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A simple, rapid and specific HPLC method has been developed and validated for the simultaneous determination of imatinib, a tyrosine kinase inhibitor, and its major metabolite, CGP74588, in human plasma. The optimization of the HPLC procedure involved several variables, of which the influences of each was studied. After a series of preliminary-screening experiments, the composition of the mobile phase and the pH of the added buffer solution were set as the investigated variables, while the resolution between imatinib and CGP74588 peaks, the retention time and the imatinib peak width were chosen as the dependent variables. Applying D-optimal design, the optimal chromatographic conditions for the separation were defined. The method proved to show good agreement between the experimental data and predictive values throughout the studied parameter range. The optimum assay conditions were achieved with a Chromolith™ Performance RP-8e 100 mm × 4.6 mm column and a mixture of methanol/acetonitrile/triethylamine/diammonium hydrogen phosphate (pH 6.25, 0.048 mol L(-1)) (20:20:0.1:59.9, v/v/v/v) as the mobile phase at a flow rate of 2 mL min(-1) and detection wavelength of 261 nm. The run time was less than 5 min, which is much shorter than the previously optimized methods. The optimized method was validated according to FDA guidelines to confirm specificity, linearity, accuracy and precision.

Warfarin is widely used anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders and exerts its anticoagulant effect by inhibiting the vitamin K epoxide reductase. To determine the impact of genetic variants of the vitamin K epoxide reductase complex subunit 1 gene (VKORC1) on the anticoagulant response to warfarin, polymorphisms in exon 1, exon 3, and 3’-untranslated region (3’ UTR) were assessed. Results: Sixty patients (34 males and 26 females) with stable INR (2–3) were selected from cardiology and anticoagulant clinic. Three VKORC1 frameshift mutations were detected. The first frameshift mutation was nucleotide deletion (91delCC) in exon 3 (1 patient). The second variation was nucleotide addition (51addCT) in exon 3 (2 patients). All the 3 patients reported bleeding during warfarin use, while no other bleeding was reported during the study period. Warfarin maintenance dose was significantly different between 3 patients with mutations and patients without mutations. The use of a fixed-dose warfarin for all patients and in range INR may not be sufficient for warfarin monitoring. Many factors including unknown ones may also play an important role in highly variable response among patients. Our data for the first time, suggested a new possible call for screening to reduce the risk of bleeding and guide for dosing.

Introduction: Estimation of target dose with high precision is a key goal in pharmaceutical studiesthat achieving this goal depends greatly on an efficient design. One of these adequate designs is adaptivedesign. The median effective dose is an important dose that is criterion for assessment the power of amedicine. The purpose of this study was estimation of the median effective dose of anti spasmodicmedicine in adaptive design and comparison the precision of the estimation with conventional paralleldesign.Materials and Methods: Seventy guinea pigs were divided into seven groups (n=10) and each groupwas studied for one dose. One of the adaptive designs that uses frequently in pharmaceutical studies isup-and-down design. In this design, the number of samples in each dose was determined. Then forestimation of median effective dose, we used a method of the combination of dose-response logistic,dose-response log-linear, linear and Emax models and R software was used for data analysis.Result: In parallel design, number of samples in each dose was 10, but in adaptive design, number ofsamples in 10−3 and 10−4 doses was 21 and other doses were 7. MSE in parallel design was 59 and inadaptive design were 21. Estimation of median effective dose in dose-response logistic was8×10−5 , indose-response log-linear8×10−6 , in Emax 8×10−7 and in linear model was 5×10−6 . Using combinationof the four models in adaptive design, median effective dose was estimated12×10−5 .Conclusion: In addition to flexibility of adaptive design that concentrates the allocation ofobservations near the target dose, it seems this design is more efficient than parallel design in medicinalstudies.

Thiacetazone (TAZ), one of the oldest known antituberculosis drugs, causes severe skin reactions in patients co-infected with tuberculosis and human immunodeficiency virus (HIV). KBF611 is a new fluorinated thiacetazone analogue that has shown strong antituberculosis effects. In order to provide valuable information for subsequent preclinical development, pharmacokinetics of KBF611 and its analogue (TAZ) were studied and compared in two animal species (mice and rabbits) following intravenous and oral administration, and pharmacokinetic parameters were characterized. According to the calculated parameters, KBF611 showed a more favourable pharmacokinetics profile than TAZ in terms of half-life (0.89 h compared with 0.57 in mice, p < 0.05, and 2.71 compared with 0.98 in rabbits, p < 0.001) and volume of distribution (1.45 l kg(-1) compared with 0.86 l kg(-1) in mice, p < 0.05, and 1.01 l kg(-1) compared with 0.41 l kg(-1) in rabbits, p < 0.001) for tuberculosis therapy. In rabbits, the oral bioavailability of KBF611 was markedly lower than mice (39% compared with 82%), which may be attributed to a higher presystemic metabolism in rabbit liver. The results of in vivo studies on the metabolism of KBF611, supported by liquid chromatography-mass spectrometry (LC-MS) analysis, showed that the incorporation of a fluorine atom to the TAZ structure made the molecule susceptible to N-deacetylation, a pathway not seen in TAZ metabolism. In summary, KBF611 could be considered a suitable candidate for further preclinical and clinical evaluation.

