Possible involvement of GABAergic and nitriergic systems for antianxiety-like activity of piperine in unstressed and stressed mice

BackgroundAn investigation was made to explore the possibility of anxiolytic activity of piperine in unstressed and stressed mice along with the underlying role of nitriergic and GABAergic modulation for the noted activity of piperine.MethodsPiperine (5, 10 and 20 mg/kg, ip) was administered to unstressed mice. In another groups of animals, piperine was administered 30 min before subjecting them to immobilization stress for 6 h. Antianxiety activity was evaluated by employing elevated plus maze, light–dark box and social interaction test. Diazepam was employed as standard anxiolytic drug.ResultsPiperine produced significant antianxiety-like activity in unstressed and stressed mice. The anxiolytic-like activity of piperine was comparable to diazepam. In unstressed mice, piperine significantly increased brain GABA levels, but could not produce any change in plasma nitrite levels. Meanwhile, in stressed mice, piperine did not produce any significant change in GABA levels, but significantly decreased nitrite levels. Pre-treatment with aminoguanidine (50 mg/kg, ip), an inducible nitric oxide synthase (NOS) inhibitor, significantly potentiated the anxiolytic-like activity of piperine, as compared to piperine and aminoguanidine alone in stressed mice. On the other hand, pretreatment with 7-nitroindazole (20 mg/kg, ip), a neuronal NOS inhibitor significantly potentiated the antianxiety-like activity of piperine, as compared to piperine and 7-nitroindazole alone in unstressed mice.ConclusionThese data suggest that the piperine produced significant anxiolytic activity in unstressed mice possibly through increase in GABA levels and inhibition of neuronal NOS. On the other hand, antianxiety activity in stressed mice might be through inhibition of inducible NOS.     

Synergistic interaction of gabapentin with tiagabine in the hot-plate test in mice: an isobolographic analysis

This study was aimed at determining the analgesic effect of gabapentin and tiagabine, two antiepileptic drugs that were administered alone and in combination at a fixed ratio of 1:1, in the acute thermal pain model (hot-plate test) in mice.Linear regression analysis was used to evaluate the dose-response relationships between logarithms of antiepileptic drug doses and their resultant maximum possible antinociceptive effects in the mouse hot-plate test. From linear equations, we calculated doses that increased the antinociceptive effect by 50% (ED₅₀ values) for gabapentin, tiagabine and their combination. The type of interaction between gabapentin and tiagabine was assessed using the isobolographic analysis.Results indicated that both antiepileptic drugs produced the definite antinociceptive effect, and the experimentally derived ED₅₀ values for gabapentin and tiagabine, when applied alone, were 504.4 mg/kg and 5.67 mg/kg, respectively.With isobolography, the experimentally derived ED_{50 mix} value for the fixed ratio combination of 1:1 was 139.31 mg/kg and significantly differed from the theoretically calculated ED_{50 add} value, which was 255.04 mg/kg (p < 0.05), indicating the synergistic interaction between gabapentin and tiagabine in the hot-plate test in mice.In conclusion, the combination of tiagabine with gabapentin at a fixed ratio of 1:1 exerted a synergistic interaction in the mouse model of nociceptive pain. If the results from this study could be extrapolated to clinical settings, the combination of tiagabine with gabapentin might be beneficial for pain relief in humans.     

Analgesic activity of 3-mono-substituted derivatives of dihydrofuran-2-one in experimental rodent models of pain

Three derivatives of dihydrofuran-2-one (L-PP, L-PP1, and L-SAL) were administered by intraperitoneal injection and their analgesic activity was assayed in several models of pain. The activity of these derivatives were tested using a hot plate test, a writhing test, capsaicin- and glutamate-induced nociception, along with two models of local anesthesia, including a test for infiltration anesthesia in guinea pigs and the modified tail immersion test in mice. The results of these in vivo experiments show that these three derivatives of dihydrofuran-2-one possess analgesic activity in rodents. The ED₅₀ values of the tested compounds are lower or comparable to the ED₅₀ values of reference compounds (acetylsalicylic acid or morphine). For the most active derivative of dihydrofuran-2-one, L-PP1 (3-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride), the ED₅₀ value was: 1.34 mg/kg, 0.79 mg/kg, 2.01 mg/kg and 3.99 mg/kg in the hot plate, writhing, capsaicin- and glutamate-induced pain tests, respectively.     

