SERUM CREATINE PHOSPHOKINASE ACTIVITY IN RABBIT DURING REGENERATION OF EXPERIMENTALLY DAMAGED MUSCLE TISSUE AND AFTER ITS STIMULATION BY TRANSPLANTED MSC

According to statistics, in modern veterinary practice, the percentage of muscle injuries among sport and working animals ranges from 40–70% of sports injuries. Quite often there are cases with muscle injuries of skeletal muscles, namely extremities. This scientific work describes the research methodology, stages of research step-by-step, and studies the relationship of dynamics of the activity of a single biochemical blood indicator. The essence of the method was to model the injury of muscle tissue performed by the skin and fascia dissection and cutting off in the area of midplane of the pelvic head of the biceps femoris muscle, measuring 1.5 x 1.5 cm to a depth of 1.5 cm of muscle tissue on 105 laboratory animals, divided into 4 groups with the use of various treatment methods. We analyze the results of one of the most effective biochemical methods for diagnosing muscle fiber of skeletal system damage and compare the activity of the enzyme creatine phosphokinase iso-enzyme depending on the stage of the study. Other research methods such as clinical, biochemical, ultrasonographic, histological research methods were recorded on 4, 7, 10, 14, 21, and 28 days. We analyzed the latest literature sources and concluded that on the 4th and 7th days, the level of creatine phosphokinase in the groups with intravenous administration, intramuscular administration of allogeneic mesenchymal stem cells is higher than the reference values but significantly lower compared to the control groups and the traditional method of treatment. But we observe a significant decrease in serum creatine phosphokinase levels in crawls on 10th day in the intravenous administration group compared to the control group of animals in 2 times, compared to traditional treatment in 1.6 times. The group of animals with intramuscular administration has reference values on the 14th day, compared with the control in 1.3 times lower, traditional treatment in 1.2 times. And on 21th day, we get reference values for a group of animals with traditional treatment. The level of creatine phosphokinase activity decreases in the control group of animals on 28th day of the research, which indicates a complete muscle rupture. The results of studies showed that the highest activity of the creatine phosphokinase enzyme during the study was shown by groups of animals with control and traditional treatment, which indicated significant structural, functional and destructive disorders of the muscle fibers of skeletal tissues with severe trauma. Thus, it is noted that the activity of the enzyme in conditions of damage of skeletal muscle tends to increase in accordance with the severity of the injury.

Clinico-toxicological effects of ceftriaxone after intramuscular administration of graded doses in Basenji dogs

Purpose: The recent ceftriaxone-induced anaemia and mortalities at the dose of 50 mg/kg in Veterinary Teaching Hospital, University of Nigeria prompted this study which sought to assess the clinicotoxicological effects of ceftriaxone (CFZ) after intramuscular administration of graded doses in Basenji dogs.Methods: The effects of CFZ on the haematological indices, physiological parameters, liver and kidney functions were assessed in 4 group of dogs (n = 4) designated A – D. They were given CFZ intramuscularly for 21 days at doses of 12, 25 and 50 mg/kg for groups A, B, C, respectively, while thecontrol (group D) received the diluent (lignocaine 0.2 mL)Results: The mean pulse and heart rate of dogs in group C were significantly (p < 0.05) higher than those of group A, B and D. Significant (p < 0.05) decrease in red blood cell count (RBC), haemoglobin concentration (Hb) and packed cell volume (PCV) was observed in group C on days 7 and 14, while on day 21, these parameters were significantly (p < 0.05) higher in group D than in the treated groups. On day 14 of CFZ administration, the alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities of dogs in group C was significantly (p < 0.05) elevated than the control group.Conclusion: These findings suggest that CFZ, at the doses of 12.5 - 25 mg/kg, appears safe in dogs as most of the adverse effects observed are reversed following the withdrawal of the drug on day 28. However, CFZ at 50 mg/kg causes anaemia, tachycardia and bilateral paralysis of the hind limbs which did not revert to normal after one week; hence, it is not recommended for use in dogs at this dose.

