PO Routes Research Articles

Disposition kinetics and tissue residues of tilmicosin following intravenous, subcutaneous, single and multiple oral dosing in geese (Anser anser domesticus)

AbstractTilmicosin (TMC), a semi‐synthetic macrolide antibiotic, is widely used in veterinary medicine due to its broad‐spectrum, bacteriostatic properties. Frequently administered in various birds species, it is likely used off‐label in geese as well. The study sought to investigate TMC's pharmacokinetics, tissue residues, in geese through in vivo experiments. The study involved longitudinal open studies on 15 healthy adult males, with three phases separated by one‐month washout periods. Geese were administered TMC through intravenous (IV, 5 mg/kg), subcutaneous (SC, 10 mg/kg), and oral (PO, 25 mg/kg for five consecutive days) routes, with blood samples drawn at specific intervals. Tissue samples were also collected for subsequent analysis at pre‐assigned times. TMC in goose plasma was quantified by a fully validated HPLC method. Plasma concentrations were quantified up to 4 hr for the PO and IV routes, and up to 10 hr in the SC route. Significant variations in bioavailability were observed between SC (87%) and PO (4%) routes. The body extraction ratio was low at 0.03, suggesting minimal ability of the liver and kidneys to eliminate TMC. Multiple oral doses showed no plasma accumulation, but tissue data revealed extensive distribution and prolonged residence, up to 120 h, suggesting a sustained therapeutic effect despite the brief plasma half‐life. Regarding the multiple PO doses, provisional withdrawal times of 6, 7.5, and 8 days were suggested for the liver, muscles, and kidneys, respectively, according to the MRL set for these matrices in chickens by EMA. In conclusion, while the practical oral administration is discouraged at the population level, SC administration of TMC may be appropriate for geese, albeit impractical for flock therapy.

Early Stage Preclinical Formulation Strategies to Alter the Pharmacokinetic Profile of Two Small Molecule Therapeutics.

Early stage chemical development presents numerous challenges, and achieving a functional balance is a major hurdle, with many early compounds not meeting the clinical requirements for advancement benchmarks due to issues like poor oral bioavailability. There is a need to develop strategies for achieving the desired systemic concentration for these compounds. This will enable further evaluation of the biological response upon a compound-target interaction, providing deeper insight into the postulated biological pathways. Our study elucidates alternative drug delivery paradigms by comparing formulation strategies across oral (PO), intraperitoneal (IP), subcutaneous (SC), and intravenous (IV) routes. While each modality boasts its own set of merits and constraints, it is the drug's formulation that crucially influences its pharmacokinetic (PK) trajectory and the maintenance of its therapeutic levels. Our examination of model compounds G7883 and G6893 highlighted their distinct physio-chemical attributes. By harnessing varied formulation methods, we sought to fine-tune their PK profiles. PK studies showcased G7883's extended half-life using an SC oil formulation, resulting in a 4.5-fold and 2.5-fold enhancement compared with the IP and PO routes, respectively. In contrast, with G6893, we achieved a prolonged systemic coverage time above the desired target concentration through a different approach using an IV infusion pump. These outcomes underscore the need for tailored formulation strategies, which are dictated by the compound's innate properties, to reach the optimal in vivo systemic concentrations. Prioritizing formulation and delivery optimization early on is pivotal for effective systemic uptake, thereby facilitating a deeper understanding of biological pathways and expediting the overall clinical drug development timeline.

Pharmacokinetics of meloxicam in pre-ruminant calves after intravenous, oral, and subcutaneous administration.

Meloxicam is routinely used for pain alleviation in pre-ruminant calves during husbandry procedures. The pharmacokinetics of a single dose (0.5 mg/kg) of meloxicam was investigated after intravenous (IV), subcutaneous (SC), and oral (PO) administration in 30 pre-ruminant calves. Each group included 10 calves. Oral meloxicam was administered at least 1 h after feeding. Plasma samples were collected for up to 168 h, and the meloxicam concentration was analysed with liquid chromatography and mass spectrometry, followed by a noncompartmental pharmacokinetic analysis. The maximum meloxicam concentrations in plasma were 1.91 ± 0.27 μg/mL and 1.77 ± 0.16 μg/mL after SC and PO routes, respectively. The time of maximum concentration was 7.6 ± 2.8 h after SC and 10.0 ± 5.7 h after PO administration. The approximate bioavailability of meloxicam was 97% for SC and PO routes. The elimination half-lives were 79.2 ± 12.4, 84.6 ± 24.8, and 84.8 ± 22.3 h after IV, SC, and PO routes, respectively. The results suggest that the therapeutic meloxicam concentrations in plasma that are required for pain relief in other species, such as horses, may be maintained for several days following a single dose (0.5 mg/kg) administered IV, SC, or PO in calves.

