Administration Of Single Oral Dose Research Articles

Gastroprotective mechanism of Talinum triangulare on ethanol-induced gastric ulcer in Wistar rats via inflammatory, antioxidant, and H+/K+-ATPase inhibition-mediated pathways

The increase in the incidence of gastric ulcer (GU) has posed major threat on public health. This research aimed to evaluate gastroprotective properties of the aqueous leaf extract of Talium triangulare (AETT) in ethanol-induced gastric ulceration. GU was induced via oral administration of single dose of 5 mLkg−1 of 90% ethanol in rats and protection of 200 mgkg−1 bw of AETT and 20 mgkg−1 bw of omeprazole was investigated for 14 d via oral treatment. Influence of AETT on anti-inflammatory, redox assays, ulcer index (UI), and gastric mucosa histological alterations were evaluated. Significant increase in myeloperoxidase (MPO) and tumor necrosis factor-alpha levels compared to untreated group established gastric inflammation in rats induced by ethanol. Gastric ulcerated group exhibited heightened oxidative stress with concurrent decline in activities of antioxidant enzymes. Ethanol exposure to rats resulted in induction of lipid peroxidation, prominently elevating gastric malondialdehyde (MDA) concentration. Nevertheless, treatment with AETT or omeprazole exhibited substantial anti-inflammatory effects within gastric mucosa by attenuating expression of markers associated with inflammation. AETT demonstrated reduction in concentrations of MDA and H2O2, thereby alleviating progression of lipid peroxidation cascades. Also, AETT exhibited mitigating effect on ethanol-induced oxidative harm by enhancing the functionality of protective enzymes and elevating glutathione (GSH) concentration. Overall, AETT exhibited enhancements in activities of cytoprotective antioxidant enzymes, mitigated impact of oxidative stress and inflammation, inhibited lipid peroxidation, and decreased UI score. These beneficial effects could be attributed to phytochemicals present in AETT including 6,10,14-trimethyl-2-pentadecanone and Phytol. Outcome of this study established the traditional herbal claims of AETT.

Comparative Pharmacokinetic Study of Standard Astaxanthin and its Micellar Formulation in HealthyMale Volunteers.

Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults. A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography-diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration (Cmax), area under concentration time curve from time of administration (0) to time (t) [AUC0-t] or to infinity ∞, [AUC0-∞], half-life (T½) and time to reach Cmax (Tmax)were calculated. The test micellar astaxanthin reached a Cmax of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin. Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.

Determination of nine components of fried Ziziphi Spinosae Semen extract in beagle dog plasma by UPLC-MS/MS and its application in pharmacokinetic research

This study established a convenient, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, swertisin, N-nornuciferine, 6-feruloylspinosin, and jujuboside B in beagle dog plasma after oral administration of fried Ziziphi Spinosae Semen(FZSS) extract. The Waters HSS-T3 C_(18) column(2.1 mm×100 mm, 1.8 μm) was used. The methanol-aqueous solution(containing 0.01% formic acid) was adopted as the mobile phase for gradient elution. The nine components and two internal standards were completely separated within 8 min. The mass spectrometry detection was performed in multiple reaction monitoring(MRM) mode by positive and negative ion switching of electrospray ionization. The analytical method was validated in terms of specificity, selectivity, linear range, accuracy, precision, recovery, matrix effect, and stability. It could meet the requirement of pharmacokinetic research after oral administration of FZSS extract to beagle dogs. The results showed that the time to reach the peak concentration(T_(max)) of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, 6-feruloylspinosin, and jujuboside B was 2.40-3.20 h, and the elimination halflife(t_(1/2)) was 2.08-6.79 h after a single-dose oral administration of FZSS to beagle dogs. The exposure of magnoflorine and spinosin was high, with a peak concentration(C_(max)) of 76.7 and 31.5 ng·mL~(-1) and an area under the curve(AUC_(0-∞)) of 581 and 315 ng·h·mL~(-1), respectively. The exposure of the remaining five compounds was lower, with a C_(max) of 0.81-13.0 ng·mL~(-1) and an AUC_(0-∞) of 6.00-106 ng·h·mL~(-1). This study provides a reference for the follow-up research of FZSS.

