Publications by authors named "Davoud Ahmadimoghaddam"

17 Publications

  • Page 1 of 1

Antinociceptive activity of . leaf extract: a mechanistic evaluation.

Res Pharm Sci 2020 Oct 19;15(5):463-472. Epub 2020 Oct 19.

Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, I.R. Iran.

Background And Purpose: , a medicinal herb, traditionally had been used for the treatment of stomachache pain. In this study, the possible efficacy of leaf methanolic extract (CBHE) and also cnicin, one of its major constituents, was measured on pain.

Experimental Approach: In this study, pain assessment tests include writhing, tail-flick (TF), and formalin- induced paw licking test (FIPLT) were used. To understand the possible mediated anti-nociceptive mechanism of CBHE, the opioid mechanism(s), and involvement of the L-arginine/ nitric oxide/cGMP/ATP-sensitive potassium channel pathway (LNCaP) were scrutinized.

Findings/results: In TF and writhing tests, CBHE (150 and 300 mg/kg, i.p) remarkably exhibited an anti-nociceptive effect compared to that of the control. Furthermore, CBHE (150 and 300 mg/kg, i.p) in comparison with the control showed a noteworthy anti-nociceptive effect ( < 0.01) in the tonic phase of FIPLT. In the writhing test, administration of selective opioid antagonist (naltrindole, nor-binaltorphimine, and naloxonazine) attenuated the anti-nociceptive effect of CBHE (300 mg/kg) in comparison with control. Moreover, pre-treatment with Nω-nitro-L-arginine methyl ester hydrochloride, L-arginine hydrochloride, and glibenclamide significantly blocked the CBHE (300 mg/kg) anti-nociception ( < 0.05) while administration of sodium nitroprusside remarkably potentiated ( < 0.05) the antinociception induced by CBHE in the tonic phase of the FIPLT. Besides, cnicin (30 mg/kg) showed noteworthy anti-nociceptive effects in writhing, TF, and FIPLT paradigms.

Conclusion And Implications: Taken together, we elucidate that both CBHE and cnicin demonstrated antinociceptive effects in behavioral tests. The possible mechanisms of CBHE antinociception may involve in various neural signaling and modulatory pathways including LNCaP and opioidergic mechanisms.
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http://dx.doi.org/10.4103/1735-5362.297849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879793PMC
October 2020

A randomized, double-blind, placebo-controlled study to assess efficacy of mirtazapine for the treatment of diarrhea predominant irritable bowel syndrome.

Biopsychosoc Med 2021 Feb 3;15(1). Epub 2021 Feb 3.

Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Shahid Fahmideh Ave, Hamadan, 6517838678, Iran.

Background: Ample evidence indicates the efficacy of serotonin type 3 (5-HT) receptor antagonists in the treatment of patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Mirtazapine is an atypical antidepressant with a well-known 5-HT receptor antagonist property. This study, therefore, was undertaken to investigate whether compared to placebo, mirtazapine would be efficacious and safe in the treatment of patients with IBS-D.

Methods: From November 2019 until July 2020, 67 patients meeting Rome IV criteria for IBS-D were randomized in a double-blind fashion into either the mirtazapine treatment group (n = 34) or the placebo treatment group (n = 33). Patients started with mirtazapine 15 mg/day at bedtime for one-week; after which the dose was increased to 30 mg/day for an additional 7-week. Outcomes included changes in the total IBS symptom severity score (IBS-SSS), Hospital anxiety and depression scale score (HADS), and IBS Quality of Life. Additionally, changes in the diary-based symptoms scores including pain, urgency of defecation, bloating, stool frequency, and stool consistency based on the 7-point Bristol Stool Form Scale (BSFS), and a number of days per week with pain, urgency, diarrhea, or bloating, once during the 1-week run-in period, and once during the last week of treatment were recorded.

Results: All analyses were performed on an Intention-to-Treat (ITT) analysis data set. The results showed compared to placebo, mirtazapine is more efficacious in decreasing the severity of IBS symptoms (P-value = 0.002). Further, at the end of the treatment period, all diary-derived symptoms except bloating showed significantly more improvement in the mirtazapine-treated subjects compared to the placebo-treated subjects. While was well-tolerated, mirtazapine also significantly improved the patients' quality of life (P-value = 0.04) and anxiety symptoms (P-value = 0.005).

