Concomitant Oral Administration Research Articles

Effect of concomitant use of esomeprazole on levodopa pharmacokinetics and clinical symptoms in patients with Parkinson's disease

BackgroundProton pump inhibitors (PPIs), which inhibit gastric acid secretion, are frequently prescribed to patients with Parkinson's disease (PD). Levodopa, the gold-standard treatment for PD, demonstrates enhanced solubility in acidic environments. Although PPIs increase gastric pH and may affect levodopa absorption, the effect of concomitant PPI use on levodopa pharmacokinetics in patients with PD remains unknown. This study aimed to investigate the effect of the concomitant use of esomeprazole, a PPI, on the pharmacokinetics of levodopa and carbidopa and clinical symptoms in patients with PD. MethodsWe prospectively enrolled 40 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and clinical symptoms before and two weeks after the concomitant use of esomeprazole. ResultsThe plasma concentrations of levodopa 30 min after concomitant oral administration of levodopa and esomeprazole were significantly lower (4.92 ± 4.10 μmol/L) than those without concomitant esomeprazole use (6.26 ± 3.75 μmol/L; p = 0.027). The plasma concentrations of carbidopa showed no significant differences with respect to concomitant esomeprazole use. Significant elevation was recorded in all subscores of the Movement Disorder Society-sponsored revision of the Unified Parkinson's disease Rating Scale scores after concomitant use of esomeprazole. No significant differences were observed between Helicobacter pylori-negative and Helicobacter pylori-positive patients. Non-elderly patients (age ≤ 70 years) tended to be more susceptible to the effect of esomeprazole on levodopa pharmacokinetics and clinical symptoms. ConclusionsThe unnecessary use of PPIs should be avoided in patients with PD, especially in non-elderly patients, to improve absorption of levodopa.

The protective effect of Lactopluse-keragen Longlife® in Mitigating the Adverse Effects of Aflatoxin in Broiler Chickens

This study aimed to investigate the potential effects of growth promoter, namely "chelated minerals," on aflatoxin-induced clinical signs, post-mortem lesions, growth performance, mortality rates, hematological, biochemical and histopathological alterations in broiler chicks. A total of 150 one-day-old Cobb broiler chicks were divided into three groups and subjected to different dietary treatments for 39 days. Control group fed on basal diet without any medication. Aflatoxin premedicated group received basal diets with 10 ppb aflatoxins. Group 3 was fed 10 ppb aflatoxins with Lactopluse-keragen Longlife® (1g/kg).Growth performance. Hematological parameters, serum biochemistry, and histopathological lesions were evaluated. The results revealed that aflatoxin supplementation had detrimental effects on growth performance, hematological parameters, serum biochemistry, and histopathological lesions in various body organs. It also resulted in increased mortality rates. However, the concurrent administration of Lactopluse-keragen Longlife® supplements successfully alleviated the hazardous effects of aflatoxin. This growth promoter improved growth rates, as demonstrated by weight gain in the treated groups. In conclusion, the concomitant oral administration of Lactopluse-keragen Longlife® proved to be an effective strategy for mitigating the adverse effects of aflatoxin in chickens. This intervention improved growth performance and ameliorated the detrimental effects of aflatoxin exposure. Continued research in this area is essential to enhance our understanding and develop optimal preventive measures against aflatoxin contamination in poultry production.

Panax ginseng ameliorates hepatorenal oxidative alterations induced by commercially used cypermethrin in male rats: experimental and molecular docking approaches

