Administration Of Oral Doses Research Articles

Neuroprotective Activity of Evolvulus alsinoides & Centella asiatica Ethanolic Extracts in Scopolamine-Induced Amnesia in Swiss Albino Mice.

AIM:To carry out the comparative nootropic, neuroprotective potentials of two medicinal plant species.MATERIAL AND METHODS:For neuroprotective activity; behavior models (elevated plus maze & morris water maze), in vivo antioxidant (superoxide dismutase, catalase, lipid peroxidation & reduced glutathione), inflammatory markers (IL-1β, IL-6 & TNF-α) and acetylcholine esterase (AChE) assessment procedures followed at different dosages i.e. 250 & 500 mg/kg of Evolvulus alsinoides and Centella asiatica ethanolic extracts. At the end of the study, it was performed histopathological analysis of the following organs: brain, heart, liver, and kidney.RESULTS:In oral administration of different doses of ethanolic extracts of both medicinal plants i.e. Sco + EEA 250 = 2.49 ± 0.29 , Sco + EEA 500 = 2.67 ± 0.36, Sco + ECA 250 = 2.33 ± 0.17, Sco + ECA 500 = 2.77 ± 0.21, Sco + EEA + ECA 250 = 2.61 ± 0.32 and Sco + EEA + ECA 500 = 2.79 ± 0.16 U/mg of protein respectively against the scopolamine induced group Sco (control) = 5.51 ± 0.35 U/mg of protein extracts shows neuroprotective and nootropic activity with reducing AChE level in the brain homogenate of swiss albino mice.CONCLUSION:Since the E. alsinoides & C. asiatica are already used in traditional Indian medicine as the neuroprotective agent and also found promising effects over inflammatory diseases, wound healing, and immunomodulatory activity. The neuroprotective effect of both plants extracts attributed to inhibition of AChE activity and improve the spatial memory formation.

Two-Week Repeated Oral Dose Toxicity Study of Mantidis Ootheca Water Extract in C57BL/6 Mice.

Background. Mantidis Ootheca (MO), described as the ootheca of Hierodula patellifera Serville, 1839, Tenodera angustipennis (Saussure, 1869), or Statilia maculate (Thunberg, 1784) in Korean Herbal Pharmacopoeia, is an important herbal material that has been traditionally used for treating several medical conditions including renal failure, spermatorrhea, and pediatric enuresis in Korea. Objective. The present study investigated the potential subacute toxicity of MO water extract during a 2-week repeated oral administration of doses of 0, 50, 150, or 450 mg/kg/day to C57BL/6 male mice by gavage. Methods. The following parameters were examined during the study period: mortality, clinical signs, body weight, hematology, serum biochemistry, gross findings, organ weight, and histopathology. All the mice were euthanized at the end of the treatment period. Results. No treatment-related changes in mortalities, clinical signs, body weight, gross finding, and organ weight change were detected after 14 days of oral MO extract administration. In addition, no meaningful MO extract treatment-related changes were observed in the hematological, serum biochemical, and histopathological parameters compared with the normal control group following treatment with doses of up to 450 mg/kg/day. Conclusion. Based on these findings, we concluded that treatment of mice with the water extract of MO did not result in significant toxicity and, therefore, it could be considered safe for further pharmacological studies.

An open label phase 1 study evaluation safety, tolerability, and maximum tolerated dose of oral administration of irinotecan in combination with capecitabine.

Oral administration of chemotherapy offers several advantages in comparison with intravenous administration. Previously, data on a new oral formulation of irinotecan have been published. The aim of the present study was to evaluate the safety, tolerability, and Maximum Tolerated Dose (MTD) of the new oral irinotecan formulation in combination with oral capecitabine. The study was an open label, phase 1, single center, extension part in which oral irinotecan was investigated in combination with capecitabine. The MTD of irinotecan in combination with capecitabine was 17.5mg/m2 once daily for 14 consecutive days in combination with capecitabine 800mg/m2 twice daily. Eligible patients were adults with metastatic or unresectable solid tumors for which no standard curative or palliative therapies existed. 14 patients were included in the extension part. No grade 3 or 4 hematologic toxicities were observed. Non-hematological toxicities included grade 1 and 2 diarrhea, fatigue, cholinergic syndrome, vomiting, and weight loss. Totally, 3 grade 3 toxicities and no grade 4 event were reported. No objective responses were observed. Five patients had stable disease lasting median 14 weeks. Capecitabine in combination with oral irinotecan could be a new treatment option offering a more convenient and patient friendly treatment strategy compared to intravenous irinotecan. The combination is fairly tolerated; however, further investigations are needed to assess the efficacy of this regimen.

