Anxiolytic-like effect of (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl)methanone (6g) in experimental mouse models of anxiety

Aim:

The present study was designed to investigate the anxiolytic activity of 6g, a novel serotonin type-3 receptor (5-HT₃) receptor antagonist in experimental mouse models of anxiety.

Materials and Methods:

The anxiolytic activity of “6g” (1 and 2 mg/kg, intraperitoneally [i.p.]) was evaluated in mice by using a battery of behavioral tests of anxiety such as elevated plus maze (EPM), light-dark (L&D) box, hole board (HB), and open field test (OFT) with diazepam (2 mg/kg, i.p.) as standard anxiolytic. None of the tested dose of “6g” affects the base line locomotion.

Results:

The new chemical entity “6g” (2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) significantly (P < 0.05) increased the percentage of time spent and number of entries in open arm in the EPM test. In the L&D test compound “6g” (2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) significantly (P < 0.05) increased the total time spent in light compartment as well as number of transitions from one compartment to other. Compound “6g” (1 and 2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) also significantly (P < 0.05) increased number of head dips, whereas significantly (P < 0.05) decreased the head dipping latency in HB test as compared to vehicle control group. In addition, 6g (2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) significantly (P < 0.05) increased the ambulation scores (square crossed) in OFT and there was no significant effect of 6g (1 and 2 mg/kg, i.p.) and diazepam (2 mg/kg, i.p.) on rearing scores.

Conclusion:

In conclusion, these findings indicated that compound “6g” exhibited an anxiolytic-like effect in animal models of anxiety.KEY WORDS: Anxiety, elevated plus maze, hole-board, 5-HT₃ receptor antagonist, open field test     

Effect of nonsteroidal anti-inflammatory drugs on colorectal distension-induced visceral pain

Objectives:

To investigate nonsteroidal anti-inflammatory drugs effectiveness in colorectal distension (CRD)-induced visceral pain model.

Materials and Methods:

Male Sprague–Dawley (250–300 g) rats were anesthetized with ketamine (50 mg/kg, intraperitoneally [i.p.]) and chlorpromazine (25 mg/kg, i.p.). Two bipolar Teflon-coated Ni/Cr wire electrodes (80-M diameter) were placed in the abdominal external oblique muscle for the recording of electromyography. Jugular vein catheter was placed for the administration of drugs. CRD method was applied to evaluate of visceral pain. All drugs (paracetamol, meloxicam, metamizole, and dexketoprofen) administered intravenously.

Results:

Paracetamol 200, 400, and 600 mg/kg did not change the visceromotor response (VMR) when compare with the control group. Meloxicam 2 and 4 mg/kg showed no effect but at doses of 6 mg/kg meloxicam significantly ([51.9 ± 6.4%] [P < 0.001]) decreased VMR compared with the control group. Metamizole 200 mg/kg did not change responses but dose of 400 and 600 mg/kg metamizole reduced VMR. Dexketoprofen 2 and 4 mg/kg did not cause a change in VMR but 6 mg/kg dose significantly reduced response compared with the control group ([43.9 ± 3.9%, 36.8 ± 2.8%, 34.8 ± 2.5%, 42.1 ± 4.8%, 40.7 ± 3.5%, 36.4 ± 2.7%, and 26.1 ± 2.2%]; from 10 min to 70 min, respectively, [P < 0.05]).

Conclusion:

Metamizole, dexketoprofen and meloxicam show antinociceptive effect with different duration of action on CRD-induced visceral pain model. This condition can be explained due to different chemical structures and different mechanisms which play a role in modulation of pain.KEY WORDS: Anti-inflammatory, rat, visceral pain     

A novel method of extraction of bamboo seed oil (Bambusa bambos Druce) and its promising effect on metabolic symptoms of experimentally induced polycystic ovarian disease

Objective:

To evaluate the potential effect of bamboo seed oil in decreasing the major metabolic symptoms associated with letrozole-induced polycystic ovarian disease using female rat model.

