Anticonvulsant activity of ethanol extracts of Vetiveria zizanioides roots in experimental mice

?Abstract

Context: Vetiveria zizanioides Linn. (Gramineae), an aromatic plant commonly known as vetiver, is traditionally used for various ailments. Ethanol and aqueous extract of this plant found extensive use in Indian folklore medicine and used in treatment of a wide range of disorders including seizure. However, the anticonvulsant activity of this plant has not been studied.

Objective: To evaluate anticonvulsant activity of ethanol extract of V. zizanioides (EEVZ) in experimental mice.

Materials and methods: Anticonvulsant activity of EEVZ was determined by maximal electroshock stimulation (MES) and pentylenetetrazole (PTZ) in mice for 8?d experimental protocol. The extract at a dose of 100, 200 and 400?mg/kg body weight was administered once by oral route.

Results: LD₅₀ value of EEVZ in mice was found at a dose of 600?mg/kg body weight. EEVZ at a dose of 400?mg/kg significantly (p?<?0.001) reduced flexion (l5.98 to 3.73?s), extension (13.73 to 0.96?s), clonus (14.07 to 4.93?s), stupor (6.29 to 1.22?s) in the MES model. Further, it increases onset of clonic (88.25 to 708.32?s/30?min) and tonic (139.52 to 1126.39?s/30?min) in the PTZ model. In the PTZ model, 33% normal control and 83% EEVZ (100?mg/kg) animals were alive, while 100% protection was achieved in standard drug phenobarbital (20?mg/kg), EEVZ (200?mg/kg) and EEVZ (400?mg/kg) animals.

Discussion and conclusion: Findings demonstrate that V. zizanioides shows significant anticonvulsant activity in mice.     

Psychopharmacological effects of Artemisia copa aqueous extract in mice

Objective: To evaluate the aqueous extract from aerial parts of Artemisia copa Phil. (Asteraceae) administered orallyfor its psychopharmacological activities in several experimental models

Methods: The extract was administered p.o. in Swiss albino mice and tested on pentobarbital-induced hypnosis, locomotor activity, exploration in the hole-board, anxiolytic like profile evaluated in the marble-burying test and anticonvulsant activity on convulsions induced by pentylenetetrazol.

Results: Artemisia copa at doses up to 1.5?g/kg produced a dose-dependent sleep induction and potentiation of sub-hypnotic and hypnotic doses of pentobarbital. The extract also produced a dose-dependent increase and decrease in the spontaneous motor activity (0.5–1.5?g/kg, respectively), no disruption or a decrease on exploratory (hole-board) behavioral profiles (0.5–1.5?g/kg respectively) and a dose-related anxiolytic-like activity as indicated by increases in the percentage of marbles they left uncovered in the marble-burying test at doses (0.5?g/kg) that do not disrupt the motor activity. In addition, the extract (1.5?g/kg) produced a significant increase in the latency time and a decrease in the duration of seizures and mortality induced by PTZ 75?mg/kg in mice.

Conclusion: These results suggest that the aqueous extract of Artemisia copa may contain sedative principles with potential anxiolytic and anticonvulsant activities.     

Hydroalcoholic extract of Urtica circularis: A neuropharmacological profile

Abstract

Context: The genus Urtica has been known since ancient times. It has known to be useful for the treatment of different human ailments.

Objective: The present work evaluated the neuropharmacological effects of a hydroalcoholic extract of Urtica circularis (Hicken) Sorarú (Urticaceae).

Materials and method: The effect on central nervous system of U. circularis hydroalcoholic extract (from leaves and stems) administered by the intraperitoneal route in mice was evaluated by several tests: Pentobarbital- and midazolam-induced hypnosis, open field, hole board, elevated plus-maze and forced swimming. Phytochemical analysis was performed by high-performance liquid chromatography.