Effect of benzothiazole/piperazine derivatives on intracerebroventricular streptozotocin-induced cognitive deficits

BackgroundIn this study, benzothiazole-piperazine compounds were synthesized by condensing the functional groups of donepezil (DNP), FK-960, and sabeluzole, which are known to have therapeutic potential against Alzheimer's disease, with the aim of obtaining new and potent anti-Alzheimer agents.MethodsInitially, acetylcholinesterase/butyrylcholinesterase enzyme inhibition activities of the synthesized test compounds were investigated by Ellman's method. Effects of the compounds on a streptozotocin (STZ) model of Alzheimer's disease (SMAD) were investigated in rats. SMAD was established by intracerebroventricular (icv) injection of STZ (3 mg/kg), bilaterally. The elevated plus maze, Morris water maze, and active avoidance tests were used to examine the effects of test compounds (1,5, and 10 mg/kg) on learning and memory parameters of icv STZ-injected rats. Effects of the test compounds on spontaneous locomotor activities of rats were examined with the activity cage test.ResultsThe compounds B2–B5 and DNP exhibited significant selective inhibitory potencies against acetylcholinesterase. Compounds B2 and B3 at 10 mg/kg doses and compounds B4 and B5 at 5 and 10 mg/kg doses, as well as the reference drug DNP (1 and 3 mg/kg), significantly improved the learning and memory parameters of animals in all cognition tests. None of the test compounds changed spontaneous locomotor activities.ConclusionResults of the present study revealed that compounds B2-B5 repaired the parameters related to the learning and memory deficits of icv STZ-injected rats. Potencies of these test compounds were comparable to the activity of DNP.     

Synergistic interaction of pregabalin with the synthetic cannabinoid WIN 55,212-2 mesylate in the hot-plate test in mice: an isobolographic analysis

BackgroundThe aim of the study was to determine the type of interaction between pregabalin (a 3^rd-generation antiepileptic drug) and WIN 55,212-2 mesylate (WIN – a highly potent non-selective cannabinoid CB1 and CB2 receptor agonist) administered in combination at a fixed ratio of 1:1, in the acute thermal pain model (hot-plate test) in mice.MethodsLinear regression analysis was used to evaluate the dose-response relationships between logarithms of drug doses and their resultant maximum possible antinociceptive effects in the mouse hot-plate test. From linear equations, doses were calculated that increased the antinociceptive effect by 30% (ED₃₀ values) for pregabalin, WIN, and their combination. The type of interaction between pregabalin and WIN was assessed using the isobolographic analysis.ResultsResults indicated that both compounds produced a definite antinociceptive effect, and the experimentally-derived ED₃₀ values for pregabalin and WIN, when applied alone, were 29.4 mg/kg and 10.5 mg/kg, respectively. With isobolography, the experimentally derived ED_{30 mix} value for the fixed ratio combination of 1:1 was 5.7 mg/kg, and differed significantly from the theoretically calculated ED_{30 add} value of 19.95 mg/kg (p < 0.01), indicating synergistic interaction between pregabalin and WIN in the hot-plate test in mice.ConclusionsIsobolographic analysis demonstrated that the combination of WIN with pregabalin at a fixed ratio of 1:1 exerted synergistic interaction in the mouse model of acute thermal pain. If the results from this study could be adapted to clinical settings, the combination of WIN with pregabalin might be beneficial for pain relief in humans.     

Synthesis and pharmacological evaluation of pyrrolidin-2-one derivatives as antiarrhythmic,antihypertensive and α-adrenolytic agents

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for α₁– and α₂ -adrenoceptors (ARs) as well as their antiarrhythmic and antihypertensive activities. The highest affinity for the α₁-AR was displayed by 1-{3-[4-(2-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 7, which binds with a pK_i = 7.13. The highest affinity for the α₂-AR was shown by 1-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 18, which binds with a pK_i = 7.29. Among the compounds tested, 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 13 had the highest prophylactic antiarrhythmic activity in epinephrine-induced arrhythmia in anesthetized rats. Its ED₅₀ value was 1.0 mg/kg intravenously (iv). The compounds with a hydroxy group in the 4-position of the phenyl ring or two substituents such as fluorine atoms in the 2 and 4 positions of the phenyl ring significantly decreased systolic and diastolic pressure in normotensive anesthetized rats at a dose of 2.5 mg/ kg iv, and their hypotensive effects lasted for longer than an hour.     

