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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.

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.

The pharmacokinetics of danofloxacin was investigated in rehabilitated California brown pelicans (

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 (

Ketamine is a glutamate N-methyl-D-aspartate receptor antagonist that is a rapid acting dissociative anesthetic. It has been proposed to be 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 standard of care. 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 min 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.

Summary: 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. : Girousse et al. show that, in mice fed a high-fat diet, adipose stromal cells (ASCs) can egress subcutaneous adipose tissue and infiltrate skeletal muscle to form ectopic adipocytes, causing metabolic disturbance. ASC trafficking is regulated by the CXCR4/CXCL12 axis, and pioglitazone intermittent treatment can prevent muscle ectopic lipid deposition. Keywords: ectopic adipocytes, adipose stem or stromal cells, intramuscular adipocyte, thiazolidinedione, type 2 diabetes, CXCR4/CXCL12, AMD3100, lymphatic system, chemotaxis

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 remained1.0 µg/ml for 20 h after i.m. dosing. Differences in rate and extent of florfenicol absorption after extravascular dosing could influence therapeutic outcomes.

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.

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 1.0 mL 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 31 days of injection. All rats were injected with a 0.1 mL 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 31 days. 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.

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 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.

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.

Olanzapine long-acting injection (OLAI) is a sustained-release depot antipsychotic for the treatment of schizophrenia in adults. Our objective was to explain the pharmacokinetics of OLAI to provide clinical insight. Simulation models and data from clinical trials are presented. Olanzapine concentrations were observed immediately upon injection. Half-life was ∼30 days, controlled by the slow rate of intramuscular absorption rather than the 30-h elimination rate-based half-life of oral olanzapine. As each injection builds on the drug still being released from previous injections, concentrations increase gradually until a steady state is reached after ∼3 months. Concentrations were similar to oral olanzapine and proportional to the dose; the average steady-state concentrations (10th-90th percentile) for the 150, 210, and 300 mg/2-week doses were 16-32, 15-55, and 20-67 ng/ml, respectively, and those for the 300 and 405 mg/4-week doses were 19-48 and 19-62 ng/ml, respectively. Peak concentrations most often occurred at 2-4 days after injection. Peak-to-trough fluctuation was greater for the 4-week dosing interval than the 2-week one, with no apparent clinical ramifications for these differences. Trough concentrations were above the lower end of the therapeutic range, even at the first injection. Long-term use up to 6 years indicated no additional accumulation. The impact of smoking and sex was similar, but less pronounced than for oral olanzapine.

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(β)), 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.

Summary Based on international recommendations and the scientific literature, the recommended injection sites for the intramuscular administration of vaccines in new-borns, infants and children under oneyear are the upper antero-lateral side of the thigh (vastus lateralis M. quadriceps) or the upper arm (M. deltoideus). For those olderthan one year it is the upper arm. The choice of these sites guarantees both the intramuscular absorption of the injected antigen and thereby maximum efficacy of the vaccine and maximum vaccination safety. With vaccination in the upper outer quadrant of the buttock there is a good chance that the vaccine will be injected into subcutaneoustissue, resulting in lowered immunogenecity. The injection needles for intramuscular administration of vaccines must be long enough to penetrate the muscle adequately (16-25mm). There are two vaccination techniques: one where the muscle mass at the injection site is pushed together, and another where the skinis stretched between the thumb and first finger. A specific length of needle should be used, depending on the vaccination technique:25 mm needles for the first technique and 16 mm for the second.

Non-aqueous or oil-in-oil emulsions may be used as reservoirs to deliver lipophilic or hydrolytically unstable drugs. Emulsions of castor oil-in-silicone oil (co/so) release drugs slowly in vitro . To investigate the potential use of such formulations as depot preparations in vivo , drug absorption and distribution from an intramuscular injection site to various organs in the rat was studied. 3 H-dexamethasone (0.1 mg/kg) was incorporated into the castor oil (disperse phase) of co/so emulsions and in castor oil-in-water (co/w) emulsions, the latter serving as control. 3 H-dexamethasone was absorbed after intramuscular injection of co/w emulsions, reaching a plasma C max of 0.078 μg/ml at 2.0 h ( T max ). For co/so emulsions, a lower C max (0.048 μg/ml) was observed with a longer T max (4.0 h). No significant difference was found between the two formulations in the area under the plasma concentration–time curve (AUC ∞ ), or in clearance (CL). Administration of 3 H-dexamethasone in the co/so emulsion improved the mean residence time (MRT) and the elimination half-life ( t 1/2 ) in comparison to the co/w emulsion. The clearance of 3 H-dexamethasone from the co/so emulsions at the injection site was also slower and at 4.0 h post-injection the amount of drug remaining in the muscle was found to be eight times higher than with the co/w emulsions. For both formulations, a high uptake of 3 H-dexamethasone was identified in the liver and kidneys whereas smaller amounts were found in other tissues. Non-aqueous emulsions could be considered as depot formulations for sustained release drug delivery, but further studies on the choice of the continuous phase are necessary to optimize effects.

