Co-administration Of Metformin Research Articles

The Comparison of Antioxidant Effect of Aspirin, Metformin, Atorvastatin and Captopril Co-administration in the Heart and Kidney Tissues of Diabetic Rats.

The present study investigated the effects of co-administration of aspirin, metformin, atorvastatin and captopril on serum lipid profile and oxidative stress in the heart and kidney of streptozotocin-induced diabetic rats. In this study, rats were randomly divided into the following eleven groups: control (Cont.), and diabetic (D), as well as 9 groups that were treated with metformin (M, 300 mg/kg) or aspirin (ASA, 120 mg/kg) alone or in different combinations with captopril (C, 50 mg/kg), or atorvastatin (AT, 40 mg/kg), as follows: (D + M), (D + ASA), (D + M + ASA), (D + M + C), (D + M + AT), (D + M + C + ASA), (D + M + C + AT), (D + M + AT + ASA), and (D + M + C + AT + ASA). The rats in treatment groups daily received drugs by gavage for six weeks. Finally, serum lipid profile and levels of oxidative markers in the heart and kidney tissues were evaluated. In diabetic rats, blood levels of glucose, cholesterol, TG (triglyceride), LDL (low-density lipoprotein), MDA (malondialdehyde) and AIP (atherogenic index of plasma) significantly increased but those of HDL (high-density lipoprotein) and total thiol as well as SOD (superoxide dismutase) and CAT (catalase) activities significantly decreased. Treatment with different combinations of C, ASA, AT and M significantly ameliorated these parameters. This study showed that co-administration of ASA, M, C and AT, could improve glucose and lipid metabolism and oxidative stress markers in the kidneys and heart tissues of diabetic rats more markedly than the administration of these drugs alone.

Influence of co-administration of Khat (Catha edulis) and metformin on metabolic syndrome in high fructose diet induced type 2 diabetes in rats

Background: Despite numerous reports regarding the associations of Khat chewing with serious health adverse effects, a significant number of people worldwide uses Khat daily, especially in its origin countries. The risk of co-administration of Khat and drugs that is high among these individuals, leading to increase probability of adverse Khat-drug interactions. Under these circumstances, it becomes important to evaluate the effect of concomitant administration of Khat and clinical drugs. Metformin is a drug of biguanide class used to the lower blood glucose concentrations in patients with type 2 diabetes mellitus (T2DM). Aim and Objectives: The aim of the study was to evaluate the beneficial or harmful effects of concomitant administration of Khat and metformin in a high fructose diet induced T2DM model. Materials and Methods: Thirty-six adult male rats weighing 120–150 g were made diabetic by feeding a high fructose diet for 4 weeks. These rats while continuing to be on high fructose diet were divided into six groups and administered orally, normal control (normal saline), normal control with Khat (1500 mg/kg), non-treated diabetic group, Khat treated group (1500 mg/kg), metformin treated diabetic (300 mg/kg), and metformin (300 mg/kg) with Khat (1500 mg/kg) treated group. All the above treatments were given for 4 weeks and their effects were studied. Results: The hyperglycemia, body weight, and lipid profile parameters were brought down significantly by Khat and metformin (P < 0.05) monotherapy; metformin being more effective than Khat. The metformin-Khat combination had a synergistic effect and resulted in much greater efficacy in ameliorating the parameters. Moreover the adverse effect of Khat like lowering of high-density lipoprotein cholesterol (HDL-C) levels was significantly mitigated by metformin-Khat combination. Conclusion: The results suggested that metformin-Khat combination had a much greater efficacy with the added advantage of reducing the adverse effects.

Metformin and cyanidin 3-O-galactoside from Aronia melanocarpa synergistically alleviate cognitive impairment in SAMP8 mice.