Materials and Methods:

A new method of microwave-assisted extraction was developed. Female rats were grouped into four with six animals each. All rats were daily administered with letrozole (1 mg/kg b.wt.) for 21 days except control, and during this period, changes in estrous cycle were observed. After letrozole treatment, Group 2 was considered negative control, Groups 3 and 4 were treated orally with bamboo oil, 0.5 ml/kg b.wt. and 1 ml/kg b.wt., respectively, for 3 weeks (five consecutive estrus cycles). Various parameters such as estrus cycle, blood sugar level, lipid profile, and weights of reproductive system were determined. The characteristics of cystic ovaries were evaluated by histopathological studies.

Results:

The isolated bamboo oil restored estrus cyclicity showed hypoglycemic and hypolipidemic effects. 1 ml/kg b.wt. of bamboo oil showed a marked glucose reduction from 254.04 ± 2.08 to 92.6 ± 1.63, and levels of total cholesterol, very low-density lipoprotein, triglyceride were reduced from 186.45 ± 2.28, 30.07 ± 2.36, 100.36 ± 2.35 to 152.14 ± 2.63, 25.94 ± 1.66, 93.32 ± 1.09, respectively. Histopathological results showed the presence of ovulation and recovery from cystic ovaries.

Conclusion:

A novel and promising drug was isolated in the treatment and maintenance of various metabolic symptoms associated with polycystic ovary disease.KEY WORDS: Bamboo seed oil, Bambusa bambos Druce, cystic ovary, estrus cycle, lipid profile, polycystic ovary disease, polycystic ovary syndrome     

Oral delivery of capsaicin using MPEG-PCL nanoparticles

Aim:

To prepare a biodegradable polymeric carrier for oral delivery of a water-insoluble drug capsaicin (CAP) and evaluate its quality.

Methods:

CAP-loaded methoxy poly (ethylene glycol)-poly(ε-caprolactone) nanoparticles (CAP/NPs) were prepared using a modified emulsification solvent diffusion technique. The quality of CAP/NPs were evaluated using transmission electron microscopy, powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared techniques. A dialysis method was used to analyze the in vitro release profile of CAP from the CAP/NPs. Adult male rats were orally administered CAP/NPs (35 mg/kg), and the plasma concentrations of CAP were measured with a validated HPLC method. The morphology of rat gastric mucosa was studied with HE staining.

Results:

CAP/NPs had an average diameter of 82.54±0.51 nm, high drug-loading capacity of 14.0%±0.13% and high stability. CAP/NPs showed a biphasic release profile in vitro: the burst release was less than 25% of the loaded drug within 12 h followed by a more sustained release for 60 h. The pharmacokinetics study showed that the mean maximum plasma concentration was observed 4 h after oral administered of CAP/NPs, and approximately 90 ng/mL of CAP was detected in serum after 36 h. The area under the curve for the CAP/NPs group was approximately 6-fold higher than that for raw CAP suspension. Histological studies showed that CAP/NPs markedly reduced CAP-caused gastric mucosa irritation.

Conclusion:

CAP/NPs significantly enhance the bioavailability of CAP and markedly reduce gastric mucosa irritation in rats.     

Achieving Therapeutic Vancomycin Levels in Pediatric Patients

Background:

Vancomycin is widely used to treat infections caused by methicillin-resistant Staphylococcus aureus. Data for dosing and monitoring of this drug in pediatric patients are lacking, and clinicians who are treating children often follow guidelines established for adults.

Objectives:

To examine the total daily doses of vancomycin required to reach therapeutic trough levels (i.e., 10–20 mg/L) in infants, children, and adolescents, and to assess the number of pediatric patients in whom therapeutic trough levels are achieved with current empiric doses (40–60 mg/kg daily).

Methods:

This chart review evaluated patients 1 month to 18 years of age for whom vancomycin was prescribed at a single institution between November 2011 and October 2012. Patients’ demographic characteristics, vancomycin dosing parameters, and subsequent steady-state trough concentrations were analyzed.

Results:

Overall, the proportion of patients who reached therapeutic trough levels with current empiric doses was 39% (74 of 188). The mean total daily dose (± standard deviation) required to achieve therapeutic trough levels was 57.8 ± 11.5 mg/kg for patients 1 to 5 months of age, 68.9 ± 15.4 mg/kg for those 6 to 23 months of age, 65.8 ± 13.0 mg/kg for those 2 to 12 years of age, and 55.7 ± 11.8 mg/kg for those 13 to 18 years of age.