To evaluate the importance of accidental intramuscular injection of NPH insulin, we measured disappearance rates of 125I-labeled NPH insulin (Protaphane) from subcutaneous and intramuscular injection sites in the thighs of 11 insulin-dependent diabetes mellitus patients. Both subcutaneous and intramuscular absorption rates were measured four times in each patient. NPH insulin was absorbed much faster when given intramuscularly than when given subcutaneously (T50% = 5.3 vs. 10.3 h, P < 0.0001). The intrapatient (day-to-day) coefficient of variation (C.V.) of T50% values (C.V. T50%) for subcutaneously injected NPH insulin in this study, where all injections were guided by ultrasound determination of the subcutaneous fat layer, was 18.4%. Intrapatient variation of absorption was significantly lower for subcutaneously than intramuscularly injected NPH insulin (C.V. T50% = 18.4 vs. 29.8%, P < 0.01) and was also lower than interpatient variation for subcutaneously injected insulin (C.V. T50% = 18.4 vs. 50%, P < 0.0001). The faster absorption rate and shorter duration of action, together with the higher day-to-day variation in absorption, led us to conclude that intramuscular injection of NPH insulin should be avoided.

Effect of potassium ion on the intramuscular absorption of some drugs has been examined using the rat thigh muscle clearance method. In the presence of K+ (

Oily solutions of various kind of drugs were injected into the hind leg of rats and the intramuscular absorption was investigated by the local clearance method. The intramuscular absorption of drugs having moderate lipid solubility was more rapid than that of the oily solvent itself and proceeded by the apparent first-order process. Apparent absorption rate constants were affected mainly by injection volume and by the physicochemical properties of drugs and oily solvents. The kinetic results are also consistent with a postulate that the drug was mainly absorbed after being transferred from the oily phase to the aqueous phase, and a fairly good correlationship between partition coefficient and the apparent absorption rate constant was obtained. In the case of drugs having extremely high partition coefficient, the absorption rates were very slow, for which the solubility of the drugs in the tissue fluid appeared to be a critical factor.

The kinetics of the absorption and elimination of pralidoxime chloride were investigated in the dog. Similar apparent elimination rate constants were obtained after intravenous, intramuscular, and oral administration. Although oral absorption occurred slowly, intramuscular absorption proceeded rapidly. With in situ techniques, it was found that no absorption occurred from the isolated stomach and duodenum but that absorption did take place from the jejunum and ileum.

The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2-3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with and initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90-155 min). The mean total plasma clearance was 11.0 ml kg-1 min-1, and the volume of distribution (Vd beta) was 1847.6 ml kg-1. Individual t1/2 beta showed a positive linear correlation with the individual Vd beta. The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3-60.8%).

Injection depth is an important parameter influencing absorption rate after intramuscular injection. A too shallow injection will, especially in the gluteal region, only reach the subcutaneous fat layer. This fat layer appears to exert a retarding effect on lipophilic drugs, which is moreover dependent on formulation factors. A cohesive mechanistic description of the variables and their interrelationships does not exist. From a review study on the relevant information it appears that the mean absorption times of drugs in aqueous or oily suspension i.m. injected is longer (weeks to months) than of drugs in solution (minutes to hours, incidentally weeks, dependent on the lipophilicity of the drug). The injection depth is an important variable since the mean absorption times are considerably longer when the drug is shallowly injected in the adipose layer. In intramuscular injection kinetics the following steps are considered to be important (in hierachical sequence): dissolution rate, solvent supply (vascularisation or perfusion), phase transfer and diffusion to the vascular system, all of them more or less susceptible to formulation, physiological variables and injection depth (in fat or muscular tissue). Dissolution and solvent supply are associated with zero order-, phase transfer and diffusion processes with first order release and absorption kinetics. In general a “mixed” order appearance in the circulation will result from a more complicated situation. After application to mucosal membranes such as buccal and vaginal walls many lipophilic drugs appear to show a depot effect resulting in larger mean absorption times (the order of magnitude is hours) than hydrophilic drugs. A similar phenomenon is seen in the intramuscular absorption. The differences can be explained by the nature of the retaining bonds and differences in histological structure. It can be concluded that the subcutaneous adipose layer has important retarding effects on the absorption of drugs which are intentionally or otherwise injected in the adipose layer.