A Network Meta-Analysis of Intravenous Versus Oral Acetaminophen for Patent Ductus Arteriosus.

The use of acetaminophen to close a PDA in preterm infants is increasing; however, the most effective route of administration is not yet known. This network meta-analysis compares the efficacy of IV versus PO routes of acetaminophen administration on clinical outcomes related to the presence of a PDA in preterm neonates. Medline, Embase, Cochrane Central Register of Controlled Trials, Embase, Web of Science, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched from inception to October 2020. A total 21 randomized controlled trials in neonates less than 37weeks at birth, comparing oral or intravenously administered acetaminophen to close a PDA based on study criteria were included. Two authors extracted data independently and in duplicate. All outcomes were binary, and a frequentist network meta-analysis was performed. After one or two courses, both PO and IV acetaminophen were efficacious in closing a PDA with oral ranking higher than IV (low confidence). Neither medication was better than no treatment for secondary outcomes of NEC or BPD (moderate and low confidence respectively). We did not test the rectal route of acetaminophen administration and cannot make generalized statements. This study suggests oral acetaminophen increases the odds of being able to close a PDA in preterm neonates when compared to IV acetaminophen.

Plasma and muscle tissue disposition of enrofloxacin in Nile tilapia (Oreochromis niloticus) after intravascular, intraperitoneal, and oral administrations

The aim of the study was to investigate the plasma and muscle pharmacokinetic of enrofloxacin (ENR) and its active metabolite ciprofloxacin (CIP) in Nile tilapia (Oreochromis niloticus) following single intravascular (IV), intraperitoneal (IP), or oral (PO) administration at 30 ± 1 °C. In this study, 234 healthy Nile tilapia (120–150 g) were used. The fish received a single IV, IP, or PO treatment of ENR at a dose of 10 mg/kg. The plasma and muscle tissue concentrations of ENR and CIP were measured using high–performance liquid chromatography with fluorescence detection and were evaluated using non–compartmental analysis. The elimination half–life, volume of distribution at steady state, and total body clearance of ENR were 21.7 h, 2.69 L/kg, and 0.09 L/h/kg, respectively. The peak plasma concentrations of ENR after IP or PO administration were 6.11 and 4.21 µg/mL at 0.25 and 2 h, respectively. The bioavailability of ENR for IP or PO routes was 78% and 86%, respectively. AUC(0–120)muscle/AUC(0–120)plasma ratios following the IV, IP, or PO administrations were 1.43, 1.49, and 1.07, respectively. CIP was detected after all routes, but the AUC0–last ratios of CIP to ENR were <1.0% for plasma and muscle. ENR was detected up to 120 h following the IV, IP, or PO administrations. The long residence time of ENR after single IV, IP, or PO administration ensured the plasma concentration was ≥1 × MIC for bacteria with threshold MIC values of 0.92, 0.72, and 0.80 μg/mL over the whole 120 h observed. However, further studies are necessary to determine the optimum pharmacokinetic/pharmacodynamics data of ENR for the treatment of infections caused by susceptible bacteria in tilapia.

Pharmacokinetics of cefquinome in rainbow trout (Oncorhynchus mykiss) after intravascular, intraperitoneal, and oral administrations.

This study aimed to determine the pharmacokinetics and bioavailability of cefquinome in rainbow trout (Oncorhynchus mykiss) following intravascular (IV), intraperitoneal (IP), and oral (PO) administrations at 14 ± 1°C. In this study, three hundred and six clinically healthy rainbow trout (110-140 g) were used. The fish received single IV, IP, and PO injections of cefquinome at 10mg/kg dose. The plasma concentrations of cefquinome were measured using HPLC-UV and were evaluated using non-compartmental analysis. Cefquinome was measured up to 96 h for PO route and 144 h for IV and IP routes in plasma. Following IV administration, t1/2ʎz , ClT , and Vdss were 18.85 h, 0.037 L/h/kg, and 0.84 L/kg, respectively. The Cmax of IP and PO routes was 9.75 and 1.64 μg/ml, respectively. The bioavailability following IP and PO administrations was 59.46% and 12.33%, respectively. Cefquinome at 10mg/kg dose may maintain T > MIC above 40% at 72 and 96 h intervals, respectively, following the IP and IV routes for bacteria with MIC values of ≤2μg/ml and at 24 h intervals following the PO route for bacteria with MIC value of ≤0.75 μg/ml. However, further studies are needed to determine in vitro and in vivo antibacterial efficacy and multiple dosage regimens of cefquinome against pathogens isolated from rainbow trout.