Comparative evaluation of two dye probes in the rat everted gut sac model for unambiguous classification of P-gp substrate and inhibitor

IntroductionP-glycoprotein (P-gp) plays a crucial role in beta-amyloid efflux from the blood–brain barrier thus becoming a promising pharmacological target in the treatment of Alzheimer's disease (AD). The increase of P-glycoprotein expression and activity by a P-gp inducer could be an effective pharmacological strategy in slowing or halting the progression of AD. Commonly used in vitro methods to classify a P-gp interacting molecule as substrate, inhibitor, modulator or inducer are not always confirmed by in vivo experiments. Here we validate the new dye-probe beta-amyloid (1–40) HiLyte Fluor? TR-labeled (Ab-HiLyte) (Anaspec) P-gp mediated transport in the ex vivo rat everted gut sac assay by using MC18 or MC266, a fully characterized P-gp inhibitor and substrate, respectively, and compare it with the commonly used dye rhodamine.MethodsMale Wistar rats' everted intestines were divided into sacs, each sac was filled with 10 μM Ab-HiLyte with or without 50 μM of MC18 or MC266. Ab-HiLyte concentrations in mucosal fluid were measured spectrophotometrically at 594 nm at each appropriate time.ResultsThe Ab-HiLyte P-gp mediated efflux had a K = 1.00 × 10^? 2 min^? 1 and t_1/2 = 68.74 min, while in the presence of MC18, the Ab-HiLyte efflux turned out to be reduced by an order of magnitude (K = 1.65 × 10^? 3 min^? 1) and the half life is extremely increased (t_1/2 = 419 min). A P-gp substrate, like MC266, determines no change in the efflux of Ab: the kinetic constant and the half life turned out to be unmodified (K = 1.81 × 10^? 2 min^? 1 and t_1/2 = 38.28 min).DiscussionThe results demonstrate that the new dye probe, Ab-HiLyte, could be a probe of choice to unequivocally distinguish between a P-gp substrate and an inhibitor. This is particularly important as different groups obtain a controversial classification of the same compound.     

Gestational manganese intoxication and anxiolytic-like effects of diazepam and the 5-HT1A receptor agonist 8-OH-DPAT in male Wistar rats

In the present study, the effects of prenatal manganese (Mn) intoxication on the anxiolytic-like effects of diazepam and the 5-HT_1A receptor agonist R-(+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) were examined. Wistar dams were exposed to MnCl₂?4H₂O at 5, 000 ppm in the drinking water for the duration of pregnancy. On the day of parturition, Mn was discontinued as an additive in the drinking water. Control rats were derived from dams that consumed tap water and had no exposure to Mn. Male offspring were tested at the age of 12 weeks. The anxiolytic-like effect was assessed in an elevated plus maze device and with the Vogel conflict test. The benzodiazepine anxiolytic diazepam (5 mg/kg, ip) increased the percentage of time spent in open arms in control rats (in comparison to saline treatment) (p < 0.05); no such effect was seen in Mn-exposed rats. Conversely, the serotoninergic 5-HT_1A agonist 8-OH-DPAT (0.3 mg/kg, ip) increased the percentage of time spent in open arms in both experimental groups. In the Vogel drinking test, an anxiolytic-like effect was also observed in both test groups (in controls this was of borderline significance). In contrast, 8-OH-DPAT did not evoke an anxiolytic-like action in control or in Mn-exposed rats in the anticonflict test. In conclusion, findings indicate that gestational Mn exposure attenuated benzodiazepine-mediated anxiolytic-like effects but not those of the 5-HT_1A receptor agonist 8-OH-DPAT.     

