Evidence for the Contribution of Gut Microbiota to Age-Related Anabolic Resistance.

Globally, people 65 years of age and older are the fastest growing segment of the population. Physiological manifestations of the aging process include undesirable changes in body composition, declines in cardiorespiratory fitness, and reductions in skeletal muscle size and function (i.e., sarcopenia) that are independently associated with mortality. Decrements in muscle protein synthetic responses to anabolic stimuli (i.e., anabolic resistance), such as protein feeding or physical activity, are highly characteristic of the aging skeletal muscle phenotype and play a fundamental role in the development of sarcopenia. A more definitive understanding of the mechanisms underlying this age-associated reduction in anabolic responsiveness will help to guide promyogenic and function promoting therapies. Recent studies have provided evidence in support of a bidirectional gut-muscle axis with implications for aging muscle health. This review will examine how age-related changes in gut microbiota composition may impact anabolic response to protein feeding through adverse changes in protein digestion and amino acid absorption, circulating amino acid availability, anabolic hormone production and responsiveness, and intramuscular anabolic signaling. We conclude by reviewing literature describing lifestyle habits suspected to contribute to age-related changes in the microbiome with the goal of identifying evidence-informed strategies to preserve microbial homeostasis, anabolic sensitivity, and skeletal muscle with advancing age.

Evaluation of epiandrosterone as a long-term marker of testosterone use.

Identification and evaluation of long-term markers is crucial in prolonging the detection window for anabolic steroid abuse in sport. Recently, sulfoconjugated epiandrosterone was identified as a potential long-term marker for the abuse of certain endogenous anabolic agents, including testosterone, which continues to be widely used as a performance enhancing agent in sport. To evaluate the applicability of epiandrosterone sulfate as a marker for testosterone use, administration studies were conducted with multiple modes of testosterone administration - transdermal, intramuscular, and subcutaneous. A modified sample preparation method was used to collect both glucuronidated and sulfoconjugated analytes of interest. Carbon isotope ratio measurements from the administration studies are presented here. Epiandrosterone was less effective than the conventionally used target compounds for detection of the low dose application (transdermal gel). With intramuscular administration, epiandrosterone was more diagnostic than with transdermal administration, but it did not prolong the detection window more than the conventional target compounds. With subcutaneous administration, the doses administered to the subjects were varied and the effect on the epiandrosterone values was dependent on the magnitude of the dose administered. Epiandrosterone does not appear to be a useful marker in the detection of low dose testosterone administration. It is responsive to higher dose administration, but it does not provide an extension of the detection window relative to conventional target compounds.

Noninvasive analysis and identification of an intramuscular fluid collection by postmortem 1H-MRS in a case of a fatal motor vehicle accident.

In a case of a fatal traffic accident, a suspicious finding was identified in the muscular tissue of the left thigh by whole-body postmortem computed tomography. To better interpret the finding, the lower extremities were investigated by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS). MRI revealed the presence of an evenly distributed intramuscular fluid and 1H-MRS of a volume within the fluid detected concentrations of acetate and lactate. The fluid was assumed to be an extravasation of an intraosseous infusion, erroneously administered to the intermediate vastus of the left thigh during resuscitation, which was later confirmed when access to resuscitation protocols was granted. Further ex situ 1H-MRS investigations of five different infusion fluids showed the possible discrimination of the fluids and further indicated the unknown fluid to be a Ringer's acetate solution. This paper presents the case-based application of postmortem intramuscular 1H-MRS and introduces the possibility of its use to differentiate exo- and endogenic fluids for forensic interpretation. Further research for this method regarding problems in forensic pathology is needed.

Population Pharmacokinetics of Danofloxacin After Single Intramuscular Dose Administration in California Brown Pelicans (Pelecanus occidentalis californicus).

The pharmacokinetics of danofloxacin was investigated in rehabilitated California brown pelicans (Pelecanus occidentalis californicus) after a single intramuscular injection at a dose of 15 mg/kg body weight. The concentration of the drug in plasma was assayed by high-pressure liquid chromatography. A sparse-sampling design was used to reduce the number of samples (1-4 venipunctures) obtained from 24 brown pelicans. A population pharmacokinetic analysis with nonlinear mixed-effects modeling was used to accommodate the sparse-sampling strategy. The nonlinear mixed-effects modeling approach measured both fixed effects (typical values for the population) and random effects (between-subject variability) for this population. A 1-compartment model best represented the concentration-versus-time data after injection. After injection, the elimination half-life, peak concentration, area under the curve, and volume of distribution were 2.76 hours, 2.5 µg/mL, 13.75 µg/h/mL, and 4.35 L/kg, respectively. Rate of absorption was highly variable among the birds. The intramuscular injection of danofloxacin in pelicans at this dose produced plasma concentrations that meet therapeutic targets for bacteria with a minimum inhibitory concentration of ≤0.25 µg/mL. This dose can be used for future studies to evaluate the efficacy of danofloxacin for treating susceptible bacteria.