Conclusions: Overall, mirtazapine seems to have a potential benefit in the treatment of patients with IBS-D, particularly those with concomitant psychological symptoms. However, further studies are warranted to determine whether these findings are replicated.

Trial Registration: Trial registration: Registration number at Iranian Registry of Clinical Trials: IRCT20120215009014N311 . Registration date: 2019-10-21.
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http://dx.doi.org/10.1186/s13030-021-00205-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860197PMC
February 2021

Pentoxifylline Attenuates Arsenic Trioxide-Induced Cardiac Oxidative Damage in Mice.

Oxid Med Cell Longev 2021 7;2021:6406318. Epub 2021 Jan 7.

Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.

This study was undertaken to evaluate the therapeutic potential effect of pentoxifylline (PTX) against arsenic trioxide (ATO)-induced cardiac oxidative damage in mice. Thirty-six male albino mice were divided into six groups and treated intraperitoneally with normal saline (group 1), ATO (5 mg/kg; group 2), PTX (100 mg/kg; group 3), and different doses of PTX (25, 50, and 100 mg/kg; groups 4, 5, and 6, respectively) with ATO. After four weeks, the blood sample was collected for biochemical experiments. In addition, cardiac tissue was removed for assessment of oxidative stress markers and histopathological changes (such as hemorrhage, necrosis, infiltration of inflammatory cells, and myocardial degeneration). The findings showed that ATO caused a significant raise in serum biochemical markers such as lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and troponin-I (cTnI), glucose, total cholesterol (TC), and triglyceride (TG) levels. In addition to histopathological changes in cardiac tissue, ATO led to the significant increase in cardiac lipid peroxidation (LPO) and nitric oxide (NO); remarkable decrease in the activity of cardiac antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx); and the depletion of the total antioxidant capacity (TAC) and total thiol groups (TTGs). PTX was able to reduce the increased levels of serum cardiac markers (LDH, CPK, cTnI, TC, and TG), cardiac LPO, and improve antioxidant markers (TAC, TTGs, CAT, SOD, and GPx) alongside histopathologic changes. However, no significant changes were observed in elevated serum glucose and cardiac NO levels. In conclusion, the current study showed the potential therapeutic effect of PTX in the prevention of ATO-induced cardiotoxicity via reversing the oxidative stress.
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http://dx.doi.org/10.1155/2021/6406318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810555PMC
January 2021

Artemisia biennis Willd.: Anti-Nociceptive effects and possible mechanisms of action.

J Ethnopharmacol 2021 Mar 21;268:113604. Epub 2020 Nov 21.

Department of Physiology, School of Medicine, Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. Electronic address:

Ethnopharmacological Relevance: Artemisia biennis Willd. (Dermane in Persian) has been used as an antinociceptive remedy in Iranian folkloric medicine.

Objective: The aim of the present study was to evaluate the anti-nociceptive effects of Artemisia biennis Willd. aerial part essential oil (ABAEO) on male Swiss mice.

Materials And Methods: Nociceptive pain techniques including acetic acid-induced writhing (AAIW), formalin-induced paw licking (FPL), glutamate-induced paw licking (GPL), and tail-flick (TF) models were applied. We assessed opioid and L-arginine-NO-cGMP-KATP pathways to detect the possible anti-nociceptive properties of ABAEO. In addition, neuropathic pain was induced by the cervical spinal cord contusion model.

Results: ABAEO (120 mg/kg) had a significant anti-nociceptive activities in comparison to the control animals (p < 0.05) in the AAIW, TF, GPL, and FPL assays. The selective opioid antagonist (naloxonazine) administration in the AAIW test alleviated the anti-nociceptive effect of ABAEO (p < 0.05). L-arginine, methylene blue, and glibenclamide treatment prevented the ABAEO anti-nociceptive effects (p < 0.05); however, sodium nitroprusside could profoundly potentiate the ABAEO-associated antinociception in the FPL (phase II) test (p < 0.05). In nociceptive pain models, Cr (one of the main constituents of ABAEO) showed significant anti-nociceptive effects (p < 0.05). Moreover, the von Frey results indicated that ABAEO could attenuate mechanical allodynia in mice.