Pharmacokinetics and bioavailability of carprofen in sheep.

The aim of this study was to determine the pharmacokinetics and bioavailability of carprofen in sheep following single intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations of a parenteral formulation at a dose of 4mg/kg. A total of eight sheep were used for the investigation. The study comprised four periods, according to a crossover design with a 21-day washout period between treatments. Plasma concentrations of carprofen were measured using HPLC-UV. Pharmacokinetic parameters were estimated by non-compartmental model analysis. Following IV administration, t1/2ʎz , ClT , and Vdss were 43.36 h, 1.98 ml/h/kg, and 121.36 ml/kg, respectively. The Cmax(obs) was 26.57 mg/ml for the IM, 23.76 mg/ml for the SC, and 15.90 mg/ml for the PO. The bioavailability following IM, SC, and PO administrations was 75.47%, 82.00%, and 62.51%, respectively. Plasma creatine kinase activity increased significantly at 3, 6, and 12 h following IM administration of carprofen. Despite differences in plasma concentrations and bioavailability among administration routes, carprofen at 4mg/kg dose may provide the plasma concentration (>1.5μg/ml) needed for analgesic effect during 144 h in all routes. However, because of the slow absorption rate after SC and PO routes, the IV route may be preferred primarily for the rapid onset in the analgesic and anti-inflammatory effect of carprofen in sheep. Despite the favorable kinetics, the muscle damage caused by IM injection limits use of carprofen via IM route.

Determination of pharmacokinetic parameters and tissue distribution characters of enrofloxacin and its metabolite ciprofloxacin in Procambarus clarkii after two routes of administration

Enrofloxacin (ENR) is widely used for treatment and prevention of bacterial pathogen infections in aquatic animals. However, limited knowledge on kinetic disposal process of ENR in crayfish (Procambrus clarkii). Therefore, the objective of this study was to explore the pharmacokinetics (PK) and tissue distribution regularities of ENR and its predominate metabolite, ciprofloxian (CIP), in crayfish following oral (PO) and intramuscular (IM) administrations. ENR and CIP concentrations in crayfish hemolymph and tissues were determined using ultra performance liquid chromatography coupled to fluorescence detection (UPLC-FLR). PK parameters of targets in hemolymph and tissues were calculated using WinNolin software based on the non-compartmental analysis. Comparative PK parameters in hemolymph showed that higher absorption and longer elimination half-life following IM route than PO treatment. For tissue distribution, high concentrations of ENR and CIP were found in hepatopancreas, and ENR and CIP levels in tissues after IM administration were higher than PO administration. The AUC0-∞ ratios of CIP and ENR in crayfish following PO and IM routes were only 1.25% and 3.56% (hemolymph), 0.71% and 6.89% (muscle), 1.03% and 1.75% (hepatopancreas), 0.65% and 6.46% (gill), respectively, and it indicated that crayfish has a low ability to transform ENR to CIP. ENR regimen suggested against susceptible strains with the minimum inhibition concentration (MIC) below 0.72 μg/mL (IM) and 0.50 μg/mL (PO) based on the values of Cmax/MIC > 8 and AUC/MIC > 125. It could serve as reference data for ENR use in crayfish and provide valuable information for the better utilization of ENR in aquatic animals.

The effect of per os vs subcutaneous 123 iodine administration on percentage thyroidal radioactive iodine uptake in normal cats.