Assessing efficacy and safety of rectally vs. intravenously administered Sibazon in treatment of generalized epileptic seizures in children

Objective: to prove the therapeutic equivalence and similar safety profile of “Sibazon, rectal solution” (international nonproprietary name: diazepam) and “Sibazon, solution for intravenous and intramuscular administration” in children with primary generalized and bilateral tonic, clonic and tonic-clonic seizures.Material and methods. An open-label, randomized clinical trial on efficacy and safety was conducted in 20 patients suffering from epilepsy with generalized seizures aged 1 to 17 years. Clinical blood and urine tests, biochemical blood analysis were used for diagnostics (glucose, total protein, albumin, total bilirubin, cholesterol, aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, alkaline phosphatase, creatinine, urea, creatinine clearance), as well as data on electrocardiographic (ECG) and electroencephalographic (EEG) studies. The patients were divided into two groups: in Group 1 (n=8), a rectal solution was used, in Group 2 (n=12) – a solution for intravenous and intramuscular administration.Results. The number of cases in which seizures were completed within 10 minutes after using the drug without resuming within subsequent 60 minutes, in Group 1 was 7 (87.5%), and in Group 2 – 9 (75.0%) (Fisher exact test (FET): p=0.617). Repeated primary generalized or bilateral tonic/clonic/tonic-clonic seizures within 24 hours after drug administration, in Group 1 were absent in 5 (62.5%) patients, in Group 2 – in 6 (50%) (FET: p=0.670); within 48 hours after drug administration – in 5 (62.5%) and 7 (58.3%) children, respectively (FET: p=1.00). Physical examination revealed no pathology in all patients at the final visit. While comparing ECG and EEG data at the final visit, no inter-group differences were found by the number of children with deviations from the norm. The results of laboratory studies confirmed that using the studied drugs had no negative effect on the main indicators of clinical and biochemical blood tests as well as clinical urine analysis.Conclusion. The effectiveness of the rectal form of Sibazon in relieving pediatric generalized epileptic seizures is comparable to that of Sibazon for intramuscular administration. The drug rectal form, due to easy-to-use administration, is preferable for outpatient practice. “Sibazon, rectal solution” is safe and has good tolerability.

Effect of Intramuscular Administration of Dexamethasone on Shortening of the Duration of Induction of Labor

Background Induction of labor refers to iatrogenic stimulation of uterine contractions to accomplish delivery prior to the onset of spontaneous labor. Induction of labor is undertaken when both of the following criteria are met: Continuing the pregnancy is believed to be associated with greater maternal or fetal risk than intervention to deliver the pregnancy, and there is no contraindication to vaginal birth. Aim of the Work to evaluate the effect of intramuscular administration of dexamethasone on the duration of vaginal delivery in women undergoing induction of labor. Patients and Methods This double-blinded randomized controlled study was conducted on 60 termed pregnant women who were divided into two groups, Dexamethasone group: injected with 2 ml of the product (dexamethasone®) 12 hours before initiation of labor induction and placebo group: injected with 2 ml distilled water 12 hours before initiation of labor induction. The two groups were induced by the same standard protocol. Determination of interval between initiation of induction and beginning of active phase, duration of active phase, duration of 2nd stage and duration 3rd stage have been detected for both groups and statistically analyzed. Results There were significant statistical differences between the two studied groups as regard rate of cervical dilatation. There were high significant statistical differences between the two studied groups as regard duration between initiation of labor induction and beginning of active phase of labor, duration of active phase of labor and duration of second and third stage of labor. Conclusion an intramuscular injection of dexamethasone before labor induction is found to shorten the duration of labor induction by decreasing the interval between the initiation of induction and the beginning of the active phase, duration of active phase and duration of second stage of labor with no observed maternal or neonatal complications.

Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV

Objectives To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration. Methods Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks). In Phase III studies, an initiation injection of 900 mg followed by continuation injections of 600 mg every 4 weeks was used. Non-linear mixed-effects modelling was performed using NONMEM® software. Results A one-compartment model with linear elimination and two parallel absorption pathways (fast and slow) with sequential zero-first-order processes adequately captured rilpivirine flip-flop pharmacokinetics after intramuscular administration of the LA formulation. The estimated apparent elimination half-life of rilpivirine LA was 200 days. None of the evaluated covariates (age, body weight, BMI, sex, race, health status and needle length) had a clinically relevant impact on rilpivirine pharmacokinetics. Conclusions The population pharmacokinetic model suitably describes the time course and associated variability of rilpivirine plasma concentrations after rilpivirine LA intramuscular administration. The monthly regimen consists of an oral lead-in period (rilpivirine 25 mg tablets once daily for 4 weeks), followed by an initiation injection of 900 mg rilpivirine LA, then 600 mg rilpivirine LA continuation injections monthly. The absence of a clinically relevant effect of covariates on rilpivirine pharmacokinetics suggests that rilpivirine LA dose adjustments for specific subgroups are not warranted.

Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits

Human serum albumin (HSA) has been widely used as a pharmaceutical excipient in Botulinum toxin serotype A (BoNT/A) products that are indicated for use in therapeutics and cosmetics. However, HSA as a human-derived material has some concerns, such as the potential risk of transmission of infectious agents, an insufficient supply, and difficulty in maintaining a certain quality. For those reasons, newly developed BoNT/A products (CORETOX®, Medytox, Inc., Republic of Korea) contained polysorbate 20, a non-human-derived excipient, to replace the HSA. However, most safety studies of polysorbate 20 have been conducted with non-invasive routes of administration, and thus there are a few studies on the safety of polysorbate 20 when administered intramuscularly. To secure the in vivo safety profile of polysorbate 20, a four-week repeated intramuscular dose toxicity study (0.02, 0.1, and 0.4 mg/kg, one injection every two weeks for a total of three injections) was conducted in 66 Sprague-Dawley (SD) rats. An intradermal irritation study was further conducted with 18 New Zealand White (NZW) rabbits. The toxicological evaluation of HSA (0.06 and 0.12 mg/kg) was also carried out as a comparative substance. Systemic and local toxicities were not observed in any of the SD rats or NZW rabbits based on clinical signs, body weight, hematology, clinical biochemistry, macroscopic findings on necropsy, histopathology of the injection site, and allergic reactions. The current study suggested that intramuscular administration of polysorbate 20 was considered to be safe at a level similar to that of HSA, which has an in vivo safety profile accumulated over the years. This provided the basis for the in vivo safety profile of polysorbate 20 administered intramuscularly and the scientific reliability of the use of polysorbate 20 as an alternative to HSA, which is used as an excipient for various pharmaceuticals in terms of its safety.

Pharmacokinetic Behaviour of Enrofloxacin after Single Intramuscular Dosage in American Black Vultures (Coragyps atratus)

The aim of the study was to investigate the intramuscular pharmacokinetics of enrofloxacin in black vultures (Coragyps atratus). The pharmacokinetics of a single intramuscular dose (10 mg/kg) of enrofloxacin was studied in six vultures. Plasma concentrations of enrofloxacin and its active metabolite, ciprofloxacin, were determined by high-performance liquid chromatography (HPLCuv). Pharmacokinetic parameters were estimated using non-compartmental and compartmental analysis. After intramuscular administration, enrofloxacin showed a rapid and complete absorption, reaching a Cmax value of 3.26 ± 0.23 μg/mL at 1.75 ± 0.53 h. A long terminal half-life of 19.58 h has been observed. Using previously published MIC values to perform a PK/PD analysis, cumulative fraction responses obtained after Monte Carlo simulation for AUC/MIC > 30, 50 and 125 were 72.93%, 72.34% and 30.86% for E. coli and 89.29%, 88.89% and 58.57% for Mycoplasma synoviae, respectively. Cumulative fraction responses obtained for Cmax/MIC index were 33.93% and 40.18% for E. coli and M. synoviae, respectively. The intramuscular administration of 10 mg/kg could be appropriate to treat infectious diseases caused by gram-positive bacteria with MIC value lower than 1 µg/mL; however, although enrofloxacin showed a slow elimination in black vultures, plasma concentrations were insufficient to reach the gram-negative stablished breakpoints.

The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers

Purpose Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. Methods We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax). Results Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was significantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was significantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8–8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30–90 min and were 2–3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this effect gradually diminished. From 240 min there was no significant difference between the ratios observed after intranasal naloxone administration. Conclusion Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose.