Evaluation of the Ecstasy influence on tramadol and its main metabolite plasma concentration in rats.

BACKGROUND: Tramadol is prone to be abused alone, or in combination with 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). It was reported that 95% of people with a history of substance abuse in the United States used tramadol in 2004. According to the WHO report in 2016, there was a growing number of tramadol abusers alone or in combination with psychoactive substances such as MDMA in particular in some Middle East countries. Higher concentrations of tramadol in plasma may lead to adverse drug reactions or lethal intoxication. In this study, the effect of MDMA on the pharmacokinetics of tramadol was examined in male rats. METHODS: The effect of MDMA on Tmax, Cmax, area under the curve, elimination rate, and half-life of tramadol and its metabolites was examined. Two control and two treatment groups were designed. The treatment groups received MDMA 18 h before the administration of tramadol. Jugular vein blood samples were analyzed by high-performance liquid chromatography with fluorescent detector to determine the concentrations of tramadol and its metabolites. Independent-sample t-test was used to define the differences between pharmacokinetic parameters of control and treatment groups. RESULTS: When tramadol administered intraperitoneally, the absorption rate of this drug was reduced, and a lower Cmax (40%) with longer Tmax (eight-fold) was achieved. MDMA exerted greater inhibitory effects on cytochrome P450 3A4 (CYP3A4) than on cytochrome P450 2D6 (CYP2D6). The M2 metabolite ratio was reduced by half, and because of the inhibition of M2 production, the M1 plasma concentration slightly increased. CONCLUSIONS: According to the obtained data, MDMA treatment affected the absorption, distribution and metabolism phases of tramadol. This treatment increased the concentration of tramadol if administered intravenously and can latent the absorption of tramadol in oral route. However, MDMA was introduced as CYP2D6 inhibitor; in this study, MDMA inhibited CYP3A4 isoenzymes as well. This finding is important for the compounds that are metabolized through CYP3A4. It can be proposed that in abusers of MDMA who only receive tramadol for medical or nonmedical purposes in short intervals, the dangers of the intravenous administration of tramadol should be considered, and if tramadol is administered orally, the desired effect may not be achieved at the routine dose.

Efficacy and safety of aluminum chloride in controlling external hemorrhage: an animal model study.

BACKGROUND: Despite all the progress in surgical science, bleeding caused by traffic accidents is still one of the challenges surgeons face in saving patients' lives. Therefore, introducing an effective method to control external bleeding is an important research priority. OBJECTIVES: This study aimed to compare the hemostatic effect of aluminum chloride versus simple suturing in controlling external bleeding. MATERIALS AND METHODS: This experimental study was conducted in Kashan, Iran. In this study, 60 male Wistar rats were randomly allocated into six groups. An incision, two centimeters (cm) long and half a cm deep, was made on each rat's shaved back skin and the hemostatic time was measured once using aluminum chloride with different concentrations (5%, 10%, 15%, 25%, and 50%) and then using the control method (controlling hemorrhage by simple suturing). The skin tissue was assessed for pathological changes. RESULTS: The hemostatic time of aluminum chloride 50%, 25%, 15%, 10% and 5% were 8.20 ± 0.919, 14.10 ± 1.37, 21.20 ± 1.31, 30.80 ± 1.68 and 42.00 ± 4.19 seconds, respectively. Also, the mean hemostasis time in the control group (suture) was 84.00 ± 4.05 seconds. The hemostatic times of different concentrations of aluminum chloride were significantly less than that of the control group. There was a statistically significant difference between every two hemostatic time. The pathologic examination showed the highest frequency of low-grade inflammation based on the defined pathological grading. CONCLUSIONS: The aluminum chloride method needs less time to control external hemorrhage compared to the control method (controlling external hemorrhage by simple suturing). Aluminum chloride is an effective agent in controlling external hemorrhage in an animal model.

Intracellular GSH Alterations and Its Relationship to Level of Resistance following Exposure to Cisplatin in Cancer Cells.

One of the major complications in cancer chemotherapy with cisplatin as one of the important medicines in treatment regimens of different cancers is the development of resistance. One of the most described cellular defense mechanisms involved in resistance is glutathione (GSH), thus in this study, the effects of cisplatin on the total intracellular GSH level (GSHi) in some sensitive and resistant variants of human cell lines (hepatocarcinoma HepG2, skin A375, cisplatin sensitive glioblastoma U373MG and cisplatin resistant glioblastoma U373MGCP, cisplatin sensitive ovary A2780S and cisplatin resistant A2780CP cells) were studied. MTT assay was performed to measure cytotoxicity of cisplatin (33.3 µM for 1 hour). Following cisplatin exposure, GSHi (per million cells) was evaluated using a photometrical assay up to 90 minutes. Our results indicate that there are significant differences between GSHi content of A2780CP and U373MGCP cells compared to other cell lines. Moreover, IC50 of cisplatin in different cells seems to have a relation with mean of GSH level in 90 minutes (GSH (mean)90). As a conclusion, it seems that resistance to cisplatin in different cell lines is more related with the diverse patterns of GSHi variations following cisplatin exposure than its original level, and/or its cellular increase or decrease. It is also suggested that GSH (mean)90 may be used as a factor for the prediction of cellular resistance to cisplatin.

Determination of MDMA and its three metabolites in the rat perfused liver.