BackgroundHistorical and recent literature disagree on whether a higher PO 131I dosage, compared to IV or SC routes, is required for successful resolution of spontaneous hyperthyroidism in cats, necessitating investigation into the effect of PO and injectable radioactive iodine administration on % thyroidal radioactive iodine uptake (RAIU).Hypothesis/ObjectivesTo investigate the effect of PO and SC routes of 123I administration on paired % thyroidal RAIU in euthyroid cats. Specifically, a 1.5‐fold difference (50% relative change) was hypothesized, which in absolute terms can be expressed as a 3.25% increase in the mean %RAIU of 7.04% after PO 123I administration to 10.56% after SC dosing.AnimalsSeven healthy euthyroid teaching‐research colony cats.MethodsA randomized, radiologist‐blinded crossover study comparing %RAIU after PO and SC 123I administration.ResultsPercentage thyroidal RAIU values (mean ± SD; 95% confidence interval) after PO (4.81% ± 1.63%; 3.30%‐6.23%) and SC (5.26% ± 2.43%; 3.01%‐7.51%) 123I administration were associated with a median within‐pair absolute difference of 0.2% (range: min, 0.1%‐max, 4.9%). Statistical significance was not achieved (P = .45). Six of 7 cats had a within‐pair absolute difference of 0.1% to 0.9% (relative change of 4%‐20%), but a single outlier cat had a within‐pair absolute difference of 4.9% (relative change of 108%).Conclusions and Clinical ImportanceThis study did not detect an effect of 123I administration route on paired % thyroidal RAIU in euthyroid cats. However, a type 2 statistical error due to small sample size is possible.

Disposition of cyadox in domesticated cats following oral, intramuscular, and intravenous administration.

Cyadox (CYX) is a synthetic antibacterial agent of quinoxaline with much lower toxic effects. A safety criterion of CYX for clinical use was established by studying the pharmacokinetics and metabolism of CYX after oral (PO), intramuscular (IM), and intravenous (IV) administration. CYX was administered in six domesticated cats (three males and three females) by PO (40mg/kg.b.w.), IM (10mg/kg.b.w.), and IV (10mg/kg.b.w.) routes in a crossover pattern. Highly sensitive liquid chromatography with ultraviolet detection (HPLC-UV) method was developed for detection of CYX and its metabolites present in plasma, urine, and feces. The bioavailability of CYX after PO and IM routes was 4.37% and 84.4%. The area under curves (AUC), mean resident time (MRT), and clearance (CL) of CYX and its metabolites revealed that CYX quickly metabolized into its metabolites. The total recovery of CYX and its main metabolites was >60% after each route. PO delivery suggesting first pass effect in cats that might make this route suitable for intestinal infection and IM injection could be better choice for systemic infections. Less ability of glucuronidation did not show any impact on CYX metabolism. The findings of present study provide detailed information for evaluation of CYX.

Pharmacokinetics and Biodistribution of Rhopalurus junceus Scorpion Venom in Tumor-Bearing Mice after Intravenous and Oral Administration

Rhopalurus junceus scorpion venom has shown potential for anticancer treatment. However, there are no scientific evidence about venom pharmacokinetic (PK) and biodistribution (BD) in tumor-bearing mice. 131I-labeled venom was administrated by intravenous (IV) and oral (PO) routes at the single dose of 12.5 mg/kg. Mice were sacrificed and blood samples, major organs, and tumor were taken at 10, 20, 40, 90, 180, 300, 480, and 1440 min. For IV route, maximum peak concentration (Cmax), elimination half-lives, total body clearance (CL), distribution volume (Vd), mean residence time (MRT), and area under curve (AUC) were 21.77 ± 2.45 %Dosis•h/mL, 12.65 ± 2.1 h, 4.59 ± 0.23 mL/h, 83.80 ± 12 mL, 12.49 ± 2.71 h, and 21.77 ± 2.45 %Dosis•h/mL, respectively. For PO route, they were 0.60 ± 0.07 %Dosis•h/mL, 9.33 ± 1.35 h, 36.94 ± 4.01 mL/h, 497.33 ± 30 mL, 12.40 ± 1.87 h, and 6.89 ± 1.18 %Dosis•h/mL, respectively. PK parameters (Cmax, CL, Vd, and AUC) showed significant differences between IV and PO routes. Bioavailability was 31.6 ± 4% for PO dose. Kidney, stomach, liver, and lung for IV and stomach, kidney, spleen, and lung for PO routes showed the major uptakes for 131I-labeled venom. In tumor tissue, after the maximum uptake for both routes, there was a consistent behavior of radioactivity respect to the major organs during the first 480 min. The PK and BD of R. junceus venom in mice depend on the administration route. These data represent a starting point for future experiments with this scorpion venom in experimental models of cancer.