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.

Development and validation of a simple, fast, and sensitive LC/MS/MS method for the quantification of oxfendazole in human plasma and its application to clinical pharmacokinetic study

The most popular standard treatments for soil transmitted helminths in humans including mebendazole, albendazole, levamisole, and pyrantel pamoate, show greatly variable efficacy against different species of parasites and have unfavorable pharmacokinetic characteristics, such as short half-life. The transition of oxfendazole, a potent broad-spectrum anthelmintic with long half-life, from veterinary medicine to human use has been considered as a promising approach. However, analytical methods for the quantitative detection of oxfendazole in human matrix are very limited and lack sensitivity. In this study, we have developed a high-performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for the quantification of oxfendazole in human plasma using albendazole as an internal standard. The established method was fully validated with lower limit of quantitation (LLOQ) of 0.5 ng/mL and linearity in the range of 0.5–1000 ng/mL; intra-day and inter-day accuracies ranged from 2.6 to 9.5% for 3 quality control levels (1.5 ng/mL, 75 ng/mL, and 750 ng/mL) and LLOQ; intra-day and inter-day precision was ≤13.6% for quality controls and ≤15.1% for LLOQ; matrix factor and extraction recovery were consistent with coefficient of variation of less than 15.0%. Other parameters including matrix selectivity, injection carryover, reinjection reproducibility, hemolysis effect, interference of analyte with internal standard, dilution integrity, freeze/thaw stability, whole blood stability, and stock solution stability were also validated and met the acceptance criteria. The assay was successfully applied to quantify oxfendazole plasma concentration in healthy adult volunteers after the administration of multiple oral doses of oxfendazole.

Enhanced Survival in Mice Exposed to Ionizing Radiation by Combination of Gamma-Tocotrienol and Simvastatin.

Ionizing radiation exposure is a major concern for active military service members, as well as civilian population. Considering that the exposure is not predictable, it is imperative that strategies to counteract radiation damage must be discovered. Recent in vitro studies performed in our laboratory demonstrated that the vitamin E analog gamma-tocotrienol (GT3) in combination with cholesterol-lowering drugs (Statins), synergistically induced endothelial thrombomodulin, an anticoagulant with radio-protective efficacy. It was hypothesized that the combination of treatment with both GT3 along with Statins would provide better radiation protection in vivo than each drug individually. CD2F1 mice were injected subcutaneously with either vehicle or single dose of GT3 (200 mg/kg body weight) 24 hours before irradiation followed by oral or subcutaneous administration of various doses of simvastatin (25, 50, and 100 mg/kg body weight) before exposure to lethal doses (11.5 and 12 Gy) of Cobalt-60 (60Co) gamma-irradiation. The combined treatment group exhibited enhanced radiation lethality protection substantially, accelerated white blood cell recovery, and augmented restoration of bone marrow cellularity when compared to the animals treated with either drug exclusively. This information clearly suggests that combined treatment could be used as a safeguard for military personnel from exposure to harmful ionizing radiation.

Influence of Obesity and Type 2 Diabetes Mellitus on the Pharmacokinetics of Tramadol After Single Oral Dose Administration.