The Release of Adipose Stromal Cells from Subcutaneous Adipose Tissue Regulates Ectopic Intramuscular Adipocyte Deposition.

Ectopic lipid deposition (ELD) is defined by excess fat storage in locations not classically associated with adipose tissue (AT) storage. ELD is positively correlated with insulin resistance and increased risk of metabolic disorders. ELD appears as lipid droplets or adipocytes, whose cell origin is unknown. We previously showed that subcutaneous AT (ScAT) releases adipocyte progenitors into the circulation. Here, we demonstrate that triggering or preventing the release of adipocyte precursors from ScAT directly promoted or limited ectopic adipocyte formation in skeletal muscle in mice. Importantly, obesity-associated metabolic disorders could be mimicked by causing adipocyte precursor release without a high-fat diet. Finally, during nutrient overload, adipocyte progenitors exited ScAT, where their retention signals (CXCR4/CXCL12 axis) were greatly decreased, and further infiltrated skeletal muscles. These data provide insights into the formation of ELD associated with calorie overload and highlight adipocyte progenitor trafficking as a potential target in the treatment of metabolic diseases.

The pharmacokinetics of ketamine following intramuscular injection to F344 rats.

Ketamine is a glutamate N-methyl-D-aspartate receptor antagonist that is a rapid-acting dissociative anesthetic. It has been proposed as an adjuvant treatment along with other drugs (atropine, midazolam, pralidoxime) used in the current standard of care (SOC) for organophosphate and nerve agent exposures. Ketamine is a pharmaceutical agent that is readily available to most clinicians in emergency departments and possesses a broad therapeutic index with well-characterized effects in humans. The objective of this study was to determine the pharmacokinetic profile of ketamine and its active metabolite, norketamine, in F344 rats following single or repeated intramuscular administrations of subanesthetic levels (7.5 mg/kg or 30 mg/kg) of ketamine with or without the SOC. Following administration, plasma and brain tissues were collected and analyzed using a liquid chromatography-mass spectrometry method to quantitate ketamine and norketamine. Following sample analysis, the pharmacokinetics were determined using non-compartmental analysis. The addition of the current SOC had a minimal impact on the pharmacokinetics of ketamine following intramuscular administration and repeated dosing at 7.5 mg/kg every 90 minutes allows for sustained plasma concentrations above 100 ng/mL. The pharmacokinetics of ketamine with and without the SOC in rats supports further investigation of the efficacy of ketamine co-administration with the SOC following nerve agent exposure in animal models.

Gene Transfer of ZMapp Antibodies Mediated by Recombinant Adeno-Associated Virus Protects Against Ebola Infections.

Vectored delivery of the ZMapp antibody cocktail (c2G4, c4G7, and c13C6) by using recombinant adeno-associated viruses (rAAVs) could be useful for preventive immunization against Ebola virus infections because rAAVs can generate long-term antibody expression. Three rAAVs (serotype 9) encoding chimeric ZMapp antibodies were produced by triple-plasmid transfection up to 10 L-scale in WAVE bioreactors using HEK293 cells grown in suspension/serum-free conditions. Efficacy of AAV-c2G4 via intravenous (i.v.), intramuscular (i.m.), and intranasal (i.n.) routes of administration was evaluated in mice with two different doses of 2.7 × 1010 and 13.0 × 1010 vector genomes (vg). The best protective efficacies after Ebola challenge were obtained with the i.v. and i.m. routes. Serum concentrations of ZMapp antibodies positively correlated with survivability. Efficacy of the rAAV-ZMapp cocktail was then evaluated at a higher dose of 30.0 × 1010 vg. It conferred a more robust protection (90% i.v. and 60% i.m.) than rAAV-c4G7 (30%) and rAAV-c13C6 (70%), both administered separately at the same dose. Delivery of rAAV-c2G4 alone achieved up to 100% protection (100% i.v. and 90% i.m.) at the same dose. In conclusion, the preventive treatment was effective in mice. However, no advantage was observed for using the rAAV-ZMapp cocktail in comparison to the utilization of the single rAAV-c2G4.