Cyanidin 3-O-galactoside (Cy3Gal) from Aronia melanocarpa has been reported to alleviate cognitive impairment. Metformin for preventing the neurodegenerative disease is attracting increasing attention. However, the neuroprotective and metabolic health promoting both of their effects are not clear. We chose the senescence accelerated mouse prone 8 (SAMP8) as a model of spontaneous learning and memory impairment. This study aimed to investigate the synergistic neuroprotective effect of metformin and Cy3Gal by behavioral and histopathological assays and metabolite analysis in SAMP8 mice. The SAMR1 mice were the normal group, and the SAMP8 mice were divided into five groups, including the SAMP8 model group, the donepezil (1 mg kg-1, ig) group, the metformin (100 mg kg-1, ig) group, the Cy3Gal (25 mg kg-1, ig) group, and the combination of metformin plus Cy3Gal (Met + Cy3Gal, 100 mg kg-1, 25 mg kg-1, ig) group. The behavior experiments showed that the SAMP8 mice treated with metformin and Cy3Gal showed improved spatial learning and memory compared to the SAMP8 model group. The number of neurons in the Met + Cy3Gal group was significantly higher than that in the SAMP8 group and the Met + Cy3Gal group showed significantly reduced Aβ aggregation in the brain, which was elevated in SAMP8 mice. Compared with SAMP8 mice, the Met + Cy3Gal group showed decreased indole, methyl esters and ketones and increased short-chain fatty acids and alcohols in feces and urine by regulating the fatty acid biosynthesis and degradation. This study confirmed the neuroprotective effects of coadministration of metformin and cyanidin 3-O-galactoside in the SAMP8 mice, and suggested its positive effect on postponing the progression of Alzheimer's disease.

The Protective Effect of Metformin against Oxandrolone-Induced Infertility in Male Rats.

Oxandrolone is a synthetic testosterone analog that is widely used among bodybuilders and athletes. However, oxandrolone causes male infertility. Recently, it was found that metformin reduces the risk of infertility associated with diabetes mellitus. This study aimed to investigate the protective effects of metformin against oxandrolone-induced infertility in male rats. Rats continuously received one of four treatments (n=7) over 14 days: control DMSO administration, oxandrolone administration, metformin administration, or co-administration of oxandrolone and metformin. Doses were equivalent to those used for human treatment. Subsequently, testicular and blood samples were collected for morphological, biochemical, and histological examination. In addition, gene expression of the testosterone synthesizing enzyme CYP11A1 was analyzed in the testes using RT-PCR. Oxandrolone administration induced male infertility by significantly reducing relative weights of testes by 48%, sperm count by 82%, and serum testosterone levels by 96% (ANOVA, P value < 0.05). In addition, histological examination determined that oxandrolone caused spermatogenic arrest, which was associated with 2-fold downregulation of testicular CYP11A1 gene expression. However, co-administration of metformin with oxandrolone significantly ameliorated toxicological alterations induced by oxandrolone exposure (ANOVA, P-value < 0.05). Metformin administration provided protection against oxandrolone-induced infertility in male rats. Further clinical studies are needed to confirm the protective effect of metformin against oxandrolone-induced infertility among athletes.

Coadministration of metformin prevents olanzapine-induced metabolic dysfunction and regulates the gut-liver axis in rats.

Olanzapine is widely prescribed for patients with mental disorders; however, it may induce metabolic dysfunction. Metformin is an efficient adjuvant for preventing olanzapine-induced metabolic dysfunction in clinical practice. Although the mechanism of how metformin prevents this metabolic dysfunction remains unknown, changes in the gut-liver axis are considered a potential explanation. Forty-eight male rats were gavaged with olanzapine and/or metformin for 35 consecutive days. Body weight, food intake, and water intake were measured daily. Histopathological and biochemical tests were performed to evaluate the metabolic dysfunction. The 16S rRNA obtained from fecal bacterial DNA was assessed. Olanzapine treatment increased the body weight, blood glucose and triglyceride levels, and the number of adipocytes in the liver. While coadministration of metformin, there was a dose-dependent reverse of the abnormal changes induced by olanzapine treatment. Both olanzapine and metformin treatments altered the composition of the gut microbiota. Bacteroides acidifaciens and Lactobacillus gasseri were possibly played a positive role in metformin-mediated olanzapine-induced metabolic dysfunction prevention. Metformin prevented olanzapine-induced metabolic dysfunction and regulated the gut microbiota in a dose-dependent manner.

Association of Insulin, Metformin, and Statin with Mortality in Breast Cancer Patients.

