Impact of diabetes mellitus on rifampicin's plasma concentration and bioavailability in patients with tuberculosis: A systematic review and meta-analysis study.

AIM OF STUDY: To assess the impact of diabetes mellitus on plasma concentration and bioavailability of rifampicin. METHODS: Web of Science, Cochrane Library, PubMed and Scopus databases were screened until September 2020 on studies reported rifampicin's plasma concentration, bioavailability among diabetic tuberculosis patients and non-diabetic tuberculosis patients. According to the presence or absence of heterogeneity, the pooled estimate was operated by a random or fixed effect model. Sensitivity analysis or subgroup analysis were conducted. Attributed risk fraction of diabetes mellitus in the incidence of low rifampicin's plasma concentration 2-h after administration was calculated. RESULTS: Seventeen studies including 3478 tuberculosis patients were included in this study. Diabetic tuberculosis patients had 1.59 folds incidence of low rifampicin's plasma concentration 2-h after administrations (risk ratio 1.59, 95% confidence interval (1.16, 2.19), p = 0.004) and lower rifampicin's plasma concentration 2-h after administrations (mean difference -1.4, 95% confidence interval (-2.65,-0.15), p = 0.03) compared with non-diabetic tuberculosis patients. The attributed risk fraction of diabetes mellitus in the incidence of low rifampicin's plasma concentration 2-h after administration was 37%. There were no significant difference in rifampicin's maximum plasma concentration, event of low maximum plasma concentration, bioavailability and half-life between both groups. CONCLUSION: Diabetes mellitus attributed with 37% of low rifampicin's plasma concentration 2-h after administration but not influenced rifampicin's maximum plasma concentration, bioavailability and half-life. The negative effect of diabetes on plasma concentration 2hours after administration was influenced by diabetes management, income level, type of tuberculosis and its recurrence.

Gastroprotective, hepatoprotective, and nephroprotective effects of thymol against the adverse effects of acetylsalicylic acid in rats: Biochemical and histopathological studies.

Acetylsalicylic acid (Aspirin) has been used for a long time as an antipyretic and analgesic. Nevertheless, aspirin use is associated with severe morbidity and death because of its detrimental impacts on several organs, including the liver, kidneys, and stomach. The current investigation sought to ascertain the influence of thymol in mitigating aspirin-mediated gastric and hepato-renal injury. This was done by 1) evaluating gastric juice volume and pH as well as pepsin and prostaglandin E2 level; 2) measuring serum biochemical parameters and proinflammatory cytokines; 3) determining tissue oxidant/antioxidant status, and 4) identifying a link with gastric, hepatic and renal histopathological changes. Forty-eight rats were segregated to six groups: normal control, Th100, Th200, ASA, Th100 + ASA, Th200 + ASA. Daily administration of aspirin (ASA, 150 mg/kg body weight) for 3 successive days induced a significant increase in gastric juice volume, pepsin activity, serum transaminases, alkaline phosphatase, urea, creatinine, tumor necrosis factor-α, myeloperoxidase, and tissue malondialdehyde levels. In contrast, a significant reduction in gastric pH, prostaglandin E2, tissue non-enzymatic antioxidant (glutathione), and enzymatic antioxidant (superoxide dismutase, glutathione peroxidase, and catalase) levels. These biochemical changes were accompanied by histological modifications that included changes to the normal gastric, hepatic, and renal architectures. Pretreatment and simultaneous oral treatment with thymol (100 or 200 mg/kg body weight) plus ASA significantly improved all biochemical and histological changes in a dose-dependent way. Thymol's antiinflammatory and antioxidative properties may contribute to its protective action. As a result, thymol may represent a promising medication for preventing aspirin-induced gastric, liver, and renal damage.

The impact of diabetes mellitus on the pharmacokinetics of rifampicin among tuberculosis patients: A systematic review and meta-analysis study.