Chronic administration of phenytoin induces efflux transporter overexpression in rats

BackgroundEfflux transporters overexpression has been proposed as one of the responsible mechanism for refractory epilepsy by preventing access of the antiepileptic drug to the brain. In this work we investigated whether phenytoin (PHT), could induce efflux transporters overexpression, at different biological barriers and to evaluate the implication it could have on its pharmacokinetics and therapeutic/toxic response.MethodsForty-two adult females Sprague Dawley divided in five groups were treated with oral doses of 25, 50 and 75 mg/kg/6 h of PHT for 3 days and two additionally groups were treated with intraperitoneal (ip) doses of 25 mg/kg/6 h or 100 mg/kg/24 h. At day 4 PHT plasma concentrations were measured and, obtained several organs, brain, parotid gland, liver and duodenum in which were analyzed for the Pgp expression. At day 4 PHT plasma concentrations were measured and several tissues: brain, parotid gland, liver and duodenum were obtained in order to analyze Pgp expression. In order to evaluate the oral bioavailability of PHT, two groups were administered with oral or intraperitoneal doses of 100 mg/kg and plasma level were measured.ResultsAn induction of the expression of efflux transporter mediated by phenytoin in a concentration-and-time dependent manner was found when increasing oral and ip doses of phenytoin, One week after the interruption of ip treatment a basal expression of transporters was recovered.ConclusionsOverexpression of efflux transporters can be mediated by inducer agents like PHT in a local-concentration dependent manner, and it is reversible once the substance is removed from the body. The recovery of basal Pgp expression could allow the design of dosing schedules that optimize anticonvulsant therapy.     

Development of a high-throughput electrophysiological assay for the human ether-à-go-go related potassium channel hERG

IntroductionDrug-induced prolongation of the QT interval via block of the hERG potassium channel is a major cause of attrition in drug development. The advent of automated electrophysiology systems has enabled the detection of hERG block earlier in drug discovery. In this study, we have evaluated the suitability of a second generation automated patch clamp instrument, the IonWorks Barracuda, for the characterization of hERG biophysics and pharmacology.MethodsAll experiments were conducted with cells stably expressing hERG. Recordings were made in perforated patch mode either on a conventional patch clamp setup or on the IonWorks Barracuda. On the latter, all recordings were population recordings in 384-well patch plates.ResultsHERG channels activated with a V_1/2 = ? 3.2 ± 1.6 mV (n = 178) on the IonWorks Barracuda versus ? 11.2 ± 6.1 mV (n = 9) by manual patch clamp. On the IonWorks Barracuda, seal resistances and currents were stable (< 30% change) with up to six cumulative drug additions and 1-min incubations per addition. Over 27 experiments, an average of 338 concentration–response curves were obtained per experiment (96% of the 352 test wells on each plate). HERG pharmacology was examined with a set of 353 compounds that included well-characterized hERG blockers. Astemizole, terfenadine and quinidine inhibited hERG currents with IC₅₀ values of 159 nM, 224 nM and 2 μM, respectively (n = 51, 10 and 18). This set of compounds was also tested on the PatchXpress automated electrophysiology system. We determined through statistical methods that the two automated systems provided equivalent results.DiscussionEvaluating drug effects on hERG channels is best performed by electrophysiological methods. HERG activation and pharmacology on the IonWorks Barracuda automated electrophysiology platform were in good agreement with published electrophysiology results. Therefore, the IonWorks Barracuda provides an efficient way to study hERG biophysics and pharmacology.     

Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various experimental seizure models in mice

This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The neurotoxicity of QUAN-0808 was investigated using the rotarod neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED₅₀ = 6.8 mg/ kg) and lower neurotoxicity (median toxic dose, TD₅₀ = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED₅₀ = 24 mg/kg) against MES-induced seizure with low neurotoxicity (TD₅₀ > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.     

Psychometric properties of the Turkish version of the Internet Addiction Test (IAT)

ObjectiveOf many instruments developed to assess Internet addiction, the Internet Addiction Test (IAT), an expanded version of the Internet Addiction Diagnostic Questionnaire (IADQ), has been the most widely used scale in English and non-English speaking populations. In this study, our aim was to investigate the psychometric properties of short and expanded versions of the IAT in a Turkish undergraduate sample.MethodOverall, 455 undergraduate students from Turkey aged between 18 and 30 participated in the study (63.53% were females). Explanatory and confirmatory factor analytic procedures investigated factor structures of the IADQ and IAT. The Internet Addiction Scale (IAS), Coping Inventory for Stressful Situations (CISS), Obsessive Compulsive Inventory—Revised (OCI-R) and Dissociative Experiences Scale (DES) were administered to assess convergent and divergent validities of the IADQ and IAT. Internal consistency and 15-day test–retest reliability were computed.ResultsIn the factorial analytic investigation, we found a unidimensional factor structure for each measure fit the current data best. Significant but weak to moderate correlations of the IADQ and the IAT with the CISS, OCI-R and DES provided empirical evidence for divergent validity, whereas strong associations with the subscales of the IAS pointed to the convergent validity of Young's Internet addiction construct. Internal consistency of the IADQ was weak (α = 0.67) and of the IAT was high (α = 0.93). Temporal reliability of both instruments was very high (α = 0.81 and α = 0.87; respectively).ConclusionThe IAT revealed promising and sound psychometric properties in a Turkish sample.     

Influence of agmatine on the protective action of numerous antiepileptic drugs against pentetrazole-induced seizures in miceA

The aim of this study was to assess the influence of agmatine (an endogenous neuromodulator/neurotransmitter in the brain) on the protective action of numerous classical and second-generation antiepileptic drugs (clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, vigabatrin, and valproate) in the mouse pentetrazole-induced clonic seizure model.The results indicate that agmatine (up to 100 mg/kg, ip, 45 min before the test) did not alter the threshold for pentetrazole-induced clonic seizures in mice. However, agmatine (100 mg/kg, ip) significantly attenuated the anticonvulsant effects of vigabatrin against pentetrazole-induced clonic seizures by elevating the ED₅₀ value of vigabatrin from 517.5 to 790.3 mg/kg (p < 0.01). In contrast, agmatine at a dose of 50 mg/kg did not significantly affect the anticonvulsant action of vigabatrin, although a reduction in the ED₅₀ value of the antiepileptic drug from 517.5 to 629.1 mg/kg was documented. Moreover, agmatine at doses of 50 and 100 mg/kg (ip) had no significant impact on the anticonvulsant action of clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, or valproate in pentetrazole-induced seizures in mice.In conclusion, the combination of agmatine with vigabatrin seems to be unfavorable due to the reduction of the anticonvulsant effect of vigabatrin after concomitant administration of agmatine in the pentetrazole-induced seizure model. Therefore, the utmost caution is advised when combining agmatine with vigabatrin in further clinical settings.     

Comparison of the effects of crocin,safranal and diclofenac on local inflammation and inflammatory pain responses induced by carrageenan in rats

BackgroundCrocin and safranal are the active substances of saffron and have many biological properties. In the present study, we compared the effects of crocin, safranal and diclofenac on local inflammation and its induced pain in rats.MethodsLocal inflammation was induced by intraplantar (ipl) injection of carrageenan (100 μl, 2%). Paw thickness was measured before and after carrageenan injection. Inflammatory pain responses including cold allodynia, mechanical allodynia and hyperalgesia were assessed using acetone spray and von Frey filament tests, respectively. The number of neutrophils in inflammatory zone was counted 6.5 h after injection of carrageenan.ResultsCarrageenan produced edema, cold allodynia, mechanical allodynia and hyperalgesia and caused neutrophil infiltration in paw tissues. Crocin at doses of 25, 50 and 100 mg/kg, safranal at doses of 0.5, 1 and 2 mg/kg and diclofenac (as a reference drug) at a dose of 10 mg/kg attenuated edema, suppressed inflammatory pain responses and decreased the number of neutrophils.ConclusionThe present study showed anti-inflammatory and antinociceptive activities for crocin, safranal and diclofenac in carrageenan model of local inflammation and inflammatory pain.     