PurposeThis study investigated the association of insulin, metformin, and statin use with survival and whether the association was modified by the hormone receptor status of the tumor in patients with breast cancer.Materials and MethodsWe studied 7,452 patients who had undergone surgery for breast cancer at Seoul National University Hospital from 2008 to 2015 using the nationwide claims database. Exposure was defined as a recorded prescription of each drug within 12 months before the diagnosis of breast cancer.ResultsPatients with prior insulin or statin use were more likely to be older than 50 years at diagnosis and had a higher comorbidity index than those without it (p < 0.01 for both). The hazard ratio (HR) for death with insulin use was 5.7 (p < 0.01), and the effect was attenuated with both insulin and metformin exposure with an HR of 1.2 (p=0.60). In the subgroup analyses, a heightened risk of death with insulin was further prominent with an HR of 17.9 (p < 0.01) and was offset by co-administration of metformin with an HR of 1.3 (p=0.67) in patients with estrogen receptor (ER)–negative breast cancer. Statin use was associated with increased overall mortality only in patients with ER-positive breast cancer with HR for death of 1.5 (p=0.05).ConclusionInsulin or statin use before the diagnosis of breast cancer was associated with an increase in all-cause mortality. Subsequent analyses suggested that metformin or statin use may have been protective in patients with ER-negative disease, which warrants further studies.

Metformin attenuates antipsychotic-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats.

Second-generation antipsychotics are the first-line medications prescribed for schizophrenic patients; however, some of them, such as olanzapine and risperidone, may induce metabolic dysfunctions during short-term treatment. Metformin is an effective adjuvant that attenuates antipsychotic-induced metabolic dysfunctions (AIMD) in clinical practice. Whether metformin can reverse AIMD and whether metformin affects the therapeutic effects of antipsychotics in animal models of schizophrenia are questions that still need to be investigated. In this study, an animal model of schizophrenia was established by consecutive injections of MK801 during the neurodevelopmental period. In adulthood, different dosages of olanzapine or risperidone treatment were administered to the schizophrenia model animals for 14days. Both therapeutic effects and metabolic adverse effects were measured by behavioral tests, histopathological tests, and biochemical tests. The coadministration of different doses of metformin with olanzapine or risperidone was used to evaluate the effects of metformin on both AIMD and the therapeutic effect of those antipsychotics. The MK801-treated rats showed schizophrenia-like behavior and variations in the shape and volume of the hippocampus. Both olanzapine and risperidone reversed the MK801-induced behavioral abnormalities as the dosage increased; however, they degenerated the hepatocytes in the liver and influenced the blood lipid levels and blood glucose levels. The coadministration of metformin did not affect the therapeutic effects of olanzapine or risperidone on behavioral abnormalities but attenuated the metabolic dysfunctions induced by those antipsychotics. Metformin attenuated the olanzapine- and risperidone-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats without reducing the therapeutic effects of the antipsychotics.

Imeglimin Does Not Induce Clinically Relevant Pharmacokinetic Interactions When Combined with Either Metformin or Sitagliptin in Healthy Subjects.

Imeglimin (IMEG) is the first in a novel class of oral glucose-lowering agents with a unique mechanism of action targeting mitochondrial bioenergetics. We assessed whether repeated co-administration of IMEG and either metformin (MET) or sitagliptin (SITA) would influence the pharmacokinetics of either MET or SITA in healthy Caucasian men. Healthy Caucasian men received either MET 850mg twice daily with placebo (n = 16) or SITA 100mg once daily with placebo (n = 16) on days 1-6, followed by MET 850mg twice daily with IMEG 1500mg twice daily or SITA 100mg once daily with IMEG 1500mg twice daily on days 7-12. Pharmacokinetic parameters were determined from blood and urine; levels of all compounds were evaluated using liquid chromatography with tandem mass spectrometry. Systemic exposure (AUC0-τ area under the plasma concentration-time curve over a dosing intervaland maximum concentration) to MET was 14% and 10% lower, respectively, when administered with IMEG. Approximately 40% of MET was excreted unchanged in urine, decreasing to 34% when given with IMEG. The 90% confidence intervals for AUC0-τ and maximum concentration indicated no effect of co-administration on systemic exposure to MET. Mean AUC0-τ and maximum concentration of SITA were similar with or without IMEG. Median times to maximum concentration were 0.7 and 1.0h and mean elimination half-lives were 8.2 and 8.7h with and without IMEG, respectively. Systemic exposure to IMEG was similar to previous phase I studies. Co-administration of IMEG with MET or SITA did not result in clinically relevant changes in systemic exposure to MET or SITA, although minor reductions in exposure (AUC0-τ and maximum concentration) and renal elimination were noted when MET was given with IMEG vs placebo. EudraCT2009-014520-40 (MET-IMEG DDI) and EudraCT2010-022926-34 (SITA-IMEG DDI).