Cypermethrin (CYP) is a synthetic pyrethroid utilized as an insecticide in agriculture and various pest eradication programs. However, it induces numerous health hazards for animals and humans. Therefore, the current study used Panax ginseng root extract (ginseng) to reduce the hepatorenal damage caused by commercially used CYP. Thirty-two male Wistar albino rats were distributed into control, ginseng (300 mg/kg B.W/day), CYP (4.67 mg/kg B.W.), and Ginseng+CYP (rats received both CYP and ginseng). All treatments were administered orally for 30 consecutive days. Cypermethrin induced harmful effects on hepatic and renal tissues through a substantial decline in body weight in addition to a considerable increase in liver enzymes, functional renal markers, and cholesterol. Also, CYP significantly decreased acetylcholinesterase (AChE) activity and increased pro-inflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)). Moreover, a marked increase in malondialdehyde level with a significant drop in reduced glutathione level and total superoxide dismutase (T-SOD) and catalase (CAT) activities was reported in the CYP group in kidney and liver tissues. Additionally, CYP exhibited affinities to bind and inhibit AChE and antioxidant enzymes (T-SOD and CAT) in rats following the molecular docking modeling. The apparent hepatorenal oxidative damage was linked with obvious impairments in the liver and kidney histoarchitecture, immunohistochemical staining of B cell lymphoma-2 (Bcl-2), and caspase-3 proteins. Ginseng reduced CYP’s oxidative alterations by repairing the metabolic functional markers, improving antioxidant status, reducing the inflammatory response, and enhancing the molecular docking evaluation. It also ameliorated the intensity of the histopathological alterations and improved the immunohistochemical staining of Bcl-2 and caspase-3 proteins in the liver and kidney tissues. Finally, concomitant oral administration of ginseng mitigated CYP-prompted hepatorenal damage through its antioxidant, anti-inflammatory, and anti-apoptotic potentials.Graphical

Effect of concomitant oral administration of ethanol on the pharmacokinetics of nicardipine in rats.

Ethanol intake can alter pharmacokinetics by increasing the solubility or enhancing the absorption of concomitant drugs. Here, a selective, sensitive and reproducible high-performance liquid chromatography-tandem mass spectrometry method for the quantitative analysis of nicardipine in rat plasma was developed using simple protein precipitation. The calibration curve was linear over a concentration range of 1-2,000 ng/ml (r2 > 0.998). Accuracy ranged from 93.4 to 112.2% and precision was within 12.1% from three independent analytical batches. Stable conditions for the quantification of nicardipine in rat plasma were established in various conditions, including sample storage and handling. The matrix effect was negligible, and recovery was consistent at three different levels of quality control sample. The method was applied to assessment for the effect of ethanol on the pharmacokinetics of nicardipine in rats. The oral bioavailability of nicardipine was increased from 5.4 to 9.4% in Sprague-Dawley rats by concomitant oral administration of ethanol whereas the half-life was not altered. The findings indicated that concomitant ethanol intake can increase systemic drug exposure by increasing gastrointestinal absorption, especially poorly soluble drugs. This study provides an insight for further investigation of the alteration of the pharmacological effect of poorly soluble drugs owing to ethanol intake.

Ameliorating effect of rutin against diclofenac-induced cardiac injury in rats with underlying function of FABP3, MYL3, and ANP

Diclofenac is a widely prescribed anti-inflammatory drug having cardiovascular complications as one of the main liabilities that restrict its therapeutic use. We aimed to investigate for any role of rutin against diclofenac-induced cardiac injury with underlying mechanisms as there is no such precedent to date. The effect of rutin (10 and 20 mg/kg) was evaluated upon concomitant oral administration for fifteen days with diclofenac (10 mg/kg). Rutin significantly attenuated diclofenac-induced alterations in the serum cardiac markers (LDH, CK-MB, and SGOT), serum cytokine levels (TNF-α and IL-6), and oxidative stress markers (MDA and GSH) in the cardiac tissue. Histopathological examination and Scanning Electron Microscopy (SEM) findings displayed a marked effect of rutin to prevent diclofenac-mediated cardiac injury. Altered protein expression of myocardial injury markers (cTnT, FABP3, and ANP) and apoptotic markers (Bcl-2 and Caspase-3) in the cardiac tissue upon diclofenac treatment was considerably shielded by rutin treatment. MYL3 was unaffected due to diclofenac or rutin treatment. Rutin also significantly improved diclofenac-induced gastrointestinal and hepatic alterations based on the observed ameliorative effects in key mediators, oxidative stress markers, histopathology examination, and SEM findings. Overall results suggest that rutin can protect the diclofenac-induced cardiac injury by lowering oxidative stress, inhibiting inflammation, and reducing apoptosis. Further research work directs toward the development of phytotherapeutics for cardioprotection.

Investigating the Potential Use of Andrographolide as a Coadjuvant in Sickle Cell Anemia Therapy

Andrographolide is one of the main active principles of Andrographolide paniculata and has been extensively explored for its therapeutic use. Current studies focus on phytotherapeutics-based adjuvant therapy to symptomatically treat sickle cell anemia (SCA) as there is no specific drug/gene therapy available to date. The present study aimed to explore the potential of andrographolide as an adjuvant therapy for SCA in the presence or absence of hydroxyurea (HU), a key drug for SCA treatment. A panel of ex vivo and in vivo experimentations was performed to explore the antisickling activity of andrographolide, followed by evaluating pharmacokinetic and pharmacodynamic (PK/PD) activities in the presence of HU. Andrographolide showed significant antisickling activity using blood from SCA patients (ex vivo) and did not show any deleterious effect to cause hemolysis using rat blood (ex vivo). It displayed a substantial decrease in HU-induced decline in splenic lymphocyte proliferation and cytokine level (TNF-α and IFN-γ) using rat splenocytes (ex vivo). Concomitant oral administration of andrographolide with HU in rats for 15 days exhibited a noticeable improvement in the RBC count and hemoglobin levels comparable to the efficacy of l-glutamine (in vivo). Simultaneous administration of andrographolide with HU caused no marked effect on any pharmacokinetic parameters of HU except the highest plasma concentration of HU and its corresponding time point, which significantly dropped and delayed, respectively (in vivo). No considerable effect of andrographolide was observed on urease and horseradish peroxidase activity (in vitro). Overall, results suggest that andrographolide has several beneficial actions to be an adjuvant therapy to symptomatically manage SCA, but it should be avoided during the prescribed therapy of HU.

Concomitant oral administration of Sulfasalazine with Febuxostat alleviates neuropathic pain hypersensitivity through inhibition of SGK-1 in the spinal cord

Concomitant oral administration of Sulfasalazine with Febuxostat alleviates neuropathic pain hypersensitivity through inhibition of SGK-1 in the spinal cord

The antiinflammatory and antifibrotic effect of olive phenols and Lactiplantibacillus plantarum IMC513 in dextran sodium sulfate–induced chronic colitis

Objectives: After a chronic intestinal injury, several intestinal cells switch their phenotype to activated myofibroblasts, which in turn release an abnormal amount of extracellular matrix proteins, leading to the onset of the fibrotic process. To date, no resolutive pharmacological treatments are available, and the identification of new therapeutic approaches represents a crucial goal to achieve. The onset, maintenance, and progression of inflammatory bowel disease are related to abnormal intestinal immune responses to environmental factors, including diet and intestinal microflora components. This study aimed to evaluate the potential antiinflammatory and antifibrotic effect of a biologically debittered olive cream and its probiotic oral administration in an experimental model of dextran sodium sulfate (DSS)–induced chronic colitis.Methods: Chronic colitis was induced in mice by three cycles of oral administration of 2.5% DSS (5 d of DSS followed by 7 d of tap water). Mice were randomly divided into five groups: 10 control mice fed with standard diet (SD), 20 mice receiving SD and DSS (SD+DSS), 20 mice receiving an enriched diet (ED) with olive cream and DSS (ED+DSS), 20 mice receiving SD plus probiotics (PB; Lactiplantibacillus plantarum IMC513) and DSS (SD+PB+DSS), and 20 mice receiving ED plus PB and DSS (ED+ PB+DSS). Clinical features and large bowel macroscopic, histologic, and immunohistochemical findings were evaluated.Results: The simultaneous administration of ED and PB induced a significant reduction in macroscopic and microscopic colitis scores compared with the other DSS-treated groups. In addition, ED and PB led to a significant decrease in the expression of inflammatory cytokines and profibrotic molecules.Conclusions: The concomitant oral administration of a diet enriched with biologically debittered olive cream and a specific probiotic strain (Lactiplantibacillus plantarum IMC513) can exert synergistic antiinflammatory and antifibrotic action in DSS-induced chronic colitis. Further studies are needed to define the cellular and molecular mechanisms modulated by olive cream compounds and by Lactiplantibacillus plantarum IMC513.