The effects of the polysorbates on the intramuscular absorption of water-soluble, micelle-free drugs were investigated in the rat. The presence of a low concentration of the polysorbates caused a pronounced decrease in the absorption rates of drugs, and the reduction was reflected in their plasma levels. Absorption rates of a drug in the muscle were dependent on the concentration rather than on the absolute amount of the surfactant. The delayed clearance seemed to be operative in various drugs and was caused by the polysorbates per se—not by the hydrolysis products.

An attempt was made to use liposomes as a carrier intended for prolonged intramuscular absorption of highly water-soluble drugs. 131I-Insulin, 14C-sucrose, 14C-inulin, and 14C-cefazolin sodium, a new derivative of cepharosporin antibiotics, were chosen as model compounds. These model drugs were dissolved in pH 7.0 buffer solution and entrapped in liposomes composed of various ratios of phosphatidyl choline, cholesterol, and dicetylphosphate. After injection in the form of such liposomal suspensions, clearance of model drugs from the intramuscular injection site was delayed to a considerable extent in comparison with the control aqueous buffer injections. It was observed that the larger the amount of cholesterol incorporation into liposomes were, the slower the drug absorption became. Although the intramuscular absorption of the drugs from the rat thigh muscle was delayed by their entrapment in liposomes, extent of the prolongation was less than that expected from their in vitro release characteristics determined by dialysis experiments. Physical stability of liposomes containing 14C-cefazolin sodium was tested in the presence of serum and muscle homogenate. It appears that liposomes are gradually hydrolysed or affected by serum thereby losing their integrity and releasing the entrapped drugs.

1. Glycopyrronium was evaluated by intramuscular, intravenous and oral routes in six adult volunteers for its efficacy as an antisialogogue as also for its action on other aspects of cholinergic activity. 2. It was found to be an effective antisialogogue of long duration of action by all three routes. When given orally the effects were delayed in onset and persisted for too long. Intramuscular and intravenous routes were useful. The intramuscular absorption of the drug is rapid and consistent. 3. Sweat gland activity was affected in a similar fashion but less consistently and other parameters were mostly unaffected. 4. Glycopyrronium 0.2 mg intramuscularly was found to be the optimal dose. Larger doses produced subjective discomfort out of proportion to a further reduction in salivary secretion. 5. Intravenous administration causes no changes in cardiovascular stability.

The pediatric patient is a unique individual who undergoes continual physiologic change from the time of conception through adolescence. The pharmacokinetics of therapeutic agents are influenced by physiologic changes that ultimately affect drug therapy. The gastric absorption of many therapeutic agents is altered by changes in gastric pH, gastric emptying, intestinal motility, biliary function, pancreatic function, and regional blood flow. Intramuscular absorption is erratic and unpredictable because of reduced skeletal muscle mass, alterations in regional blood flow, and physical activity. Percutaneous absorption is increased in the neonate due to increased water content and decreased thickness of the stratum corneum. The distribution of many therapeutic agents is increased in the neonate and infant because of an increase in extracellular fluid and total body water, alterations in tissue binding, and decreased plasma protein binding. The metabolic capacity and elimination processes of the newborn are greatly reduced compared to the adult; hepatic function is approximately one-half that of adults and renal elimination is similarly reduced. Hepatic function in the infant and young child may actually exceed that in the adult due to the increase in hepatic metabolic surface area to body weight ratio. Renal function matures relatively quickly in the neonate and approaches adult drug renal elimination rates within the first year of life. There is a lack of clinical research that defines therapeutic guidelines in the pediatric patient for specific drugs. However, an understanding of these physiologic changes that take place during growth and development in the pediatric patient will facilitate optimal drug therapy in this patient population. Following the initiation of drug therapy, the continued physiologic changes taking place in the pediatric patient necessitate continual therapeutic drug monitoring and periodic dosage adjustments. These special considerations challenge and enhance the responsibility of the pharmacist as a key member in assuming safe and effective pediatric drug therapy.