Results: A total of 300?mg/kg i.p. of the extract produced a significant prolongation of pentobarbital- (40?mg/kg i.p.; 60.1?min versus 25.4?min) and midazolam- (50?mg/kg i.v.; 53.4?min versus 25.1?min) induced sleeping time. The extract’s administration caused a marked reduction of the head-dipping response (DE₅₀: 373?mg/kg i.p.) in the hole-board test. Urtica circularis extract (DE₅₀: 46?mg/kg i.p.) reduced the spontaneous locomotor activity in the open field test. Flumazenil and atropine significantly antagonized the extract’s effect on the locomotor activity. No motor coordination disturbance was observed in the rota rod test at any doses. In the forced swimming test, the extract did not produce any change in the immobility time and it had no significant effects in elevated plus maze test. The phytochemical analysis revealed the presence of chlorogenic acid, vanillic acid, caffeic acid, vicenin-2, p-cumaric acid, ferulic acid, vitexin and isovitexin.

Conclusion: This study revealed that U. circularis hydroalcoholic extract possesses sedative activity, facilitating GABAergic and cholinergic transmission.     

Anticonvulsant activity of solasodine isolated from Solanum sisymbriifolium fruits in rodents

Context: Solanum sisymbriifolium Lam. (Solanaceae), commonly known as sticky nightshade, is traditionally used for central nervous system (CNS) disorders. Although solasodine has been isolated from this plant, little is known about its anticonvulsant and CNS depressant actions.

Objective: We investigated anticonvulsant and CNS depressant effects of solasodine isolated from S. sisymbriifolium using several experimental models.

Materials and methods: Swiss albino mice (n?=?6) were employed for pentylenetetrazole (PTZ) and picrotoxin (PCT)-induced convulsions and thiopental-induced sleep time. Different groups of Wistar albino rats (n?=?6) were subjected to maximal electroshock (MES) test. Solasodine, a steroidal glycoalkaloid, was isolated from dried fruits of S. sisymbriifolium and identified by GC-MS.

Results: The results showed that intraperitoneal (i.p.) injection of solasodine (25?mg/kg) significantly delayed (p < 0.01) latency of hind limb tonic extensor (HLTE) phase in the PCT-induced convulsions. In the MES model, solasodine significantly reduced (p < 0.001) duration of HLTE at 25, 50, and 100?mg/kg, i.p. in a dose-dependent manner. Interestingly, solasodine did not produce any significant reduction in PTZ-induced convulsions. Prior treatment of solasodine (25, 50, and 100?mg/kg, i.p.) significantly potentiated thiopental-provoked sleep in a dose-dependent manner (p < 0.001).

Discussion and conclusion: Our study, for the first time, shows potent anticonvulsant and CNS depressant activities of solasodine. It is likely that solasodine, in part, is responsible for the anticonvulsant and sedative properties of S. sisymbriifolium. The future study should focus on the exact mechanism of action of solasodine.     

Anxiolytic effects of orcinol glucoside and orcinol monohydrate in mice

Abstract

Context: Anxiety is a common psychological disorder, often occurring in combination with depression, but therapeutic drugs with high efficacy and safety are lacking. Orcinol glucoside (OG) was recently found to have an antidepressive action.

Objective: To study the therapeutic potential of OG and orcinol monohydrate (OM) as anxiolytic agents.

Materials and methods: Anxiolytic effects in mice were measured using the elevated plus-maze, hole-board, and open-field tests. Eight groups of mice were included in each test. Thirty minutes before each test, mice in each group received one oral administration of OG (5, 10, or 20?mg/kg), OM (2.5, 5, or 10?mg/kg), the positive control diazepam (1 or 5?mg/kg), or control vehicle. Each mouse underwent only one test. Uptake of orcinol (5?mg/kg) in the brain was qualitatively detected using the HPLC-MS method.

Results: OG (5, 10, and 20?mg/kg) and OM (2.5 and 5?mg/kg) increased the time spent in open arms and the number of entries into open arms in the elevated plus-maze test. OG (5 and 10?mg/kg) and OM (2.5 and 5?mg/kg) increased the number of head-dips in the hole-board test. At all tested doses, OG and OM did not significantly affect the locomotion of mice in the open-field test. Orcinol could be detected in the mouse brain homogenates 30?min after oral OM administration, having confirmed that OM is centrally active.

Discussion and conclusion: The results demonstrated that OG and OM are anxiolytic agents without sedative effects, indicating their therapeutic potential for anxiety.     

Sedative, anxiolytic and antidepressant activities of Citrus limon (Burn) essential oil in mice

We examined the sedative, anxiolytic and antidepressant effects of essential oil (EO) of leaves from Citrus limon, which has been used as one of the most popular compounds in Brazilian traditional herbal medicine. The effects of EO were demonstrated by open-field, elevated-plus-maze, rota rod, pentobarbital-induced sleeping time, and forced swimming tests in mice. In the open-field test, EO at the doses of 50, 100 and 150 mg/kg, after oral administration, significantly decreased the number of crossings, grooming, and rearing. In the elevated-plus-maze (EPM) test, EO increased the time of permanence and the number of entrances in the open arms. On the contrary, the time of permanence and the number of entrances in the closed arms were decreased. In the rota rod test, EO did not alter motor coordination and, thus, was devoid of effects, as related to controls. In the pentobarbital-induced sleeping time test, EO at the same doses significantly increased the animals sleeping time duration. Since EO, at the doses of 50, 100 and 150 mg/kg, did not show a sedative effect in the open field test, these three doses were used in the forced swimming test, producing a decrease in the immobility time, similarly to that of imipramine (positive control). However, the antidepressant effects of EO were not altered by the previous administration of paroxetine. In addition, effects of EO in the forced swimming test were totally blocked by reserpine pretreatment. In conclusion, the present work evidenced sedative and anxiolytic effects of EO that might involve an action on benzodiazepine-type receptors, and also an antidepressant effect where noradrenergic and serotoninergic mechanisms will probably play a role.     

Toxic rather than neuropharmacological effect of Ternstroemia sylvatica fruits and identification of 28-O-[β-l-6-rhamnopyranosyl]-R1-barrigenol as a new compound with toxic effects in mice

Abstract

Context: Fruits of Ternstroemia sylvatica Schltdl. and Cham. (Theaceae) are used in Mexican traditional medicine to alleviate anxiety, sleep disorders and seizures; however, the active principles have not been identified.

Objective: To identify the neuroactive principles of T. sylvatica fruits using neuropharmacological tests on mice.

Materials and methods: The methanol and aqueous extracts of pericarp or seeds of T. sylvatica fruits were intraperitoneally administered (1–562?mg/kg, single doses) to mice. The exploratory cylinder, hole board, open field, Rota-rod and sodium pentobarbital-induced hypnosis tests were used to evaluate the CNS depressant effect after 30?min single administration of extracts. From aqueous seeds extract, triterpene glycoside 28-O-[β-l-6-rhamnopyranosyl]-R₁-barrigenol was isolated an active compound.

Results: Crude extracts of T. sylvatica fruits, separated from seed and pericarp, showed sedative effect in mice. The aqueous (ED₅₀?=?4.9?±?0.8?mg/kg) seed extracts is the most active among them. This extract also decrease locomotor activity and disrupt motor coordination of mice. This extract was also the most toxic extract (LD₅₀?=?5.0?±?1.4?mg/kg; i.p.). The triterpene glycoside 28-O-[β-l-6-rhamnopyranosyl]-R₁-barrigenol was identified in this extract as one of the active sedative compounds (ED₅₀?=?0.12?±?0.01?mg/kg) also with toxic effect (LD₅₀?=?1.11?±?0.23?mg/kg).

Conclusion: The results suggest that T. sylvatica fruits has toxic activity rather than CNS depressant activity in mice and that this effect might be related to the presence of 28-O-[β-l-6-rhamnopyranosyl]-R₁-barrigenol, one of the active principles of T. sylvatica fruits with sedative and toxic effect.     

A possible mechanism for anxiolytic and antidepressant effects of alpha- and beta-amyrin from Protium heptaphyllum (Aubl.) March

In the present study, we examined the anxiolytic and antidepressant effects of the mixture of alpha- and beta-amyrin (AMY), pentacyclic triterpenes isolated from the stem bark resin of Protium heptaphyllum. These effects of AMY were demonstrated by the open-field, elevated-plus-maze, rota rod, forced swimming, and pentobarbital-induced sleeping time tests, in mice. In the open-field test, AMY at the doses of 10, 25 and 50 mg/kg, after intraperitoneal or oral administrations, significantly decreased the number of crossings, grooming, and rearing. All these effects were reversed by the pre-treatment with flumazenil (2.5 mg/kg, i.p.), similarly to those observed with diazepam used as a positive standard. In the elevated-plus-maze test, AMY increased the time of permanence and the number of entrances in the open arms. On the contrary, the time of permanence and the number of entrances in the closed arms were decreased. All these effects were also completely reversed by flumazenil, an antagonist of benzodiazepine receptors. In the pentobarbital-induced sleeping time test, AMY at the same doses significantly increased the animals sleeping time duration. In the rota rod test, AMY did not alter motor coordination and, thus, was devoid of effects, as related to controls. Since AMY, at the doses of 10 and 25 mg/kg, showed a sedative effect in the open field test, lower doses (2.5 and 5.0 mg/kg) were used in the forced swimming test, producing a decrease in the immobility time, similarly to that of imipramine, the positive control. The effect of AMI was greater when it was administered 15 min after imipramine (10 mg/kg). However, the antidepressant AMY effects were not altered by the previous administration of paroxetine, a selective blocker of serotonin uptake. In addition, AMY effects in the forced swimming test were totally blocked by reserpine pretreatment, a drug known to induce depletion of biogenic amines. In conclusion, the present work evidenced sedative and anxiolytic effects of AMY that might involve an action on benzodiazepine-type receptors, and also an antidepressant effect where noradrenergic mechanisms will probably play a role.     

Pharmacokinetics,distribution, and disposition of esaxerenone,a novel,highly potent and selective non-steroidal mineralocorticoid receptor antagonist,in rats and monkeys

1.?Esaxerenone (CS-3150) is a novel non-steroidal mineralocorticoid receptor antagonist. The pharmacokinetics, tissue distribution, excretion, and metabolism of esaxerenone were evaluated in rats and monkeys.

2.?Following intravenous dosing of esaxerenone at 0.1–3?mg/kg, the total body clearance and the volume of distribution were 3.53–6.69?mL/min/kg and 1.47–2.49?L/kg, respectively, in rats, and 2.79–3.69?mL/min/kg and 1.34–1.54?L/kg, respectively, in monkeys. The absolute oral bioavailability was 61.0–127% in rats and 63.7–73.8% in monkeys.

3.?After oral administration of [¹⁴C]esaxerenone, the radioactivity was distributed widely to tissues, with the exception of a low distribution to the central nervous system. Both in rats and in monkeys, following oral administration of [¹⁴C]esaxerenone the main excretion route of the radioactivity was feces.

4.?Five initial metabolic pathways in rats and monkeys were proposed to be N-dealkylation, carboxylation, hydroxymethylation, O-glucuronidation, and O-sulfation. The oxidized metabolism was predominant in rats, while both oxidation and glucuronidation were predominant in monkeys.     

Alteration of pentylenetetrazole-induced seizure threshold by chronic administration of ginger (Zingiber officinale) extract in male mice

Abstract

Context: Zingiber officinale Roscoe (Zingiberaceae), or ginger, used in traditional Chinese medicine, has antioxidant activity and neuroprotective effects. The effects of this plant on clonic seizure have not yet been studied.

Objective: The present study evaluated the anticonvulsant effect of ginger in a model of clonic seizures induced with pentylenetetrazole (PTZ) in male mice.

Materials and methods: The anticonvulsant effect of Z. officinale was investigated using i.v. PTZ-induced seizure models in mice. Different doses of the hydroethanolic extract of Z. officinale (25, 50, and 100?mg/kg) were administered intraperitonal (i.p.), daily for 1 week before induction of PTZ. Phenobarbital sodium (30?mg/kg), a reference standard, was also tested for comparison. The effect of ginger on to the appearance of three separate seizure endpoints, e.g., myoclonic, generalized clonic, and tonic extension phase, was recorded.

Results: Hydroethanolic extract of Z. officinale significantly increased the onset time of myoclonic seizure at doses of 25–100?mg/kg (55.33?±?1.91 versus 24.47?±?1.33?mg/kg, p?<?0.001) and significantly prevented generalized clonic (74.64?±?3.52 versus 47.72?±?2.31?mg/kg, p?<?0.001) and increased the threshold for the forelimb tonic extension (102.6?±?5.39 versus 71.82?±?7.82?mg/kg, p?<?0.01) seizure induced by PTZ compared with the control group.

Discussion and conclusion: Based on the results, the hydroethanolic extract of ginger has anticonvulsant effects, possibly through an interaction with inhibitory and excitatory systems, antioxidant mechanisms, and oxidative stress inhibition.     

Sedative,anticonvulsant and behaviour modifying effects of Centranthus longiflorus ssp. longiflorus: a study of comparison to diazepam

The aqueous extract of Centranthus longiflorus ssp. longiflorus (CLE) was investigated for sedative, anticonvulsant and behaviour modifying activity using thiopental sleeping, caffeine induced convulsion and forced swimming depression tests. When the effects of the aqueous extract of CLE (100 mg/kg) was compared to diazepam, it showed similar sedative and anticonvulsant effects to those produced by diazepam (5 mg/kg).     

Anti-inflammatory,Antinociceptive, and Neuropharmacological Activities of Clerodendron viscosum.

Abstract

The crude methanol extract of Clerodendron viscosum. Vent. (Verbenaceae) leaves was evaluated for its anti-inflammatory, antinociceptive, and neuropharmacological activities. When given orally to rats at doses of 200 and 400 mg/kg of body weight, the extract showed a significant (p < 0.001) anti-inflammatory activity against carrageenan-induced rat paw edema comparable with the standard drug phenylbutazone at the dose of 100 mg/kg of body weight. It also produced a significant writhing inhibition in acetic acid–induced writhing in mice at the oral dose of 250 and 500 mg/kg of body weight (p < 0.001), which was comparable with the standard drug diclofenac sodium at the dose of 25 mg/kg of body weight. Moreover, when given intraperitoneally to albino mice, it potentiated the pentobarbital-induced sleeping time (p < 0.001), decreased the open field score in open field test (p < 0.001), decreased the number of holes crossed from one chamber to the other in the hole-cross test (p < 0.001), and decreased the head dip responses in the hole-board test (p < 0.001) at the dose of 250 and 500 mg/kg of body weight. The overall results tend to suggest the anti-inflammatory, antinociceptive, and central nervous system depressant activities of the crude methanol extract of Clerodendron viscosum..     

Bioactive non-sterol triterpenoid from Streblus asper: microwave-assisted extraction,HPTLC profiling,computational studies and neuro-pharmacological evaluation in BALB/c mice

Context: In folk medicine, the stem bark of Streblus asper Lour. (Moraceae) has been reported to possess anticonvulsant activity. However, no systematic/scientific validation is available.

Objective This study explores the constituents in the stem bark, their biosassy-guided isolation and their efficacy in neuro-pharmacological disorders, for validating the traditional claims.

Materials and methods: Microwave-assisted extraction (MAE) technique was employed to obtain the crude extract. The n-hexane, dichloromethane and aqueous fractions were prepared and phytoconstituents were ascertained by phytochemical tests. The isolated compound, betulin, was characterized by different physicochemical and spectral methods, including HPTLC. Finally, neuro-pharmacological evaluations were conducted at 100, 200, 400?mg/kg b.w., p.o. (25, 50, 100?mg/kg b.w. for betulin) doses in BALB/c mice.

Results: The n-hexane fraction (400?mg/kg), and isolated compound betulin (100?mg/kg), showed maximum anticonvulsant activity in maximal electroshock (87.84% and 85.14% seizure inhibition), and isoniazid induced convulsion models (88.85% and 83.18% seizure inhibition), respectively. A dose-dependent attenuation of epileptic seizures was observed, probably through GABArgic mechanism of anticonvulsant action. Moreover, the antidepressant study was also conducted using behavioural models and the results expound that n-hexane and dichloromethane fractions (400?mg/kg) significantly reduced the duration of immobility, as compared to the control.

Discussion and conclusion: This study reports some novel aspects like applying an environmentally benign/green approach of MAE, neuro-pharmacological screening and use of docking studies, for the first time, on the plant S. asper. The findings present a rational explanation for its use in traditional medicine, for the management of neuro-pharmacological disorders.     

Olive oil and its phenolic compounds (hydroxytyrosol and tyrosol) ameliorated TCDD-induced heptotoxicity in rats via inhibition of oxidative stress and apoptosis

Context: Naturally occurring polyphenols including olive oil (OO) and its constituents hydroxytyrosol (HT) and tyrosol (TY), consumed in the Mediterranean diet, have shown to treat various ailments due to their remarkable antioxidant properties.

Objective: The present study investigates the hepatoprotective effects of OO and its phenolic compounds HT and TY against TCDD-induced hepatotoxicity in male Wistar rats.

Materials and methods: TCDD was administered at a dose of 100?ng/kg p.o. for 20?d. Administration of OO (10?ml/kg; oral), HT (0.5?mg/kg; oral), and TY (30?mg/kg; i.p) was started 5?d prior to TCDD administration, and continued for 25?d with or without TCDD administration. At the end of the experiment (25?d), blood was taken for biochemical analyses and liver for the measurement of macromolecular damages, antioxidant status, expressions of CYP1A1, and apoptotic factors.

Results: TCDD administration resulted in significant (p?<?0.05) increase in the level of hepatic stress markers ALT (101.6?±?3.07?IU/l), AST (295.0?±?3.0?IU/l), and ALP (266.66?±?3.7?IU/l). Also, biochemical analyses of liver reported elevation in nitrite and protein carbonyl content and depletion of NQO1 and HO. However, OO, HT, and TY restored the antioxidant status. Protein expressions by Western Blot technique showed an increase in the level of CYP1A1 and Bax and a decreased level of Bcl-2 on TCDD treatment, and vice versa on OO, HT, and TY treatment.

Discussion and conclusion: Our work concludes that dietary supplementation of OO, HT, and TY could serve as a potential preventive drug for TCDD-induced hepatotoxicity.     

The availability of carfecillin and its phenol moiety in rat and dog

1. Studies have shown that hydrolysis of carfecillin to carbenicillin and phenol in vitro occurs in blood, liver and gut tissues of rat and dog. Extremely rapid hydrolysis was observed in the blood and liver of the rat.

2. Absorption studies in intestinally-perfused rats showed that following administration of either [¹⁴C]phenol or [phenol-¹⁴C]carfecillin, the half-life values of radioactivity in the intestinal lumen were 6?min and 47?min respectively.

3. Following oral administration of phenol to rats and dogs at 300?mg/kg and 40?mg/kg respectively, maximum plasma concn. of phenol were 26 μg/ml and 7.8 μg/ml. However, following oral administration of carfecillin to rats and dogs at dose levels of 3000 and 800?mg/kg respectively, no significant amounts of free phenol or intact carfecillin were detected (< 1 μg/ml). The very low concentrations of phenol found after carfecillin administration and the concomitant absence of acute phenol toxicity is explained by the slow absorption of carfecillin and its slow hydrolysis to phenol in the gut lumen.

4. In the dog, phenol which enters the portal circulation as carfecillin appears to undergo significant ‘first pass’ metabolism by the liver, while no such effect was observed if free phenol was administered.     

Pharmacokinetics of a new histamine H2-receptor antagonist,Z-300, in rat and dog

1. The plasma level of Z-300 reached a maximum (C_max) at 30?min after the oral administration of Z-300 to dog, and disappeared from the systemic circulation with a halflife of 8-9 h. The bioavailability of Z-300 was 52% after the oral administration of Z-300, 3?mg/kg. At doses ranging from 3 to 30?mg/kg, C_max and AUC (area under the plasma concentration-time curve) were proportional to the dose. 2. The plasma level of Z-300 reached C_max at 10?min after the oral administration of Z-300 to rat, and disappeared from the systemic circulation with a half-life of 0.8-1.6 h. The bioavailability of Z-300 was 39% after the oral administration of Z-300, 10?mg/kg, and there was a non-linear relationship between the plasma level-time profile of Z-300 and the administered dose (3-50?mg/kg). 3. The binding of Z-300 to plasma protein was 92% in man, 65% in dog and 25% in rat. It is suggested that these species differences were due to the content of α₁-acid glycoprotein (α₁-AG), because Z-300 bound more strongly to α₁-AG than to albumin.     

Formulation,development and optimization of raloxifene-loaded chitosan nanoparticles for treatment of osteoporosis

Abstract

Context: Osteoporosis (OP) is a disease of skeletal system and is associated with fragility fracture at the hip, spine and wrist. Various drugs have been used to treat OP. One of them is raloxifene hydrochloride (RLX), a second-generation selective estrogen receptor modulator (SERM) approved by the USFDA. RLX possesses only 2% absolute bioavailability (BA) by oral route due to its extensive first-pass metabolism.

Objective: The purpose of the current research work was to develop and evaluate RLX-loaded chitosan nanoparticles (CS-NPs) for treatment of OP with enhanced BA.

Materials and methods: The RLX-loaded CS-NPs were prepared by gelation of CS with tripolyphosphate (TPP) by ionic cross-linking. Formulation was optimized and in vitro drug release and in vivo study were performed.

Results and discussions: CS-NPs were formed by the ionic gelation method. The particle size, entrapment efficiency and loading efficiency varied from 216.65 to 1890?nm, 32.84 to 97.78% and 23.89 to 62.46%, respectively. Release kinetics showed diffusion-controlled and Fickian release pattern. In vivo study indicated higher plasma drug concentration with NPs administered intranasally as compared to drug suspension administered through oral route (p?<?0.05). A significantly higher drug concentration in plasma was achieved in 10?min after nasal administration with respect to oral administration.

Conclusion: The results suggest that RLX-loaded CS-NPs have better BA and would be a promising approach for intranasal (i.n.) delivery of RLX for the treatment of OP.     

Comparative Effects of Medetomidine Enantiomers on in vitro and in vivo Microsomal Drug Metabolism

Abstract: The effects of dexmedetomidine, a selective α₂-adrenoceptor agonist, and its levo enantiomer (MPV-1441), on in vitro microsomal P450-dependent drug-metabolizing activities as well as on in vivo aminopyrine elimination and hexobarbital sleeping time were studied. Both enantiomers inhibited the oxidative metabolism of several model substrates and testosterone in rat liver microsomal incubations. Microsomal activities derived from control animals or rats pretreated with phenobarbital were more sensitive to inhibitory effects of dexmedetomidine than those from rats treated with 3-methylcholanthrene. Enzyme activities in human liver microsomes were also inhibited by dexmedetomidine. Retardation of the elimination of aminopyrine was dose-dependent; elimination was marginally retarded with doses up to 100 μg/kg (from 17 to 23 min.; both enantiomers). Higher doses of the levo enantiomer prolonged aminopyrine half-life to 78 (1 mg/kg) and 162 min. (10 mg/kg). The hexobarbital sleeping time was prolonged by the dose of 1 mg/kg of the levo enantiomer (128 min. versus 20 min. in controls), while the dose of 0.1 mg/kg had no effect (23 versus 20 min.). These studies indicate that both enantiomers of medetomidine are inhibitors of microsomal drug metabolism in vitro, but significant effects on aminopyrine elimination or hexobarbital sleeping time are apparent only at doses, which do not allow the use of dexmedetomidine because of excessive sedative effect.     

Alterations in brain amino acid metabolism and inhibitory effects on PKC are possibly correlated with anticonvulsant effects of the isomeric mixture of α- and β-amyrin from Protium heptaphyllum

Abstract

Context: α- and β-Amyrin (AMY) from Protium heptaphyllum (Aubl) March (Burseraceae) is found in Brazil and used in diverse inflammation-related diseases. This species presents a central action, as previously described.

Objective: The objectives were to evaluate the anticonvulsant effect of AMY in mice and to verify the mechanism of action.

Material and methods: Seizures were induced by pentylenetetrazole followed by acute or subchronic treatments (5–25?mg/kg, p.o. and i.p.) and determination of brain amino acids (10 and 25?mg/kg, i.p., 7?d).

Results: In the acute treatment, AMY (10, 25, and 50?mg/kg, p.o.) increased the latency to the first convulsion (FC) by 30, 44, and 40% and time to death (TD) by 36, 52, and 42%, respectively. When administered intraperitoneally, the same doses increased FC by 62, 75, and 73% and TD by 76, 82, and 119%, respectively. Combined with polymixin or staurosporine, AMY (25?mg/kg, i.p.) increased TD by 61 and 63%, respectively, as related to each drug alone. When subchronically administered (25 and 50?mg/kg, i.p.) increased FC by 75 and 101% and TD by 86 and 124%, respectively. AMY increased taurine (116 and 76%) and tyrosine concentrations (135 and 110%) in basal ganglia and hippocampus, respectively, and decreased by 68, 65, and 62% glutamate, aspartate, and GABA in basal ganglia.

Conclusion: Thus, the AMY anticonvulsant activity is related to the GABAergic system and may be linked to the inhibition of the signaling cascade of PKC as well as to alterations in amino acids metabolism.     

Comparison of the Intramuscular,Intranasal or Sublingual Routes of Midazolam Administration for the Control of Soman‐Induced Seizures*

Abstract: This study evaluated the anticonvulsant effectiveness of midazolam to stop seizures elicited by the nerve agent soman when midazolam was administered by different routes (intramuscular, intranasal or sublingual) at one of two different times after the onset of seizure activity. Guinea pigs previously prepared with cortical electrodes to record brain electroencephalographic activity were pre‐treated with pyridostigmine (0.026 mg/kg, intramuscularly) 30 min. before challenge with a seizure‐inducing dose of the nerve agent soman (56 µg/kg, subcutaneously), and 1 min. later, they were administered 2.0 mg/kg atropine sulfate admixed with 25.0 mg/kg 2‐PAM Cl (intramuscularly). Groups of animals were administered differing doses of midazolam by the intramuscular, intranasal or sublingual route at either the onset of seizure activity or 40 min. after the onset of seizure activity that was detected in the electroencephalographic record. When given immediately after seizure onset, the anticonvulsant ED₅₀ of intramuscular midazolam was significantly lower than that of intranasal midazolam, which in turn was significantly lower than sublingual midazolam at that time. At the 40‐min. treatment delay, the anticonvulsant ED₅₀s of intramuscular or intranasal midazolam did not differ and both were significantly lower than the sublingual route. Higher doses of midazolam were required to stop seizures at the 40‐min. treatment delay time compared to immediate treatment. The speed of seizure control for intramuscular or intranasal midazolam was the same while sublingual midazolam acted significantly slower. Midazolam was effective in treating soman‐induced seizures when given by all three routes, but with differences in potency and speed of action.