Background and ObjectivesThe number of overweight, obese and diabetic patients is constantly increasing. Metabolic disorders may affect the pharmacokinetics of drugs, e.g., by altering the activity of cytochrome P450 (CYP) isoenzymes. Tramadol is a commonly used analgesic metabolised mainly via CYP2D6 to its active metabolite, O-desmethyltramadol. The aim of the study was to assess the influence of overweight, obesity and type 2 diabetes mellitus on tramadol and O-desmethyltramadol pharmacokinetics.MethodsAll patients received a single oral dose (100 mg) of tramadol. The plasma concentrations of tramadol and O-desmethyltramadol were measured with the validated high-performance liquid chromatography method with fluorescence detection. The pharmacokinetic parameters of tramadol and O-desmethyltramadol were calculated by non-compartmental methods.ResultsAfter nephrectomy, the patients were divided into four groups—a control group (n = 12, mean [SD] age 61 [14] years, body mass index (BMI) 22 [2] kg/m2, CLcr (creatinine clearance) 74 [30] mL/min); an overweight group (n = 15, mean [SD] age 63 [11] years, BMI 27 [1] kg/m2, CLcr 81 [35] mL/min); an obese group (n = 12, mean [SD] age 57 [8] years, BMI 33 [4] kg/m2, CLcr 113 [51] mL/min); and an obese and diabetic group (n = 9, mean [SD] age 64 [10] years, BMI 33 [4] kg/m2, CLcr 87 [35] mL/min). Apart from the time to first occurrence of maximal concentration (tmax), there were no significant differences in the pharmacokinetic parameters of tramadol and O-desmethyltramadol among the groups. Moreover, there were no significant differences in the O-desmethyltramadol/tramadol ratios among the four groups of patients after nephrectomy.ConclusionsNo significant differences were found in the pharmacokinetics of tramadol and O-desmethyltramadol, indicating that the opioid can be administered to overweight, obese and diabetic patients without dosage adjustment.

Evaluation of Age-Related Pyrethroid Pharmacokinetic Differences in Rats: Physiologically-Based Pharmacokinetic Model Development Using In Vitro Data and In Vitro to In Vivo Extrapolation.

An in vitro to in vivo (IVIVE) extrapolation based-physiologically based pharmacokinetic (PBPK) modeling approach was demonstrated to understand age-related differences in kinetics and how they potentially affect age-related differences in acute neurotoxic effects of pyrethroids. To describe the age-dependent changes in pyrethroid kinetics, it was critical to incorporate age-dependent changes in metabolism into the model. As such, in vitro metabolism data were collected for 3 selected pyrethroids, deltamethrin (DLM), cis-permethrin, and trans-permethrin, using liver microsomes and cytosol, and plasma prepared from immature and adult rats. Resulting metabolism parameters, maximum rate of metabolism (Vmax) and Michaelis-Menten constant (Km), were biologically scaled to respective in vivo parameters for use in the age-specific PBPK model. Then, age-dependent changes in target tissue exposure, i.e., brain Cmax, to a given pyrethroid were simulated across ages using the model. The PBPK model recapitulated in vivo time-course plasma and brain concentrations of the 3 pyrethroids in immature and adult rats following oral administration of both low and high doses of these compounds. A single model structure developed for DLM was able to describe the kinetics of the other 2 pyrethroids when used with compound- and age-specific metabolism parameters, suggesting that one generic model for pyrethroids as a group can be used for early age-sensitivity evaluation if appropriate metabolic parameters are used. This study demonstrated the validity of applying IVIVE-based PBPK modeling to development of age-specific PBPK models for pyrethroids in support of pyrethroid risk assessment of potentially sensitive early age populations in humans.

Pharmacokinetics of meloxicam during multiple oral or intramuscular dose administration to African grey parrots (Psittacus erithacus).

OBJECTIVE To determine the pharmacokinetics of meloxicam in African grey parrots (Psittacus erithacus) during administration of multiple doses. ANIMALS 6 healthy African grey parrots. PROCEDURES Meloxicam was administered at each of 3 dosages (1 mg/kg, IM, q 24 h, for 7 days; 1 mg/kg, PO, q 24 h, for 12 days; and 1.6 mg/kg, PO, q 24 h, for 7 days) with an 8-week washout period between treatments. Blood samples were collected 12 and 24 hours after each drug administration (times of presumptive peak and trough drug concentrations) for pharmacokinetic analysis. Birds were visually assessed during all experiments and monitored for changes in selected plasma and urine biochemical variables after administration of the drug at 1.6 mg/kg. RESULTS Mean trough plasma concentrations at steady state were 10.7 and 9.16 μg/mL after meloxicam administration at 1 mg/kg, IM, and 1 mg/kg, PO, respectively. Plasma drug accumulation was evident (accumulation ratios of 2.04 ± 0.30 [IM treatment] and 2.45 ± 0.26 [PO treatment]). Plasma and urine N-acetyl-β-d-glucosaminidase activities were significantly increased at the end of meloxicam treatment at 1.6 mg/kg. CONCLUSIONS AND CLINICAL RELEVANCE Plasma concentrations of meloxicam were maintained at values greater than effective analgesic concentrations described for other avian species. Although administration of meloxicam at a dosage of 1 mg/kg IM and PO daily for 1 week and 12 days, respectively, was not associated with adverse clinical effects in this population, further studies are needed to assess the efficacy and safety of the drug during prolonged treatment and the clinical relevance of its accumulation.