Single-Dose Oral Toxicity Study of Chloroform Extract of Kaffir Lime (Citrus hystrix DC.) Leaves in Wistar Rats (Rattus norvegicus Berkenhout, 1769)

Leaves of kaffir lime (Citrus hystrix) are commonly used as a seasoning in various Indonesian and Southeast Asian dishes. Phytochemical studies reported various secondary metabolites that possess medicinal properties. Before exploring their potential as therapeutic agent, a series of toxicity studies must be conducted to assess the toxicity and safety levels. This research aimed to study the single-dose acute oral toxicity of chloroform extract of kaffir lime leaves (CECHL) in female Wistar rats (Rattus norvegicus) as experimental animals. The procedure followed OECD Test Guideline No.420 with the dose 2000 mg/kg bw for 14 days (Sighting study). Parameters consisted of mortality, clinical signs of sublethal effect based on changes in general appearance and daily activity/behavior, hematological profile, and blood clinical biochemistry. Neither mortality nor sublethal effects were found during the experiment. All blood parameter values (erythrocytes, leukocytes, thrombocytes, ALT, AST, creatinine, BUN, glucose, cholesterol, and triglycerides) were within reference interval, indicating that CECHL is not harmful to normal physiology. In conclusion, single-dose oral administration of CECHL is safe, no-observed-adverse-effect-level (NOAEL) at dose 2000 mg/kg bw or included in Category 5 based on the Globally Harmonized System of Classification and Labeling of Chemicals (GHS).

Preparation of Chitosan Nanoparticle from Crab Shells and Evaluation of ‎Analgesic and Anti-inflammatory Activities of Chitosan-loaded ‎Haematostaphisbarteri Hook. f. Stembark Extract

Haematostaphis barteri Hook. f. is a tree belonging to the Family Anacardiaceae whose morphological parts have been used for decades for treating various diseases in Northern Nigeria. This study aimed to prepare chitosan nanoparticles from crab shells and evaluate the analgesic and anti-inflammatory activities of chitosan loaded with stembark extract from H. barteri. Phytochemical screening of extract, preparation of chitosan, and evaluation of analgesic and anti-inflammatory activities were carried out following standard procedures. The qualitative phytochemical analysis of the extract revealed the presence of alkaloids, saponins, tannins, flavonoids, and cardiac glycosides while steroids, triterpenes and anthracenes were absent. The LD50 of the crude methanol extract in Wistar albino rats was determined to be greater than 5000 mg/kg body weight and after 14 days of single dose oral administration. No signs of toxicity were recorded. Prepared chitosan nanoparticle loaded with extract has a yield of 26.54 %, particle size of 210 ± 1.01 nm, zeta potential of 25.4 ± 1.02 V, drug entrapment efficiency of 68.4 %, cumulative drug release of 88.24 % and swelling index of 58.14 %. The extract produced a dose-dependent analgesic and anti-inflammatory activity. The chitosan-loaded extract produced the highest inhibition of writhing and paw oedema diameter in the rats, which was significant (p < 0.05) when compared with the normal controls and standards. In conclusion, the study showed that chitosan-loaded stembark extract from H. barteri possessed more potential analgesic and anti-inflammatory activities than those delivered without chitosan nanoparticles. The study further affirms the potential usefulness use of the stembark extract for the treatment of pain and inflammation.

Bioequivalence Study of Tebipenem Pivoxil in Healthy Chinese Adults.

Tebipenem pivoxil (TP) is a carbapenem and is applied against pneumonia, otitis media, and sinusitis. This study compared the pharmacokinetics (PK) and safety of a test (T) preparation and reference (R) preparation of TP in healthy Chinese adults. This study was a single-center, randomized, open, single-dose (fasting/postprandial) oral administration, two-agent, two-sequence, two-cycle, crossover bioequivalence trial. A total of 60 participants were enrolled (24 fasting and 36 postprandial). All participants were randomly assigned to the TR sequence and RT sequence. Subsequently, they switched T sequences or R sequences 7 days later. PK blood samples were collected according to the protocol, plasma TP concentration was determined by liquid chromatography-mass spectrometry, main PK parameters were calculated based on a non-compartment model, and adverse events were recorded during the test. In the feeding arm, the geometric mean ratio of maximum concentration (Cmax) was 89.84% (90% confidence interval 84.33-95.70), the geometric mean ratio of area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration (AUC0-t) was 86.80% (83.62-90.10), and the geometric mean ratio of area under the plasma concentration-time curve from time 0 to infinity time of quantifiable concentration (AUC0-∞) was 86.90% (83.73-90.20), which were within the acceptable range of bioequivalence (80-125%). In the fasting arm, the geometric mean ratio of Cmax was 96.07% (89.62-102.99), the geometric mean ratio of AUC0-t was 93.09% (90.47-95.78), and the geometric mean ratio of AUC0-∞ was 93.09% (90.48-95.77), which was within the acceptable range of bioequivalence (80-125%). Hence, the T preparation and R preparation of TP had bioequivalence in the fasting arm and feeding arm of the clinical trial. In addition, all adverse events were mild, and no severe adverse events were noted. Preparations T and R of TP were bioequivalent in the fasting and postprandial groups in clinical trials, and TP was safe.

