Multiple Intramuscular Administration Research Articles

Tissue depletion of tylosin after multiple intramuscular administration in calves and piglets

Tylosin (TYL) is widely used to treat different bacterial infections in calves and piglets; however, there is no information available about the withdrawal period necessary for growing calves and piglets to be safe for human consumption. A high-performance liquid chromatography method with ultraviolet-visible light detection was adapted and validated for the determination of TYL in calf and piglet tissues. The procedure is based on the isolation of the TYL compound from edible calf and piglet tissues (muscle, liver, kidneys, and fat with skin) with satisfactory recovery (81.55 ± 10.49) and specificity. The residue depletion of TYL in calves and piglets was assessed after a dose of 10 mg/kg body weight/day administered orally for 5 consecutive days. After the treatment was discontinued, residue concentrations were detected in tissues till the 11th and 19th day in calves and piglets, respectively. The highest TYL concentrations were measured in the liver, in both species. Based on the results presented in this study, it could be assumed that a withdrawal period of 12 days for calves and 20 days for piglets before slaughter would be sufficient to ensure consumer safety.

Study of the safety and immunogenicity of VLP-based vaccine for the prevention of rotavirus infection in neonatal minipig model

In Russia, almost half of the cases of acute intestinal infections of established etiology in 2022 are due to rotavirus infection (RVI). There is no specific treatment for rotavirus gastroenteritis. There is a need to develop modern, effective and safe vaccines to combat rotavirus infection that are not capable of multiplying (replicating) in the body of the vaccinated person. A promising approach is to create vaccines based on virus-like particles (VLPs). Study of the safety and immunogenicity of a vaccine against rotavirus infection based on virus-like particles of human rotavirus A in newborn minipigs with multiple intramuscular administration. Newborn minipigs were used as an animal model in this study. The safety of the tested vaccine was assessed based on thermometry data, clinical examination, body weight gain, clinical and biochemical blood parameters, as well as necropsy and histological examination. When studying the immunogenic properties of the Gam-VLP-rota vaccine in doses of 30 and 120 µg, the cellular, humoral and secretory immune response was studied. The results of assessing the general condition of animals during the immunization period, data from clinical, laboratory and pathomorphological studies indicate the safety of the vaccine against human rotavirus infection based on VLP (Gam-VLP-rota) when administered three times intramuscularly. Good local tolerance of the tested vaccine was demonstrated. The results of the assessment of humoral immunity indicate the formation of a stable immune response after three-time immunization with Gam-VLP-rota, stimulation of the production of antigen-specific IgG antibodies and their functional activity to neutralize human rotavirus A. It was shown that following the triple immunization with the minimum tested concentration of 30 µg/dose, animals developed a cell-mediated immune response. The results of the IgA titer in blood serum and intestinal lavages indicate the formation of both a systemic immunological response and the formation of specific secretory immunity to human rotavirus A. Thus, three-time intramuscular immunization of minipigs with the Gam-VLP-rota vaccine forms stable protective humoral and cellular immunity in experimental animals. Evaluated vaccine is safe and has good local tolerability.

Safety Assessment of Cefquinome Following Multiple Intramuscular Administration Regarding Haematology of Cow Calves

The present study was carried out to investigate haematological alterations induced after repeated intramuscular administration of cefquinome at the dose rate of 2 mg.kg -1 body weight in five healthy male cow calves. Blood samples were collected before administration of the drug which served as control (day 0). After administration of drugs, blood samples were collected at day 1 st , 2 nd , 3 rd , 4 th , 5 th and 6 th from jugular vein into Ethylene Diaminetetraacetic Acid Tripotassium Salt (K3EDTA) coated vacutainers for haematological parameters (Hemoglobin, Packed cell volume, total leukocyte count and differential leukocyte count) analysis. The results of the study clearly demonstrated that repeated intramuscular administration of cefquinome in therapeutic doses produced non-significant difference (p<0.05) in values of haematological parameters in cow calves when compared with control values (0 day). Lack of clinical signs of adverse reactions and absence of significant difference in haematological parameters following intramuscular administration, may open a new avenue for insight into the strategy for clinical treatment of various bacterial diseases in cow calves.

Determination of Marbofloxacin residues in Rabbit Tissues by HPLC

The present study was designed to evaluate marbofloxacin residues in different rabbit tissues after multiple intramuscular administrations. For that purpose, rabbits were divided into two groups; the first group (n=21) administered 2mg/kg marbofloxacin for five successive days, while the second group (n=3) were untreated and served as controls. Tissues were collected at the 1st, 3rd, 5th, 7th, 9th, 15th and 21stday after the last dose post administration of the drug. Liver, kidneys, pectoral muscle and thigh muscles, spleen, heart, blood and lung from each rabbit were taken, extracted and marbofloxacin residues were analyzed using high-performance liquid chromatographic method with ultraviolet detection. Results indicated a widespread distribution of marbofloxacin in the most tested tissues. It remained within detectable level till the 5th day in liver and serum while it continues till the 7th in kidneys day following the last dose. Therefore, muscles of rabbits treated with marbofloxacin could be consumed safely following the 1st day post treatment, while liver and kidneys could be consumed safely in the 3rd day after treatment without any hazards on consumers as the residual level below the recommended MRL (150µg/kg).