Sulfasalazine alleviates neuropathic pain hypersensitivity in mice through inhibition of SGK-1 in the spinal cord

Diurnal variations in pain hypersensitivity are common in chronic pain disorders. Temporal exacerbation of neuropathic pain hypersensitivity is dependent on diurnal variations in glucocorticoid secretion from the adrenal glands. We previously demonstrated that spinal expression of serum- and glucocorticoid-inducible kinase-1 (SGK-1) is associated with glucocorticoid- induced exacerbation of pain hypersensitivity, but there are no available strategies to inhibit SGK-1 in the spinal cord. By screening a clinically approved drug library (more than 1,200 drugs), we found that sulfasalazine (SSZ) has inhibitory effects on SGK-1. SSZ is a prodrug composed of 5-aminosalicylic acid and sulfapyridine linked by NN bond, which is therapeutically effective for inflammatory bowel diseases. However, the NN bond in SSZ was necessary for its inhibitory action against SGK-1. Although intrathecal injection of SSZ to nerve-injured mice significantly alleviated mechanical pain hypersensitivity, no significant anti- neuropathic pain effects of SSZ were detected after oral administration due to its low bioavailability and limited spinal distribution, which were associated with efflux by the xenobiotic transporter breast cancer resistance protein (BCRP). Concomitant oral administration of SSZ with febuxostat (FBX), which is an approved drug to inhibit BCRP, improved the distribution of SSZ to the spinal cord. The concomitant oral administration with FBX also increased the anti-neuropathic pain effects of SSZ. Our study revealed a previously unrecognized pharmacological effect of SSZ to alleviate SGK-1-induced painful peripheral neuropathy, and concomitant oral administration of SSZ with FBX may also be a preventative option for diurnal exacerbation of neuropathic pain hypersensitivity.

Ginseng attenuates fipronil-induced hepatorenal toxicity via its antioxidant, anti-apoptotic, and anti-inflammatory activities in rats.

Fipronil (FPN) is a relatively new and broad spectrum insecticide that induces toxic effects to animals and humans through induction of oxidative stress. Ginseng is a medicinal plant that has antioxidant, anti-inflammatory, and anti-apoptotic activities. Thus, the current study was conducted to evaluate the anti-toxic potential of ginseng aqueous extract (GAE) against FPN-induced hepatorenal toxicity in rats. Thirty-two male Wistar albino rats were randomly allocated into four equal groups. Rats of the control group received distilled water. The second group was administrated with GAE at a dose of 200mg/kg b.w. orally day by day for 6weeks. The third group was intoxicated with FPN at a dose of 4.85mg/kg b.w. orally day by day for 6weeks. The fourth group was administrated with GAE 2h before FPN intoxication. Intoxication of rats with FPN significantly elevated the activities of serum alanine aminotransferase and aspartate aminotransferase and serum levels of urea and creatinine, as well as increased malondialdehyde level and protein expressions of caspase-3 and cyclooxygenase-2 in hepatic and renal tissues. However, it significantly decreased hepatic and renal GSH content and catalase activity. In addition, it induced histopathological alterations in hepatic and renal tissue architectures. Conversely, concomitant oral administration of GAE ameliorated the FPN-induced biochemical, pathological, and histochemical alterations in both hepatic and renal tissues. This study indicated that ginseng attenuates FPN-induced hepatorenal toxicity, possibly via its antioxidant, anti-apoptotic, and anti-inflammatory properties. Graphical Abstract CAL ABSTRACTPHIRAG.

Effect of IS01957, a para-coumaric acid derivative on pharmacokinetic modulation of diclofenac through oral route for augmented efficacy.

Diclofenac is one of the world's largest selling nonsteroidal anti-inflammatory drugs. The major concerns related to oral diclofenac therapy are gastrointestinal and cardiovascular side effects for which explicitly emphasis has been given to use it at lowest effective dose for the shortest duration. On the other hand, IS01957 has been designed under the purview of anti-inflammatory drug and bioavailability enhancer. IS01957 have dual action on inflammation and nociception with acceptable safety profile. In the quest for a suitable combination with improved therapeutic efficacy and better tolerability, pharmacodynamic and pharmacokinetic interaction studies were performed for diclofenac with or without IS01957 in mice model. Results showed that IS01957 enhanced both anti-inflammatory effect and plasma concentration of diclofenac upon concomitant oral administration. These interesting results steered to enumerate the possible role of IS01957 towards diclofenac pharmacokinetics through a panel of mechanistic investigations: (a) BCRP dependent ATPase activity was markedly interfered by IS01957; (b) IS01957 increased the intestinal permeability of diclofenac in the single pass in-situ perfusion model; (c) IS01957 inhibited the CYP2C9 catalyzed diclofenac 4-hydroxylation in human liver microsomes. Immunoblotting results suggest that diclofenac action was improved significantly in the presence of IS01957 involving MAPK pathways. Finally acute gastric damage study showed that IS01957 in combination with diclofenac was better to improve the desired PGE2 level as compare to alone. In nutshell, IS01957 have potential to augment the efficacy of diclofenac through pharmacokinetic modulation. Further investigations are required for dose reduction of diclofenac to combat its liabilities before going into clinical setting.