Pharmacokinetics and safety evaluation in healthy Chinese volunteers of alkaloids from leaf of Alstonia scholaris: A multiple doses phase I clinical trial

BackgroundAlstonia scholaris (Apocynaceae) was reported to be a rich source of indole alkaloids, which exhibited remarkably bioactivities. The leaf of A. scholaris has been used in ‘dai’ ethno-medicine for treatment of respiratory diseases, and the defined indole alkaloids from leaf of A. scholaris has been registered as investigational new botanical drug (No. 2011L01436) and was approved for phase I/II clinical trials by China Food and Drug Administration (CFDA). PurposeThe aim of the trial is to evaluate the safety and explore the relationship of dosing frequency and pharmacokinetics after oral administration of capsule of alkaloids from leaf of A. scholaris (CALAS) at different doses. MethodsIn this randomized, open-labelled, single-center clinical trial, the safety and pharmacokinetics of CALAS were assessed in eligible healthy Chinese volunteers after oral administration of different doses. Each volunteer (n = 10 per group) received single dose of CALAS from 20 mg, 40 mg, 80 mg to 120 mg orally. The pharmacokinetics of CALAS was investigated in healthy Chinese subjects’ plasma by a fully-validated LC-MS/MS method. Safety was assessed biochemically and clinically throughout the study, and drug re-excitation research was conducted to verify the correlation between investigational product and minor adverse events. The trial was registered on August 26, 2015 (http://www.chictr.org.cn/showproj.aspx?proj=11736), number ChiCTR-IPR-15006976. Results40 subjects completed the study, and as a result, vallesamine had the highest concentration in plasma of healthy volunteers, and the AUC exposure level in each compounds in turn is vallesamine > scholaricine > 19-epischolaricine > picrinine. For the safety evaluation of CALAS, two cases of minor adverse events were observed during the trial, but the drug re-excitation research indicated that these two adverse events were related to the individual's physiological variation. ConclusionPharmacokinetic characteristics of each ingredient showed different patterns. 19-epischolaricine, vallesamine and picrinine were match to the linear pharmacokinetic characteristics, but scholaricine conformed to the characteristics of nonlinear pharmacokinetics. The CALAS was safe in healthy subjects under the current dose regimen.

GENERAL AND SPECIFIC STRUCTURAL CHANGES OF LYMPHOID ORGANS IN THE HIGH DOSE APPLICATION OF SODIUM SELENITE

PURPOSE: to evaluate experimentally the features of structural and functional changes in lymphoid organs under the conditions of oral administration of high doses of sodium selenite and after its termination. MATERIAL AND METHODS. The study was conducted on 30 sexually mature male Wistar rats, weighing 200-220 g. The morphometric research of the thymus, group lymphoid nodules, mesenteric lymph nodes, spleen, and laboratory investigation of blood were performed. The animals were divided into 3 groups depending on the nature of the study. The first (control) group consisted of intact rats. Animals of groups 2 and 3 were orally administered sodium selenite, at a rate of 5 mg/kg of mass for 5 days. Morphofunctional studies of lymphoid organs in group 2 were performed on day 6, in group 3 – on day 14. RESULTS. The degree of severity and directional effect of structural and changes are determined by the functional specialization of the studied organs. CONCLUSION. Signs of endotoxicosis indicate evident structural and functional changes in the lymphoid organs after five times administration of sodium selenite. Canceling the administration helps to improve the organism's reserve capacity and adapt to altered metabolic processes.