Pharmacokinetics of levosulpiride after single and multiple intramuscular administrations in healthy Chinese volunteers

The main purpose of this study was to evaluate the pharmacokinetics of levosulpiride in humans after single and multiple intramuscular injections. Six males and six females received single dose of either 25mg or 50mg levosulpiride, or multiple doses of 25mg every 12h for 5 consecutive days. In the single 25mg study, the mean peak plasma concentration (Cmax) was 441ng/mL, the mean area under the concentration–time curve from 0 to 36h (AUC0–36) was 1724ngh/mL, and the mean elimination half-life (t1/2) was 7.0h. In the single 50mg study, the mean Cmax was 823ng/mL, the mean AUC0–36 was 3748ng·h/mL, and the mean t1/2 was 6.8h. After multiple doses of 25mg levosulpiride, the average plasma concentration (Cav) was 136ng/mL, the fluctuation index (DF) was 3.60, and the accumulation ratio (R) was 1.2. Levosulpiride injections appeared to be well tolerated by the subjects, and can be used for successive administration.

Pharmacokinetics of Cephalexin after Intravenous and Single and Multiple Intramuscular Administration to Rabbit

Cephalexin is a first generation cephalosporin widely used in rabbits. Its spectrum includes Pasteurella multocida and Staphylococcus aureus. These bacteria, together with Bordetella bronchiseptica, are the main cause of respiratory infections. Although many textbooks on rabbit therapeutics report the use of cephalexin, including administration schedules, there are not published papers on the pharmacokinetics of cephalexin after IV and IM administration to rabbit. Therefore, the objective of the present study was to describe cephalexin disposition in rabbits after intravenous and single and multiple intramuscular administrations. Three administration schedules were studied: single IV administration (10 mg/kg), single IM administration (10 mg/kg) and multiple IM administration (2.5 mg/kg/6). Serial blood samples were collected over a 24 h period. Cephalexin plasma concentrations were determined by microbiological method using Kocuria rhizophila ATCC 9341 as microorganism test. No statistical differences were observed between routes of administration for any of the estimated PK parameters. The unique difference was observed on bioavailability between intramuscular administration schedules. Elimination half-life was 1.45, 1.09 and 1.91 h for the single IV, single IM and multiple IM administration, respectively. Bioavailability after single and multiple IM administration was 47 and 97.5%, respectively. After multiple IM administration maximum and minimum plasma concentration at steady state were 2.77 and 0.34 µg/ml, while Cmax after single IM administration was 9. 22 µg/ml. Considering that for betalactams the PK/PD breakpoint recommended for efficacy (T > MIC) should be 50 –80% and that the reported MIC for most gram-positive organisms and Pasteurella multocida is ≤1.0 μg/ml, the present study demonstrates that a single IM dose of 10 mg/kg/24 h is enough to maintain therapeutic concentrations for a 24 hours period. When a 2.5mg/kg dose is used administration every 6 hours is recommended.

A clinical phase I study on intramuscular imipenem/cilastatin sodium

The safety and pharmacokinetics of imipenem/cilastatin sodium (IPM/CS) were evaluated in comparative studies using single intramuscular injection, intravenous infusion or multiple intramuscular administration. The studies were done employing 30 healthy volunteers. Adverse effects were observed in 5 of 18 volunteers in the single intramuscular dose study. One of them complained of mild itching and mild pain at the injection site, and the other 4 volunteers had mild pain at the injection sites. With the other methods of administration, no adverse effects were observed. No other abnormal physical findings nor abnormal laboratory test values were observed in any of the studies. Imipenem (IPM) was absorbed rather slowly through the muscles, resulting in a low maximum plasma concentration (Cmax) and a prolonged half life (T1/2) upon intramuscular injection compared to the results obtained upon intravenous infusion. The total areas under the curves obtained with these 2 methods were similar, however. Cilastatin (CS) was absorbed rapidly after intramuscular injection, and the Cmax obtained was higher than that obtained for IPM. The T1/2 and the AUC of CS obtained with intramuscular injection were similar to those obtained with intravenous infusion. Cumulative urinary recovery rates obtained with these 2 different routes of administration were not different. Detectable urinary levels of IPM were maintained much longer upon intramuscular injection than upon intravenous infusion. In the multiple dose study, neither IPM nor CS showed tendency to accumulate.