Conclusions:

Common empiric vancomycin dosing regimens (40–60 mg/kg daily) are not high enough to achieve trough levels of 10–20 mg/L in the majority of pediatric patients. Given these data, the authors suggest a starting dose of 60 mg/kg daily for patients 1 to 5 months of age and those 13 to 18 years of age and a starting dose of 70 mg/kg daily for patients 6 months to 12 years of age.     

Neuroprotective effect of Tinospora cordifolia ethanol extract on 6-hydroxy dopamine induced Parkinsonism

Objective:

The present study investigates the neuroprotective activity of ethanol extract of Tinospora cordifolia aerial parts against 6-hydroxy dopamine (6-OHDA) lesion rat model of Parkinson''s disease (PD).

Materials and Methods:

T. cordifolia ethanol extract (TCEE) was standardized with high performance thin layer chromatography using berberine. Experimental PD was induced by intracerebral injection of 6-OHDA (8 μg). Animals were divided into five groups: sham operated, negative control, positive control (levodopa 6 mg/kg) and two experimental groups (n = 6/group). Experimental groups received 200 and 400 mg/kg of TCEE once daily for 30 days by oral gavage. Biochemical parameters including dopamine level, oxidative stress, complex I activity and brain iron asymmetry ratio and locomotor activity including skeletal muscle co-ordination and degree of catatonia were assessed.

Results:

TCEE exhibited significant neuroprotection by increasing the dopamine levels (1.96 ± 0.20 and 2.45 ± 0.40 ng/mg of protein) and complex I activity (77.14 ± 0.89 and 78.50 ± 0.96 nmol/min/mg of protein) at 200 and 400 mg/kg respectively when compared with negative control group. Iron asymmetry ratio was also significantly attenuated by TCEE at 200 (1.57 ± 0.18) and 400 mg/kg (1.11 ± 0.15) when compared with negative control group. Neuroprotection by TCEE was further supported by reduced oxidative stress and restored locomotor activity in treatment groups.

Conclusion:

Results show that TCEE possess significant neuroprotection in 6-OHDA induced PD by protecting dopaminergic neurons and reducing the iron accumulation.KEY WORDS: Complex I activity, dopamine, iron asymmetry, levodopa, neurodegeneration     

Coumarin compounds of Biebersteinia multifida roots show potential anxiolytic effects in mice

Background

Traditional preparations of the root of Biebersteinia multifida DC (Geraniaceae), a native medicinal plant of Irano-Turanian floristic region, have been used for the treatment of phobias as anxiolytic herbal preparation.

Methods

We utilized the phobic behavior of mice in an elevated plus-maze as a model to evaluate the anxiolytic effect of the plant extract and bio-guided fractionation was applied to isolate the active compounds. Total root extract, alkaline and ether fraction were administered to mice at different doses 30 and 90 min prior to the maze test. Saline and diazepam were administered as negative and positive controls, respectively. The time spent in open and closed arms, an index of anxiety behavior and entry time, was measured as an index of animal activity.

Results

The total root extract exhibited anxiolytic effect which was comparable to diazepam but with longer duration. This sustained effect of the crude extract was sustained for 90 min and was even more after injection of 45 mg/kg while the effect of diazepam had been reduced by 90 min. The anxiolytic effect factor was only present in the alkaline fraction and displayed its effect at lower doses than diazepam while pure vasicinone as the previously known alkaloid did not shown anxiolytic effect. The effect of the alkaline fraction was in a dose dependent manner starting at 0.2 mg/kg with a maximum at 1.0 mg/kg. Bio-guided fractionation using a variety of chromatographic methods led to isolation and purification of three coumarin derivatives from the bioactive fraction, including umbelliferone, scopoletin, and ferulic acid.

Conclusion

For the first time, bio-guided fractionation of the root extract of B. multifida indicates significant sustained anxiolytic effects which led to isolation of three coumarin derivatives with well-known potent MAO inhibitory and anti-anxiety effects. These data contribute to evidence-based traditional use of B. multifida root for anxiety disorders.     