Aripiprazole and impulse control disorders: higher risk with the intramuscular depot formulation?

Dopamine agonists have been associated with an increased risk of developing impulse control disorders (ICDs). The US Food and Drug Administration (FDA) issued a safety warning in 2016 of a possible association between ICDs and aripiprazole. Recently, one large epidemiological study has confirmed this risk. In the present study, we aim to determine whether the safety signal of ICDs associated with aripiprazole detected by the FDA is replicated in the European pharmacovigilance database (EudraVigilance). We searched for all suspected spontaneous cases of ICDs associated with aripiprazole in EudraVigilance up to 23 February 2017. To assess the association between ICD cases and each dopamine agonist drug, we calculated the proportional reporting ratios (PRRs). Among 4 905 110 events of all types recorded in EudraVigilance, we found 160 cases of ICDs associated with aripiprazole. Aripiprazole fulfilled the criteria to generate a safety signal; PRR (95% confidence interval): 16.39 (13.97-19.24). Notably, the association seemed the strongest for the depot formulation of aripiprazole; PRR (95% confidence interval): 27.13 (17.22-42.75). Our analysis of the data contained in EudraVigilance confirms the safety signal detected last year by the FDA. Interestingly, for the first time, we show that the association seems the strongest for the intramuscular depot formulation of aripiprazole.

The contribution of the in-vivo fate of an oil depot to drug absorption.

Sustained release of lipophilic compounds can be achieved with oil depots. These parenteral formulations are generally injected in the vastus lateralis and deltoid muscle. It is known that the absorption rate differs between these two muscles. The reason for this is not fully understood. The aim of the current study was to investigate the fate of an oil depot in different tissues to elucidate whether the disappearance rate of oil is the cause of observed differences in absorption rate. A study with healthy volunteers was conducted to determine 1.0mL oil depots in the vastus lateralis and deltoid muscle for two weeks. The spatial distribution of the oil depots was determined using MRI. Additionally, a study in rats was conducted to microscopically examine the oil immediately and after 31days of injection. All rats were injected with a 0.1mL oil depot with and without benzyl alcohol (BOH), a commonly used excipient in oil depots. In humans, it was shown that all oil depots were equal in volume and surface area directly after injection. Moreover, the disappearance rate for all oil depots was similar; within one week there was no depot visible anymore by MRI. This in contrast to the depots in rats, which were still microscopically visible after 31days. It is concluded from these observations that the oil is dispersed to small droplets in the course of time. The resulting increase in surface area does not lead to an increase in absorption rate however. The results of this paper show that the variation in drug absorption as found for the two muscles is not caused by a distinction in surface areas or disappearance rates of the oil depots. Therefore, it is argued that the local tissue drainage (e.g. lymph flow) plays a considerable role in drug absorption from oil depots, whereby the lymph flow differs between the muscles.

Efeitos sedativos da administração intranasal ou intramuscular de midazolam associado ou não ao butorfanol em periquito autraliano (Melopsitacus undulatus) / Sedative effects of intranasal or intramuscular administration of midazolam with or without butorphanol in budgerigards (Melopsitacus undulatus)

Frequentemente o médico-veterinário é requisitado para realização de diversos procedimentos em aves, os quais geralmente necessitam de sedação ou anestesia geral. Este trabalho teve como objetivo comparar os efeitos sedativos do midazolam (5 mg.kg-1) associado ou não ao butorfanol (1 mg.kg-1) pelas vias de administração intranasal ou intramuscular. Sete periquitos australianos foram submetidos a quatro tratamentos em delineamento do tipo crossover com 15 dias de intervalo. Foram avaliados os períodos de latência, tempos de decúbito dorsal, tempos de sedação, tempos de recuperação, grau de sedação e qualidade de recuperação. Os resultados paramétricos foram avaliados por análise de variância de uma via seguida por teste de Student- Newman-Keuls e os dados não paramétricos foram submetidos ao teste Kruskal-Wallis ambos com 5% de significância. A técnica intranasal demonstrou melhores graus de sedação; no entanto, concluiu-se que ambos os protocolos e as vias de administração avaliados são seguras e viáveis para sedação em periquito australiano.

Often veterinarians have attended various species of birds to perform clinical procedures, which require sedation or general anesthesia. The aim of this study was compare the intranasal or intramuscular sedative effects of midazolam (5 mg.kg-1) with or without butorphanol (1 mg.kg-1). Seven budgerigards (Melopsitacus undulates) were submitted in a crossover design to four treatments. The procedures were performed with 15 days washout. Were evaluated the on set time, dorsal recumbency time duration, total sedation period, total recovery time, sedation degree and recovery quality. The parametric results were analised by one way ANOVA following Student-Newman-Keuls test and non-parametric datas were submitted to Kruskal-Wallis test, both with 5% significance. The intranasal technical demonstrates best degrees of sedation, however, this study concluded that both protocols and the administration routes are safe and viable for sedation in budgerigards

Da-Cruz Triple Tool: cómo hacer simple y precisa la cirugía de implante glúteo intramuscular / Da-Cruz Triple Tool: como fazer de forma simples e com precisão a cirurgia de colocação de implantes glúteos intra-musculares / Da-Cruz Triple Tool: how to make simple and accurate the intramuscular gluteal implant surgery

El Da-Cruz Triple Tool es un instrumento multifuncional diseñado para la colocación de implantes glúteos intramusculares. Tiene 3 funciones; a saber: disector, separador y medidor. Consiste en 2 piezas para su uso articulado o por separado. Como disector logra la profundidad y el grosor deseables del músculo glúteo mayor a través de maniobras precisas que provocan menos trauma; por consiguiente, ayuda a obtener una mejor recuperación y resultados. Al mismo tiempo faculta para elevar los espacios abiertos y controlar adherencias o sangrados. La función de medidor permite calcular la dimensión cefalocaudal y la anchura del espacio para escoger el implante adecuado. Con el entrenamiento adecuado en el uso de esta herramienta y la implementación de medidas pre, trans y postoperatorias bien definidas, cualquier cirujano plástico puede obtener resultados consistentemente exitosos en la colocación de implantes glúteos intramusculares (AU)

The Da-Cruz Triple Tool is a multifunctional instrument designed for intramuscular gluteal prosthesis implantation that functions as a dissector, retractor and sizer. The Triple Tool is composed of 2 blades that can be articulated together or utilized independently. As a dissector, it achieves the proper depth and thickness of the gluteus maximus muscle through very precise manoeuvres that result in minimal trauma. As a retractor, it raises the flap to provide an appropriate view of the pocket, allowing the surgeon to control any bleeding or adhesions. As a sizer, it displays the cephalocaudal dimension and width of the pocket, allowing the surgeon to select the appropriate implant size. Precise dissection, efficient retraction and accurate sizing results in a surgery with better outcomes and faster recoveries. With the appropriate training and proper implementation, any plastic surgeon can obtain consistent successful results performing intramuscular gluteal prosthesis implantation (AU)

Da-Cruz Triple Tool é uma ferramenta multi-funcional desenhada para a cirurgia de colocação de implantes glúteos intra-musculares. Cumpre três funções essenciais para esse procedimento, a saber: dissecador, separador e medidor. Consiste em duas peças utilizadas em uso articulado ou em separado. Como dissecador propicía a correta profundidade e espessura do músculo glúteo maior, abrindo um espaço com uma dimensão controlada através de manobras precisas que produzem poucos traumas; pelo que resulta em melhor recuperação e em melhores resultados finais. Em simultâneo possibilita a elevação dos espaços abertos (separador) controlando aderências ou sangrados. A função medidor permite calcular a dimensão céfalocaudal e a largura do espaço para acolher o implante adequado. O uso desta ferramenta possibilita a obtenção dos melhores resultados quando associado à implementação de medidas pré, trans e post operatórias bem definidas, bastando para tal um treino adequado do cirurgião plástico (AU)

Effect of exposure routes on the relationships of lethal toxicity to rats from oral, intravenous, intraperitoneal and intramuscular routes.