Objectives Imipramine has been used for over four decades (early reports in 1960s) for the treatment of nocturnal enuresis, although the reason for its effect is not clear. Imipramine is a tertiary amine, which may act both in the periphery and/or pass through the blood-brain barrier (BBB) in unionized form and exhibit a central effect. Since imipramine has anti-cholinergic properties, some believe it may exert its anti-enuretic effect by affecting peripheral cholinergic receptors, i.e. its anti-enuretic effect may be due to peripheral anti-cholinergic properties, whereas others think it can pass through the BBB and interact with central nervous system (CNS) receptors. If the anti-enuretic effect of imipramine is due to its peripheral anti-cholinergic effects, its entrance into the CNS is unnecessary. Therefore, the synthesis of a form of imipramine that can exhibit peripheral anti-cholinergic effects but does not have CNS adverse effects would have a safer drug profile in this case. On the other hand, if the anti-enuretic effect of imipramine is primarily due to its action on the CNS, a form of imipramine that cannot pass through the BBB has no effect on nocturnal enuresis treatment and thus may help to clarify the mechanism of action of imipramine in nocturnal enuresis treatment. Methods This article describes the synthesis and evaluation of the anti-cholinergic effect of a new bis derivative of imipramine, which contains two imipramine units in its structure. Key findings The compound exhibited anti-cholinergic activity comparable with that of imipramine on isolated guinea pig ileum. Conclusions Being a quaternary ammonium, this compound is not expected to be able to cross the BBB and thus would cause fewer CNS side effects.

Sex differences are observed in the development of tolerance to the antinociceptive effect of opioid drugs such as morphine, but the precise underlying mechanism remains unclear. There are evidences about the interaction between gonadal hormones and neuromodulatory systems including opioidergic and glutamatergic systems. We examined the sex differences and the role of gonadal hormones on the glutamate level in the nucleus accumbens in morphine tolerant rats using in vivo microdialysis. A microdialysis probe was implanted into the left nucleus accumbens core of rats and CSF (cerebrospinal fluid) dialysates were collected. The concentration of glutamate was measured by high-performance liquid chromatography with a fluorescence detector. The results showed that after chronic morphine administration, tolerance to antinociceptive effects of morphine was significantly greater in male rats (P

Benzodiazepines (BZDs) are widely used in clinical practice as anxiolytics, hypnotics, anticonvulsants and muscle relaxants. However, they have some undesired effects including memory problems. In continuing our research on novel benzodiazepine ligands, we are looking for ligands with less adverse effects. Previously, 4 novel derivatives of 2-phenoxy phenyl-1,3,4-oxadiazole were synthesized as agonists of BZD receptors. In this study, the pharmacological effects of novel compounds were evaluated. Pentobarbital induced loss of righting reflex, elevated plus maze, open-field locomotor activity and passive avoidance test were used to evaluate the sedative-hypnotic, anxiolytic and amnesic effects of compounds respectively. The results revealed that the novel compounds with NH2, SH and SCH3 substituents at the 2-position of the oxadiazole ring increase righting reflex time significantly. In the elevated plus maze test none of the derivatives increased open arm duration and open arm entry indicating no anxiolytic properties. Moreover, the novel compounds didn’t influence step-down latencies in the mice. The fact that the hypnotic activity of these compounds were significantly reduced by flumazenil, confirmed that this effect is mediated by BZD receptors.

This study was designed to evaluate and determine the free radical scavenging activity and total flavonoid content of the ethanol extract of six Iranian Achillea. species (A. micrantha. Willd Asteraceae, A. filipendula. Lam., A. millefolium. L., A. tenuifolia. Lam., A. vermicularis. Trin and A. wilhelmsii. C. Koch.) (Asteraceae) and investigate the possible composition-activity relationship. The free radical scavenging activity of the extracts was characterized by the DPPH scavenging test. The total flavonoid content of the extracts was determined using the colorimetric technique by AlCl3 reagent. Two of six extracts [A. micrantha. (IC50 = 32.92 µg/ml) and A. millefolium. (IC50 = 49.43 µg/ml)] revealed a suitable free radical scavenging activity. The strongest activity was found for A. micrantha. (IC50 = 32.92 µg/ml), whereas the activity of A. wilhelmsii. (IC50 = 118.90 µg/ml) was significantly lower than the others. On the other hand, the extracts of A. vermicularis. (58.17 µg/mg) and A. wilhelm...

The current experiments were designed to study the antinociceptive effects of intrathecal (i.t.) administration of cannabinoid CB1 receptor and 2-adrenoceptor drugs in the nociceptive processing and also their receptor interactions. Different doses of a cannabinoid receptor agonist, CP 55,940, and an 2-adrenoceptor agonist, clonidine induced a dose-dependent antinociception in both phases of the formalin test. CP 55,940-induced antinociception was reduced by pretreatment of a selective cannabinoid CB1 receptor antagonist, SR 141716A, but not by pretreatment with an 2-adrenoceptor antagonist, yohimbine in both phases of the test. However, yohimbine and SR 141716A attenuated the antinociception induced by clonidine in the early phase but not in the late phase of the test. While SR 141716A by itself did not influence pain behaviour, the reversal effect of clonidine by SR 141716A indicate that clonidine stimulate the release of endocannabinoid(s). In conclusion, our findings may suggest that: (1) spinal cannabinoid and 2-adrenoceptor systems are able to induce antinociception in both phases of formalin test, and (2) the cannabinoid system may be involved in the antinociception induced by adrenoceptors in the early phase.

A series of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles was designed and synthesized as anticonvulsant agents. Conformational analysis and superimposition of energy minima conformers of the designed molecules on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at para position of benzylthio moiety had the best anticonvulsant activity. It seems this effect is mediated through benzodiazepine receptors mechanism.