The mechanism of the inhibition caused by polysorbate 80 on the intramuscular absorption of water-soluble drugs was studied. It was found that the absorption pattern of isonicotinamide was different from that of polysorbate 80. The inhibition of the absorption requires the existence of polysorbate 80 at the site of injection. Histological studies showed that there is no correlation between the inhibition in absorption and the local effect of polysorbate 80 which was found to cause some inflammation at the site of injection. The influence of polysorbate 80 on the capillary permeability was investigated. This was done by intravenous pre-administration of polysorbate 80, sympatholytic agent or conjugated estrogen. No difference in the intramuscular absorption of the tested drugs in the presence or absence of polysorbate 80, whether the animals were pretreated or not, could be demonstrated. Therefore, the inhibition in the intramuscular absorption of these drugs could not be attributed to a direct nor indirect effect of polysorbate 80 on the capillary walls. It was suggested that the permeation of drug through the intercellular spaces of muscle fibers and connective tissues is the more dominant process.

Various chemicals or mixtures of chemicals were tested as vehicle for a reliable parenteral application of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to experimental animals. Great differences were observed in speed of absorption following subcutaneous or intramuscular absorption of 14 C-TCDD. The best results were obtained with subcutaneous TCDD injection using a mixture of toluene/DMSO (1 + 2) as vehicle: 3 and 5 days after treatment the percentage of administered dose remaining at the injection site was about 10 and 2%, respectively.

The mechanism of the absorption inhibitory effect of surfactants on the intramuscular absorption of drugs was investigated. The following observations were demonstrated. 1) All surfactants used in this study whether nonionic or ionic caused solubilization of muscle protein. A good correlation between the solubilization of muscle protein and the absorption inhibitory effect was also found except in the case of the nonionic surfactant HCO-120. 2) The effect of hyaluronidase in the absence or presence of various concentrations of polysorbate 80 on the intramuscular absorption of drugs of different molecular weight was examined. The coexistence of hyaluronidase and polysorbate 80 greatly affected the absorption of drugs. This was depending upon the molecular size of diffused drug and the concentration of surfactant. It was found that increasing the concentrations of polysorbate 80 in the presence of hyaluronidase was accompanied by an inhibition in the absorption of isonicotinamide and abolishment of the accelerating effect of hyaluronidase on the absorption of 14C-sucrose, but it could not show any effect on the absorption of 14C-inulin. 3) The permeability coefficient of gelatin-sodium chondroitin sulfate mixed membrane in the presence of polysorbate 80 was decreased significantly. From these results, it can be concluded that the surfactants interacted with proteins and mucopolysaccharides which are the main components of connective tissue, consequently the intramuscular absorption of drugs was extremely inhibited.

The rates of absorption of a variety of compounds from the tibialis anterior muscle of the rat were determined. The substances studied were aqueous solutions of isotopically labeled benzylpenicillin, hexamethonium, glucose, ouabain, urea and water. The disappearance of the radioactivity from muscle was found to be exponential with time and to be described by a single rate constant. The rates were very similar and averaged 0.159/min. The absorption rates of the various substances (molecular weights 20–585) did not appear to vary with their diffusion coefficients but were affected by vasoactive substances. The results suggest that blood flow rather than diffusion is the rate limiting step for absorption from muscle.

Biopharmaceutical factors of the formulation of injections such as the effect of buffer components, osmotic pressure, and pH of injection solutions were studied using the rat thigh muscle clearance method and in vitro diffusion experiment using muscle slice. 1) It has been shown that the intramuscular absorption of isonicotinamide, a model neutral drug, was hardly affected at all by the buffer components and that of isonicotinic acid, a model anionic drug, was independent for buffer components except potassium ion. 2) Change of the absorption patterns of isonicotinic acid and isonicotinamide due to osmotic pressure of injection solutions was interpreted in terms of a nonspecific, reversible change in the muscle. 3) It was also shown that remarkable reduction of the rate of absorption from acidic solutions was closely related to the irreversible functional change caused by morphological damage.