Effect of preoperative oral medication of Diclofenac sodium, Ibuprofen and Etoricoxib on the effectiveness of maxillary infiltration anaesthesia in patients with irreversible pulpitis: A Randomized Clinical Study

Introduction Preoperative pain of endodontic origin, has its effect on the patient‘s attitude towards the endodontic treatment. Dental anxiety associated with the above may cause ineffective anaesthesia of the tissues of interest. To assess the efficacy of preoperative oral single-dose administration of three non-steroidal anti-inflammatory drugs namely, Diclofenac sodium 50 mg, Ibuprofen 200 mg and Etoricoxib 60 mg and on the effectiveness of infiltration anaesthesia in patients with irreversible pulpitis of maxillary first molars. Material and Methods Sixty (n=60) patients with a chief complaint of moderate to severe pain of endodontic origin participated in the study. Patients were asked to indicate their pain scores on a visual analog scale (VAS) and then they were divided into three groups of n=20. Then according to their groups, the patients received a single dose of Diclofenac sodium 50 mg, Ibuprofen 200 mg and Etoricoxib 60 mg one hour before administration of the infiltration anaesthesia with 2% lignocaine containing 1:80,000 epinephrine. The patients indicated their pain score on VAS after one hour of drug administration and again after completion of the access opening. Differences in the pain scores at these three intervals were noted. Data was collected and analyzed using SPSS v.20 software and subjected to descriptive statistics, one-sample t-test and one-way ANOVA test with the acceptance level of significance set at p<0.05. Results Diclofenac sodium 50 mg, Ibuprofen 200 mg and Etoricoxib 60 mg had shown a gradual decrease in mean pain scores after the completion of access opening, which was statistically significant (p<0.05). Etoricoxib 60 mg (p=0.01) showed lower mean pain scores compared to Diclofenac sodium 50 mg and Ibuprofen 200 mg. Conclusion Within the limitations of the present study, Etoricoxib significantly lower mean pain scores when compared with the other two groups. Key Words Drug efficacy, Non-steroidal anti-inflammatory drugs, Visual Analog

Phase I Pharmacokinetics Study of Oral Administration of Esperavir® (INN: Molnupiravir) (LLC "PROMOMED RUS", Russia)

Introduction. The pandemic of the new coronavirus infection COVID-19 (Coronavirus Disease 2019) was caused by a single-stranded RNA virus SARS-CoV-2 (Severe acute respiratory syndrome-related coronavirus 2). Molnupiravir is an antiviral drug with activity against RNA viruses including SARS-CoV-2. Molnupiravir exerts the antiviral effect by introducing copy errors during viral RNA replication – by that the replication of SARS-CoV-2 inhibits. For oral administration of molnupiravir the drug Esperavir® has been registered in Russia.Aim. The aim is pharmacokinetics study of Esperavir®, capsules 200 mg (the manufacturer is JSC "Biokhimic", LLC "PROMOMED RUS", Russia, as registration certificate holder) by a single dose (800 mg) and multiple doses oral administration (800 mg twice a day with a gap of 12 hours between doses) in healthy volunteers in a phase I pharmacokinetics study, comparison the obtained data of pharmacokinetic parameters with the literature data.Materials and methods. The clinical and analytical phases of the pharmacokinetic study as well as pharmacokinetic analyses have been performed as a part of a clinical trial of the drug Esperavir®, capsules 200 mg (the manufacturer is JSC "Biokhimic", LLC "PROMOMED RUS", Russia, as registration certificate holder). Chromatographic separation and detection by Nexera XR high-performance liquid chromatograph with triple quadrupole tandem mass spectrometry LCMS-8040 (Shimadzu Corporation, Japan). The pharmacokinetic parameters were calculated with the Boomer pharmacokinetic analysis add-in for Microsoft Excel (Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA 92606, USA). Descriptive pharmacokinetic statistics were calculated with Microsoft Excel (Microsoft Corporation, USA).Results and discussion. Pharmacokinetic parameters for cohort 1 (800 mg single dose of Esperavir®) and for cohort 2 (800 mg of Esperavir® twice a day with a gap of 12 hours between doses) were calculated. Averaged pharmacokinetic profiles of mean NHC concentrations over time in linear and log-linear scales were plotted. The geometric mean of Cmax and T1/2, the median, minimum and maximum of Tmax showed the comparability of the obtained data after a single dose administration of 800 mg of Esperavir® and the available literature data.Conclusion. According to the concentrations from the analytical phase of the pharmacokinetic study the pharmacokinetic parameters were calculated, averaged pharmacokinetic profiles in linear and log-linear scales were plotted after a single dose and multiple doses of the drug Esperavir®, capsules (the manufacturer is JSC "Biokhimic", LLC "PROMOMED RUS", Russia, as registration certificate holder). The comparability of the obtained data and the available literature data was shown. The results justified the study of the subsequent phases of clinical trials of Esperavir®.