The post-training administration of tricyclic antidepressant imipramine impairs memory consolidation in the passive avoidance task. The present study investigated the effects of intrahippocampal (i.h.) injection of adrenoceptor agents on imipramine-induced (2-8 microg/rat) amnesia. The administration of the alpha1-adrenoceptor agonist phenylephrine (0.05 microg/rat) and the alpha1-adrenceptor antagonist prazosin (0.5 microg/rat) did not alter the effect of imipramine. The lower doses of phenylephrine (0.005 and 0.015 microg/rat) impaired, while the higher dose of the drug (0.025 and 0.05 microg/rat) improved retention. The effect of phenylephrine was not altered by prazosin (0.5 and 1 microg/rat) pretreatment, although prazosin alone decreased retention latencies. The alpha2-adrenoceptor antagonist yohimbine (0.5 and 1 microg/rat) decreased the response induced by imipramine. However, the alpha2-adrenoceptor agonist clonidine (0.08 microg/rat) did not alter the effect of the drug. Clonidine (0.15 and 0.3 microg/rat) by itself decreased, while yohimbine (1 and 2 microg/rat) increased retention latencies. Yohimbine pretreatment attenuated the effect of clonidine. It is concluded that alpha2-adrenoceptor mechanism(s) may be involved in imipramine-induced impairment of memory.

The problem of drug dependence still remains unresolved. In the present study the effects of an essential oil of Pimpinella anisum (Umbeliferae) on the expression and acquisition of conditioned place preference (CPP) induced by morphine in mice were investigated. Subcutaneous (s.c.) injections of morphine (2-5 mg/kg) produced place preference in a dose-dependent manner. Furthermore, intraperitoneal (i.p.) injection of the essential oil of P. anisum (0.125-0.5 ml/kg) induced conditioned place aversion (CPA). The mice which have received the essential oil of the P. anisum (0.125-0.5 ml/kg, i.p.) as well as the oil with morphine (5 mg/kg, s.c.) reduced the morphine effect. Administration of the essential oil of P. anisum (0.125-0.5 ml/kg, i.p.) on the test day did not show any effect on morphine action. It appeared that pre-administration with bicuculline (GABA(A) receptor antagonist) (1.5 mg/kg, i.p., 20 min before essential oil) diminished the effect of the essential oil of the P. anisum on morphine which induced CPP, but this result was not found for the GABA(B) receptor antagonist, CGP35348 (200 and 400 mg/kg, i.p., 10 min before essential oil). In conclusion, it appeared that the essential oil of the P. anisum may reduce the morphine effects via a GABAergic mechanism.

New derivatives of 2-[2-(2-Chlorophenoxy)phenyl]-1,3,4-oxadiazole as candidates for agonistic effect on benzodiazepine receptors were synthesized. Conformational analysis and superimposition of energy minima conformers of the novel compounds on estazolam, a known benzodiazepine agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. In pharmacological evaluation, anticonvulsant activity of the compounds determined by pentylenetetrazole-induced lethal convulsion and maximal electroshock tests. The results showed that the introduction of an amino substituent in position 5 of 1,3,4- oxadiazole ring generates compound 6 that has a considerable effect. Compound 8 with a hydroxyl substituent on position 5 of 1,3,4- oxadiazole ring showed a relatively mild anticonvulsant activity, which was significantly weaker than that of diazepam and compound 6. Anticonvulsant effects of active compounds were antagonized by flumazenil, an antagonist of benzodiazepine receptors, indicating the involvement of benzodiazepine receptors in these effects.

Effects of different doses of adenosine receptor agonists and antagonists on naloxone-induced jumping and diarrhea in morphine-dependent mice were studied. The adenosine A 1 receptor agonists, N 6 -cyclohexyladenosine (CHA: 0.1, 0.25 and 0.5 mg kg −1 ) and R -isomer of N 6 -phenylisopropyladenosine (R-PIA: 0.1, 0.3 and 1 mg kg −1 ), decreased jumping and diarrhea induced by naloxone in morphine-dependent mice. The adenosine A 1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX: 0.3–9 mg kg −1 ), increased jumping but decreased diarrhea. The adenosine A 2 receptor agonist, 5′-( N -cyclopropyl)-carboxamidoadenosine (CPCA), decreased jumping and diarrhea. However, the adenosine A 2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX: 0.5 and 1 mg kg −1 ), did not elicit any response in this respect. DPCPX (0.3 and 3 mg kg −1 ), decreased the inhibition of jumping and diarrhea induced by CHA (0.5 mg kg −1 ), while DMPX (0.5 and 1 mg kg −1 ), decreased the inhibition of diarrhea induced by CPCA (0.1 mg kg −1 ). It is concluded that jumping induced by naloxone in morphine-dependent mice may be modified by the adenosine A 1 receptor mechanism(s) and diarrhea induced by the opioid receptor antagonist could be mediated by the adenosine A 1 and A 2 receptors.

1. The effect of γ-aminobutyric acid (GABA) receptor agonists and antagonists on acquisition of a step-down passive avoidance learning in mice was measured in the presence and absence of physostigmine. 2. Intraperitoneal injection of different doses of the anticholinesterase drug physostigmine (0.1–0.3 mg/kg) increased acquisition in mice dose dependently. The maximum response was obtained with 0.3 mg/kg of the drug. Higher doses of the drug impaired acquisition of the learned response. To show the effect of the GABAergic system on acquisition, GABA A receptor agonists and antagonists were challenged against 0.2 mg/kg of physostigmine. 3. Administration of the GABA A receptor agonist muscimol but not the GABA B receptor agonist baclofen decreased the acquisition of the learned task. However, the improvement induced by physostigmine (0.2 mg/kg) was decreased by both muscimol and baclofen. A combination of both agonists caused a higher inhibitory effect on the physostigmine response. 4. Pretreatment of animals with the higher doses of GABA A receptor antagonists bicuculline and picrotoxin but not the GABA B receptor antagonist phaclofen impaired learning. Both the GABA A and GABA B receptor antagonists reduced the learning improvement induced by physostigmine. The inhibitory effects of the GABA A and GABA B receptor antagonists are lost when combined together. 5. Bicuculline, picrotoxin or phaclofen increased the impairment of learning induced by muscimol, whereas a combination of either of the antagonists with baclofen did not alter the learning. The GABA A antagonists reduced the inhibitory effect of muscimol, whereas a higher dose of phaclofen increased the inhibition of the physostigmine response induced by muscimol and baclofen on physostigmine-induced learning improvement. 6. Phaclofen decreased but a higher dose of bicuculline increased the baclofen-induced inhibition of physostigmine effect. 7. It is concluded that both GABA A and GABA B activation inhibit improvement of acquisition induced by physostigmine.

The effect of nicotine was tested on retrieval 24 h after training on a passive avoidance task. Intraperitoneal (i.p.) injection of nicotine (0.25–1.5 mg/kg) increased the step-down latency in mice dose dependently. Pretreatment with the nicotinic receptor antagonist mecamylamine (0.5–1 mg/kg) decreased, whereas pretreatment with the dopamine D 1 receptor antagonist SCH 23390 ( R -(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1 H -3-benzazepine-7-ol maleate) (0.01, 0.05 and 0.1 mg/kg) and the β-adrenoreceptor antagonist propranolol (10 mg/kg) increased the nicotine response. The dopamine receptor D 2 receptor antagonist sulpiride (5–10 mg/kg), the anti-muscarinic agent atropine (2.5–10 mg/kg), the peripheral nicotinic receptor antagonist hexamethonium (0.01–0.5 mg/kg), the α-adrenoceptor antagonist phenoxybenzamine (1 and 10 mg/kg) and the peripheral dopamine D 2 receptor antagonist domperidone (5 and 10 mg/kg) did not change the response induced by nicotine. Single administration of the antagonists did not cause response; however, a high dose of domperidone (10 mg/kg) and propranolol alone increased the step-down latencies. It may be concluded that a nicotinic receptor mechanism is involved in the nicotine-induced improvement of memory retrieval.

Summary Background The required time for hair removal by chemical depilatories has always been a concern and depends on different parameters including permeation into the hair shaft. Objectives In an attempt to improve this process, it was decided here to investigate the possibility of decreasing depilation time of thioglycolates, widely used depilatories, using penetration enhancers. Methods Urea, sodium dodecyl sulfate, dimethylsulfoxide (DMSO), ethanol (75 and 96%), NaCl, and peppermint and orange oils were used as penetration enhancers, and their effect on depilatory time of thioglycolates, represented as tear resistance time (TRT) of hair shaft under a constant tensile stress, was studied. The effects of temperature and hydration on TRT were also investigated. Results Results showed that ethanol (75%), DMSO, and peppermint oil (ethanolic solution) were able to significantly reduce TRT up to two times from about 6 to 3.5 min. Other enhancers were not able to change TRT. Results also revealed that increase in temperature from 20 to 37 °C reduces TRT by about 4 times. Hydration in boiling water also reduced TRT significantly about 1.5 times. Conclusions Present results show that it is possible to reduce depilation time by penetration enhancers. Such improvement can increase users' compliance and might provide other advantages like decreased skin irritation.

Warfarin is widely used anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders and exerts its anticoagulant effect by inhibiting the vitamin K epoxide reductase. To determine the impact of genetic variants of the vitamin K epoxide reductase complex subunit 1 gene (VKORC1) on the anticoagulant response to warfarin, polymorphisms in exon 1, exon 3, and 3'-untranslated region (3' UTR) were assessed.Sixty patients (34 males and 26 females) with stable INR (2-3) were selected from cardiology and anticoagulant clinic. Three VKORC1 frameshift mutations were detected. The first frameshift mutation was nucleotide deletion (91delCC) in exon 3 (1 patient). The second variation was nucleotide addition (51addCT) in exon 3 (2 patients). All the 3 patients reported bleeding during warfarin use, while no other bleeding was reported during the study period. Warfarin maintenance dose was significantly different between 3 patients with mutations and patients without mutations. The use of a fixed-dose warfarin for all patients and in range INR may not be sufficient for warfarin monitoring. Many factors including unknown ones may also play an important role in highly variable response among patients. Our data for the first time, suggested a new possible call for screening to reduce the risk of bleeding and guide for dosing.

New analogues of nifedipine, in which the ortho nitrophenyl group of position 4 is replaced by 1-methyl-4-nitro-5-imidazolyl or 1-methyl-5-imidazolyl with a nitrooxy group at the 3-ester position were synthesized, and the antihypertensive activity of the compounds was examined by the tail-cuff method and compared with TNG and nifedipine. Compounds 11 g, 11 i-11 m, 11 o, 11 r, and 11 v showed activity similar to nifedipine and TNG.