Effect of calcium on anxiolytic activity of diazepam and verapamil in rats

Objective:

To analyze the role of calcium in anxiety and its effect on anxiolytic activity of diazepam and verapamil.

Materials and Methods:

Study was conducted using female albino rats in light and dark arena; a nonconflicting animal experimental model for anxiety. Animals were divided into six groups with six animals in each group. Test drugs, calcium gluconate (10 mg/kg), diazepam (1 mg/kg), verapamil (5 mg/kg), calcium + diazepam, and calcium + verapamil were administered intraperitoneally. Percentage of time spent in light arena and number of entries into light arena were the two parameters observed for 5 min after 30 min of drug administration. ANOVA test was used for statistical analysis.

Results:

Compared to the control group, diazepam group, and calcium group, only calcium + diazepam group showed considerable increase in mean percentage of time spent in light arena. However, this increase was statistically insignificant. In the case of total number of entries into light arena, animals in calcium + diazepam group showed statistically significant increase in total number of entries into light arena when compared to calcium group and diazepam group.

Conclusion:

Results of the study suggest that calcium may enhance the anxiolytic activity of diazepam, but has no effect on anxiolytic activity of verapamil.     

Effects of Ocimum sanctum and Camellia sinensis on stress-induced anxiety and depression in male albino Rattus norvegicus

Objective:

The aim of this study was to study the ameliorative effects of Ocimum sanctum and Camellia sinensis on stress-induced anxiety and depression.

Materials and Methods:

The study was carried out using male albino rats (200 ± 50 g). The effect of O. sanctum and C. sinensis was evaluated for anxiety and depression using elevated plus maze (EPM) test, open field test (OFT), forced swim test (FST), and tail suspension test (TST).

Result:

Restraint stress (3 h/day for six consecutive days) induced a significant reduction in both the percentage number of entries and time spent in open arms in EPM, and these changes were reversed with post-treatment of aqueous extract of O. sanctum and C. sinensis (100 mg/kg for 6 days). Restraint stress-induced (a) increased latency and (b) decreased ambulation and rearing were also reversed by O. sanctum and C. sinensis in OFT. A significant increase in immobility period was observed in FST and TST after restraint stress. O. sanctum and C. sinensis significantly reduced the immobility times of rats in FST and TST.

Conclusion:

O. sanctum and C. sinensis possess anxiolytic and antidepressant activities.     

Antitumor and antioxidant status of Terminalia catappa against Ehrlich ascites carcinoma in Swiss albino mice

Objective:

The present study was undertaken to evaluate the antitumor and antioxidant status of ethanol extract of Terminalia catappa leaves against Ehrlich ascites carcinoma (EAC) in Swiss albino mice.

Materials and Methods:

The leaves powder was extracted with Soxhlet apparatus and subjected to hot continuous percolation using ethanol (95% v/v). Tumor bearing animals was treated with 50 and 200 mg/kg of ethanol extract. EAC induced in mice by intraperitoneal injection of EAC cells 1 × 10⁶ cells/mice. The study was assed using life span of EAC-bearing hosts, hematological parameters, volume of solid tumor mass and status of antioxidant enzymes such as lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) activities. Total phenolics and flavonoids contents from the leaves extract were also determined.

Results:

Total phenolics and flavonoids contents from the leaves extract were found 354.02 and 51.67 mg/g extract. Oral administration of ethanol extract of T. catappa (50 and 200 mg/kg) increased the life span (27.82% and 60.59%), increased peritoneal cell count (8.85 ± 0.20 and 10.37 ± 0.26) and significantly decreased solid tumor mass (1.16 ± 0.14 cm²) at 200 mg/kg as compared with EAC-tumor bearing mice (P < 0.01). Hematological profile including red blood cell count, white blood cell count, hemoglobin (11.91 ± 0.47 % g) and protein estimation were found to be nearly normal levels in extract-treated mice compared with tumor bearing control mice. Treatment with T. catappa significantly decreased levels of LPO and GSH, and increased levels of SOD and CAT activity (P < 0.01).