Concomitant use of tramadol and venlafaxine – evaluation of antidepressant-like activity and other behavioral effects in rats

BackgroundThe aim of this study was to evaluate antidepressant-like effect (Porsolt test), locomotor activity and motor coordination of joint administration of tramadol (TRM) and venlafaxine (VEN) in rats.MethodsThe tests were performed on male Wistar rats after single and chronic treatment (7 and 14 days) with TRM intraperitoneally (ip) and VEN orally (po) administered once a day. The controls were given 0.5% carboxymethylcellulose (CMC) solution (0.5 ml per rat, ip and po).ResultsIt was found that combination of TRM (5 mg/kg ip) with VEN (20 mg/kg po) caused an increased antidepressant effect compared to TRM and VEN administered alone, with no effect on locomotor activity or motor coordination in rats, which may be of clinical significance.It was also observed that reduced time of active swimming of animals in Porsolt test with an increased dose (10 and 20 mg/kg) and time of administration (7 and 14 days) of TRM were correlated with a decreased locomotor activity in rats. It may indicate the development of tolerance to TRM’s antidepressant effect in rats during chronic treatment with doses higher than 5 mg/kg.ConclusionIt can be expected that combination of low doses of TRM and VEN could potentially be feasible and relatively safe in cases with acute pain with co-existing depression, however, further investigations are needed.     

Effect of combined treatment with mirtazapine and risperidone on the MK-801-induced changes in the object recognition test in mice

BackgroundSeveral clinical reports have suggested that the mirtazapine-induced augmentation of risperidone activity may effectively improve treatment of the negative and certain cognitive symptoms of schizophrenia.MethodsThe aim of the present study was to evaluate the effect of mirtazapine and risperidone, given separately or jointly, on the impact of MK-801(an NMDA receptor antagonist), given prior to the first introductory session, on the object recognition memory in mice. To this end, we used the object recognition test in which animals were tested for the ability to discriminate between an old, familiar and a novel object. Mirtazapine (2.5 or 5 mg/kg) and risperidone (0.01 mg/kg) were given 30 min before MK-801, and MK-801 (0.1 or 0.2 mg/kg) was administered 30 min before the first introductory session. Memory retention was evaluated 1.5 h after the introductory session.ResultsThe obtained results showed that MK-801 (0.2 mg/kg) decreased memory retention when given before the introductory session. Co-treatment with risperidone (0.01 mg/kg) and mirtazapine (2.5 or 5 mg/kg) abolished the effect of MK-801, whereas those drugs given separately did not change the action of MK-801.ConclusionsThe obtained results suggest that mirtazapine may enhance the antipsychotic-like effect of risperidone in the animal test modeling some cognitive symptoms of schizophrenia. Further studies are necessary to elucidate its mechanism of action.     

Influence of orphenadrine upon the protective activity of various antiepileptics in the maximal electroshock-induced convulsions in mice

Orphenadrine is an anticholinergic drug used in the treatment of Parkinson’s disease, and is also known to exert nonspecific antagonistic activity at the phencyclidine binding site of the N-methyl-D-aspartate (NMDA) receptor. The aim of this study was to assess the anticonvulsant properties of orphenadrine and to evaluate its effect on the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures in mice. Orphenadrine given at a dose of 5.65 mg/kg elevated the electrical seizure threshold from 5.7 (5.4 – 6.1) to 6.8 (6.3–7.3) mA, while a dose of 2.8 mg/kg was ineffective. The ED₅₀ values of orphenadrine administered 10,30 and 120 min before maximal electroshock-induced convulsions were 16.8 (11.3–25.1), 17.8 (15.7–20.0) and 25.6 (23.3–28.3) mg/kg, respectively. Orphenadrine at a sub-threshold dose of 2.8 mg/kg significantly enhanced the anticonvulsant activity of valproate by reducing its ED₅₀ value from 315.8 (270.0–369.4) to 245.9 (207.1–292.0) mg/kg without affecting the free plasma levels of valproate. However, orphenadrine failed to enhance the protective activity of carbamazepine, phenytoin, phenobarbital, lamotrigine, topiramate, or oxcarbazepine against maximal electroshock-induced seizures.     