Pharmacokinetics and Biodistribution of Rhopalurus junceus Scorpion Venom in Tumor-Bearing Mice after Intravenous and Oral Administration

Introduction:Rhopalurus junceus scorpion venom has shown potential for anticancer treatment. However, there are no scientific evidence about venom pharmacokinetic (PK) and biodistribution (BD) in tumor-bearing mice.Methods:131I-labeled venom was administrated by intravenous (IV) and oral (PO) routes at the single dose of 12.5 mg/kg. Mice were sacrificed and blood samples, major organs, and tumor were taken at 10, 20, 40, 90, 180, 300, 480, and 1440 min.Results:For IV route, maximum peak concentration (Cmax), elimination half-lives, total body clearance (CL), distribution volume (Vd), mean residence time (MRT), and area under curve (AUC) were 21.77 ± 2.45 %Dosis·h/mL, 12.65 ± 2.1 h, 4.59 ± 0.23 mL/h, 83.80 ± 12 mL, 12.49 ± 2.71 h, and 21.77 ± 2.45 %Dosis·h/mL, respectively. For PO route, they were 0.60 ± 0.07 %Dosis·h/mL, 9.33 ± 1.35 h, 36.94 ± 4.01 mL/h, 497.33 ± 30 mL, 12.40 ± 1.87 h, and 6.89 ± 1.18 %Dosis·h/mL, respectively. PK parameters (Cmax, CL, Vd, and AUC) showed significant differences between IV and PO routes. Bioavailability was 31.6 ± 4% for PO dose. Kidney, stomach, liver, and lung for IV and stomach, kidney, spleen, and lung for PO routes showed the major uptakes for 131I-labeled venom. In tumor tissue, after the maximum uptake for both routes, there was a consistent behavior of radioactivity respect to the major organs during the first 480 min.Conclusion:The PK and BD of R. junceus venom in mice depend on the administration route. These data represent a starting point for future experiments with this scorpion venom in experimental models of cancer.

Pharmacokinetics of tapentadol in laying hens and its residues in eggs after multiple oral dose administration

ABSTRACT1. The aim of the study was to evaluate the pharmacokinetics (PKs) of tapentadol (TAP), a novel opioid analgesic, in laying hens after intravenous (IV) and oral (PO) administration and to quantify the concentrations of TAP residues in eggs.2. Twenty healthy laying hens were divided into three groups: A (n = 6), B (n = 6) and C (n = 8). The study was conducted in two phases. Groups A and B received TAP by IV and PO routes at the dose of 1 and 5 mg/kg, respectively.3. No visible adverse effects were observed after administration of the drug. TAP plasma concentrations were detectable up to 4 h following administration. Following IV administration, TAP plasma concentrations were only higher than the minimal effective concentration (148 ng/ml) reported for humans for 1 h. After single PO administration, plasma concentrations of TAP would not conform to software algorithms and the PK parameters were not calculated. TAP concentration following multiple PO doses at 5 mg/kg for 5 d was found to be higher and more persistent (12 h vs. 7 h) in yolk compared with albumen.4. This is the first PK study on the novel atypical opioid TAP in laying hens. Further studies are required to investigate the analgesic efficacy and actual effective plasma concentration of TAP in this species.

Comparative effects of Mitragyna speciosa extract, mitragynine, and opioid agonists on thermal nociception in rats

This study sought to compare the effects of Mitragyna speciosa (Korth.) Havil. extract, alkaloids fraction, and mitragynine, a μ-opioid receptor agonist, to that of morphine and oxycodone in a test of thermal nociception. In Experiment 1, male Sprague–Dawley rats were administered test articles intraperitoneally (IP) 30min prior to testing to compare the effects of M. speciosa articles to opioid reference compounds on the hotplate assay. Test articles were vehicle, 10mg/kg morphine, 3mg/kg oxycodone, 300mg/kg M. speciosa extract, 75mg/kg M. speciosa alkaloids fraction, or 30mg/kg mitragynine. To mirror consumer usage, Experiment 2 sought to determine whether M. speciosa articles retained their biological activity when given orally (PO). Test articles were vehicle, 6mg/kg oxycodone, 300mg/kg M. speciosa extract, or 100mg/kg mitragynine with hotplate tests conducted 30 and 60min after administration. Mitragynine produced antinociceptive effects similar to the reference opioid agonists when administered IP and PO routes. These data suggest that M. speciosa extracts containing significant quantities of mitragynine may warrant consideration for further studies in primate self-administration models to yield insight into the abuse liability of this commercially available product.

