg) doses. Nemifitide (0.3 mg/kg) and desipramine (5.0 mg/kg) significantly increased swimming in the FSL rats after just 5 days of treatment, but fluoxetine (5.0 mg/kg) did not. Nemifitide (0.3 mg/kg) and fluoxetine (5.0 mg/kg) had long-lasting effects, but desipramine (5.0 mg/kg) did not.Conclusions These findings support the value of developing nemifitide and its analogs as potential antidepressants.     

Anti-inflammatory effect of theophylline in rats and its involvement of the glucocorticoid-glucocorticoid receptor system

Although theophylline has been suggested to have an anti-inflammatory effect, there have been few reports to show the in vivo effect and the mechanism of anti-inflammatory activity of theophylline experimentally. To reveal the anti-inflammatory activity of theophylline, we studied the effect of theophylline and its metabolites on carrageenan-induced edema in rat foot pad. Subcutaneous injection of theophylline (5 - 100 mg/kg) inhibited carrageenan-induced edema dose-dependently. Theophylline metabolites, that is, 1-methylxanthine, 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid (equimolar dose to 50 mg/kg of theophylline), did not inhibit the edema significantly. The inhibitory effect of theophylline on carrageenan-induced edema disappeared by pretreatment with aminoglutethimide, an inhibitor of glucocorticoid synthesis and with mifepristone, an antagonist of the glucocorticoid receptor. These results suggest that theophylline itself has anti-inflammatory activity and the glucocorticoid-glucocorticoid receptor system is involved in the anti-inflammatory activity of theophylline.