3,4-Methylenedioxymethamphetamine (MDMA) is one of the most commonly abused illicit drugs in the world. We developed a rapid and simple high-performance liquid chromatography with a fluorescence (FL) detector method to determine MDMA and its metabolites, such as 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxyamphetamine (HMA) and its main unstable metabolite 3,4-dihydroxymethamphetamine (HHMA) besides the internal standards, in a perfusion medium. The separation of analytes was performed at 25°C on a Chromolith® C18 (100 × 4.6 mm) column from Merck (Darmstadt, Germany) without any derivatization. The FL detector wavelength was fixed at 285 nm for excitation and at 320 nm for emission. Acetonitrile:phosphate buffer (0.02 M) at pH = 3 (5:95 v/v) was used as the mobile phase. The elution order was HHMA, HMA, MDA and MDMA with a retention time of 1.7, 2.6, 6.1 and 7.4 min, respectively. The method was validated according to the FDA bioanalytical method validation guideline. The limits of quantifications (LOQs) obtained for MDMA, MDA, HMA and HHMA were 1, 1, 1.5 and 5 ng/mL, respectively. The repeatability of relative standard deviation was  <11% (except for LOQs). This method was applied successfully to determine MDMA and its metabolites in rat liver perfusion samples. To our knowledge, this is the first method introduced for the determination of HHMA as a free form with an FL detector.

Effect of essential oils, hydrating agents, and ethanol on hair removal efficiency of thioglycolates.

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.

Determination of the role of calcium on instability of neurotoxic metabolite of ecstasy by HPTLC-mass.

BACKGROUND: Ecstasy is one of the popular illicit drugs in the world and its usage has been recently increased in Iran. This compound can destroy the serotonergic neurons and produces cognitive and psychopathology diseases. 3,4-dihydroxymethamphetamine (HHMA) which is the main metabolite of this compound, seems to be responsible for this effect. However, no consensus has been reached among the researchers about its role. This disagreement between the researches may be due to failure in determination of HHMA as free form in physiological fluids. In this study, the stability of this crucial metabolite of ecstasy was examined in different mediums. METHODS: The stability of HHMA was studied in the perfusion medium and water at 100 and 10 ng/mL concentrations. Moreover, the effect of temperature (0-25°C), pH (3-10), calcium chloride (0-150 g/L) and ethylenediaminetetraacetic acid (EDTA) on the stability of HHMA was also examined. RESULTS: Our result suggested that the free form of HHMA could be degraded in the perfusion medium. The rate of this degradation has direct proportion to temperature (at 25°C = 0.037 min-1 and at 0°C = 0.002 min-1). Calcium chloride and sodium bicarbonate are two responsible components in this instability. Moreover, the alkaline pHs and increasing the shaking time can accelerate this effect. Although, while degradation was prevented at pH=3, EDTA could only reduce this rate about 30%. CONCLUSIONS: Calcium cation can act as an accelerator of HHMA degradation. Therefore, the perfusion medium should not contain Ca2+ and the pH of medium is better to be adjusted at acidic range. Since, the internal cellular source of calcium is endoplasmic reticulum system, it can be assumed that, this cation may change HHMA and dopamine to reactive compounds that can bind covalently to the cysteinyl group of biological compounds and damage cellular components.

Evaluation of health related quality of life in irritable bowel syndrome patients.

BACKGROUND: Quality of life (QOL) is an important measure in the management of Irritable Bowel Syndrome (IBS). Controversy exists in the findings of studies evaluating QOL in IBS subtypes, and little is known about this issue in Iranian patients. Determination of the factors affecting QOL in IBS patients may influence treatment outcomes. The aims of this study are to: 1) compare QOL between subtypes in a sample of Iranian IBS patients, 2) determine the factors associated with QOL in IBS. METHODS: This cross sectional study included two hundred and fifty IBS patients with the mean age (± standard deviation) of 31.62 (± 11.93) years that were referred to outpatient gastroenterology clinic. IBS patients were diagnosed based on Rome-3 criteria by a gastroenterologist, and then they were categorized into three subtypes according to the predominant type of bowel habit. The "QOL specific for IBS", "Stait-trait anxiety inventory", and "Beck depression inventory-2" questioners were used to evaluate QOL, anxiety, and depression symptoms, respectively. RESULTS: The mean QOL scores in IBS mixed subtype (71.7 ± 25.57), constipation predominant subtype (80.28 ± 25.57), and diarrhea predominant subtype (76.43 ± 19.13) were not different. (P value: 0.05) In multivariate linear regression analysis, anxiety symptom scores were inversely correlated with QOL scores. [Standardized beta: -0.43, (95% confidence interval: -0.70, -0.39), P value: < 0.01] CONCLUSION: It seems reasonable to manage anxiety symptoms properly in IBS patients since this might increase their QOL.

Serum anti-cyclic citrullinated peptide antibodies may predict disease activity in rheumatoid arthritis.

To define the relationship between serum anti-cyclic citrullinated peptide antibodies (anti-CCP) and disease activity, and to construct a new disease activity index by using anti-CCP in rheumatoid arthritis (RA). One hundred and five RA patients were included. Disease activity based on DAS28-ESR and serum anti-CCP was measured. There was correlation between serum anti-CCP and DAS28-ESR. (R (2) = 0.71, P value < 0.01). New disease activity index was developed by replacing anti-CCP with ESR in DAS28-ESR. There was correlation between new model and DAS28-ESR. (R (2) = 0.91, P value < 0.01) The new composite index best cut-off values corresponding to DAS28-ESR values of 2.6, 3.2, and 5.1 were 3.21, 3.38, and 4.74, respectively. There was agreement between new model and DAS28-ESR for determination of patients in different disease activity categories. (Kappa = 0.71, P value < 0.01). The new disease activity index that applies serum anti-CCP may predict disease activity in RA.

Synthesis of a quaternary bis derivative of imipramine as a novel compound with potential anti-enuretic effect.

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.