Effectiveness of Single-Dose Oral Pilocarpine Administration in Patients with Sjögren's Syndrome.

In this study, we evaluated the effectiveness of a single-dose oral pilocarpine administration on tear film (TF), as well as dry eye and dry mouth symptoms, in 53 eyes of 27 Sjögren syndrome (SS) patients who were experiencing dry mouth. To evaluate the changes in tear volume, a digital video-meniscometer was used to measure the radius of the lower central tear meniscus curvature (R, mm) of each eye at prior to the administration of 5 mg oral pilocarpine, and at 15 (R:(15)), 30 (R:(30)), and 60 (R:(60)) minutes after administration. The fluorescein breakup time (FBUT, seconds) and ocular and oral dryness symptoms were evaluated before and at 60 min after administration using a visual analogue scale (VAS, mm). A significant increase in R was observed at 15 and 30 min after administration compared to that at prior to administration. FBUT showed significant improvement at 60 min after administration, and the VAS score for ocular and oral dryness symptoms was found to have decreased significantly at 60 min after administration. A single-dose administration of 5 mg oral pilocarpine had a beneficial effect on TF, as well as on ocular and oral dryness symptoms, in patients with SS.

Post-stress Social Interaction and 3-Cyano-N-(1,3-Diphenyl-1H-Pyrazol-5-yl) Benzamide Treatment Attenuate Depressive-like Behavior Induced by Repeated Social Defeat Stress

Persistent stress increases the probability for developing depression significantly thereafter. Repeated social defeat stress is a widely used model to investigate depressive-like behavior in preclinical models. Hence, the repeated social defeat stress model provided an ideal animal model, through which the hypotheses of prevention and treatment can be investigated. We have successfully induced depressive-like behavior for male C57BL/6J mice with this model. Here, we reported that certain level of during-stress social interactions with single female or multiple male peer(s) exerted a positive role in preventing the development of depressive-like behavior induced by repeated social defeat stress. Our data suggested that the stress-susceptible mice may benefit from positive social interaction, which reduces the chance for depressive-like behavior development. Since numerous studies indicate that the metabotropic glutamate receptor 5 (mGluR5) plays an important role in various cognitive functions, we further investigate the treatment effect of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) on the depressive-like behavior induced by repeated social defeat stress. Most importantly, robust anti-depressant effects have been achieved through modulating the mGluR5 function. We found that single oral dose administration of CDPPB (20 mg/kg), to some extent, alleviated the social avoidance behaviors for the stress-susceptible mice. Our data implies that the CDPPB, a positive allosteric modulator of mGluR5, is a promising anti-depressant candidate with limited side effect.

Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair.

Gefitinib (GEF) is a clinical medication for the treatment of lung cancer targeting the epidermal growth factor receptor (EGFR). However, its efficacy is remarkably limited by low solubility and dissolution rates. In this study, two cocrystals of GEF with co-formers were successfully synthesized using the recrystallization method characterized via Powder X-ray Diffraction, Fourier Transform Infrared Spectroscopy, and 2D Nuclear Overhauser Effect Spectroscopy. The solubility and dissolution rates of cocrystals were found to be two times higher than those of free GEF. In vitro cytotoxicity studies revealed that the cocrystals enhanced the inhibition of cell proliferation and apoptosis in A549 and H1299 cells compared to free GEF. In mouse models, GEF@TSBO demonstrated targeted, safe, and effective antitumor activity with only one-dose administration. Mechanistically, the GEF cocrystals were shown to increase the cellular levels of damaged DNA, while potentially downregulating PARP, thereby impairing the DNA repair machinery and leading to an imbalance between DNA damage and restoration. These findings suggest that the cocrystallization of GEF could serve as a promising adjunct to significantly enhance the physicochemical and biopharmaceutical performance for lung cancer treatment, providing a facial strategy to improve GEF anticancer efficiency with high bioavailability that can be orally administrated with only one dose.