The improvement of pain behavior and sciatic nerves morphology in mice model of painful diabetic neuropathy upon administration of ginger (Zingiber officinale Roscoe.) extract and its pungent compound, 6-shogaol

Background: 6-Shogaol is one of the bioactive compounds from ginger (Zingiber officinale Roscoe.) that had been widely used in many diseases. This research was aim to investigate the effect of ginger extract and its pungent compound, 6-shogaol on pain behavior and sciatic nerve morphology in mice model of painful diabetic neuropathy. Materials and Methods: Seventy-two male BALB/c mice were divided into nine groups. Diabetes was induced by single intraperitoneal injection of streptozotocin (STZ) 110 mg/kg body weight (BW). The mice were considered diabetic when the serum glucose level was at least 200 mg/dL. Thermal and mechanical hyperalgesia was measured using tail-flick latency and Randall–Selitto test once a week. Daily oral administration of 6-shogaol doses 5, 10, and 15 mg/kg BW, ginger extract doses 100, 200, and 400 mg/kg BW, or gabapentin dose 100 mg/kg BW was started at week 4. Diabetic mice without treatment and mice without STZ induction were used as controls. At week 7, the mice were euthanized, and paraffin sections of 1% osmium tetroxide-stained sciatic nerve samples were observed. Results: Ginger extract and 6-shogaol, but not gabapentin, produced dose-dependent lowering blood glucose effect. However, the mean of serum glucose level was not

Interaction of cyclosporine with phenobarbital in cats: a preliminary study

Phenobarbital (PB) decreases the cyclosporine (CsA) blood level in humans. However, the interaction of PB with CsA has not been reported in cats. This study investigated the effects of multiple doses of PB on the pharmacokinetics of CsA in three healthy cats. The treatments included oral CsA 5 mg/kg alone and oral CsA 5 mg/kg plus PB 5 mg/kg for 4 weeks. Co-administration of PB with CsA resulted in significant decreases in the oral bioavailability of CsA though both the first pass and elimination phases. These preliminary results suggest that oral administration of multiple doses of PB increases the required CsA dosage in CsA-based immunosuppressive therapy in cats.

Paromomycin sulfate is an effective treatment for balantidiasis in captive cynomolgus monkeys.

There are few effective antimicrobial agents against Balantidium coli infection. The effect of paromomycin sulfate (PS) against B. coli was confirmed in this study of 596 captive cynomolgus monkeys. In several trials, the minimum dose and duration of oral administration of PS were 25 mg/day for 5 + 5 days, with a 2-day withdrawal interval. To facilitate daily PS administration, pumpkin cakes supplemented with PS were made, which not only resulted in precise effects but also increased the efficiency of preparation and administration of PS by the animal care staff. No cysts or trophozoites were detected at 14 or 16 days after the last treatments. There were no obvious differences in blood and biochemical parameters between before and after administration of PS. These results indicate that PS is effective for elimination of B. coli without hematological side effects. These data could contribute to the control of microbiological pathogens during veterinary care and colony management in primate facilities.

Phenylbutazone blood and urine concentrations, pharmacokinetics, and effects on biomarkers of inflammation in horses following intravenous and oral administration of clinical doses.

Phenylbutazone (PBZ) is a potent mon-steroidal anti-inflammatory drug used commonly in performance horses. The objectives of the current study were to describe blood and urine concentrations and the pharmacokinetics of PBZ and its metabolites following intravenous (IV) and oral administration and to describe the duration of pharmacodynamic effect. To that end, 17 horses received an IV administration and 18 horses an oral administration of 2 g of PBZ. Blood and urine samples were collected prior to and for up to 96hours post drug administration. Whole blood samples were collected at various time points and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. Concentrations of PBZ and eicosanoids were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and non-compartmental pharmacokinetic analysis performed on concentration data from IV and oral administration. Serum concentrations of PBZ and its metabolites were below the limit of quantitation at 96hours post administration. The volume of distribution at steady state, systemic clearance, and terminal half-life was 0.194±0.019L/kg, 23.9±4.48mL/h/kg, and 10.9±5.32hours, respectively. The terminal half-life following oral administration was 13.4±3.01 (paste) and 15.1±3.96hours (tablets). Stimulation of PBZ treated whole blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of TXB2 , PGE2 , LTB4 and 15-HETE production for a prolonged period of time post drug administration. The results of this study suggest that PBZ has a prolonged anti-inflammatory following IV or oral administration of 2 g to horses.

Pharmacokinetic Study of Compound K in Japanese Subjects After Ingestion of Panax ginseng Fermented by Lactobacillus paracasei A221 Reveals Significant Increase of Absorption into Blood.

Compound K (CK) is a metabolite of a saponin in Panax ginseng, formed from ginsenoside, a triterpenoid glycoside, by human intestinal bacteria. Lactobacillus paracasei A221 isolated from fermented food can hydrolyze (deglycosylate) the main ginsenoside, ginsenoside Rb1, and generate CK. However, the pharmacokinetics of L. paracasei A221 fermented ginseng (FG) and nonfermented ginseng (NFG) have not been investigated so far. The aim of this study was to investigate the pharmacokinetics of CK after oral administration of single doses of FG and NFG in healthy Japanese adults. An open-label, randomized, single-dose, two-period, crossover study was conducted in 12 Japanese healthy volunteers (five men and seven women, aged 40-60 years). All subjects were equally allocated into two groups and administered tablets containing FG or NFG. Until 24 h after the administration, blood samples were sequentially collected, plasma concentrations of CK were measured, and the pharmacokinetic parameters were calculated. We also expected restoration of decreased testosterone level as one of the beneficial effects of FG and measured plasma total testosterone concentrations in male volunteers. The means of Tmax, Cmax, and area under the concentration-time curve (AUC) were significantly different between the two groups. In the FG group, AUC0-12h (ng h/mL) and AUC0-24h (ng h/mL) were, respectively, 58.3- and 17.5-fold higher than those in the NFG group. Moreover, mean testosterone concentration in the FG group significantly increased 24 h after administration. These results showed that the main ginsenoside metabolite of ginseng, CK, produced by L. paracasei A221 has potential utility in health maintenance in healthy middle-aged and old Japanese adults.

RABBIT GROWTH, CARCASS CHARACTERISTIC, DIGESTION, CAECAL FERMENTATION, MICROFLORA, AND SOME BLOOD BIOCHEMICAL COMPONENTS AFFECTED BY ORAL ADMINISTRATION OF ANAEROBIC PROBIOTIC (ZAD®)

The current research designed to study the influences of diverse doses of oral administration of anaerobic probiotic (ZAD®) on growth performance, carcass characteristic, digestibility coefficient, caecal activity, microflora and some blood biochemical components of growing rabbits. At 6 weeks (average body weight 539.87±13.35 g), one hundred and eighty weaned male rabbits from New Zealand White (NZW) were randomly distributed to four groups. The control group received orally 0.0 ZAD®; the experimental groups administrated orally with 0.25, 0.5 and 1.0 ml ZAD®/rabbit/day, respectively. The experimental period lasted for 8 weeks. Groups 0.25 ZAD® and 0.5 ZAD® had improved feed conversion ratio and body weight gain and the lowest mortality rate. In comparison with the control and 1.0 ZAD® groups, the groups 0.25 ZAD® and 0.5 ZAD caused a significant increase (P≤0.05) in nitrogen utilization, nutritive value and digestibility coefficients. The different doses of ZAD® had improved dressing percentage and percentage of edible parts, although parts of total non-edible were decreased (P≤0.001) compared to the group of control. As well as, cecum activity (caecum pH, total volatile fatty acids, acetic, propionic and butyric acid) were improved significantly by administrated orally different doses of probiotic ZAD® 0.25, 0.5 and 1.0 ml/rabbit/day compared with the control group. The opposite trend was observed in ammonia concentration which had been reduced significantly by administrated all doses of ZAD®. In addition, a total number of anaerobic bacteria were less than those of total microbial count and coliform group but, they have the same trend of decreasing the number as the amount of anaerobic probiotic ZAD® increased. Also, fermentation of lactobacilli take the opposite trend as the amount of probiotic ZAD® increased the lactobacilli number increased. As streptococci isolated was lower than lactobacilli group. As the concentration of probiotic ZAD® increased isolates numbers decreased, also lactobacilli enumeration increased. The serum total protein, albumin, globulin, and albumin: globulin concentration of rabbits received probiotic ZAD® groups were significantly augmented compared with the group of control. On the contrary, levels of creatinine and urea in rabbit serum were not significantly affected by probiotic oral administration ZAD®. Alanine aminotransferase and aspartate aminotransferase enzymes of serum were significantly decreased with augmenting levels of ZAD®. Serum levels of total cholesterol (TC), lipoproteins of low density (LDL), very low-density lipoproteins, triglycerides, total lipids, and LDL: lipoproteins of high density (HDL) ratio were significantly decreased with augmenting levels of ZAD®. But, the HDL: TC and HDL: LDL ratio augmented significantly with probiotic oral administration ZAD® levels.

Safety and Efficacy of HQP1351, a 3rd Generation Oral BCR-ABL Inhibitor in Patients with Tyrosine Kinase Inhibitor—Resistant Chronic Myelogenous Leukemia: Preliminary Results of Phase I Study

Background: HQP1351, a novel, potent 3rd generation TKI, was designed to treat patients with chronic myeloid leukemia (CML) resistant to current TKI-therapies including those with T315I mutation.Aims: A single-agent, open-label dose escalation and dose expansion Phase I study to assess the safety, preliminary efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) properties of orally administered HQP1351 in the TKI-resistant patients with chronic phase (CP) or accelerated phase (AP) CML.Methods: HQP1351 was administered once every other day (QOD) in 28-days cycles at 11 dose cohorts ranging from 1mg to 60 mg. The eligible patients received treatments until disease progression or intolerable toxicities. The primary efficacy endpoint in the CML AP and CP patients, was complete hematological response (CHR) and major cytogenetic response (MCyR) respectively, MCyR includes partial cytogenetic response (PCyR) and complete cytogenetic response (CCyR).Blood samples were collected at various time points on Day 1-2 and Day 27-28 during cycle 1 for PK analyses. BCR-ABL inhibition was evaluated using tyrosine phosphorylation of CRKL and STAT5 in peripheral blood mononuclear cell (PBMCs) collected from the patients before and 4, 8, 24 and 48 hours post HQP1351 treatments on Day 1, 15 and 27 during cycle 1.Results:From November 2016 to July 2018, 70 patients (CP n=58 and AP n=12) enrolled received ≥1 cycle of HQP1351-treatment, only 1 patient withdrew from the study due to disease progression. Median age was 39 (range: 23-59) years. Median interval from CML diagnosis to starting HQP1351-treatment was 6.1 (1.1-14.7) years. Sixty-one (87%) patients received ≥2 prior lines of TKI-therapy. Fifty-three (76%) patients had BCR-ABL mutations and 45 (64%) had T315I mutation at baseline.With a median follow-up of 4.1 (1.0-21.2) cycles, HQP1351 was well-tolerated in all dose cohorts other than the 60mg cohort. In all patients, 67 (96%) patients experienced ≥1 treatment related adverse events (TRAEs) and 44 (63%) experienced TRAE(s) of grade 3-4 (Table 1). There was no patient withdrawal from the study because of TRAEs. Two out of 3 patients in the 60mg cohort experienced dose-limiting toxicity(DLT) and HQP1351 at 50mg QOD was considered as MTD.The anti-leukemic activities of HQP1351 were observed in this study. Sixty-five (93%) patients including 58 (100%) CP and 7 (58%) AP patients achieved CHR at the dose of 2mg to 60mg within 3 cycles. In 47 evaluable patients receiving HQP1351-treatment ≥3 cycles, 24 (51%) achieved MCyR including 21 (54%) CP and 3 (38%) AP patients at the dose of 12mg to 50mg, and 14 (30%) patients achieved CCyR including 12 (31%) CP and 2 (25%) AP patients. Total 6 (15%) CP patients achieved MMR. More than 65% of the patients achieved MCyR or MMR at the end of cycle 3. HQP1351 was highly active in patients with or without T315I mutation at baseline (Table 2).Following oral administration of HQP1351 at doses ranging from 1mg to 60 mg, the peak concentration was reached at 2-8 hrs. The elimination appeared to be linear with a mean terminal T1/2 of 15.3-36.5 hrs on Day 1, 18.8-42.5 hrs on Day 27, respectively. The ratios for AUC0-t and Cmax of HQP1351 on Day 27 versus Day 1 ranged from 1.03 to 2.12 and from 0.78 to 1.93, respectively. Thus, HQP1351 exhibited an approximately dose proportional increase in Cmax and AUC0-t following single or multiple oral administration dose ranging from 1 to 60 mg. PD study results demonstrated that reduction of CRKL phosphorylation was schedule and dose-dependent, ≥50% reduction was observed at doses ranging 12mg-60mg.Conclusions: The preliminary results of the phase 1 study showed that HQP1351, a novel 3rd-generation TKI, is safe and highly active in treatment of the TKI-resistant patients with CP-CML and AP-CML,with or without T315I mutation. DisclosuresChen:HealthQuest Pharma Inc.: Employment. Men:HealthQuest Pharma Inc.: Employment. Liu:HealthQuest Pharma Inc.: Employment. Sun:HealthQuest Pharma Inc.: Employment. JI:HealthQuest Pharma Inc.: Employment. Wang:HealthQuest Pharma Inc.: Employment. Hu:HealthQuest Pharma Inc.: Employment. Zou:HealthQuest Pharma Inc.: Employment. Yan:HealthQuest Pharma Inc.: Employment. Huang:Ascentage Pharma Group Inc.: Employment; HealthQuest Pharma Inc.: Employment. Yang:Ascentage Pharma Group Inc.: Employment. Zhai:Ascentage Pharma Group Inc.: Employment.

Antioxidant activity and hepatoprotective effect of &lt;i&gt;Cichorium intybus&lt;/i&gt; (Kasni) seed extract against carbon tetrachloride-induced liver toxicity in rats

Purpose: To assess the antioxidant and hepatoprotective activity of the aqueous-methanol extract of Cichorium intybus seeds (C. intybus) against carbon tetrachloride (CCl4)-induced liver toxicity in albino Wistar rats.Method: The seed extract of C. intybus was prepared in aqueous methanol (20:80) via Soxhlet solvent extraction process. CCl4 (0.8 mL/kg) was administered to induce hepatic damage in Wistar rats. The seed extract (100, 250 and 500 mg/kg doses) and a 25 mg/kg dose of silymarin (as standard drug) were administered orally to separate groups of albino Wistar rats for 14 days. Blood samples from the rats were analyzed for biochemical markers for hepatic injury. The tissue samples of the rats were subjected to histopathological studies as well as analyzed for liver antioxidants.Results: The results for biochemical markers revealed that the rats treated with the extract (500 mg/kg dose) showed a maximum elevation of catalase (48.90 μmole of H2O2 consumed/min/mg protein), glutothione peroxidase (22.1 mg GSH consumed/min/mg protein), superoxide dismutase (14.2 units/min/mg protein), and a reduction in glutathione (18.1 μmole of GSH/mg protein). Serum biochemical parameters including serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphate (ALKP), and direct bilirubin were significantly (p < 0.01) increased in the treated groups. Oral administration of different doses of C. intybus seed extract significantly (p < 0.01) protected the hepatic cells from impairment. The biochemical markers and hematological parameters were also normal in extract-treated rats in contrast to the standard (silymarin) and control groups.Conclusion: The results show that C. intybus plant is potential a good natural source of natural hepatoprotective and antioxidants agents.Keywords: Cichorium intybus, Antioxidant, Hepatoprotective Biomarkers, Silymarin, Hematological parameters

Sensitive inexpensive chromatographic determination of an antimicrobial combination in human plasma and its pharmacokinetic application

This study represents simple inexpensive chromatographic determination of ciprofloxacin (CIP) and tinidazole (TIN) simultaneously in human plasma using HPLC-DAD followed by a pharmacokinetic application. C18 column was used as stationary phase with isocratic elution of a mobile phase composed of acetic acid solution (2%) and acetonitrile (85: 15, v/v) and ornidazole as internal standard (IS) with UV detection at 318 nm. The two drugs and the IS were separated at 6.55, 7.91 and 11.07 min for CIP, TIN and IS, respectively, with good selectivity and sensitivity for their analysis in presence of plasma matrix components and the drugs' metabolites. Sample preparation involved only protein precipitation without any complicated extraction procedures decreasing analysis time. For method validation, FDA regulations for analysis in biological fluids were followed. Pharmacokinetic (PK) study on six healthy volunteers was conducted after single oral dose administration of 500 and 600 mg of CIP and TIN, respectively. Dugs' plasma levels were followed for 12 or 72 h post dosing for CIP and TIN, respectively, and different PK data for the two drugs were calculated and they were comparable to the reported values demonstrating successful future application of the presented method in PK, bioequivalence and bioavailability studies.