Protective role of Roflumilast against cadmium-induced cardiotoxicity through inhibition of oxidative stress and NF-κB signaling in rats

Cadmium (Cd), a potent cardiotoxic environmental heavy metal, induces oxidative stress and membrane disturbances in cardiac myocytes. Phosphodiesterase (PDEs) retards the positive inotropic effects of β-adrenoceptor activation by decreasing levels of cAMP via degradation. Hence, PDE inhibitors sensitize the heart to catecholamine and are therefore, used as positive inotropic agents. The present study was designed to probe the potential attenuating effects of the selective PDE4 inhibitor (Roflumilast, ROF), on cardiac biomarkers, lipid profile, lipid peroxidation products, antioxidant status and histology of cardiac tissues against Cd-induced cardiotoxicity in rats. Rats were randomly distributed into four different groups: group 1, served as the normal control group. Group 2, served as the toxic control group and were administered Cd (3 mg/kg, i.p.) for next 7 days. Groups 3 and 4, served as treatment groups that received Cd with concomitant oral administration of ROF doses (0.5 and 1.5 mg/kg), respectively for 7 days. Serum samples of toxic control group rats resulted in significant (P < 0.001) increase in lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total cholesterol (TC), triglycerides (TG) and low density lipoproteins (LDL) levels with concomitant decrease in high density lipoproteins (HDL) levels in serum which were found reversed with both of ROF treatment groups. Cd also causes significant increased (P < 0.001) in myocardial malondialdehyde (MDA) contents while cardiac glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) enzyme activities were found decreased whereas both doses of ROF, significantly reversed these oxidative stress markers and antioxidant enzymes. Cardiotoxicity induced by Cd also resulted in enhanced expression of non-phosphorylated and phosphorylated form of NF-κB p65 and decreased expression of glutathione-S-transferase (GST) and NQO1 which were found reversed with ROF treatments, comparable to normal control group. Histopathological changes were also improved by ROF administration as compared to Cd treated rats alone. In conclusion, Roflumilast exhibited attenuating effect against Cd-induced cardiac toxicity.

New HPLC–MS method for rapid and simultaneous quantification of doxycycline, diethylcarbamazine and albendazole metabolites in rat plasma and organs after concomitant oral administration

A sensitive and relatively fast, cost-effective high-performance liquid chromatographic method coupled with mass spectrometer (HPLC-MS) is herein reported for the first time for a simultaneous quantification of plasma and organs concentration of three therapeutic agents that are widely used in treatment of lymphatic filariasis (LF), namely, doxycycline (DOX), diethylcarbamazine (DEC) and albendazole (ABZ) metabolites. The method was developed and validated as per ICH and FDA guidelines and successfully employed to quantify DOX, DEC and ABZ metabolites (albendazole sulfoxide (ABZ-OX) and albendazole sulfone (ABZ-ON)) in the plasma and organs of Sprague Dawley rats after oral concomitant administration of the above mentioned therapeutic agents. Importantly, a simple, one-step protein precipitation and extraction method was used to extract the four compounds efficiently with a recovery in the range of 79.88 ± 5.02%–90.71 ± 5.13%, 85.72 ± 7.22%–93.17 ± 5.55%, 94.38 ± 7.35%–101.00 ± 8.88% and 94.38 ± 7.35%–99.87 ± 10.22% in plasma and organs for DOX, DEC, ABZ-OZ and ABZ-ON, respectively. Separation of all analytes was performed on a Xselect CSH™ C18 HPLC column (Waters, 3.0 x 150 mm, 3.5 μm particle size) with gradient elution employing a mobile phase consisting of 0.1% v/v formic acid in water and methanol with a run time of 20 min. Quantification was carried out employing a single, quadruple MS detector operated with single ion monitoring (SIM) mode and the ion transitions at m/z of 445.4, 200.2, 282.3 and 298.3 for DOX, DEC, ABZ-OX and ABZ-ON respectively. The MS response for plasma samples was linear across the concentration range of 2.5–2500 ng/mL for DOX, 0.5–500 ng/mL for DEC, 1–1000 ng/mL for ABZ-OX and ABZ-ON with a correlation coefficient (r2) ≥ 0.998. The method was selective, precise and accurate. This method allowed us to get an insight into the pharmacokinetics and biodistribution of the three therapeutic agents after simultaneous oral administration to Sprague Dawley rats. This bioanalytical method could provide a reliable, reproducible and excellent tool for routine therapeutic drug monitoring of the above mentioned therapeutic agents and also support other clinical pharmacokinetic-based studies.

Effects of urban coarse particles inhalation on oxidative and inflammatory parameters in the mouse lung and colon

BackgroundAir pollution is a recognized aggravating factor for pulmonary diseases and has notably deleterious effects on asthma, bronchitis and pneumonia. Recent studies suggest that air pollution may also cause adverse effects in the gastrointestinal tract. Accumulating experimental evidence shows that immune responses in the pulmonary and intestinal mucosae are closely interrelated, and that gut-lung crosstalk controls pathophysiological processes such as responses to cigarette smoke and influenza virus infection. Our first aim was to collect urban coarse particulate matter (PM) and to characterize them for elemental content, gastric bioaccessibility, and oxidative potential; our second aim was to determine the short-term effects of urban coarse PM inhalation on pulmonary and colonic mucosae in mice, and to test the hypothesis that the well-known antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of PM inhalation.ResultsThe collected PM had classical features of urban particles and possessed oxidative potential partly attributable to their metal fraction. Bioaccessibility study confirmed the high solubility of some metals at the gastric level. Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 15 days at a concentration relevant to episodic elevation peak of air pollution. Coarse PM inhalation induced systemic oxidative stress, recruited immune cells to the lung, and increased cytokine levels in the lung and colon. Concomitant oral administration of NAC reversed all the observed effects relative to the inhalation of coarse PM.ConclusionsCoarse PM-induced low-grade inflammation in the lung and colon is mediated by oxidative stress and deserves more investigation as potentiating factor for inflammatory diseases.

Effect of Tinidazole on Norfloxacin Disposition.

Co-administration of norfloxacin (NFX) and tinidazole (TNZ) has been used for the treatment of gastrointestinal and urinary tract infections. Concomitant oral administration of NFX with TNZ may affect NFX absorption and consequently its blood concentration and pharmacological effect. The present study was undertaken to investigate the effect of TNZ at the usual clinical dosage on the pharmacokinetics of NFX in healthy volunteers. This study was conducted as an open-label, randomized, two-way crossover experimental design. After an overnight fast, subjects were randomized to receive a single oral dose of NFX 400 mg alone and the fixed-dose combination (FDC) of NFX /TNZ 400 mg/600mg on two different occasions separated by 1 week washout period between treatments. Blood samples were collected up to 24 h postdose, and plasma was analyzed for NFX concentrations by using HPLC. The pharmacokinetic properties of NFX after FDC administration were compared with NFX administered alone. Twelve healthy subjects were enrolled (6 in each part), and all subjects completed the study. None of the participants showed any sign of adverse drug reactions during or after the completion of the study. The 90% confidence interval (CI) between NFX alone and when co-administered with TNZ indicated the presence of an interaction between NFX and TNZ, which would significantly increase the systemic rate and exposure of NFX absorption. The co-administration of TNZ with NFX increased the AUC and Cmax of NFX significantly compared with administration of NFX alone. The AUC and Cmax of NFX alone were 6.0 µg.hr/mL (2.3-9.8) and 0.87 µg/mL (0.4-1.6), respectively whereas the corresponding AUC and Cmax values after administration of FDC were 7.1 µg.hr/mL (4.0-10.6) and 0.97 µg/mL (0.4-1.7), respectively. The respective geometric mean ratios of NFX for AUC and Cmax with TNZ were 1.197 [90% CI, 0.941-1.522] and 1.087 (90% CI, 0.807 -1.463) compared with NFX alone. Both Tmax and Ka of NFX showed a significant decrease after administration of the combination compared to administration of NFX alone. The peak plasma concentration reached at 1.3 h (0.6-2.4) and 1.9 h (0.4-4.4) after oral administration of FDC and NFX alone, respectively. Both NFX and TNZ were well tolerated. The interaction of TNZ with fluroquinolones should be investigated to determine whether this interaction is limited to NFX or if other fluroquinolones have the same pharmacokinetic interactions. Further studies are necessary to determine the role of P-gp and other transporters on NFX disposition and pharmacokinetics. Additionally, the influence of TNZ on the physiological activity of GIT should be investigated.