Conclusion:

T. catappa exhibited antitumor effect by modulating LPO and augmenting antioxidant defense systems in EAC bearing mice. The phenolic and flavonoid components in this extract may be responsible for antitumor activity.KEY WORDS: Antioxidant, Ehrlich ascites carcinoma, flavonoids, Terminalia catappa, total phenolic     

Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation

Aim:

Co-administration of diltiazem can reduce the dosage of cyclosporine (CsA) in patients with renal transplantation. In this study, we investigated how diltiazem altered the relationship between MDR1 genetic polymorphisms and CsA concentration in Chinese patients with renal transplantation.

Methods:

A total of 126 renal transplant patients were enrolled. All the patients received CsA (2–4 mg·kg⁻¹·d⁻¹), and diltiazem (90 mg/d) was co-administered to 76 patients. MDR1-C1236T, G2677T/A, and C3435T polymorphisms were genotyped. The whole blood concentration was measured using the FPIA method, and the adjusted trough concentrations were compared among the groups with different genotypes.

Results:

In all patients, MDR1-C1236T did not influence the adjusted CsA trough concentration. With regard to MDR1-3435, the adjusted CsA trough concentration was significantly higher in TT carriers than in CC and CT carriers when diltiazam was co-administered (58.83±13.95 versus 46.14±7.55 and 45.18±12.35 ng/mL per mg/kg, P=0.011), and the differences were not observed in patients without diltiazam co-administered. With regard to MDR1-2677, the adjusted CsA trough concentration was significantly higher in TT carriers than in GG and GT carriers when diltiazam was co-administered (61.31±12.93 versus 52.25±7.83 and 39.70±7.26 ng/mL per mg/kg, P=0.0001). The differences were also observed in patients without diltiazam co-administered (43.27±5.95 versus 35.22±7.55 and 29.54±5.35 ng/mL per mg/kg, P=0.001). The adjusted CsA trough blood concentration was significantly higher in haplotype T-T-T and haplotype T-T-C carriers than in non-carriers, regardless of diltiazem co-administered.

Conclusion:

MDR1 variants influence the adjusted CsA trough concentration in Chinese patients with renal transplant, and the influence more prominent when diltiazem is co-administered.     

Anti-inflammatory effect of aqueous extracts of spent Pleurotus ostreatus substrates in mouse ears treated with 12-O-tetradecanoylphorbol-13-acetate

Aims:

To evaluate the application of spent Pleurotus ostreatus substrates, enriched or not with medicinal herbs, as a source of anti-inflammatory compounds.

Subjects and Methods:

P. ostreatus was cultivated on five different substrates: Barley straw (BS) and BS combined 80:20 with medicinal herbs (Chenopodium ambrosioides L. [BS/CA], Rosmarinus officinalis L. [BS/RO], Litsea glaucescens Kunth [BS/LG], and Tagetes lucida Cav. [BS/TL]). The anti-inflammatory activity of aqueous extracts of spent mushroom substrates (SMSs) (4 mg/ear) was studied using an acute inflammation model in the mouse ear induced with 2.5 μg/ear 12-O-tetradecanoylphorbol13-acetate (TPA).

Results:

Groups treated with BS/CA, BS/RO, and BS/LG aqueous extracts exhibited the best anti-inflammatory activity (94.0% ± 5.5%, 92.9% ± 0.6%, and 90.4% ± 5.0% inhibition of auricular edema [IAO], respectively), and these effects were significantly different (P < 0.05) from that of the positive control indomethacin (0.5 mg/ear). BS/TL and BS were also able to reduce TPA-induced inflammation but to a lesser extent (70.0% ± 6.7% and 43.5% ± 6.6% IAO, respectively).

Conclusions:

Spent P. ostreatus substrate of BS possesses a slight anti-inflammatory effect. The addition of CA L. to mushroom substrate showed a slightly synergistic effect while RO L. had an additive effect. In addition, LG Kunth and TL Cav. enhanced the anti-inflammatory effect of SMS. However, to determine whether there is a synergistic or additive effect, it is necessary to determine the anti-inflammatory effect of each medicinal herb.KEY WORDS: Anti-inflammatory activity, medicinal herbs, Pleurotus ostreatus, spent mushroom substrate     

Anti-inflammatory and anti-hyperalgesic effect of all-trans retinoic acid in carrageenan-induced paw edema in Wistar rats: Involvement of peroxisome proliferator-activated receptor-β/δ receptors

Objective:

In this study, we investigated the role of peroxisome proliferator-activated receptors (PPAR)-β/δ receptors in carrageenan-induced inflammation and in the anti-inflammatory effects of all-trans retinoic acid (ATRA).

Materials and Methods:

The λ-carrageenan (0.1 ml of 1% w/v) was injected into intra-plantar (i.pl.) region of the hind paw to produce acute inflammation. Paw volume was measured by using the mercury plethysmography. Further, mechanical and thermal hyperalgesia (TH) were assessed by using the dynamic plantar aesthesiometer and plantar test apparatus, respectively. In addition, markers of oxido-nitrosative stress were assessed spectrophotometrically in the hind paw tissue 5 h post-carrageenan.

Results:

An i.pl injection of carrageenan has produced a marked mechanical hyperalgesia (MH) and TH in ipsilateral paw, which was associated with significant elevated oxido-nitrosative stress. Treatment with ATRA (5 mg/kg/p.o/4 days) and GW0742, a selective PPAR-β/δ receptor agonist (0.1 mg/kg/i.p/4 days), significantly decreased the paw volume, mechanical and TH as compared to vehicle control. Administration of GSK0660, selective PPAR-β/δ receptor antagonist, at a dose of (0.3 mg/kg/i.p/4 days), did not produce a significant effect on carrageenan-induced paw edema, MH and TH. However, co-administration of GSK0660 (0.3 mg/kg/i.p/4 days) along with both ATRA (5 mg/kg/p.o/4 days) and GW0742 (0.1 mg/kg/i.p/4 days), significantly reverse the decreased paw edema, MH, and TH. These observed ameliorative effects on inflammatory pain symptoms are correlated with the extent of reduction of oxido-nitrosative stress.

Conclusion:

From above findings, it can be concluded that ATRA exerts anti-inflammatory and anti-hyperalgesic effect, possibly through activation of PPAR-β/δ and subsequent reduction of oxido-nitrosative stress.     

Prophylactic role of coenzyme Q10 and Cynara scolymus L on doxorubicin-induced toxicity in rats: Biochemical and immunohistochemical study

Objective:

The study aims to evaluate the protective effects of coenzyme Q10 (CoQ10) and Cynara scolymus L (CS) on doxorubicin (dox)-induced toxicity.

Materials and Methods:

Sixty male rats were divided into six groups. Group 1 as a control. Group 2 received dox (10 mg/kg) intraperitoneally. Group 3 received CoQ10 (200 mg/kg). Group 4 received CS (500 mg/kg). Group 5 received CoQ10 (200 mg/kg) and dox (10 mg/kg). Group 6 received CS (500 mg/kg) and dox (10 mg/kg). The rats were then evaluated biochemically and immunohistochemically.

Results:

Dox produced a significant deterioration of hepatic and renal functional parameters. Moreover, an upsurge of oxidative stress and nitrosative stress markers. The expression of alpha-smooth muscle actin (α-SMA) was increased and proliferating cell nuclear antigen (PCNA) expression was decreased. Administration of CoQ10 and CS resulted in a significant improvement of hepatic and renal functional parameters, and an improvement of both α-SMA and PCNA.

Conclusion:

It is concluded that pretreatment with CoQ10 and CS is associated with up-regulation of favorable protective enzymes and down-regulation of oxidative stress. That can be advised as a supplement to dox-treated patients.KEY WORDS: Alpha-smooth muscle actin, doxorubicin, nitrosative, oxidative, proliferating cell nuclear antigen     

Effect of esomeprazole on the pharmacokinetics of carbamazepine

Objective:

Present study was carried out to evaluate effect of esomeprazole on the pharmacokinetics of carbamazepine in rabbits.

Materials and Methods:

Study was conducted at Department of Pharmacology, Postgraduate Institute of Medical Education and Research from March to October 2007. In a parallel design study, carbamazepine 40 mg/kg/day was given orally for 14 days. On day 15, blood samples were taken at various time intervals between 0 and 24 hours. In esomeprazole group, carbamazepine was administered for 14 days as above. On day 8, esomeprazole 2.8 mg/kg/day along with carbamazepine 40 mg/kg/day was administered till 14 days and blood samples were drawn on 15^th day. Plasma levels of carbamazepine were assayed by high-performance liquid chromatography and pharmacokinetic parameters were calculated.

Results:

In all groups there was a decrease in the AUC_0-24 when carbamazepine was coadministered with esomeprazole. The decrease in AUC_0-24 (22.78 ± 4.71 to 10.46 ± 2.29), C_max (2.76 ± 0.77 to 1.412±1.08), T_max (2.83 ± 0.17 to 3 ± 0.40) was statistically significant (P < 0.05) when esomeprazole was given along with carbamazepine. Additionally, absorption and elimination constant were also altered significantly.

Conclusions:

These results suggest that concomitant use of esomeprazole alters the pharmacokinetics of carbamazepine. Confirmation of these results in human studies will warrant changes in carbamazepine dose or frequency when esomeprazole is coadministered.     

Preclinical pharmacokinetics of TPN729MA,a novel PDE5 inhibitor,and prediction of its human pharmacokinetics using a PBPK model

Aim:

TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model.

Methods:

The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance (CL) values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg.

Results:

After a single intravenous administration of TPN729MA at a dose of 1 mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL·min⁻¹·kg⁻¹ in rats and 26.3 mL·min⁻¹·kg⁻¹ in dogs, and the steady-state volumes of distribution (V_ss) were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 mg, and the predicted T_max, C_max and AUC values were within 2-fold of the observed values.

Conclusion:

TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans.     

Reduced exposure of imatinib after coadministration with acetaminophen in mice

Purpose:

Imatinib is an efficacious drug against chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) due to selective inhibition of c-KIT and BCR-ABL kinases. It presents almost complete bioavailability, is eliminated via P450-mediated metabolism and is well tolerated. However, a few severe drug-drug interactions have been reported in cancer patients taking acetaminophen.

Materials and Methods:

Male ICR mice were given 100 mg/kg single dose of imatinib orally or imatinib 100 mg/kg (orally) coadministered with acetaminophen intraperitoneally (700 mg/kg). Mice were euthanized at predetermined time points, blood samples collected, and imatinib plasma concentration measured by HPLC.

Results:

Imatinib AUC_0-12 was 27.04 ± 0.38 mg·h/ml, C_max was 7.21 ± 0.99 mg/ml and elimination half-life was 2.3 hours. Acetaminophen affected the imatinib disposition profile: AUC_0-12 and C_max decreased 56% and 59%, respectively and a longer half-life was observed (5.6 hours).

Conclusions:

The study shows a pharmacokinetic interaction between acetaminophen and imatinib which may render further human studies necessary if both drugs are administered concurrently to cancer patients.     

Inhibition of central angiotensin-converting enzyme with enalapril protects the brain from ischemia/reperfusion injury in normotensive rat

Background and the Purpose of the study

Central Angiotensin Converting Enzyme (ACE) has an important role on cerebral microcirculation and metabolism. However, its role in terms of protecting the brain from ischemic/reperfusion (I/R) injury are debatable. This study evaluated the role of ACE, using enalapril as ACE inhibitor, in protection of the brain from I/R injury during transient focal cerebral ischemia (TFCI) in normotensive rat.

Method

Male Sprague Dawley rats (280–320g) randomly assigned to control ischemic and enalapril pre-treated ischemic groups. Enalapril was injected intraperitoneally 1 h before middle cerebral artery occlusion (MCAO) at the dose of 0.03 or 0.1 mg/kg. Cerebral ischemia was induced by 60 min MCAO followed by 24 hrs reperfusion. After evaluation of neurological deficit scores (NDS) the animal was sacrificed for assessment of cerebral infarction and edema.