BACKGROUND AND AIMS: Diabetes mellitus has a negative impact on the treatment outcome of tuberculosis, increasing the incidence of treatment failure and relapse. There is a scarcity of knowledge concerning the impact of diabetes mellitus on the pharmacokinetics of rifampicin. This study was conducted to evaluate the impact of diabetes mellitus on the pharmacokinetics of rifampicin among patients with tuberculosis. METHODS: We explored the Web of Science, Cochrane Library, PubMed, and Scopus databases for articles that reported the pharmacokinetic parameters of rifampicin in diabetic and nondiabetic patients with tuberculosis published until September 2020. Based on the presence or absence of heterogeneity, pooled estimates were calculated using a random or fixed effect model. RESULTS: Seven studies were relevant and included in this study. The Tmax of rifampicin increased in diabetic patients with tuberculosis compared with nondiabetic patients with tuberculosis (MD 0.84, 95% CI (0.32, 1.35), p = 0.002). No significant differences were detected in rifampicin Cmax (MD 0.18, 95% CI (-0.52, 0.88), p = 0.61), AUC0-24 (SMD -0.02, 95% CI (-0.34, 0.30), p = 0.90), Vd (MD -3.89, 95% CI (-11.17, 3.38), p = 0.29), CL (MD -0.13, 95%CI (-0.88, 0.61), p = 0.72), and MRT (MD 1.89, 95% CI (-0.03, 3.81), p = 0.05) between diabetic and nondiabetic patients with tuberculosis. CONCLUSION: Diabetes mellitus increased the Tmax of rifampicin without further impact on other rifampicin pharmacokinetic parameters such as Cmax, AUC0-24, Vd, CL and MRT. Early therapeutic drug monitoring of rifampicin is necessary for diabetic tuberculosis patients.

Could Cisplatin Loading on Biosynthesized Silver Nanoparticles Improve Its Therapeutic Efficacy on Human Prostate Cancer Cell Line and Reduce Its In Vivo Nephrotoxic Effects?

Nanotechnology is a possible solution to the drawbacks of cancer therapy because it decreases the clinical side effects of chemotherapeutic drugs and increases their clinical activity. Thus, this work compared the in vitro cytotoxic activity and in vivo side effects of cisplatin (CP) with those of CP-loaded green silver nanoparticles (CP-AgNPs). The cytotoxic activity of CP, green AgNPs, and CP-AgNPs against PC-3, a human prostate cancer cell line, was assessed using MTT assay. CP-AgNPs had a superior cytotoxic effect on PC-3 cells with a 50% inhibition of viability (IC50) of 27.05 µg/mL, followed by CP with an IC50 of 57.64 µg/mL and AgNPs with an IC50 125.4 µg/mL. To evaluate in vivo side effects, 40 male adult Wistar rats were assigned into four groups and intraperitoneally injected with normal saline (control), CP (2.5 mg/kg body weight), green AgNPs (0.1 mL/kg body weight), and CP-AgNPs (2.5 mg/kg body weight). Intraperitoneal CP injection caused a substantial reduction in erythrocyte and leukocyte counts and hemoglobin concentration and a marked increase in urea and creatinine levels and disturbed the renal oxidant/antioxidant status. Furthermore, it caused noticeable structural alterations and significant upregulation of renal Bax and caspase-3 mRNA along with a significant downregulation of B-cell lymphoma 2 mRNA expressions. The loading of CP on green AgNPs significantly relieved the CP-induced pathological alterations and considerably enhanced its therapeutic effectiveness on PC-3 cells. These outcomes reflect the possible use of CP-AgNPs as a more efficient and safer anticancer agent than free CP.

Chitosan propolis nanocomposite alone or in combination with apramycin: an alternative therapy for multidrug-resistant Salmonella Typhimurium in rabbits: in vitro and in vivo study.

Introduction. The emergence of multidrug-resistant Salmonella Typhimurium strains has increased the need for safe, alternative therapies from natural sources with antibacterial properties.Hypothesis/Gap Statement. There are no published data regarding the use of chitosan propolis nanocomposite (CPNP) either alone or in combination with antibiotics as antimicrobials against S. Typhimurium, especially in Egypt.Aim. This study evaluated the antibacterial activities of five antimicrobials [apramycin, propolis, chitosan nanoparticles (CNPs), chitosan propolis nanocomposite (CPNP) and CPNP +apramycin] against ten virulent and multidrug-resistant (MDR) S. Typhimurium field strains recovered from diarrheic rabbits through in vitro and in vivo study.Methodology. The expression levels of three virulence genes of S. Typhimurium strains were determined by quantitative reverse-transcription PCR (RT-qPCR) after exposure to sub-inhibitory concentrations of apramycin, propolis, CNPs, CPNP alone, and CPNP +apramycin. Additionally, 90 New Zealand rabbits were divided into control and experimentally S. Typhimurium-infected groups. The infected rabbits were orally administered saline solution (infected-untreated); 10 mg apramycin/kg (infected-apramycin-treated); 50 mg propolis/kg (infected-propolis-treated); 15 mg CPNP/kg (infected-CPNP-treated) and 15 mg CPNP +10 mg apramycin/kg (infected-CPNP +apramycin-treated) for 5 days.Results. The RT-qPCR analysis revealed different degrees of downregulation of all screened genes. Furthermore, the treatment of infected rabbits with CPNP or CPNP +apramycin significantly improved performance parameters, and total bacterial and Salmonella species counts, while also modulating both oxidative stress and altered liver and kidney parameters.Conclusion. This work demonstrates the use of CPNP alone or in combination with apramycin in the treatment of S. Typhimurium in rabbits.