The lethal toxicity values (log 1/LD(50)) of 527 aliphatic and aromatic compounds in oral, intravenous, intramuscular and intraperitoneal routes were used to investigate the relationships of log 1/LD(50) from different exposure routes. Regression analysis shows that the log 1/LD(50) values are well correlated between intravenous and intraperitoneal or intramuscular injections. However, the correlations between oral and intravenous or intraperitoneal routes are relatively poor. Comparison of the average residuals indicates that intravenous injection is the most sensitive exposure route and oral administration is the least sensitive exposure route. This is attributed to the difference in kinetic process of toxicity testing. The toxic effect of a chemical can be similar or significantly different between exposure routes, depending on the absorption rates of chemicals into blood. Inclusion of hydrophobic parameter and fractions of ionic forms can improve the correlations between intravenous and intraperitoneal or oral routes, but not between intraperitoneal and oral routes. This is due to the differences of absorption rate in different exposure environments from different routes. Several factors, such as experimental uncertainty, metabolism and toxic kinetics, can affect the correlations between intravenous and intraperitoneal or oral routes.

Decellularized skeletal muscle as an in vitro model for studying drug-extracellular matrix interactions.

Several factors can affect drug absorption after intramuscular (IM) injection: drug solubility, drug transport across cell membranes, and drug metabolism at the injection site. We found that potential interactions between the drug and the extracellular matrix (ECM) at the injection site can also affect the rate of absorption post-injection. Using decellularized skeletal muscle, we developed a simple method to model drug absorption after IM injection, and showed that the nature of the drug-ECM interaction could be investigated by adding compounds that alter binding. We validated the model using the vitamin B12 analog cobinamide with different bound ligands. Cobinamide is being developed as an IM injectable treatment for cyanide poisoning, and we found that the in vitro binding data correlated with previously published in vivo drug absorption in animals. Commercially available ECM products, such as collagen and GelTrex, did not recapitulate drug binding behavior. While decellularized ECM has been widely studied in fields such as tissue engineering, this work establishes a novel use of skeletal muscle ECM as a potential in vitro model to study drug-ECM interactions during drug development.

Absorption and disposition of florfenicol after intravenous, intramuscular and subcutaneous dosing in alpacas.

The objectives of this study were to define disposition and systemic availability of florfenicol in alpacas. Administration of 20 mg/kg doses to 8 male alpacas by i.v., i.m. and s.c. routes was performed by randomized, 3-way crossover design. Clearance and steady state volumes (Vdss) after i.v. injection were 5 ml/min/kg and 775 ml/kg respectively. Mean residence time (MRT) and terminal phase half-life (T1/2λz) were 2.8 h and 2 h respectively. Maximum serum concentrations (Cmax) after i.m. were higher than s.c. administration (p = 0.034). After s.c. dosing, T1/2λz and MRT were greater than after i.m. injection (p < 0.001; p = 0.006 respectively). Mean absorption time (MAT) after s.c. dosing was also prolonged (p = 0.006). Fractional absorption of florfenicol after i.m. and s.c. was not different (p > 0.05). Serum florfenicol concentrations remained >1.0 µg/ml for 20 h after i.m. dosing. Differences in rate and extent of florfenicol absorption after extravascular dosing could influence therapeutic outcomes.

Bioavailability and pharmacokinetic profile of levofloxacin following intravenous, intramuscular and oral administration in turkeys.

1. The pharmacokinetics and bioavailability of levofloxacin in turkeys were investigated after a single intravenous (IV), intramuscular (IM) and oral (PO) administration of 10 mg/kg body weight. 2. The concentrations of levofloxacin in plasma samples were assayed using a microbiological assay method and pharmacokinetic parameters were calculated by non-compartmental analysis. 3. Following IV administration, the elimination half-life (t0.5(ß)), volume of distribution at steady state (Vdss) and total body clearance (Cl) were 4.49 h, 1.31 l/kg and 0.23 l/h/kg, respectively. 4. After single IM and PO administrations at the same dose, levofloxacin was rapidly absorbed as indicated by an absorption half-life (t0.5ab) of 1.02 and 0.76 h, respectively; maximum plasma concentrations (Cmax) of 5.59 and 5.15 µg/ml were obtained at a maximum time (Tmax) of 2 h for both routes and levofloxacin bioavailability (F) was 96.5 h and 79.9% respectively after IM and PO administration. In vitro plasma protein binding of levofloxacin was 24.3%. 5. Based on these pharmacokinetic parameters, a dose of 10 mg/kg body weight given intramuscularly or orally every 24 h in turkeys can maintain effective plasma concentrations with bacterial infections with (minimum inhibitory concentration) MIC90 > 0.1 µg/ml.