Conclusion: Our observation revealed the anti-nociceptive effects of ABAEO in male mice. These effects could include, at least in part, modulating glutamatergic mechanisms via opioid systems. Our data output also indicates activating the L-arginine-NO-cGMP-KATP system in ABAEO anti-nociceptive activities.
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http://dx.doi.org/10.1016/j.jep.2020.113604DOI Listing
March 2021

Biochemical and Histological Evidence on the Protective Effects of (Persian Shallot) as an Herbal Supplement in Cadmium-Induced Hepatotoxicity.

Evid Based Complement Alternat Med 2020 17;2020:7457504. Epub 2020 Jun 17.

Department of Internal Medicine and Gastroenterology, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran.

Materials And Methods: Thirty-six male Wistar rats were divided into six groups: groups 1, 2, and 3 received vehicle, Cd (100 mg/L/day by drinking water), and extract (200 mg/kg/day; orally), respectively. Groups 4, 5, and 6 were Cd groups which were treated with extract (50, 100, and 200 mg/kg/day, respectively). After 2 weeks, liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) and also oxidative stress biomarkers including lipid peroxidation (LPO), total antioxidant capacity (TAC), total thiol molecule (TTM), and the histopathological changes were determined using standard procedure.

Results: The findings showed that Cd caused a remarkable rise in levels of serum hepatic enzymes such as ALT ( < 0.001), AST ( < 0.01) and ALP ( < 0.001) compared with the control group. In addition, Cd led to the decreasing of the levels of TTM ( < 0.001) and TAC ( < 0.001) and increasing of LPO ( < 0.001) in liver tissue in comparison with the control group. In this regard, remarkable vascular congestion, hepatocellular degeneration, and vacuolization were observed in hepatic tissue of Cd-treated rats. Following the administration of extract, a significant improvement was observed in the functional and oxidative stress indices of hepatic tissue alongside histopathologic changes.

Conclusion: The current study indicated that the extract might prevent hepatic oxidative injury by improving oxidant/antioxidant balance in rats exposed to Cd.
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http://dx.doi.org/10.1155/2020/7457504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317314PMC
June 2020

A Behavioral Study of Promethazine Interaction with Analgesic Effect of Diclofenac: Pain Combination Therapy.

J Pharmacopuncture 2020 Mar;23(1):18-24

Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

Objectives: Pain is considered as a cause of sickness and the most prevalent symptom which makes people visit a physician. Nowadays, combination therapy is becoming useful to relieve chronic and postsurgical pain. The aim of this study was to study the promethazine (as an antihistamine) interactions with antinociceptive effect of diclofenac (as a non-steroidal anti-inflammatory drugs).

Methods: In initial part of the study, we investigate the analgesic effect of diclofenac. Using writhing test, we demonstrate that diclofenac significantly reduces writhe response induced by acetic acid in a dose-dependent manner. In this study, we evaluate the combination effect of promethazine on diclofenac analgesic effect.

Results: We observed that diclofenac inhibited pain in the dose dependent manner which means that by increasing dose of diclofenac a significant decrease in pain was observed. This experimental setup allowed calculation of the dose that caused 50% antinociception (ED50) for diclofenac. The ED50 for diclofenac in this study was determined to be 9.1 mg/kg according our previous study. Additionally, promethazine was showed a dose-dependent inhibition of writhes. The combination of different doses of promethazine (2, 4, 6 mg / kg) with diclofenac ED50 (9.1 mg / kg) was injected to mice. Promethazine 4 and 6 mg / kg in combination with diclofenac had significantly led to increase analgesic effect of diclofenac.

Conclusion: In conclusion, these results add important information to the existing knowledge on combination of diclofenac and antihistamine in pain therapies to be used in clinical practice and maybe helpful in designing the future guidelines.
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http://dx.doi.org/10.3831/KPI.2020.23.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163387PMC
March 2020

The Efficacy of Colloidal Oatmeal Cream 1% as Add-on Therapy in the Management of Chronic Irritant Hand Eczema: A Double-Blind Study.

Clin Cosmet Investig Dermatol 2020 25;13:241-251. Epub 2020 Mar 25.

Department of Clinical Pharmacy, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

Background: Irritant contact dermatitis (ICD) is the most frequent cause of hand eczema (HE). There is promising evidence with the use of topical oatmeal compounds in the management of inflammation- and itch-responses associated with diverse dermatologic conditions. This study aimed to evaluate the clinical benefit of colloidal oatmeal cream in the management of chronic irritant HE.

Methods: From October 2018 to November 2019, 79 patients with diagnosis of chronic irritant HE were allocated into either intervention or control groups by block randomization method. Besides fluocinolone 0.025% ointment for the first 2 weeks of treatment period, patients in the intervention and control groups were asked to use colloidal oatmeal 1% cream or base cream for additional 4 weeks as monotherapy. Changes in the HE severity based on the hand eczema severity index (HESCI) score, pruritus severity based on the visual analogue scale (VAS), and impact of skin disorder on patients quality of life based on the Dermatology Life Quality Index (DLQI) from baseline to weeks 2, 4, and 6 were assessed in the study groups.

Results: Fifty subjects, 26 in intervention and 24 in control, completed the course of the study. The results indicated, though relatively comparable decrease in mean HESI and VAS scores was observed in both groups by the end of week 2, thereafter until end of the study a non-return of symptoms to baseline conditions was observed in the intervention group, while there was a significant return of symptoms to baseline conditions in the control group (p value<0.001 in both conditions). Further, a noticeable improvement in the DLQI score was seen in the intervention group compared with the control group (p value<0.001).

Conclusion: Findings demonstrate that colloidal oatmeal, a natural product with proven barrier protection, moisturization, anti-inflammatory, and soothing properties, can have ameliorative effects on eczema severity symptoms in patients with chronic irritant HE.
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http://dx.doi.org/10.2147/CCID.S246021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103792PMC
March 2020

The role of ghrelin and tumor necrosis factor alpha in diazinon-induced dyslipidemia: insights into energy balance regulation.

Pestic Biochem Physiol 2019 Jun 19;157:138-142. Epub 2019 Mar 19.

Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.

The evidence shows that organophosphate compounds (OPCs), as toxic agents that stimulate the cholinergic system, can increase the incidence of metabolic disorders such as dyslipidemia. In the present study, we focused on the role of tumor necrosis factor alpha (TNF-α) and serum leptin and ghrelin in Diazinon (DZN)-induced dyslipidemia. The rats were randomly divided into five groups comprising eight animals, and all were treated via oral gavage for 28 consecutive days as follows: group one received only corn oil daily, while groups two through five received different doses of DZN dissolved in corn oil equal to 1/40, 1/20, 1/10 and 1/5 of the LD50 daily, respectively. The alteration of the serum lipid profile, such as triglycerides, high-density lipoprotein (HDL) and very-low-density lipoprotein (VLDL), was confirmed the occurrence of dyslipidemia in the range of doses 1/20-1/5 LD50 of DZN. Although no changes were found in the serum leptin levels, a significant increase was observed in the size of adipocytes, as well as in the TNF-α and ghrelin serum levels, and in the accumulation of epididymal fat, especially at a dose of 1/5 LD50 of DZN. It seems that interactions among the inflammatory reaction, cholinergic pathways and ghrelin secretion may be effective causes of DZN-induced dyslipidemia.
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http://dx.doi.org/10.1016/j.pestbp.2019.03.013DOI Listing
June 2019

The occurrence of acetaminophen/codeine as an adulterant in herbal analgesic supplements in Hamadan, Iran: A pilot study.

Complement Ther Med 2019 Feb 20;42:223-225. Epub 2018 Nov 20.

Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran. Electronic address:

Analgesics, such as acetaminophen (APAP) and codeine (COD), are used to adulterate medicinal herbs and/or herbal supplements. This study evaluated the APAP and COD levels in 60 herbal supplement and/or herb-based medicine samples collected from apothecaries in Hamadan, Iran. The samples were analysed using a high-performance liquid chromatography (HPLC) system. The results showed that 15% of the samples contained 38900-165200 ng/g and 31.1-603.3 ng/g of APAP and COD, respectively. Due to the side-effects of analgesic drugs in human, control of these drugs is recommended in herbal supplements.
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http://dx.doi.org/10.1016/j.ctim.2018.11.018DOI Listing
February 2019

Thymoquinone attenuates hepatotoxicity and oxidative damage caused by diazinon: an study.

Res Pharm Sci 2018 Dec;13(6):500-508

Department of Pathology, School of Medicine, and Clinical education Research center, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.