The effect of Tributyltin on thyroid follicular cells of adult male albino rats and the possible protective role of green tea: a toxicological, histological and biochemical study

IntroductionTributyltin is one of the important and wide-spread persistent organic contaminants that accumulate in the food chain. It is suspected to cause endocrine-disrupting effects in mammals, due in part to its possible transfer through marine food chains and to the consumption of contaminated seafood.Aim of the workWas to study the possible toxic effect of Tributyltin on thyroid follicular cells of adult male albino rats and to evaluate the possible protective role of green tea.Material and methodsForty-five adult male albino rats were included and randomly divided into 3 equal groups: a control group (Group I); Group II: received tributyltin chloride (TBT) dissolved in corn oil orally in a dose of 5 mg/kg for 30 days. Group III: received tributyltin chloride in the same dose with concomitant oral administration of green tea extract for 30 days. At the end of the experiment, the animals were sacrificed and blood samples were subjected to hormonal assay for T3, T4 and TSH levels. Malondialdehyde and reduced glutathione were assessed. The thyroid tissue was processed for histological and ultrastructure examination. The colloid area of thyroid follicles was evaluated morphometrically and statistically analyzed.ResultsA significant decrease in T3 and T4 levels and serum reduced glutathione in the group II when compared with the other groups. Furthermore, a significant increase in serum Malondialdehyde and TSH levels was recorded in group II treated group by comparison to the other two groups. Histopathological and ultrastructural changes of thyroid gland follicles were detected in tributyltin treated rats; the follicular cells appeared swollen and vacuolated. Epithelial stratification was noticed in some foci with excessive vacuolation of the colloid. Dilated rough endoplasmic reticulum filled with flocculent material and increased number of lysosomes were also detected together with variation in shape and size of the nuclei. A marked improvement in the histological features of thyroid follicles was noticed in group III.ConclusionTributyltin induces oxidative stress in rats as well as anti-thyroid effect. The green tea extract is useful in combating tissue injury that is a result of tributyltin toxicity.

Effects of Caffeic Acid and Quercetin on In Vitro Permeability, Metabolism and In Vivo Pharmacokinetics of Melatonin in Rats: Potential for Herb-Drug Interaction.

Melatonin is a popular dietary supplement and also considered as pharmaceutical product for sleep disorders. Caffeic acid and quercetin are widely distributed in leafy vegetables, fruits, tea extract, and both are used as natural antioxidant. There is an immense concern for health researchers to study the herb/food-drug interactions of melatonin. It is mainly metabolized by CYP1A2 in human so that herbs/foods containing cytochrome P450 (CYP) inhibitors can affect pharmacokinetics of melatonin. By considering pharmacokinetic aspects, the present study was undertaken to evaluate the effects of caffeic acid and quercetin on Caco-2 cells permeability, metabolism, CYP1A inhibition in vitro assay systems and a single dose pharmacokinetics of melatonin in vivo rats. The effects of caffeic acid and quercetin on melatonin permeability were tested in Caco-2 cells. Metabolic stability and CYP1A activity were investigated in rat liver microsomes (RLMs) using probe substrates (melatonin/phenacetinin vitro). Melatonin and phenacetin were incubated in RLMs with or without caffeic acid and quercetin, and the IC50 values were determined. The pharmacokinetics of melatonin conducted in rats after a single dose (15mg/kg) pre-treatment with caffeic acid, quercetin and caffeic acid plus quercetin followed by oral dose of melatonin at 5mg/kg. Analysis of all samples was with LC-MS/MS. Caffeic acid and quercetin did not alter Caco-2 permeability of melatonin in apical to basolateral direction and vice versa. Melatonin was metabolized in rat liver microsomes, which was inhibited by both caffeic acid and quercetin through CYP1A. The concomitant oral administration of melatonin along with 15mg/kg of caffeic acid or quercetin or caffeic acid plus quercetin significantly (p<0.05) increased the AUC0-t of melatonin by 30.0, 66.7 and 114.0%, respectively. The apparent oral rat plasma clearance (CL/F) of melatonin also decreased significantly (p<0.05) by 28.78, 47.87 and 50% in presence of caffeic acid, quercetin and caffeic acid plus quercetin, respectively. These findings suggest that caffeic acid and quercetin improved oral exposure of melatonin via CYP1A inhibition pathway.

Incompatibility of Paracetamol with Pediatric Suspensions Containing Amoxicillin, Azithromycin and Cefuroxime Axetil

The main objective of this work was to use the Differential Scanning Calorimetry (DSC) and FTIR spectroscopy to study the possible drug-drug or drug-excipient (s) interaction in case of concomitant oral administration of paracetamol with the most common used antibiotics for children. Amoxicillin, azithromycin, cefuroxime axetil and their commercially available suspensions, Amoxil®, Azithromax® and Zinnat® were used. DSC curves for paracetamol, pure antibiotics, commercially available antibiotics and all binary mixtures used in this study showed drug-drug or drug-excipient (s) physical interaction and indicated a possible chemical interaction. To confirm chemical drug-drug or drug-excipient (s) interaction additional ATR-IR spectra for all samples used in this study were obtained. Results obtained from ATR-IR spectra showed drug-excipient (s) interaction in Zinnat®, Azithromax® and binary mixture Azithromax®-paracetamol, while chemical drug-drug interaction was not observed. From this study it can be concluded that the concomitant oral administration of paracetamol with commercially available antibiotics used in this study is not recommended and duration of two hours between the oral administrations of these drugs is strongly recommended to avoid drug-drug or drug-excipient (s) interaction.

Apremilast reversed carfilzomib-induced cardiotoxicity through inhibition of oxidative stress, NF-κB and MAPK signaling in rats

Carfilzomib (CFZ), is a potent, selective second generation proteasome inhibitor, used for the treatment of multiple myeloma. The aim of the present study was to investigate the possible protective effect of apremilast (AP) on the CFZ -induced cardiotoxicity. Rats were randomly divided into four groups: Group 1, served as the control group, received normal saline. Group 2, served as the toxic group, received CFZ (4 mg/kg, intraperitoneally [i.p.]). Groups 3 and 4, served as treatment groups, and received CFZ with concomitant oral administration of AP in doses of 10 and 20 mg/kg/day, respectively. In the present study, administration of CFZ resulted in a significant increase in serum aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase-MB (CK-MB), which were reversed by treatment with AP. CFZ resulted in a significant increase in heart malondialdehyde (MDA) contents and decrease in cardiac glutathione (GSH) level and catalase (CAT) enzyme activity which were significantly reversed by treatment with AP. Induction of cardiotoxicity by CFZ significantly increased caspase-3 enzyme activity which were reversed by treatment with AP. RT-PCR analysis revealed an increased mRNA expression of NF-κB, ERK and JNK which were reversed by treatment with AP in cardiac tissues. Western blot analysis revealed an increased expression of caspase-3 and NF-κB p65 and a decrease expression of inhibitory kappa B-alpha (Iκbα) with CFZ, which were reversed by treatment with AP. In conclusion, apremilast showed protective effect against CFZ-induced cardiotoxicity.

Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancer-associated fibroblast accumulation.

We previously demonstrated that cancer-associated fibroblasts (CAFs) accumulate at tumor sites through the interaction between a chemokine, CCL3, and its receptor, CCR5, in the late phase of colitis-associated colon carcinogenesis. Here we examined the effect of a CCR5 antagonist, maraviroc, on tumor growth arising from the orthotopic injection of mouse or human colon cancer cell lines into the cecal wall by focusing on CAFs. Orthotopic injection of either cell line caused tumor formation together with leukocyte infiltration and fibroblast accumulation. Concomitant oral administration of maraviroc reduced tumor formation with few effects on leukocyte infiltration. In contrast, maraviroc reduced the intratumor number of α-smooth muscle actin-positive fibroblasts, which express epidermal growth factor, a crucial growth factor for colon cancer cell growth. These observations suggest that maraviroc or other CCR5 antagonists might act as novel anti-CRC drugs to dampen CAFs, an essential cell component for tumor progression.