Co-administration of Selenium Nanoparticles and Metformin Abrogate Testicular Oxidative Injury by Suppressing Redox Imbalance, Augmenting Sperm Quality and Nrf2 Protein Expression in Streptozotocin-Induced Diabetic Rats.

Selenium nanoparticles (SeNPs) and metformin (Met) elicit individually protective effects against testicular oxidative injury in diabetic rats. However, the combined effects of both compounds have not been investigated. We investigated the effects of SeNPs and Met individual/co-treatment on testicular oxidative injury in diabetic rats. Diabetes was induced by a single intraperitoneal administration of streptozotocin (STZ-40mg/kg bwt). The rats were equally divided into 6 groups: Group one-non-diabetic; group two-diabetic untreated; and group six-non-diabetic received citrate buffer (2mL/kg bwt), while group three, four, and five received SeNPs (0.1mg/kg bwt), Met (50mg/kg bwt), and SeNPs/Met combined respectively, for 42days. Results revealed that SeNPs, as well as Met treatment significantly (p < 0.001), lowered blood glucose levels and improved relative organ weights in treated rats than those of the untreated group. Moreover, a synergistic effect was observed in the co-administration group. Additionally, combined treatment elicited better effect, in augmenting the pituitary and testicular hormone (LH, FSH, prolactin, and testosterone) levels, marker enzymes/protein associated with steroidogenesis (3-βHSD, 17-βHSD, and StAR protein), and sperm functional parameters than those of individual treatment groups, when compared with control. Furthermore, the combinatorial effects of SeNPs and Met surpassed their influence in attenuating testicular oxidative stress/inflammation and upregulation of Nrf2 protein expression in diabetic rats when compared with control. Overall, normal rats, co-treated with SeNPs and Met, did not reveal any deleterious effect. Therefore, SeNPs and Met combined treatment may better improve testes function in diabetic conditions than an individual regimen.

Bifidobacterium bifidum G9-1 ameliorates soft feces induced by metformin without affecting its antihyperglycemic action.

Recent studies of metformin, the first-line drug for type 2 diabetes, have reported the involvement of gut microbiota in the mechanism underlying its antihyperglycemic effect. However, the mechanisms underlying the development of diarrhea and bloating, which are adverse effects of metformin, are unclear, and these effects decrease the quality of life of metformin-receiving patients with diabetes. In this study, we focused on the effects of metformin on gut microbiota. Namely, we examined the effects of Bifidobacterium bifidum G9-1 (BBG9-1), which has the ability to improve dysbiosis, on the changes in gut microbiota and occurrence of soft feces (increased fecal water content) during the administration of metformin. The results showed that coadministration of BBG9-1 and metformin suppressed metformin-mediated changes in the gut microbiota and, thus, soft feces. Meanwhile, BBG9-1 did not influence the antihyperglycemic effect of metformin. Based on these results, we believe that BBG9-1, which could improve gut microbiota, suppresses metformin-induced soft feces without influencing the drug’s antihyperglycemic effect.

Treatment with the anti-diabetic drug metformin ameliorates betel-nut induced carcinogenesis in a murine model.

Metformin, a widely used anti-diabetic drug has gained enormous attention as an anticancer agent. This study seeks to investigate the efficacy of metformin in ameliorating aqueous extract of betel-nut (AEBN) and arecoline induced carcinogenesis in a murine model. Swiss albino mice were exposed to AEBN (2 mg ml-1) and arecoline (10 μg ml-1) in drinking water for 16 weeks followed by co-administration of metformin (75 mg kg-1 or 150 mg kg-1) for 4 or 8 weeks. Histological changes and oxidative stress were assessed by haematoxylin and eosin staining, TBARS assay and protein carbonylation assay respectively. Lipid profile was determined using an automated analyzer. Expression of total and phosphorylated AMPK, ACC and p53 were determined by immunoblotting. AEBN and arecoline induced dyslipidemia by downregulating AMPK (Thr-172) and activating ACC (Ser-79); they also downregulated tumor suppressor p53 (Ser-15). Metformin treatment induced AMPK-dependent alleviation of dyslipidemia in a dose and time dependent manner, upregulated p53 (Ser-15), restored tissue architecture and reduced oxidative stress in tissues of AEBN and arecoline treated mice. This study establishes that betel nut induces dyslipidemia through its alkaloid, arecoline by inhibition of AMPK (Thr-172) and activation of ACC (Ser-79) and highlights the therapeutic potential of metformin for treatment of betel-nut induced carcinogenesis, indicating the repurposing of the old drug in a new avenue.

Metformin administration increases the survival rate of doxorubicin-treated mice.

Background: The chemotherapeutic agent doxorubicin (DOX), an anthracycline broadly used to treat different types of cancers, induces several side effects, including cardiotoxicity, hepatotoxicity, and nephrotoxicity, in a time- and dose-dependent manner. Metformin (MET) is an antidiabetic drug used as a first-line treatment for type-2 diabetes, and is reported to work against various various drug-induced toxicities. This study aimed to investigate whether the administration of MET prophylactically suppresses DOX-induced toxicity, and prolongs the survival following DOX treatment. Methods: Fifty mice were divided into four groups, and each group received different treatments. The animals in the control group received a single injection of saline. The animals in the DOX group received a single dose of DOX (25 mg/kg). The animals in the MET group received MET on a daily basis. The animals in the DOX+MET group received only a single dose of DOX and daily doses of MET. The animals were observed on a daily basis for determining their body weight and evaluating the survival rate of the four study groups. Results: DOX accelerated the mortality rate of the animals in the DOX-treated group. Co-administration of MET and DOX increased the survival rate of the mice. Conclusion: The results of this study demonstrated that the administration of MET can reduce DOX-induced toxicity and increase the survival rate among chemotherapy-treated mice.

Ефективність сумісного застосування метформіну та ліпофлавону за умов метаболічного синдрому в щурів

У чоловіків молодого та середнього віку, які страждають на метаболічний синдром (МС) та ожиріння, досить поширеними є випадки порушень статевої функції. Сучасні дані щодо ефективності застосування метформіну за порушень чоловічої репродуктивної функції є досить суперечливими. Таким чином, пошук нових мішеней для таргетної терапії патологій, пов’язаних з МС, є одним з найважливіших завдань сучасної фундаментальної та прикладної медицини. Мета дослідження – оцінка ефективності метформіну та його комбінації з ліпофлавоном за введення щурам-самцям з МС за основними критеріальними показниками гонадопротекторної дії. У дослідах використовували самців щурят з початковою масою тіла 50–70 г, віком 3 тижні. Тварин було розподілено на 4 групи по 12 у кожній: 1– інтактні; 2 – тварини, які замість питної води отримували 10 % розчин фруктози протягом 60 днів (модель МС); 3 – тварини з МС, яким внутрішньошлунково вводили метформін у дозі 266 мг/кг протягом останніх 30 днів споживання фруктози; 4 – сумісне введення на фоні МС метформіну та ліпофлавону (внутрішньоочеревинно) у дозі 3,1 мг/кг м. т. (за кверцетином) протягом останніх 30 днів споживання фруктози. Показано, що введення ліпофлавону до схеми лікування МС метформіном сприяло оптимізації гонадопротекторної дії за рахунок відновлення про/антиоксидантного статусу тестикулярного середовища, про що свідчить позитивна модуляція активності компонентів антиоксидантного захисту (активність СОД, вміст церулоплазміну та вміст відновленого глутатіону), зниження рівня ПОЛ і відновлення стероїдогенної активності сім’яників. Отримані результати свідчать на користь того, що сумісне введення метформіну та ліпофлавону виявилось більш ефективним для корекції наслідків МС на репродуктивну функцію, ніж окреме застосування базового препарату метформіну.

Co-administration of omega-3 fatty acids and metformin showed more desirable effects than the single therapy on indices of bone mineralisation but not gluco-regulatory and antioxidant markers in diabetic rats