EXTH-56. CSF PENETRATION COMPARISON OF TWO ORAL FORMULATIONS OF APL-101 IN A PRE-CLINICAL NON-HUMAN PRIMATE MODEL

Abstract Vebreltinib (APL-101) is a potent c-Met inhibitor which has shown efficacy in murine pre-clinical models and is under clinical trial evaluation for several cancer types, including adult high-grade glioma. The capsule formulation (APL-101-Cap) was reformulated as a pill (APL-101-Pill) with the expectation of increasing bioavailability. We determined and compared the plasma pharmacokinetics (PK) and cerebrospinal fluid (CSF) penetration of APL-101-Cap and APL-101-Pill in a non-human primate (NHP) model. METHODS: Seven animals, previously developed as serial CSF access models, were utilized across all studies. One NHP was studied with both formulations. Both formulations were administered orally as a single drug/single dose in serial studies, followed by serial plasma and CSF sample collections from 0-96 hours. Dosages: APL-101-Cap 3.25 mg/kg (n = 3) or 6.5 mg/kg (n = 4) and APL-101-Pill 5 mg/kg (n = 4). The resulting plasma concentrations from each formulation were quantified by LC-MS/MS. PK parameters were calculated via noncompartmental methods, and results were analyzed to assess CNS penetration (AUCCSF:AUCPlasma) and compare formulations. RESULTS: Mean (range) for plasma and CSF PK exposure [AUCLAST (hr*ng/mL)] reported. APL-101-Cap plasma exposure, regardless of dose, was more variable than APL-101-Pill. APL-101-Pill had lower exposure in both plasma (AUC 1893.0 (841-2865)] and CSF [AUC 27.7 (5.0-65.0)] than APL-101-Cap regardless of dose [(3.25 mg/kg): plasma AUC 9621.0 (1331-23132) and CSF AUC 688.0 (24-1352); 6.5 mg/kg: plasma AUC 6208.0 (1424-19800) and CSF AUC 606.0 (34-1179)]. CNS penetrance was higher with APL-101-Cap (3.2% [0.5-5.8%] at 3.25mg/kg; 4.2% (2.4-6%) at 6.5 mg/kg), but also more variable when compared to APL-101-Pill (1.2% [0.6-2.3%]). For APL-101-Cap, one animal at 3.25 mg/kg and two animals at 6.25 mg/kg had undetectable CSF concentrations. CONCLUSION: In this NHP model, single-dose oral administration of APL-101-Pill resulted in lower, but less variable plasma and CSF exposure compared to APL-101-Cap. APL-101-Cap CSF exposure was unaffected by dose escalation.

A Phase 1 Study to Evaluate the Pharmacokinetics of Single High Doses of Iptacopan

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway. Inhibition of the complement system represents a potential mechanism for treatment of several diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. At the current clinical dose of 200 mg twice daily, the steady-state area under the concentration curve (AUC) and peak concentration (C max) are 25,600 ng•hr/L and 4,120 ng/mL, respectively. In this randomized, participant-blinded, placebo-controlled phase 1 study, we evaluated the pharmacokinetics (PK) of single high doses of iptacopan. Methods: Iptacopan single doses of 400 mg (n=6), 800 mg (n=9), and 1200 mg (n=9) were included in this study, representing ≤6-fold higher doses than the clinical dose of 200 mg twice daily. The study population included healthy men and women aged 18-55 years. The log-transformed PK parameters AUC and C max were analyzed separately using a linear model with treatment as fixed effect. Results: Twenty-four patients received iptacopan and 8 received placebo. The median age of participants in the 400-, 800-, and 1200-mg groups was 51.5, 35, and 36 years, respectively. Following a single oral administration, iptacopan was rapidly absorbed with C max at 1.06, 2.00, and 2.52 hours for 400-mg, 800-mg, and 1200-mg doses, respectively ( Table). Variability (CV% geometric-mean) in iptacopan plasma concentrations were low to moderate (16.6%-30.6%) at C max. After administration, iptacopan plasma concentration-time profiles increased over the dose range of 400 to 1200 mg and were biphasic, with an inflection point at approximately 12 hours ( Figure). Compared to the 200-mg twice daily steady-state PK, the 1200-mg single dose resulted in C max and AUC exposure multiples of 4.0- and 6.5-fold, respectively. The mean apparent elimination half-life was similar across all doses, ranging from 20 to 21 hours. Iptacopan was well tolerated with no moderate or severe treatment-emergent adverse events reported. Conclusion: Iptacopan was rapidly absorbed after administration of single oral doses ranging from 400 to 1200 mg. Variability in iptacopan plasma concentrations were low to moderate over the dose range studied and half-lives were similar. Supratherapeutic, single doses up to 1200 mg were well tolerated and resulted in substantial multiples of iptacopan systemic exposure.

Acute and Sub-Acute Toxicity Evaluation of the Crude Methanolic Extract of Justicia schimperiana Leaf in Wistar Albino Rats.