Thymoquinone (TQ) is the main active constituent of seeds. The objective of this study was to explore the protective effects of TQ on diazinon (DZN)-induced liver toxicity in the mouse model. The animals were divided into five groups of 6 each and treated intraperitoneally. Group 1 received the vehicle, group 2 was given 16 mg/kg DZN, group 3 received 5 mg/kg TQ, and groups 4 and 5 were treated with 1.25 and 5 mg/kg of TQ as well as 16 mg/kg DZN, respectively. Finally, butyrylcholinesterase (BChE), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) serum activity as well as nitric oxide (NO), lipid peroxidation (LPO), total antioxidant capacity (TAC), total thiol molecule (TTM), and histopathological experiments were evaluated in the liver samples. Our findings showed that DZN caused a significant increase in ALT ( < 0.01), AST ( < 0.001), ALP ( < 0.001) serum levels, LPO ( < 0.001) and NO ( < 0.001), the depletion of the TAC ( < 0.05) and TTM ( < 0.001), and structural changes in the liver tissue. Following TQ administration, a significant improvement was observed in the oxidative stress biomarkers in the liver tissue. In addition, our biochemical findings were correlated well to the histopathological examinations. In conclusion, the data from this study indicate that the administration of TQ may prevent liver damage by preventing free radical formation in animals exposed to DZN.
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http://dx.doi.org/10.4103/1735-5362.245962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288994PMC
December 2018

Occurrence of bacterial and toxic metals contamination in illegal opioid-like drugs in Iran: a significant health challenge in drug abusers.

Daru 2018 Sep 29;26(1):77-83. Epub 2018 Jun 29.

Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, P.O. Box 8678-3-65178, Hamadan, Iran.

Background: The toxic metals and/or bacterial contaminants in illicit drugs are the main health problems in drug users worldwide. Hence, the potential risks of these contaminants were evaluated in some of the illicit drugs during 2015 and 2016.

Methods: The metals analysis were performed using graphite furnace atomic absorption spectrophotometry. In addition, all microbiological analysis stages, including handling procedures, dilution, and culture media, were conducted in accordance with the US Pharmacopeia (USP) which are harmonized with the European Pharmacopoeia (EP).

Results: In the present study, the highest lead (Pb; 138.10 ± 75.01 μg/g) and chromium (Cr; 447.38 ± 20.27 μg/g) levels were detected in opium samples. In addition, the highest prevalence of microbial contamination was observed in opium samples, and the lowest was recorded in heroin samples. Clostridium tetani, with about 50% of contaminant, was the most common bacteria in the analyzed samples.

Conclusions: Our results indicate that Pb exposure as well as bacterial contamination could be the major threats for drug users. Graphical Abstract ᅟ.
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http://dx.doi.org/10.1007/s40199-018-0205-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154484PMC
September 2018

Protective effect of amlodipine on diazinon-induced changes on oxidative/antioxidant balance in rat hippocampus.

Res Pharm Sci 2018 Aug;13(4):368-376

Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, I.R. Iran.

Oxidative stress (OS) is a main mechanism in organophosphorus poisoning. The effects of calcium channel blockers have been confirmed in decreasing of oxidative stress. In the current study, the effects of amlodipine (AM), as a calcium channel blocker, were evaluated on oxidative damages induced by diazinon (DZN) in hippocampus tissue of Wistar rats. Forty-two rats were divided into six groups and treated intraperitoneally for two weeks. Group 1 served as control received vehicle, group 2 was treated with 9 mg/kg of AM, group 3 (positive control) received DZN (32 mg/kg), Groups 4, 5, and 6 were treated with 3, 6, and 9 mg/kg of AM adjunct with DZN (32 mg/kg), respectively. After 14 days, all the animals were sacrificed under anesthesia and hippocampus tissue and blood samples were collected for biochemical analysis and histopathology experiments. The results showed that DZN caused significant increase in lipid peroxidation ( < 0.001), nitric oxide ( < 0.001) and lactate dehydrogenase ( < 0.001) levels, depletion of total antioxidant capacity ( < 0.01), and structural changes in hippocampus tissues. Following AM administration, a significant improvement was observed in oxidative biomarkers in hippocampus tissues. Additionally, our biochemical findings were related well with histopathological examinations. In conclusion, the data of this study indicated that AM administration may prevent oxidative damages via improving of energy production and preventing of free radical formation in DZN-exposed animals.
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http://dx.doi.org/10.4103/1735-5362.235164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040164PMC
August 2018

Multidrug and toxin extrusion proteins (MATE/SLC47); role in pharmacokinetics.