Synthesis and antiviral activities of a novel class of thioflavone and flavonoid analogues

A novel class of thioflavone and flavonoid derivatives has been prepared and their antiviral activities against enterovirus 71 (EV71) and the coxsackievirus B3 (CVB3) and B6 (CVB6) were evaluated. Compounds 7d and 9b showed potent antiviral activities against EV71 with IC₅₀ values of 8.27 and 5.48 μM, respectively. Compound 7f, which has been synthesized for the first time in this work, showed the highest level of inhibitory activity against both CVB3 and CVB6 with an IC₅₀ value of 0.62 and 0.87 μM. Compounds 4b, 7a, 9c and 9e also showed strong inhibitory activities against both the CVB3 and CVB6 at low concentrations (IC₅₀=1.42?7.15 μM), whereas compounds 4d, 7c, 7e and 7g showed strong activity against CVB6 (IC₅₀=2.91–3.77 μM) together with low levels of activity against CVB3. Compound 7d exhibited stronger inhibitory activity against CVB3 (IC₅₀=6.44 μM) than CVB6 (IC₅₀>8.29 μM). The thioflavone derivatives 7a, 7c, 7d, 7e, 7f and 7g, represent a new class of lead compounds for the development of novel antiviral agents.     

In vitro assessment of paraoxon effects on GABA uptake in rat hippocampal synaptosomes

Treating organophosphate poisoning is achieved mainly using compounds with anticholinergic characteristics. Nevertheless currently the focus of attention is aimed at examining their interference with other neurotransmitter systems. The present investigation studied the potential interactions between paraoxon and GABA uptake in hippocampal synaptosomes. Wistar rats weighing 200–250 g were used. Hippocampal synaptosomes were prepared and incubated with [³H] GABA in the presence of different doses of paraoxon for 10 min at 37 °C; and were then layered in chambers of a superfusion system and the [³H] GABA uptake was measured. Our finding revealed that mean GABA uptake decreased by 21%, 42%, 37%, 20%, and 8% of the corresponding control values in the presence of paraoxon concentrations of 0.01, 0.1, 1, 10, and 100 μM, respectively which was significant at 0.1 and 1 μM of paraoxon (P < 0.05). In conclusion, micromolar concentrations of paraoxon were shown to interfere with GABA uptake in hippocampal synaptosomes, which indicates the GABA transporters may play a role in organophosphate-induced convulsions.     

A randomized,controlled trial of a clinical pharmacist intervention in microdiscectomy surgery – Low dose intravenous ketamine as an adjunct to standard therapy

AimThe hypothesis that postoperative pain would be reduced by using 1 μg/kg/min of ketamine, both intra- and post-operatively, for lumbar microdiscectomy surgery was assessed by measuring morphine consumption. Patient side effects were reported.MethodsForty-five patients undergoing microdiscectomy surgery were randomized under double-blind conditions into three groups: Group1 (G1) received normal saline, Group 2 (G2) ketamine (1 μg/kg/min) intra-operatively and Group 3 (G3) ketamine (1 μg/kg/min) both intra- and post-operatively. Morphine consumption, pain scores, nausea and vomiting, CNS disorders were recorded for 24 h post surgery. This study was conducted by applying the concept of a clinical pharmacist intervention.ResultsThe time for the first analgesia demand dose was significantly shorter (P < 0.05) in G117 ± 1.7 min than for G2 and G3. In G3 morphine consumption 6, 12, and 24 h after surgery was 3 ± 2.26, 9.2 ± 2.11 and 26.9 ± 2.71 mg. Total morphine consumption was significantly lower for G3 than for G1 or G2 (P < 0.05). The visual analog scale score (VAS) values were significantly lower in G3 (P < 0.05) than for the other groups during the first 24 h. The rate of nausea and vomiting was significantly higher in G1 vs G3 (P < 0.05). No difference in drug induced CNS disturbances was observed among the groups.ConclusionsUsing 1 μg/kg/min of ketamine hydrochloride intra- and post-operatively for microdiscectomy surgery could be an adjunct therapy to reduce postoperative morphine consumption minimizing its side effects.Collaborative clinical pharmacy practice on the basis of pharmacology had an effective role in improving the general outcome of microdiscectomy surgery.