Tolerability and Pharmacokinetic Comparison of Oral, Intramuscular, and Intravenous Administration of Levosulpiride After Single and Multiple Dosing in Healthy Chinese Volunteers

PurposeThe aim of this study was to characterize the pharmacokinetic (PK) properties and assess the safety profiles of different formulations of levosulpiride in healthy Chinese volunteers. MethodsLevosulpiride was administered to 42 healthy male and female (1:1) subjects in tablet (PO) and injectable (IM and IV) dosage forms. Blood samples were collected at regular intervals after single and multiple drug administration. The concentration of levosulpiride in plasma was determined by a validated liquid chromatography tandem mass spectrometry method. Noncompartmental analysis was performed to estimate PK parameters. One-way ANOVA was used to test for linearity and assess the effect of sex on the PK properties of the drug. Adverse effects were monitored using investigators’ questionnaires and subjects’ spontaneous reports, vital sign measurements, hematology, clinical chemistry, and electrocardiography. FindingsLevosulpiride exhibited linear pharmacokinetic properties over the dose range of 25 to 100 mg by PO route and 25 to 75 mg by IM route. The corresponding mean AUC0−t increased from 449 to 1443 ng/h/mL and from 2874 to 7559 ng/h/mL, respectively. After repeated PO and IM administration, steady state was reached on day 4 of multiple dosing with accumulation index of 1.8 and on day 2 of multiple dosing with accumulation index of 1.3, respectively. The bioavailability of levosulpiride via IM and PO routes was 96.8% and 23.4%, respectively. No significant differences were observed on PK properties between male and female subjects. More than half (23 of 42 [54.8%]) of healthy volunteers experienced one or more adverse events in total, including constipation, diarrhea, drowsiness, skin rash, and extrapyramidal reactions. ImplicationsThe regimen of 50-mg levosulpiride tablets 3 times daily and 50-mg levosulpiride injection (IM) twice daily provided similar accumulation coefficient, and the former reached steady state much more slowly. The bioavailability of levosulpiride after oral administration was poor and the absorption rate was slower compared with IM administration, which imply delayed clinical efficacy for patients with dyspepsia or neuropsychiatric disorders. On multiple dosing, levosulpiride exhibited poor tolerability with high incidence of adverse reactions. There was no need to adjust administration regimen based on sex. ClinicalTrials.gov Identifier: NCT02481583.

Pharmacokinetic Evaluations of Sulpiride After Intravenous, Intramuscular, and Oral Single-Dose Administration in Jennies (Equus asinus)

Sulpiride is an antipsychotic human drug. It is commonly used to encourage ovulation in noncycling mares and to stimulate lactation in adoptive mares. No pharmacokinetic data are available for donkeys. The aim of this study was to assess the pharmacokinetics profile of sulpiride after intravenous (IV), intramuscular (IM), and oral (PO) administrations in healthy jennies. Animals (n = 6) were treated with sulpiride, 1 mg/kg by IV, IM, and PO routes according to a randomized cross-over design (3 × 3 Latin square). Blood samples (5 mL) were collected at predetermined times and analyzed using a validated high performance liquid chromatography with fluorescence detection method. IV and IM administrations gave similar curves, but they were not bioequivalent. The IM average bioavailability was 73.5%. After PO administration, the drug plasma concentrations were low and consequently both area under the curve and bioavailability (9.4%) were low. This finding could be because of the physicochemical features of the drug. Indeed, considering that sulpiride is a weak base, existing in the ionized form at gastric and physiological pH, it is unsurprising that it is poorly absorbable, especially in equine species whose gastric pH is particularly acidic. In conclusion, injective routes are definitely preferable to PO dosing because of the very low F% via this route.

Acetaminophen (Paracetamol)

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles (hq@palliativedrugs.com).

Analysis and Toxicity of Plain (PMP) and Blended (PMT) Indian Pan Masala (PM).