This study evaluates the acute and sub-acute toxicity of 80% methanolic extracts of the leaves of Justicia schimperiana in Wistar albino rat models. Dried powdered leaves of Justicia schimperiana were macerated in 80% methanol. The experiment was conducted in accordance with the Organization for Economic Co-operation and Development guideline 423 for acute and 407 for sub-acute toxicity testing. A single dose of 5000 mg/kg extract was orally administered to three female rats for the acute toxicity study. The plant extract was administered orally for 28 days in daily dosages of 250, 500, and 1000 mg/kg for the sub-acute study. Animals in a control group were given distilled water. A total of 40 rats (5 rats/group/sex) were used for the sub-acute toxicity testing. Daily food intake and weekly body weight measurements were done. The rats were sacrificed at the end of the 28-day treatment period for hematological, biochemical, and histopathological tests. One-way analysis of variance and Kruskal-Wallis tests were employed for the analysis. The single-dose oral administration of the plant resulted in no deaths or serious morbidity. The median lethal dose was >5000 mg/kg. The 28-day oral treatment of the plant extract had no significant effect on general behavior, food intake, organ weight, biochemical parameters, or the majority of the hematological markers, with the exception of the decrease in hemoglobin and hematocrit in the 1000 mg/kg extract-treated groups compared to the controls. Both sexes experienced significant weight increases at all dosage levels. With the exception of minor alterations in a few of the organs, no significant histological change was identified. It is concluded that the single-dose and repeated-dose 28-day oral administration of the methanolic leaf extract of Justicia schimperiana is relatively safe.

Solubility enhancement of fexofenadine using self-nano emulsifying drug delivery system for improved biomimetic attributes

Fexofenadine is a poorly water-soluble drug, which limit its bioavailability and ultimately therapeutic efficacy. Liquid self-nano emulsifying drug delivery system (L-SNEDDs) is an approach that can enhance the solubility of fexofenadine by increasing its surface area and reducing the particle size, which increases the rate and extent of drug dissolution. In this investigation, L-SNEDDs of fexofenadine was made up using surfactants and co-surfactant. The SNEDDS formulation was optimized using a pseudo-ternary phase diagram and characterized. The optimized L-SNEDDS incorporated fexofenadine were thermodynamically stable and showed mean droplet size and zeta potential of 155nm and -18mV, respectively unaffected by the media pH. In addition, the viscosity, and refractive index were observed 18.4 and 1.49cps, respectively for optimized L-SNEDDS fortified fexofenadine. The results of Fourier transform infrared spectroscopy revealed an insignificant interaction between the fexofenadine and excipients. A drug loading efficiency of 94.20% resulted with a complete in vitro drug release in 2h, compared with the pure drug, which demonstrate significant improvement in the efficacy. Moreover, these results signify that on further in vivo assessment L-SNEDDS fortified fexofenadine can indicate improvement in pharmacokinetic and clinical outcome. Thus, the investigation revealed that, the L-SNEDDs incorporated fexofenadine was most effective with a mixture of surfactant and co-surfactant with improved solubility intend to relieve pain associated with inflammation with single-dose oral administration.

Evaluation of the toxicity of the hydroethanolic extract of the stem bark of Virola elongata (Benth.) Warb. in in vitro and in vivo models

Ethnopharmacological relevanceVirola elongata (Benth.) Warb. (Myrsticaceae), referred to as “mucuíba" in Mato Grosso, is a native tree species that can be found in the Amazon Rainforest regions of South America and the Tropical Forests of Central America. The macerated extracts from the stem bark of this tree have been traditionally used to address various health issues, including gastric ulcers, infections, inflammations, and other ailments. In scientific literature, V. elongata has demonstrated pharmacological properties such as antiulcer, gastroprotective, antiproliferative, antimitotic, and psychoactive effects. Nevertheless, it is important to note that the safety profile of V. elongata has not been thoroughly established. Aim of the studyTo evaluate the toxicity of the hydroethanolic extract of the stem bark of Virola elongata (HEVe) in experimental models in vivo and in vitro. Materials and methodsHEVe was obtained by macerating the stem bark powder in 70% hydroethanolic solution (1:10 w/v). The cytotoxicity of HEVe (3.125–200 μg/mL) was evaluated by Alamar blue assay in Chinese hamster ovary epithelial cells (CHO-k1) and human gastric adenocarcinoma (AGS). Genotoxicity assessment of HEVe (10, 30, or 100 μg/mL) was performed in CHO-k1 cells by the micronucleus test. The acute toxicity of HEVe was assessed by single-dose oral administration (2000 mg/kg) in mice of both sexes. The subacute toxicity of HEVe was assessed by oral administration of 300, 600, and 1200 mg/kg of the extract over 30 days in rats. Clinical observations of toxicological parameters were noted and pooled every 6 days. After the treatment period, blood was collected for hematological and biochemical analyses, and some organs were removed for macroscopic and histopathological analyses. ResultsHEVe did not show cytotoxicity in CHO-K1 and AGS cells (IC50 > 200 μg/mL) and did not cause DNA damage in CHO-k1 cells. Oral administration of HEVe in a single dose of 2000 mg/kg did not result in the death of the mice, with a reduction in body weight variation (33.03%, p < 0.05) and an increase in the relative weight of the stomach (12 0.82%, p < 0.05) in male mice, and increased relative weight of the spleen (25.00%, p < 0.01) in female mice. In the assessment of subacute toxicity, HEVe did not result in the death of the animals over the 30 days. A reduction (p < 0.05) in water consumption of 36.65% and 34.12% was observed in the groups treated with 300 and 600 mg/kg, respectively, of HEVe on D6., and the urine excretion of animals treated with 600 mg/kg of HEVe showed an increase (p < 0.05) throughout the experiment, with a maximum value of 46.72% on D12. The blood counts showed that the dose of 300 mg/kg reduced (p < 0.05) the absolute number of lymphocytes, while the doses of 300, 600, or 1200 mg/kg of HEVe reduced the red blood cell count in whole blood by 24.84% (p < 0.01), 16.72% (p < 0.05), and 22.14% (p < 0.01), and the absolute number of monocytes (p < 0.05) in 59.77%, 65.51%, and 79.81%, respectively. As for the biochemical parameters, the glucose level found increased by 22.41% (p < 0.05) only at the highest dose, while creatinine was reduced by 44.71% (p < 0.05) at the dose of 300 mg/kg of HEVe. In animals treated with the three doses tested, plasma levels of AST and alkaline phosphatase showed a reduction (p < 0.05) with the vehicle group. However, the hematological and biochemical changes observed are within the physiological limits for this animal species. No macroscopic and histopathological changes were observed in the organs of the animals treated with the three doses of HEVe within 30 days. ConclusionThe results showed that HEVe did not show cytotoxicity or genotoxicity in vitro. HEVe proved to be safe in rodents in both acute and subacute toxicity tests. In rats, the no-observed-adverse-effect level (NOAEL) dose was greater than 1200 mg/kg p. o. in rats.

Clinical Pharmacology of Brigatinib: A Next-Generation Anaplastic Lymphoma Kinase Inhibitor.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30-240 mg, the median time to reach maximum plasma concentration ranged from 1 to 4 h. In patients with advanced malignancies, brigatinib showed dose linearity over the dose range of 60-240 mg once daily. A high-fat meal had no clinically meaningful effect on systemic exposures of brigatinib (area under the plasma concentration-time curve); thus, brigatinib can be administered with or without food. In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transit absorption compartments was found to adequately describe brigatinib pharmacokinetics. In addition, the population pharmacokinetic analyses showed that no dose adjustment is required based on body weight, age, race, sex, total bilirubin (<1.5× upper limit of normal), and mild-to-moderate renal impairment. Data from dedicated phase I trials have indicated that no dose adjustment is required for patients with mild or moderate hepatic impairment, while a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended for patients with severe hepatic impairment, and a reduction of approximately 50% (e.g., from 180 to 90 mg) is recommended when administering brigatinib to patients with severe renal impairment. Brigatinib is primarily metabolized by cytochrome P450 (CYP) 3A, and results of clinical drug-drug interaction studies and physiologically based pharmacokinetic analyses have demonstrated that coadministration of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with a strong or moderate CYP3A inhibitor cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (strong CYP3A inhibitor) or approximately 40% (moderate CYP3A inhibitor), respectively. Brigatinib is a weak inducer of CYP3A in vivo; data from a phase I drug-drug interaction study showed that coadministration of brigatinib 180 mg once daily reduced the oral midazolam area under the plasma concentration-time curve from time zero to infinity by approximately 26%. Brigatinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations in vitro. Exposure-response analyses based on data from the ALTA (ALK in Lung Cancer Trial of AP26113) and ALTA-1L pivotal trials of brigatinib confirm the favorable benefit versus risk profile of the approved titration dosing regimen of 180 mg once daily (after a 7-day lead-in at 90 mg once daily).

1651-P: Elevated FGF21 Levels after Total Pancreatectomy and in Response to Single-Dose Glucagon Receptor Antagonism in Humans

Fibroblast growth factor 21 (FGF21) is a liver-secreted peptide hormone reportedly improving metabolic homeostasis, partly via reduced hunger for sugar, fat, protein and alcohol. Exogenous glucagon has been shown to increase circulating FGF21 levels, but the role of endogenous glucagon for the control of FGF21 secretion remains unknown. To elucidate the relationship between endogenous glucagon and FGF21 in humans, we investigated the effect of chronic pancreatic glucagon depletion and acute glucagon receptor antagonism, respectively, on FGF21 levels. Nine totally pancreatectomized subjects (7 men, 2 women, age 61.3 ± 10.3 years, BMI 22.6 ± 4.8 kg/m2) and 9 matched control subjects (6 men, 3 women, age 65.9 ± 8.8 years, BMI 23.9 ± 2.7 kg/m2) underwent two randomized, double-blinded test days 24 hours after single-dose oral administration of either the glucagon receptor antagonist LY2409021 (300 mg) or placebo. FGF21 levels were measured both in the fasting state and in response to an oral glucose tolerance test (OGTT). The pancreatectomized patients exhibited significantly increased mean fasting FGF21 levels compared to the control subjects (493 ± 429 vs 108 ± 58 pg/mL, P=0.02). In the control subjects, administration of LY2409021 significantly increased mean fasting levels of FGF21 (216 ± 117 vs 108 ± 58 pg/mL, P=0.004) whereas fasting FGF21 levels in the pancreatectomized patients were unaffected by LY2409021. In both groups, FGF21 levels increased in response to the OGTT, with no significant treatment effect of LY2409021. Our results suggest that both chronic glucagon depletion and acute antagonism of the glucagon receptor mediate an increase in FGF21 levels in humans, pointing to direct or indirect effects of glucagon as important regulators of FGF21 secretion. Disclosure M.F.G.Grøndahl: Speaker's Bureau; Novo Nordisk A/S. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. C.T.Juel: None. A.Lund: Speaker's Bureau; Novo Nordisk. S.Haedersdal: Consultant; Novo Nordisk. M.M.Andersen: None. J.S.Svenningsen: None. M.Gillum: None. B.Hartmann: Stock/Shareholder; Bainan Biotech. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. Funding Aase and Ejnar Danielsen's Foundation; Novo Nordisk Foundation (LY2409021); Eli Lilly and Company

Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CLpro inhibitors against SARS-CoV-2

A series of peptidomimetic compounds containing benzothiazolyl ketone and [2.2.1] azabicyclic ring was designed, synthesized and evaluated in the hope of obtaining potent oral 3CLpro inhibitors with improved pharmacokinetic properties. Among the target compounds, 11b had the best enzymatic potency (IC50 = 0.110 μM) and 11e had the best microsomal stability (t1/2 > 120 min) and good enzyme activity (IC50 = 0.868 μM). Therefore, compounds 11b and 11e were chosen for further evaluation of pharmacokinetics in ICR mice. The results exhibited that the AUC(0-t) of 11e was 5143 h*ng/mL following single-dose oral administration of 20 mg/kg, and the F was 67.98%. Further structural modification was made to obtain compounds 11g-11j based on 11e. Among them, 11j exhibited the best enzyme inhibition activity against SARS-CoV-2 3CLpro (IC50 = 1.646 μM), the AUC(0-t) was 32473 h*ng/mL (20 mg/kg, po), and the F was 48.1%. In addition, 11j displayed significant anti-SARS-CoV-2 activity (EC50 = 0.18 μM) and low cytotoxicity (CC50 > 50 μM) in Vero E6 cells. All of the above results suggested that compound 11j was a promising lead compound in the development of oral 3CLpro inhibitors and deserved further research.

Pharmacokinetics of Marbofloxacin Following Oral Administration in Lactic Acid Pretreated Broiler Chickens

Background: It is hypothesized that feeding lactic acid as a feed additive has the potential to alter the pharmacokinetics of many antimicrobial drugs being used for the treatment of infectious disease in general and marbofloxacin in particular; leading to either increased or decreased efficiency. Hence, the present study was planned to explore the effects of lactic acid pre-treatment on the pharmacokinetics of marbofloxacin after oral administration in broiler chickens. Methods: The pharmacokinetics of marbofloxacin was investigated following single dose oral administration (5 mg/kg) in lactic acid pre-treated (8 gm/l each, oral, 10 days) broiler chickens. The plasma concentration of marbofloxacin was determined by ultra-high-performance liquid chromatography to workout pharmacokinetic profile of marbofloxacin using non compartment model. Result: The AUC (area under curve) of marbofloxacin declined from 14.70 ìg·h/mL to 6.16 ìg·h/mL after pre-treatment of lactic acid. Similarly, the average values of maximum plasma concentration (Cmax) of drug decreased from 2.11 ìg/mL to 0.98 ìg/mL and mean body clearance (ClB) increased from 0.47 L/h/kg to 1.03 L/h/kg. The average elimination half-lives (t½â) of marbofloxacin before and after pre-treatment with lactic acid were 4.89 h and 2.81 h, respectively. Furthermore, the investigation revealed alteration of pharmacokinetic parameters evident in lactic acid pre-treated broiler chickens (as compared to non pre-treated birds) requiring adjustment of dosage regimens.