The effect of ethanol on the intramuscular absorption of water-soluble drugs from the rat thigh muscle was investigated. The presence of ethanol caused a pronounced decrease in the absorption rate of drugs, and the reduction was reflected by the decrease in plasma concentrations. It was also found that the absorption rate of drugs from the site of injection depends mainly on the concentration rather than the absolute amount of ethanol. A direct relationship between the relative viscosity of the injectable solution and the inhibitory absorption was demonstrated at lower concentrations of ethanol, but not at higher concentration. This shows that the inhibitory absorption effect of ethanol cannot be adequately explained by simple physicochemical factors, such as viscosity, but the existence of other factors must be acting. A constant intravenous infusion of ethanol showed no effect on the intramuscular absorption of drug. Furthermore, ethanol did not significantly change the permeability of the isolated mesentery to drug molecules. On the other hand, the connective tissue permeability was significantly decreased by the presence of ethanol and had a good correlation to the inhibitory effect of ethanol on the intramuscular absorption of drugs. From these observations, it can be concluded that the mechanism of the inhibitory effect of ethanol is mainly due to its influence on the extracellular spaces and the connective tissues permeability.

Six male and six female volunteers each received a single intramuscular injection of cephradine, a new cephalosporin antibiotic, once weekly for 3 consecutive weeks. The drug was injected into the gluteus maximus, vastus lateralis, or deltoid muscle groups. Injection sites were rotated each week so that each subject received an injection into each muscle. Pharmacokinetic evaluation of serum concentrations and urinary excretion data indicated a sex difference with respect to the rate and extent of cephradine absorption from the three injection sites. Smaller areas under the curve and absorption rate constants were observed for females after injection into each muscle group. The most striking difference was observed when cephradine was injected into the gluteus maximus muscle, where the exponential function describing the alpha phase was observed to be 1.16 +/- 0.17 hr(-1) for females and 2.70 +/- 0.34 hr(-1) for males. Total area under the mean serum concentration-time curves, mean time to peak, and peak height parameters consistent with the slower rate of absorption and lesser bioavailability in females were observed. These results show that the vastus lateralis or deltoid muscle groups are preferable to the gluteus maximus as injection sites because of the more rapid rates of drug absorption from those muscles.

The absorption characteristics and kinetics of practically water-insoluble drugs following intramuscular injection of their aqueous suspensions were investigated by the local clearance method in the m. gastrocnemius of the rat. The plot of the cube root of the residual fraction of the drug in the injection site versus time gave a good straight line. Between the absorption rate constant (j) and the initial drug concentration (C0) or injection volume (V0), the relationship jvC0g V0h was observed experimentally (g=-0.55 and h=-0.32). Comparison of j values among various compounds having different solubilities in saline (Cs') but similar colloidal properties (particle size distribution and sedimentation volume) showed that a plot of log j against log Cs'gave a linear relationship with a slope close to 0.5. The absorption rate constant (j) increased with decreasing particle size on condition that the other colloidal properties changed little. This increase was remarkable in the region of mean particle diameter (Dss) less than 2-3 μm, while it was gradual or slight in the region above this. The results could be explained by a kinetic model in which the dissolution (diffusion) process from the particle agglomerate formed by injection was assumed to be a rate-limiting step for the drug absorption. The effect of the type or concentration of the macromolecular dispersing agent was also examined in detail.

The intramuscular absorption characteristics and kinetics of practically water-insoluble drugs, which were solubilized in water with nonionic surfactants, were studied by the local clearance method in the m. gastrocnemius of the intact rat. The solubilized drugs were absorbed approximately according to 1st order kinetics. Their absorption rates were controlled by the distribution coefficient (K, micellar phase/water phase) as well as the injection volume (V0) and the surfactant concentration (Cs0), but depended little on the vehicle viscosity under the present experimental conditions. A model, based on the assumptions that the drug is distributed instantaneously between the micellar and water phases in the depot and that the drug molecules in both phases are transported into the vascular systems by diffusion at different rates, was proposed to account for the kinetic features of the process. It predicted that the plot of the 1st order absorption rate constant (k) against 1/Cso or 1/K would be approximately linear when the injection volume was fixed, the surfactant absorption was very slow, and the contribution of the drug entrapped in micelles to the absorption was much smaller than that of the free drug. The experimental results agreed well with these predictions, except for the systems of very high surfactant concentration. Experimentally, k was inversely proportional to V01/3 and this was explained reasonably by the model.