Pharmacokinetics of enrofloxacin after multiple subcutaneous and intramuscular administrations in adult ostriches

1. The objective of the study was to evaluate the comparative pharmacokinetic behaviour of enrofloxacin in adult ostriches after single and multiple intramuscular (IM) and subcutaneous (SC) administrations. In addition, tissue tolerance was evaluated. 2. Enrofloxacin was well absorbed, but showed a short permanence after both administration routes. After multiple dose administrations the maximum and minimum peak plasma concentrations were very similar for both routes, obtaining a steady state phase from the second dose that extended until the last evaluated administration. 3. There was no significant accumulation after multiple IM or SC doses; however, there were differences in a fluctuation index after multiple intramuscular administrations that could be related to muscle damage. 4. The different microbiological efficacy indicators (PK/PD indices) obtained, the pharmacokinetic behaviour and CK serum concentrations suggest that subcutaneous enrofloxacin administration of 15 mg/kg every 12 h produce and maintain an efficient concentration of antibiotic that is a safer and more effective therapeutic option than intramuscular administration.

Transduction of Full-length Dystrophin to Multiple Skeletal Muscles Improves Motor Performance and Life Span in Utrophin/Dystrophin Double Knockout Mice

Duchenne muscular dystrophy (DMD) is a fatal, progressive, muscle-wasting disease caused by defects in the dystrophin. No viral vector except the helper-dependent adenovirus vector (HDAdv) can package 14-kilobase (kb) full-length dystrophin complementary DNA (cDNA), and HDAdv is considerably safer than old-generation adenovirus vectors because of the large-size deletion in its genome. We have generated HDAdv that carries myc-tagged murine full-length dystrophin cDNA (HDAdv-myc-mFLdys). We injected it into multiple proximal muscles of 7-day-old utrophin/dystrophin double knockout mice (dko mice) (which typically show symptoms quite similar to human DMD) because the proximal muscles are affected in DMD patients. Eight weeks after the injections, the transduced dystrophin was widely expressed, and we found a significant reduction in centrally nucleated myofibers and the restoration of the dystrophin-associated proteins, beta-dystroglycan (beta-DG) and alpha-sarcoglycan (alpha-SG), as well as neuronal nitric oxide synthase (nNOS). The injected dko mice also showed an increase in body weight, an improvement in motor performance, and a prolongation of life span. Using HDAdv, we could treat DMD model mice even by transferring the therapeutic gene into multiple skeletal muscles. Our results suggest that multiple intramuscular administrations of HDAdv carrying full-length dystrophin cDNA may reduce symptoms and compensate for lost functions in DMD patients.

Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to dairy goats.

Twelve (12) lactating dairy goats (46-71 kg body wt at study initiation) were divided into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two route (intravenous, i.v.; intramuscular, i.m.), two-period crossover design, with a 2-week washout between injections. After another 2-week washout period, the goats were dosed with ceftiofur sodium i.m. for 5 consecutive days at either 1.1 or 2.2 mg CFAE/kg. The goats from the 2.2 mg/kg multiple dose group were dried off and the i.v. kinetic study repeated. After all injections, blood samples were obtained serially for determination of combined serum concentrations of ceftiofur and metabolites. After intravenous doses of 1.1 and 2.2 mg/kg, the harmonic means of the terminal phase half-lives were 171.8 and 233 min, respectively, for lactating does. The harmonic mean of the terminal phase half-life after an i.v. dose of 2.2 mg/kg in non-lactating does was 254 min. The AUC0-infinity was significantly less and the clearance significantly greater during lactation. After i.m. doses of 1.1 and 2.2 mg/kg, the harmonic mean terminal phase half-lives were 163 and 156 min, respectively. The i.m. bioavailability of ceftiofur sodium in goats was 100%, and the AUC0-infinity was dose-proportional from 1.1-2.2 mg CFAE/kg body weight. After five daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE, there was minimal accumulation of drug in serum as assessed by Cmax, and serum concentrations were dose-proportional after the multiple dosing regimen.

Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to sheep.

Twenty-four sheep (38.0-54.1 kg body wt) were allocated into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two-route (intravenous, i.v.: intramuscular, i.m.), two-period crossover design, with a two-week washout between injections. After another two-week washout period, 12 sheep were selected and dosed with ceftiofur sodium i.m. for five consecutive days at either 1.1 or 2.2 mg CFAE/kg. After all injections, blood samples were obtained serially for determination of serum concentrations of ceftiofur and metabolites. The terminal phase half-lives derived from the last 3-5 concentration-time points were 350 and 292 min (harmonic means) after i.v. doses of 1.1 and 2.2 mg/kg, respectively, and 389 and 459 min after i.m. doses of 1.1 and 2.2 mg/kg, respectively. The i.m. bioavailability of ceftiofur sodium in sheep was 100%, and the area under the curve from time 0 to the limit of quantitation (AUC0 LOQ) was dose-proportional from 1.1-2.2 mg CFAE/kg body wt in sheep. After 5 daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE/kg there was minimal accumulation of drug in serum as assessed by the observed maximum serum concentration (Cmax), and serum concentrations were dose-proportional after the multiple dosing regimen.