Efficacy of grape seed hydro-alcoholic extract in the treatment of experimentally Pasteurella multocida infected rabbits.

Pasteurellosis is one of the rabbit's most bacterial severe diseases and leads to considerable financial damages in large production systems worldwide. Antibiotic use in animals may lead to antibiotic residues in animal products, including meat. Therefore, this study was designed to evaluate the potential role of grape seed extract (GSE) in treating Pasteurella multocida infection in rabbits. For this purpose, 45 weaned male New Zealand rabbits were divided into three groups; control, infected and infected-GSE treated. Experimental P. multocida infection in rabbits induced a remarkable decrease in body weight, body weight gain, as well as microcytic hypochromic anaemia, leucocytosis, neutrophilia and lymphocytopenia. Also, a significant increase in the hepatic and renal injury biomarkers, in interleukin-6, total globulin, α, ß and γ globulins, as well as a marked reduction in total protein and albumin, were recorded in the P. multocida-infected rabbits. Treatment of infected rabbits with GSE modulated most of these altered parameters. This study endorses the administration of GSE for the treatment of Pasteurellosis in rabbits. Further studies are required to identify the possible additional effects, appropriate doses and duration of the GSE therapy in rabbits Pasteurellosis.

Comparative effect of administration and discontinuation of sildenafil and/or clomipramine on the hepatic, cardiac and testicular tissues of male rats.

In this study, we examined the adverse consequences of prolonged treatment with sildenafil and/or clomipramine (CLO) on the hepatic, cardiac and testicular tissues of rats. Additionally, we investigated the potential effects of treatment discontinuation. To this end, 60 adult male rats were randomly assigned into six groups and were orally treated with 4.5 mg sildenafil /kg BW (SLD) and 9 mg/ kg BW (SHD), 2.25 mg CLO/kg BW (CLO), 4.5 mg sildenafil/kg BW + 2.25 mg CLO/kg BW (SLD-CLO) and 9 mg sildenafil/kg BW + 2.25 mg CLO/kg BW (SHD-CLO) while the control rats received 0.5 ml distilled water for 8 weeks. Then, five rats from each group were sacrificed and the other five rats were left untreated for another four weeks to recover from the drug treatment. Long-term administration of sildenafil and/or CLO led to oxidative stress, inflammation and structural changes in the liver, heart and testis, reduction in sperm count and motility, an increase in abnormalities, and a reduction in serum testosterone, FSH and LH levels. All tested parameters returned to the normal state following the four-week discontinuation of sildenafil. Additionally, all the alterations caused by long-term administration of CLO, SLD-CLO and SHD-CLO were significantly improved during the recovery period.

Nanotechnology improves the therapeutic efficacy of gemcitabine against a human hepatocellular carcinoma cell line and minimizes its in vivo side effects.

Nanotechnology has become a promising approach for addressing cancer therapy limitations because it reduces side effects and increases the efficacy of antineoplastic agents. Therefore, this research was designed to compare the in vitro therapeutic efficacy and in vivo adverse effects of gemcitabine (GEM) and gemcitabine-loaded silver nanoparticles (GEM-AgNPs). GEM molecules were successfully attached to AgNP surfaces with a homogenous and spherical shape. The zeta size of AgNPs and GEM-AgNPs was 79.35 ± 3.2 and 75.1 ± 7 nm, respectively. The anticancer effect of AgNPs and GEM-AgNPs was investigated against a human hepatocellular carcinoma cell line (HepG2), and cytotoxic activity was evaluated by MTT assay. Apoptosis/necrosis and cell cycle arrest were also assessed. The cytotoxic activity was recorded in a concentration-dependent way. The findings have shown that GEM-AgNPs induced a better cytotoxic effect with an IC50 value of 13.63 µg/mL compared to GEM (IC50 value of 24.19 µg/mL) or AgNPs alone (IC50 value of 50.6 µg/mL). GEM-AgNPs induced pre-G1 arrest and apoptotic/necrotic cell death. Our in vivo analysis involved the use of 40 male rats assigned equally into the control rats, and rats injected intraperitoneally with GEM (134 mg/kg), AgNPs (1 mg/kg), and GEM-AgNPs (134 mg/kg). GEM and GEM-AgNPs were administered on the 1st, 7th, and 14th day of the experiment. Intraperitoneal GEM injection induced marked hematological, biochemical, hepatorenal, and histopathological alterations, while the loading of GEM in AgNPs to some extent ameliorated these alterations and significantly improved its therapeutic efficacy against HepG2 cells. These findings indicate the potential use of GEM-AgNPs in the clinical setting for anticancer treatment.

Anti-arthritic effect of ß-caryophyllene and its ameliorative role on methotrexate and/or leflunomide-induced side effects in arthritic rats.

AIM: Rheumatoid arthritis (RA) is the most widespread inflammatory arthropathy, which causes severe disability. It is highly important to ameliorate the side effects caused by different drugs used to treat RA. Therefore, this study assessed the potential role of ß-caryophyllene (BCP) in treating adjuvant-induced arthritis (AIA), increasing the efficacy of methotrexate (MTX) and/or leflunomide (LEF), and ameliorating their side effects. MATERIAL AND METHODS: AIA was induced in rats by injecting complete Freund's adjuvant. The rats were divided into different groups such as sham group; control group; monotherapy groups, including BCP (300 mg/kg), MTX (1 mg/kg), and LEF (10 mg/kg); and combined groups, including MTX + BCP, LEF + BCP, MTX + LEF, and MTX + LEF + BCP groups. KEY FINDINGS: Monotherapy with BCP or MTX or LEF as well as MTX + LEF significantly reduced paw thickness and arthritic index; the histopathological changes in hind paw joints were recovered; and oxidative stress and tumor necrosis factor-alpha (TNF-α) levels in arthritic rats were reduced. The co-administration of BCP and MTX and/or LEF significantly improved the therapeutic efficacy of MTX and/or LEF and significantly reduced the myelosuppressive and hepatotoxic effects of MTX and/or LEF. Taken together, BCP could be used with MTX and/or LEF for the treatment of RA to reduce the side effects of the drugs and increase their efficacy.

Protective effect of N-acetylcysteine on fenitrothion-induced toxicity: The antioxidant status and metabolizing enzymes expression in rats.

The existence of fenitrothion (FNT) in the soil, water, and food products has harmful effects on non-target organisms. Therefore, this study was conducted to evaluate the hepatotoxic, nephrotoxic and neurotoxic effects of FNT and the possible ameliorative effect of N-acetylcysteine (NAC), a precursor of intracellular GSH, on FNT-induced toxicity. For this purpose, thirty-two adult male albino rats were allocated into control group and groups treated with NAC (200 mg/kg), FNT (10 mg/kg) and FNT + NAC via gastric tube daily for 28 days. FNT intoxication significantly reduced food intake, water intake, body weight, and body weight gain and altered the expression of phase I and phase II xenobiotic-metabolizing enzymes-cytochrome P450 (CYP1A1) and glutathione S-transferase (GSTA4-4). In hepatic, renal and brain tissues, FNT induced oxidative stress, hepatopathy, nephropathy, and encephalopathy, and significantly increased pro-inflammatory cytokines. Furthermore, FNT exposure significantly elevated the level of hepatic and renal injury biomarkers and significantly inhibited the brain acetylcholinesterase activity. Co-administration of NAC with FNT modulated most of these altered biochemical, oxidative and inflammatory markers and restored the xenobiotic-metabolizing enzymes expression and histological structures. Our study indicated the involvement of oxidative damage, inflammation, and alteration of xenobiotic-metabolizing enzymes expression in FNT-induced toxicity and revealed that they were significantly improved by NAC co-treatment. These findings suggest that NAC administration might protect against FNT-induced toxicity in non-target organisms, including humans.

Chlorella vulgaris ameliorates testicular toxicity induced by deltamethrin in male rats via modulating oxidative stress.

This study was carried out to investigate the potential effects of Chlorella vulgaris (CV) on testicular function and oxidant/antioxidant status in normal and deltamethrin-intoxicated rats. Forty adult male rats were drenched either with normal saline, CV (50 mg/kg), deltamethrin (DM) (3 mg/kg), or CV combined with DM, daily for 8 weeks. At the end of the protocol, the epididymal sperm quality was evaluated and the testicular superoxide dismutase (SOD), catalase enzyme (CAT) and malondialdehyde (MDA), and the serum testosterone levels were estimated. Normal rats treated with CV showed a significant increase in the total sperm number/epididymal tail, testicular SOD, and CAT levels with a significant decrease in the testicular MDA. Deltamethrin intoxication significantly decreased the proportions of motile and live sperm, the testosterone concentration, the testicular SOD and CAT levels, whereas it significantly increased the proportion of abnormal sperm and the testicular MDA. Chlorella vulgaris treatment significantly ameliorated the adverse effects of DM-intoxication and restored most of the parameters to levels that are comparable to those of the control group. In conclusion, CV administration improved the testicular function of normal rats and ameliorated the effect of severe oxidative stress conditions.