Although metformin (Met) is the most recommended anti-diabetogenic drug in type 2 diabetic state, the drug is known to compromise bone integrity. Like metformin, omega-3 fatty acids (ω-3) have gluco-regulatory action; however, it aids bone health. Therefore, the present study investigated the effects of ω-3 and/or metformin in diabetic rats. Fifty rats of ten animals per group were divided into the following: Control; Diabetic untreated; Diabetic + ω-3; Diabetic + metformin (metfm) and Diabetic + ω-3 + metf groups. Diabetes was induced by the administration of streptozotocin (65 mg/kg b.w., i.p.), 15 min after the administration of nicotinamide (110 mg/kg b.w., i.p.). Five days afterwards, treatments started and they lasted for 28 days. ω-3 and metformin were administered at 200 and 180 mg/kg b.w., p.o. respectively. The results showed that the induced diabetes was characterised by significant increases in calcium to phosphorus ratio, tartrate resistant acid phosphatase (TRAP), glucose and insulin resistance; but significant decreases in parathyroid hormone(PTH), phosphorus, TAC and hepatic glycogen. Relative to the diabetic control, treatments with ω-3 or metformin caused significant elevations in hepatic glycogen, total alkaline phosphatase (TALP), osteocalcin, PTH, estradiol, and calcium; however, significant decreases in TRAP and glucose. Co-administration of ω-3 and metformin caused more desirable effects on TALP, c-terminal telopeptide of type 1 collagen, estradiol and calcium to phosphorus ratio compared to the single administration. Relative to ω-3, melatonin showed a more favourable effect on calcium to phosphorus ratio; however, the former proved to have more desirable actions on insulin and TAC. Hence, it was concluded that the combined but not the single administration of ω-3 and metformin could be preferably used in the management of bone health in diabetic state.

Coadministration of metformin or spironolactone enhances efficacy of rosiglitazone in management of PCOS

The aim of this study was to compare the efficacy and safety of adding metformin or spironolactone to rosiglitazone in women with polycystic ovary syndrome (PCOS). This is a prospective non-randomized study in a tertiary care with at in a tertiary care endocrine clinic. Women (n = 138) diagnosed with PCOS on the basis of Rotterdam criteria 2003 were categorized into three groups on the basis of drug intake as – rosiglitazone (R), rosiglitazone with spironolactone (R + S), and rosiglitazone with metformin (R + M). Clinical, biochemical, hormonal, and insulin sensitivity parameters were assessed at baseline and after six months of follow up. There was a significant improvement in number of menstrual cycles per year and Ferriman Gallwey (FG) score in all three groups after 6 months. Plasma insulin (0, 2 h), HOMA-IR and serum total testosterone levels decreased after six months in all the three groups. The inter group comparison showed higher efficacy of R + S in improving hyperandrogenism whereas R + M was most effective in decreasing body weight and plasma insulin levels compared to R and R + S (p<.05). Treatment of women with PCOS using rosiglitazone alone and in combination with spironolactone or metformin is safe and efficacious with limited adverse events however randomized trials with longer duration of follow up are warranted.

Co-administration of Thiamine Pyrophosphate and Metformin in Type 2 Diabetes

Co-administration of Thiamine Pyrophosphate and Metformin in Type 2 Diabetes

Effects of naringenin on renal expression of organic cation transporter 1 and 2 proteins and metformin disposition in diabetic rats

Abstract Modulation of metformin transporters could affect its pharmacokinetics/pharmacodynamics. The effects of naringenin on the renal tubular Organic Cation Transporter 1 (OCT1) and 2 (OCT2) protein expressions and subsequently the metformin clearance in diabetic rats are hereby investigated. Male Sprague Dawley rats were divided into 7 groups. Animals were daily treated orally with metformin (250 mg/kg) or naringenin (60 mg/kg) alone or both for 56 days. Blood glucose tests were done. Serum, urine, and kidney samples were collected. Naringenin alone or in combination with metformin significantly increased creatinine clearance and lowered plasma metformin concentrations in diabetic rats compared to controls. OCT1 and OCT2 protein expressions in renal tissues were unchanged in diabetic rats treated with either naringenin or metformin, respectively. However, co-administration of metformin and naringenin upregulated OCT2 expression in diabetic rats. Naringenin may stimulate renal uptake/excretion of metformin by increasing OCT2 protein expression which facilitates metformin clearance in diabetic rats.