Results

TFCI induced cerebral infarctions (283±18 mm³), brain edema (4.1±0.4%) and swelling (9.8±1.5%) with NDS of 3.11±0.36. Non-hypotensive dose of enalapril (0.03 mg/kg) improved NDS (1.37±0.26), reduced cerebral infarction (45%), brain edema (54%) and swelling of the lesioned hemispheres (34%) significantly. However, hypotensive dose of enalapril (0.1 mg/kg) could improve neurological activity (1.67±0.31) and failed to reduce cerebral infarction (276±39 mm³) and swelling (10.4±1.4%).

Conclusion

In the rat model of transient focal cerebral ischemia, inhibition of angiotensin converting enzyme with non-hypotensive doses of enalapril has the benefit of improving neurological activity, reducing cerebral infarction, brain swelling and edema of acute ischemic stroke. Therefore, it is reasonable to conclude that central renin-angiotensin system may participate in ischemic/reperfusion injury of the cerebral cortex.     

Effect of quercetin on lipopolysaccharide induced-sickness behavior and oxidative stress in rats

Objectives:

Gram-negative infections and control infusion of recombinant cytokines in human have been shown to induce sickness behavior characterized by fever, prolong sleep, decreased food and water intake, reduced mobility, depression, and anxiety. Therefore, the present study was undertaken to investigate the effect of bioflavonoid quercetin in lipopolysaccharide (LPS)-induced sickness behavior.

Materials and Methods:

Wistar albino rats were divided into six groups (n=6). Three groups received vehicle and two doses of quercetin (2 and 25 mg/kg, i.p.) respectively for 2 weeks before being challenged with LPS (1 mg/kg, i.p). One group received vehicle for 2 weeks and was challenged with saline on day 15. The per se effect of quercetin (2 and 25 mg/kg, i.p.) was also seen after 2 weeks of dosing. LPS-induced sickness behavior in rats was quantified by measuring time in social exploration, anxiety, food and water consumption, and weight loss. Levels of cytokines (TNF-α, IL-1β, and IL-6) and oxidative stress in rat brain were also analyzed.

Results:

Quercetin (2 and 25 mg/kg) administration significantly (P<0.05) attenuated LPS-induced sickness behavior by modulating cytokines production as well inhibiting LPS-induced oxidative stress.

Conclusions:

Adequate intake of dietary flavonoids (like quercetin) may help promote recovery from sickness behavior.     

A study to investigate capsaicin-induced pressure response in vagotomized rats

Objectives:

Capsaicin is used to evoke pulmonary C reflexes and produces complex pressure responses along with apnea/tachypnea, and bradycardia. In the present study, the mechanisms involved in capsaicin-induced pressure responses were explored.

Materials and Methods:

Tracheal, jugular venous, and femoral artery cannulations were performed in anesthetized adult rats. Blood pressure, respiratory excursions, and electrocardiogram were recorded. Cardiorespiratory reflex changes evoked by jugular venous injection of capsaicin (10 μg/kg) were recorded in vagotomized and antagonist pretreated animals.

Results:

Capsaicin produced triphasic pressure response exhibiting immediate hypotension, intermediate recovery, and delayed hypotension. Time-matched respiratory changes showed apnea, bradypnea, and tachypnea, respectively. Bradycardia occurred at immediate and intermediate phases. After vagotomy, immediate hypotension was abolished; the intermediate recovery was potentiated as hypertensive response; and the delayed hypotension persisted. In case of respiration, the immediate bradypnea persisted and delayed tachypnea was abolished; while heart rate changes at immediate and intermediate phases were abolished. Antagonists of α₁-adrenoceptor (prazosin or terazosin, 0.5 mg/kg), β-adrenoceptor (propranolol, 1 mg/kg), AT₁ receptor (losartan, 10 mg/kg) and Ca²⁺ channel (diltiazem, 1 mg/kg) failed to block the capsaicin-induced intermediate hypertensive response in vagotomized animals.

Conclusions:

These observations implicate the existence of mechanisms other than adrenergic, angiotensinergic, or Ca²⁺ channel-dependent mechanisms for mediating the capsaicin-induced intermediate hypertensive response in vagotomized animals.KEY WORDS: Adrenoceptor antagonist, capsaicin, diltiazem, losartan, prazosin, propranolol