Betel leaf combined with areca nut is known as betel quid pan masala (PM), and tobacco with areca nut, catechu and lime is pan masala (PMT) blended with gulkhand. These narcotics are popular among young and old individuals. A prima facia chemical analysis and a toxicity assessment of PM in mice were conducted to study the relationship between longtime consumption of PM and health hazards. Chemical analysis of different types of PM was done employing HPLC, GLC, AAS, ES, TLC, GCMS and sequential extraction for PAH, pesticides, metals and minerals, electrolytes, drugs and xenobiotics. Ethanolic PM extracts were tested by IP and PO routes in inbred Swiss mice. PAH, which are known xenobiotics for pre-cancerous lesions, were significantly high (p<0.01) in Rajaniganda and Pan Parag Zarda. Isomers of DDT and BHC, which principally act on nerves and muscles, were also high (p<0.01) in PM. The enhanced metal and mineral content of PM results in massive oral fibrosis. There is a high level of narcotics in PM, especially nicotine, a potentially cancerous agent in the gastrointestinal tract. Experimental studies with different extracts of plain and blended PM in mice fed for 16 and 90 days revealed no effect on blood and organ weights (kidney, heart, spleen and liver), but we did observe attenuated testis. However, in the bone marrow of the mice, chromosomes were most affected in the mice fed PM-Zarda blend for 3 months. The chromosomal abnormalities included ploidy, loss, breaks, gaps, deletions and exchanges in ring chromosomes. The PM caused sperm head anomalies (narrow, blunt, triangular and banana shapes), and the sperm were irregular, amorphous, tailless and rudimentary, with the maximum effect among the groups fed PM for 3 months. Significantly higher levels (p<0.01) of testis glycogen, cholesterol and protein were found. The group fed for 16 days showed no change in red blood corpuscles (RBC), white blood corpuscles (WBC), hemoglobin and erythrocyte sedimentation counts.

Study on BALB/c mice with EV71 infection by diverse inoculation routes

To study the characteristics of EV71 JN200804 strain infection in one-day old BALBI c mjce and to establish a animal model of EV71 infection , and to provide information and technical support for the evaluation of the EV71 vaccine and antiviral medicine. One-day old BALBic mice were infected with EV71 JN200804 strain through oral( PO) ,intracranial(IC) ,intraperitoneal (IP), intramuscular (IM) routes, respectively. All mice were sacrificed at paralysis of hind limbs and collected organs for viral isolation, RT -PCR and pathological examination, and the electrophysiology were detected before sacrifice. All mice infected through IC, IP and IM routes were paralyzed in hind limbs at 4-5 days and died at 7 days about, the hypokinesia and lethargy of mice were observed through PO routes. The viruses could be isolated and detected in the muscle from mice infected through IC, IP and IM routes and in the spinal cord through IC routes by viral isolation and RT-PCR. The neurogenic and myogenic disorders were detected by electromyography. Histopathologically, the varied pathologic changes were observed in the mouse cerebellum , spinal cord , muscle , heart, lung, liver and kidney. EV71 JN200804 strain can infect one-day old BALBI c mice and induce paralysis of hind limbs, its animal infection model may apply to study of EV71 infection pathogenesis and antiviral medicine, and evaluation of the EV71 vaccine.

Pharmacokinetics of Sulpiride After Intravenous, Intramuscular, and Oral Single-Dose Administration in Nurse Mares

Sulpiride (SLP) is an antipsychotic drug used in humans. Although no pharmacokinetic data are available for horses, it is commonly used to encourage ovulation in noncycling mares and to stimulate lactation in adoptive mares. The aim of this study is to assess the pharmacokinetics profile of SLP after intravenous (IV), intramuscular (IM), and oral (PO) administrations in normal horses. Animals (n = 6) were treated with 1 mg/kg SLP, administered by IV, IM, and PO routes according to a randomized crossover design (3 × 3 Latin square). Blood samples (5 mL) were collected at a programmed time and analyzed using a validated with fluorescence detection method. SLP was present at a detectable concentration up to 24 hours postadministration for all routes, except for one animal in the PO group. IV and IM administrations gave similar curves, with an IM average bioavailability of 118.0%. These high values were mainly the result of the profile generated by two horses, in which a secondary concentration peak occurred in the terminal phase of the curve. After PO administration, AUC0-∞, and consequently bioavailability (20.4%), was low. This finding could be owing to the physicochemical features of the drug. Indeed, considering that SLP is a weak base, existing in the ionized form at gastric and physiological pH, it is unsurprising that it is poorly absorbable, especially in horses with a particularly acidic gastric pH. In conclusion, injective routes are definitely preferable to PO dosing because of the low bioavailability using this route.