Influence of coadministration of metformin and methanolic stem extract of Anisopus mannii N.E.Br. (Apocynaceae) on glucose homeostasis and lipid profile in streptozotocin/nicotinamide-induced diabetic rats

Background: Although the antihyperglycemic activity of stem extracts of Anisopus mannii (AM; an antidiabetic ethnomedicinal plant utilized in Northwestern Nigeria) has been reported, the effects of coadministration of the extracts with glibenclamide, a commonly used antihyperglycemic agent, are not known. Aims and Objectives: The objectives were to determine the effect of simultaneous administration of AM methanolic stem extract with glibenclamide using streptozotocin/nicotinamide-induced diabetic rats. Materials and Methods: After permission from the departmental ethics committee, male Wistar rats were assigned to five groups: Vehicle-treated normal control; vehicle-treated diabetic control; diabetic rats treated with either glibenclamide (0.6 mg/kg) or methanolic stem extract of AM (200 mg/kg), and singly or in combination. Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed at days 14 and 28 of treatment, while lipid profile and the contents of hepatic and skeletal muscle glycogen were determined at the end of the study (day 29). Results: When combined, the AM extract significantly reduced (P < 0.05) the effect of glibenclamide in lowering the total area under the OGTT curve as well as the FBG level and in increasing the contents of hepatic and skeletal muscle glycogen as well as the blood level of high-density lipoprotein cholesterol. The two treatments also significantly reduced each other’s effect in lowering triglycerides, low-density lipoprotein, and total cholesterol. Conclusion: The methanolic stem extract of AM (200 mg/kg) combined with glibenclamide (0.6 mg/kg) reduced each other’s beneficial effects on glucose homeostasis and lipid profile in streptozotocin/nicotinamide-induced diabetic rats.

Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine

Metformin and berberine are often combined for treating diabetes. In the present study, we evaluated the drug-drug pharmacokinetic interaction between metformin and berberine after oral co-administration in vivo and the underlying mechanism. As revealed by comparison with the metformin-only group, berberine significantly decreased the maximum plasma concentration (Cmax), area under the curve from 0 to 4 h (AUC0–4h), and urinary and bile excretion, and increased the kidney tissue concentration of metformin in rats. The non-everted intestinal sac study showed that berberine inhibited the absorption of metformin, and in transfected Madin-Darby canine kidney (MDCK)-rat organic cation transporter 1 (MDCK-rOCT1), MDCK-rat organic cation transporter 2 (MDCK-rOCT2), and MDCK-rat multidrug and toxin extrusion 1 (MDCK-rMATE1) cells, berberine significantly inhibited metformin transport mediated by OCT1, OCT2, and MATE1 in a concentration-dependent manner with half-maximal inhibitory concentration (IC50) values of 18.8, 1.02, and 10.7 μM, respectively. In contrast, co-administration of metformin increased the Cmax and AUC0-4h of berberine with no significant difference in pharmacokinetics parameters between co-administration and berberine-only groups. Furthermore, metformin increased kidney and liver concentrations and reduced the urinary and biliary excretion of berberine. Metformin (≥1 or ≥0.3 mM) decreased berberine transport in MDCK-rOCT1, MDCK-rOCT2, and MDCK-rMATE1 cells. However, metformin did not affect berberine concentration in MDCK-multidrug resistance protein 1 cells. These results suggest that the combination of metformin and berberine induced a pharmacokinetic interaction by cooperatively inhibiting OCT and MATE1-mediated transport.

Effect of Red Ginseng Extract on the Pharmacokinetics and Efficacy of Metformin in Streptozotocin-Induced Diabetic Rats.

The purpose of this study was to investigate the effect of red ginseng extract on the pharmacokinetics (PK) and efficacy of metformin in streptozotocin-induced diabetic rats. The diabetes mellitus rat model was established by intraperitoneally administering multiple doses of streptozotocin (30 mg/kg, twice on day 1 and 8), and diabetic rats received metformin 50 mg/kg with or without single or multiple administration of Korean red ginseng extract (RGE, 2 g/kg/day, once or for 1 week). RGE administration did not affect the plasma concentration and renal excretion of metformin. Further, diabetic rats were administered metformin (50 mg/kg) and RGE (2 g/kg) alone or concomitantly for 5 weeks, and both regimens decreased the fasting blood glucose and glycated hemoglobin (Hb-A1c) levels. Furthermore, fasting blood glucose levels were reduced by metformin or RGE administered alone but recovered to the control level following co-administration, suggesting that the effect was additive. However, triglyceride and free fatty acid levels were not different with metformin and RGE treatment alone or in combination. Biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol levels were not different among the three treatment groups. In conclusion, RGE and metformin showed an additive effect in glycemic control. However, the co-administration of RGE and metformin did not cause PK interactions or affect biochemical parameters including the free fatty acid, triglyceride, AST, ALT, or cholesterol levels.