Int J Biochem Cell Biol 2013 Sep 5;45(9):2007-11. Epub 2013 Jul 5.

Department of Pharmacology and Toxicology Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.

Mammal multidrug and toxin extrusion protein 1 (MATE 1) encoded by SLC47A1 gene was described in 2005 as an efflux transporter that mediates proton-coupled organic cation secretion. Shortly after, other isoforms (MATE2 and MATE2-K, both encoded by SLC47A2 gene) were identified. In the kidney and liver, MATEs work in concert with organic cation transporters (OCTs), together representing an eliminatory pathway for organic cations. Over 40 clinically used drugs and several endogenous compounds are known substrates or inhibitors of MATEs and the list is constantly growing. These transporters are supposed to modulate pharmacokinetics/toxicokinetics and to play a role in drug resistance and (patho)physiological processes. Drug-drug interactions on MATE transporters and polymorphisms in SLC47A genes may affect renal excretion of substrate drugs, such as metformin, resulting in inadequate pharmacotherapy or occurrence of toxic effects. Expression and function of MATEs in tissues other than kidney and liver remain to be elucidated.
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http://dx.doi.org/10.1016/j.biocel.2013.06.022DOI Listing
September 2013

Transfer of metformin across the rat placenta is mediated by organic cation transporter 3 (OCT3/SLC22A3) and multidrug and toxin extrusion 1 (MATE1/SLC47A1) protein.

Reprod Toxicol 2013 Aug 3;39:17-22. Epub 2013 Apr 3.

Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.

In our previous studies we described functional expression of organic cation transporter 3 (OCT3) and multidrug and toxin extrusion 1 (MATE1) protein in the rat placenta. Since metformin is a substrate of both OCT3 and MATE1, in this study we used the model of dually perfused rat placenta to investigate the role of these transporters in metformin passage across the placenta. We observed concentration-dependent transplacental clearance of metformin in both maternal-to-fetal and fetal-to-maternal directions; in addition metformin crossed the placenta from the fetal to maternal compartment even against its concentration gradient. This transport was completely inhibited by MPP(+), a common OCT3 and MATE1 inhibitor. Furthermore, we observed that the oppositely directed H(+)-gradient can drive the secretion of metformin from placenta to maternal circulation, confirming apical efflux of metformin from trophoblast by MATE1. In conclusion, we suggest an important role of OCT3 and MATE1 in the transplacental transfer of metformin.
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http://dx.doi.org/10.1016/j.reprotox.2013.03.001DOI Listing
August 2013

Organic cation transporter 3 (OCT3/SLC22A3) and multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter in the placenta and fetal tissues: expression profile and fetus protective role at different stages of gestation.

Biol Reprod 2013 Mar 7;88(3):55. Epub 2013 Mar 7.

Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.

In our previous study, we described synchronized activity of organic cation transporter 3 (OCT3/SLC22A3) and multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter in the passage of organic cations across the rat placenta and the role of these transporters in fetal defense; in this study, we hypothesized that changes in placental levels of OCT3 and MATE1 throughout gestation might affect the fetal protection and detoxification. Using quantitative RT-PCR, Western blot analysis, and immunohistochemistry, we were able to detect Oct3/OCT3 and Mate1/MATE1 expression in the rat placenta as early as on Gestation Day (gd) 12 with increasing tendency toward the end of pregnancy. Comparing first versus third trimester human placenta, we observed stable expression of OCT1 and decreasing expression of OCT2 and OCT3 isoforms. Contrary to the current literature, we were able to detect also MATE1/MATE2 isoforms in the human placenta, however, with considerable inter- and intraindividual variability. Using infusion of 1-methyl-4-phenylpyridinium (MPP(+)), a substrate of OCT and MATE transporters, into pregnant dams, we investigated the protective function of the placenta against organic cations at different gds. The highest amount of MPP(+) reached the fetus on gd 12 while from gd 15 onward, maternal-to-fetal transport of MPP(+) decreased significantly. We conclude that increased expression of placental OCT3 and MATE1 along with general maturation of the placental tissues results in significantly lower transport of MPP(+) from mother to fetus. In contrast, decreasing expression of OCT3 and MATE1 in human placenta indicates these transporters may play a role in fetal protection preferentially at earlier stages of gestation.
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http://dx.doi.org/10.1095/biolreprod.112.105064DOI Listing
March 2013

Synchronized activity of organic cation transporter 3 (Oct3/Slc22a3) and multidrug and toxin extrusion 1 (Mate1/Slc47a1) transporter in transplacental passage of MPP+ in rat.

Toxicol Sci 2012 Aug 26;128(2):471-81. Epub 2012 Apr 26.

Department of Pharmacology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.

The aim of the present study was to investigate the expression, localization, and function of organic cation transporter 3 (Oct3, Slc22a3) and multidrug and toxin extrusion protein 1 (Mate1, Slc47a1) in the rat placenta. Using qRT-PCR and Western blotting techniques, we demonstrated abundant Oct3 and Mate1 mRNA and protein expression achieving significantly higher levels than those in the maternal kidney (positive control). Immunohistochemical visualization revealed preferential localization of Oct3 on the basolateral, i.e., fetus facing side of the placenta, whereas Mate1 positivity was located in the labyrinth area predominantly on the apical, i.e., maternal side of the placenta. To investigate the role of these transporters in the transplacental pharmacokinetics, the in situ method of dually perfused rat term placenta was employed in open- and closed-circuit arrangements; 1-methyl-4-phenylpyridinium (MPP(+)) was used as a model substrate of both Oct3 and Mate1. We provide evidence that Oct3 and Mate1 cause considerable asymmetry between maternal-to-fetal and fetal-to-maternal transport of MPP(+) in favor of fetomaternal direction. Using closed-circuit experimental setup, we further describe the capacity of Oct3 and Mate1 to transport their substrate from fetus to mother even against a concentration gradient. We conclude that Oct3, in a concentration-dependent manner, takes up MPP(+) from the fetal circulation into the placenta, whereas Mate1, on the other side of the barrier, is responsible for MPP(+) efflux from placenta to the maternal circulation. These two transport proteins, thus, form an efficient transplacental eliminatory pathway and play an important role in fetal protection and detoxication.
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http://dx.doi.org/10.1093/toxsci/kfs160DOI Listing
August 2012

Olomoucine II and purvalanol A inhibit ABCG2 transporter in vitro and in situ and synergistically potentiate cytostatic effect of mitoxantrone.

Pharmacol Res 2012 Mar 6;65(3):312-9. Epub 2011 Dec 6.

Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.

Inhibition of cyclin-dependent kinases by specific small molecules, purine cyclin-dependent kinase inhibitors (CDKi), has become a promising strategy for cancer treatment. Although pharmacodynamic properties of these compounds have been studied extensively, their pharmacokinetic behavior has not been addressed in detail. In this study, we investigated possible inhibitory effect of five purine CDKi on breast cancer resistance protein (ABCG2) transport activity employing in vitro transport and accumulation methods in MCDKII cells transduced with human ABCG2. Hoechst 33342 and glyburide were used as model ABCG2 substrates for these experiments. In addition, in situ method of dually perfused rat term placenta was utilized to confirm our in vitro results at the organ level. Fumitremorgin C was used as a model inhibitor of ABCG2 for comparison purposes. We demonstrate significant inhibition of ABCG2 by four of the five CDKi tested. Regarding their ABCG2-inhibitory potencies, the investigated compounds can be ranked as follows: purvalanol A>olomoucine II≈fumitremorgin C>roscovitine≈bohemine, with slight differences among substrates, concentrations and methods used. Based on our findings, it is reasonable to expect a substantial impact of the studied CDKi on the pharmacokinetic and pharmacodynamic behavior of concomitantly administered ABCG2 substrates. Moreover, using combination index method of Chou-Talalay, we confirmed that the strongest inhibitors, purvalanol A and olomoucine II, can synergistically potentiate cytostatic effect of mitoxantrone, an ABCG2 substrate, in ABCG2 expressing cell lines.
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http://dx.doi.org/10.1016/j.phrs.2011.11.017DOI Listing
March 2012