Development and optimization of a sublingual tablet formulation for physostigmine salicylateThis study is aimed to design and optimize a sublingual tablet formulation of physostigmine salicylate, an effective drug in Alzheimer's disease and nerve gas poisoning, by means of the D-optimal experimental design methodology. Polyvinyl pyrrolidone, lactose, starch 1500 and sodium starch glycolate were used in the formulations as independent variables. Tablets were prepared by the direct compression method and evaluated for their physical properties (tablet hardness, disintegration time and friability), which were regarded as responses in a D-optimal design. Due to the significance of the special cubic model for data fitted, compared to other models, it was used to examine the obtained results. Response surface plots were plotted to study the tablet properties and the optimized overlay plot was generated based on the results and targets considered for the responses. After verification of the optimum checkpoint formulations, an optimized formulation was chosen due to its desirable physical properties and closely observed and predicted values. Drug assay, content uniformity of the dosage unit, drug dissolution and accelerated stability studies were done on the optimum formulation as further experiments. All the obtained results complied with the requirements of a sublingual tablet formulation.

This study is aimed to design and optimize a sublingual tablet formulation of physostigmine salicylate, an effective drug in Alzheimer’s disease and nerve gas poisoning, by means of the D-optimal experimental design methodology. Polyvinyl pyrrolidone, lactose, starch 1500 and sodium starch glycolate were used in the formulations as independent variables. Tablets were prepared by the direct compression method and evaluated for their physical properties (tablet hardness, disintegration time and friability), which were regarded as responses in a D-optimal design. Due to the significance of the special cubic model for data fitted, compared to other models, it was used to examine the obtained results. Response surface plots were plotted to study the tablet properties and the optimized overlay plot was generated based on the results and targets considered for the responses. After verification of the optimum checkpoint formulations, an optimized formulation was chosen due to its desirable physical properties and closely observed and predicted values. Drug assay, content uniformity of the dosage unit, drug dissolution and accelerated stability studies were done on the optimum formulation as further experiments. All the obtained results complied with the requirements of a sublingual tablet formulation., Cilj rada bio je dizajnirati i optimirati sublingvalne tablete fizostigmin salicilata, lijeka učinkovitog u terapiji Alzheimerove bolesti i intoksikacije nervnim plinovitim otrovima, koristeći metodologiju D-optimalnog eksperimentalnog dizajniranja. U formulacijama su kao nezavisne varijable korišteni polivinil pirolidon, laktoza, škrob 1500 i natrijev škrobni glikolat. Tablete su pripravljene metodom izravne kompresije. Njihova fizikalna svojstva (tvrdoća, vrijeme dezintegracije i lomljivost) evaluirana su kao zavisna varijabla u D-optimalnom dizajniranju. Rezultati su najbolje slijedili specijalni kubični model, pa je taj model upotrijebljen za ispitivanje rezultata. Nacrtane su krivulje ovisnosti za proučavanje svojstava tableta. Na temelju njih izrađen je i optimirani prekrivni prikaz prema rezultatima i postavljenim ciljevima za odgovor na lijek. Poslije provjere najboljih kontrolnih formulacija, izabrana je jedna optimirana formulacija temeljem svojih poželjnih fizičkih značajki te uočenih i predviđenih vrijednosti. Ispitivanje lijeka, jednolikosti sadržaja, oslobađanja lijeka i pokusi ubrzanog starenja provedeni su na optimiranoj formulaciji. Dobiveni rezultati odgovaraju zahtjevima za tablete za sublingvalnu primjenu.

Gamma-ray spectrometric analyses were performed on sediment samples from the coast of Khuzestan province (south west of Iran, neighbor to Iraq and Kuwait) to study the concentration of natural as well as man-made radioactive sources. The coast of Khuzestan, which extends for approximately 400 km is mainly soft areas of mud flats within different ecosystems including river mouth, estuaries, creeps, and small bays. Suspended material from the Iranian rivers including Arvand (Karun), Bahmanshir, Jarrahi, and Zohreh has settled to form these extensive soft areas. Eighty three samples were taken at different points along the coast in undisturbed areas at intervals of about 5 km since Fall 2005 to Winter 2006. Collection was carried out during low-tide, where it was possible to collect sediments from the wet region that was covered by sea water during the high tide. At each of the sample sites, a sampling area of about 1 m(2) was considered. All samples were of a muddy nature, and were left to dry in open air before drying in the oven at 105 degrees C for 2-3 days to remove all water content. The average activity concentration of the radionuclides (226)Ra (30 Bq/Kg), (232)Th (11 Bq/kg), (238)U (18 Bq/kg), and (137)Cs (2.6 Bq/kg) along the shore of Khuzestan reaches are much less than the values commonly assigned as the world average. Nevertheless in case of (40)K which is a long lived naturally occurring radionuclide, the result (481 Bq/kg) was higher than the world average which could be due to a large Kuwaiti oil spill and also fallout and deposition of tremendous amount of fly ashes which resulted from ignited Kuwaiti oil fields during the 2nd Persian Gulf war (1990-91). For man-made (137)Cs and naturally occurring (232)Th, the western and eastern parts of Khuzestan shore showed higher concentrations than the middle part (Khooriat or creeps). For the long lived naturally occurring radionuclide (40)K and Gulf war (238)U (anti armor shells), there were no significant differences (P0.05) among the three regions.

Several studies have shown that cannabinoids have anticonvulsant properties that are mediated through activation of the cannabinoid CB1 receptors. In addition, endogenous cannabinoid compounds (endocannabinoids) regulate synaptic transmission and dampen seizure activity via activation of the same receptors. The aim of this study was to evaluate the possible interactions between antiepileptic effects of cannabinoid compounds and diazepam using electroshock-induced model of seizure in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, fixed current intensity 35 mA, stimulus duration 0.2 s) and tonic hindlimb extension was taken as the endpoint. All experiments were performed on groups of ten mice and the number of animals who did not display seizure reported as percent protection. Intraperitoneal (i.p.) administration of diazepam (0.25-2 mg/kg) and CB1 receptor agonist WIN55212-2 (0.5-4 mg/kg) dose dependently produced an antiepileptic effect evaluated in terms of increased percentage of protection against electroshock-induced seizure. Logistic regression analysis indicated synergistic interactions in anticonvulsant action after co-administration of diazepam and WIN55212-2 in fixed-ratio combination of 3:1 (diazepam:WIN55212-2), while an additive effect was resulted after co-administration of 1:1 and 1:3 fixed-ratio combinations. Administration of various doses of the endocannabinoid reuptake inhibitor, AM404, did not produce any effect on electroshock-induced seizure. Moreover, co-administration of AM404 and diazepam did not produce significant interaction in antiepileptic properties of these compounds. Administration of the fatty acid amide hydrolase inhibitor, URB597, produced significant antiepileptic effect. Co-administration of URB597 and diazepam led to an antagonistic interaction in protection against shock-induced seizure. Co-administration of different doses of the cannabinoid CB1 receptor antagonist, AM251 did not alter the antiepileptic effect of diazepam in the electroshock-induced seizure test. These results demonstrate that endocannabinoid system participates in the modulation of seizure and combination of small doses of exogenous CB1 receptor agonists with diazepam may have effective consequences in seizure control. Furthermore, inhibiting the endocannabinoid degradation could be more efficacious in modulating seizure than preventing their uptake. This study also suggests that the effects of cannabinoids on epilepsy depend on the relative cannabinoid responsiveness of GABAergic and glutamatergic neurotransmission. While, the antiepileptic effects of cannabinoid compounds are likely by affecting excitatory glutamate neurotransmission, the antagonistic interaction between cannabinoid compounds and diazepam to protect seizure is due to the cannabinoid action on inhibitory GABAergic system.

This study reports the development of liposomal system for a potent antitumor drug, topotecan. To achieve this goal conventional and PEGylated liposomes were prepared according to a factorial design by hydration method followed by extrusion. Parameters such as type of lipid, percentage of cholesterol, percentage of phosphatidylglycerols, percentage of polyethylene glycol (PEG)-lipids, and drug to lipid molar ratio were considered as important factors for the optimizing the entrapment and retention of topotecan inside the liposomes. The size and zeta-potential of the PEGylated and conventional liposomes were measured by particle size analyzer and zeta-potentiometer, respectively. The stability and release characteristics of PEGylated liposome loaded topotecan were compared with conventional liposomes and free topotecan. The optimized PEGylated [distearoyl phosphatidylcholine (DSPC)/cholesterol/ distearoyl phosphatidylglycerol (DSPG)/ distearoyl phosphatidylethanolamine-PEG(2000) (DSPE-PEG(2000)); 7:7:3:1.28] and related conventional [DSPC/cholesterol/DSPG; 7:7:3] liposomes showed a narrow size distribution with a polydipersity index of 0.15 and 0.10, an average diameter of 103.0 +/- 13.1 and 95.2 +/- 11.10 nm, and with drug loading of 11.44 and 6.21%, respectively. Zeta-potential was -10 +/- 2.3 and -22 +/- 2.8 mV for PEGylated and conventional liposomes, respectively. The results of stability evaluation showed that the lactone ring of topotecan was notably preserved upon liposome encapsulation. PEGylated liposomes containing topotecan showed a significant decrease (P < 0.001) in release rate in comparison with conventional leptosomes. These results indicate the suitability of PEGylated liposomes in controlling topotecan release. The prepared liposomes (especially PEGylated liposomes) as those described here may be clinically useful to stabilize and deliver topotecan for the treatment of cancer.

Background: In recent years some Iranian pediatricians have used folic acid empirically as an appetite-enhancing drug in poor-appetite, low-weight children. Many parents have expressed their satisfaction with this treatment but until now no study has been done to confirm or exclude folic acid as an appetite enhancer. Methods: In order to determine if complementary folic acid has any effect on preschool children’s appetite, 61 3–5-year-old children (27 girls and 34 boys) whose weight/age and weight/height ratios were below the 25 centile and whose parents regarded them as having poor appetite were randomly assigned to receive either folic acid (1 mg/day) or placebo for 20 days. The primary outcome measures were any appetite changes during and 1 month after the end of the intervention, measured by means of a questionnaire completed by parents on the 20th and 60th days. Secondary measures were mean weight gain on the 30th and 60th days. Results: Children who received folic supplement had a significantly better appetite on the 20th day than those who received placebo (mean difference of appetite score: 1.7; 95% confidence interval: 0.1–3.4; P = 0.04) and significantly more children receiving folic acid were reported to have increased appetite than the placebo group (P = 0.03). But 40 days after the end of the intervention there was no difference between the two groups. Weight gain did not significantly differ between groups. Conclusions: Although folic acid appears to improve preschool children’s appetite, further study is necessary to determine whether it has any effect on growth as an adjunctive to management protocols of low appetite for undernourished children.

Summary Objective To determine the frequency of medication errors that occurred during the preparation and administration of IV drugs in an intensive care unit. Setting The study was conducted in a 12-bed intensive care unit of one of the largest teaching hospitals in Tehran. Design Data were collected over 16 randomly selected days at different medication round times, between July and September 2006. A trained observer accompanied nurses during intravenous (IV) drug rounds. Medication errors were recorded during the observation times of IV drug administration and preparation. Drugs with the highest rate of use in the intensive care unit (ICU) were selected. Details of the process of preparation and administration of the selected drugs were compared to an informed checklist which was prepared using reference books and manufacturers’ instructions. Results We observed a total of 524 preparations and administrations. The calculated number of opportunities for error was 4040. The number of errors identified were 380/4040 (9.4%). Of those, 33.6% were related to the preparation process and 66.4% to the administration process. The most common type of error (43.4%) was the injection of bolus doses faster than the recommended rate. Amikacin was involved in the highest rate of error (11%) among all the selected medications. It was found that the IV rounds conducted at 9:a.m. had the highest rate of error (19.8%). No significant correlation was found between the rate of error and the nurses’ age, sex, qualification, work experience, marital status, and type of working contract (permanent or temporary). Conclusions Since our system is devoid of a well-organized reporting system, errors are not detected and consequently not prevented. Administrators need to take the initiative of developing systems that guarantee safe medication administration.

Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Cannabinoid CB1 receptors are co-localized with dorsal horn interneurons containing gamma-aminobutyric acid (GABA). In this study, we investigated the interaction between intrathecally administered cannabinoid and GABA(B) receptor agonists and antagonists in the modulation of formalin-induced pain at the spinal level. Intrathecal pretreatment of rats with a cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide] (SR141716A, 30 microg) decreased the analgesic effect of the intrathecal administration of the GABA(B) receptor agonist, baclofen (0.125 microg and 0.25 microg). Intrathecal administration of the GABA(B) receptor antagonist, saclofen (30 microg), 10 min before administration of the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexano (CP55940), did not affect the analgesia produced by the cannabinoid receptor agonist. Our results confirm that intrathecal administration of cannabinoid and GABA(B) receptor agonists have analgesic effects and that spinal antinociceptive effects of GABA(B) receptor agonists are likely through endocannabinoid modulation.

A series of new 5-substituted analogues of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole and its chlorinated derivatives was designed and prepared. Conformational analysis and superimposition of energy minima conformers of the compounds on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Rotarod and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 5 of 1,2,4-triazole ring especially in chlorinated derivatives had the best effect which was comparable with diazepam.

Corticosteroids exert dual enhancing or impairing effects on cognitive functions. While their memory-enhancing effects have been well investigated, the mechanisms involved in their amnestic effects are not completely understood. Thus, we examined the role of alpha-adrenoceptors on dexamethasone-induced amnesia using step-through passive avoidance test in rat. Intracerebroventricular (i.c.v.) injection of dexamethasone (5 and 10 microg per rat) decreased the retention latencies. Likewise, intraperitoneal administration of alpha(2)-adrenoceptor agonist clonidine (0.1-0.3 mg kg(-1)) but not alpha(2)-adrenoceptor antagonist yohimbine (0.5-2 mg kg(-1)) decreased the retention latency. Yohimbine pre-treatment decreased the amnestic effects of dexamethasone or dexamethasone plus clonidine. On the other hand, intraperitoneal administration of alpha(1)-adrenoceptor agonist phenylephrine (0.5-2 mg kg(-1)) per se increased, while prazosin at 2 mg kg(-1) decreased the retention latency. Administration of phenylephrine before dexamethasone completely reversed the amnestic effect of the latter, while prozosin did not affect dexamethasone-induced amnesia. These data suggest that dexamethasone may induce its amnestic effect through activation of alpha(2)-adrenoceptors, leading to decreased alpha(1)-adrenergic activity.

New analogues of nifedipine, in which the ortho nitrophenyl group of position 4 is replaced by 1-methyl-4-nitro-5-imidazolyl or 1-methyl-5-imidazolyl with a nitrooxy group at the 3-ester position were synthesized, and the antihypertensive activity of the compounds was examined by the tail-cuff method and compared with TNG and nifedipine. Compounds 11 g, 11 i-11 m, 11 o, 11 r, and 11 v showed activity similar to nifedipine and TNG.

In this study, the influences of nicotinic receptor agents on baclofen-induced antinociception in the tail-flick test have been studied. Intraperitoneal administration of baclofen (2.5, 5 and 10 mg/kg) to mice induced a dose-dependent antinociception in the tail-flick test. Subcutaneous injection of nicotine (0.5-2.5 mg/kg) also caused a dose-dependent antinociceptive response. Intracerebral (10 and 20 microg/mouse) but not intraperitoneal administration of hexamethonium (5 and 10 mg/kg) to mice decreased the response of both nicotine and baclofen. However, administration of the GABA(B) antagonist CGP 35348 (100 and 200 mg/kg) decreased the response induced by baclofen but not by nicotine. It is concluded that at least part of the baclofen-induced antinociception may be mediated through a nicotinic mechanism.

In the present study, cross-tolerance between nicotine and morphine in mice has been investigated. Mice were treated subcutaneously with three doses of morphine (12.5, 25 and 50 mg/kg) once daily, for 3 days in order to produce tolerance to morphine and nicotine antinociception. Tolerance only developed in the high dose group. On the 4th day, the antinociceptive effect of three test doses of morphine (3, 6 and 9 mg/kg) or nicotine (0.01, 0.05 and 0.1 mg/kg) were assessed. Tolerance to the responses of both drugs were observed. Intraperitoneal administration of nicotine (2 mg/kg) three times a day for a period of 12 days, also induced tolerance to the antinociceptive effects of both morphine and nicotine. When animals were tested on the 13th day, the antinociceptive responses of morphine or nicotine were reduced. Another group of animals was treated with low doses of morphine daily (12.5 or 25 mg/kg) plus nicotine (2 mg/kg) three times daily for 3 days. In this group of animals, the antinociception to either morphine or nicotine was tested. Combination of both drugs caused an increase in tolerance to either drug. It is concluded that there is cross-tolerance between the two drugs.

A series of experiments examined the effect of the adenosine receptor agonists N 6 - cyclohexyladenosine (CHA), N 6 - p phenylisopropyladenosine ( R- PIA ) and 5′-N- ethylcarboxamidoadenosine (NECA); the adenosine receptor antagonists theophylline, caffeine and 8-phenyltheophylline (8-PT), and the adenosine uptake inhibitor dipyridamole on acquisition of a single trial passive avoidance learning by mice. The adenosine receptor agonists CHA (0.05, 0.1, 0.2 and 0.4 mg/kg) and R- PIA (0.0625, 0.125, 0.25 and 0.5 mg/kg) administered 1 h before the training session decreased retention dose dependently while the other adenosine receptor agonist NECA (0.0025, 0.005 and 0.01 mg/kg) had no effect. The response induced by the adenosine receptor agonists CHA and R- PIA was attenuated by the pretreatment of animals with low doses of the adenosine receptor antagonists 8-PT (2.0 mg/kg) and theophylline (25 mg/kg) but not with higher doses of the antagonists. The higher doses of the antagonists decreased the passive avoidance. Dipyridamole (7.5, 15, 30, 60 and 120 mg/kg) showed no significant effect. It is concluded that adenosine A1 receptor activation decreases the acquisition of a passive avoidance response.

The efficacy of naloxone and morphine on acute toxicity of T-2 toxin, a potent cytotoxic trichothecene mycotoxin, was investigated. In this study, mice received naloxone (4 or 8 mg/kg, sc) or morphine (5 or 15 mg/kg, sc) 24, 18, 1 hr before and 6 hr after ip injection of 2 or 1.8 mg/kg of T-2 toxin, respectively. In addition, naloxone (8 mg/kg, sc) were administered at 13, 7, 1 hr before, and 5 hr after T-2 toxin administration (1.8 mg/kg, ip). The acute lethal toxicity and change in body and organ weights (including liver, spleen, and kidneys) were evaluated. The acute lethal toxicity of T-2 toxin was reduced by administration of the first regimen of naloxone (8 mg/kg, sc). It also caused a protective effect against T-2 toxin-induced weight changes. On the other hand, morphine increased T-2 toxin-induced lethality (although not statistically significant). It could be concluded that opioid agonists may exacerbate the lethal toxicity of T-2 toxin-induced shock and opioid antagonists such as naloxone could antagonize this shock.

The efficacy of diphenhydramine, triazolam, diltiazem, and ketotifen on the acute toxicity of T-2 toxin, a potent cytotoxic trichothecene mycotoxin, was investigated. Mice were received triazolam (20 or 40 mg/kg, sc), diltiazem (5 mg/kg, sc), or diphenhydramine (50 mg/kg, sc) 24, 18, 1 hr before and 6 hr after injection of T-2 toxin (1.8 mg/kg, ip). In other experiments, mice were either administered ketotifen (70 mg/kg, sc) 13, 7, 1 hr before and 5 hr after T-2 toxin (1.8 mg/kg, ip) or ketotifen (40 or 70 mg/kg, ip) 4 hr before T-2 toxin (1.8 mg/kg, ip). The acute lethal toxicity and change in body and organ weights (including liver, spleen, and kidneys) were evaluated. Among these drugs, only diphenhydramine prolonged the survival times. When mice received ketotifen (70 mg/kg, sc) 13, 7, 1 hr before and 5 hr after T-2 toxin (1.8 mg/kg, ip), it caused a protective effect against T-2 toxin-induced splenomegally and weight change. Triazolam (20 or 40 mg/kg, sc) also produced a protective effect against T-2 toxin-induced weight change. It is concluded that antihistamines might have some protective effects against acute T-2 toxin toxicity..

The efficacy of two free radical scavengers, selenium and zinc, and a microsomal epoxide hydrolase–inducing agent, cis-stilbene oxide on the acute toxicity of T-2 toxin, a potent cytotoxic trichothecene, was investigated. Mice were pretreated daily for 3 consecutive days with either zinc sulfate (4.4 mg/kg, intraperitoneally [i.p.]), sodium selenite (1, 2, and 3 mg/kg i.p.) or cis-stilbene oxide (50 mg/kg i.p.). A full 24-hr after the final dosing with these agents, mice were given T-2 toxin (2, 2.5, or 3 mg/kg i.p.). The acute lethal toxicity of T-2 toxin (2.5 mg/kg) was reduced by administration of only sodium selenite (3 mg/kg) and cis-stilbene oxide (50 mg/kg). No significant effect on weight gain was observed. Nat. Toxins 5:133–135, 1997. © 1997 Wiley-Liss, Inc.