Dose regimen optimization of cephalothin for surgical prophylaxis against Staphylococcus aureus and coagulase negative staphylococci in dogs by pharmacokinetic/pharmacodynamic modeling.

First generation cephalosporins such cephalothin of cefazolin are indicated for antimicrobial prophylaxis for clean and clean contaminated surgical procedures because its antimicrobial spectrum, relative low toxicity and cost. Anesthesia and surgery could alter the pharmacokinetic behavior of different drugs administered perioperative by many mechanisms that affect distribution, metabolism or excretion processes. Intravenous administration of the antimicrobial within 30 and 60 min before incision is recommended in order to reach therapeutic serum and tissue concentrations and redosing is recommended if the duration of the procedure exceeds two half-life of the antimicrobial. To the author's knowledge there are no pharmacokinetic studies of cephalothin in dogs under anesthesia/surgery conditions. The aim of this study was (1) to evaluate the pharmacokinetics of cephalothin in anesthetized dogs undergoing ovariohysterectomy by a nonlinear mixed-effects model and to determine the effect of anesthesia/surgery and other individual covariates on its pharmacokinetic behavior; (2) to determine the MIC and conduct a pharmacodynamic modeling of time kill curves assay of cephalothin against isolates of Staphylococcus spp. isolated from the skin of dogs; (3) to conduct a PK/PD analysis by integration of the obtained nonlinear mixed-effects models in order to evaluate the antimicrobial effect of changing concentrations on simulated bacterial count; and (4) to determine the PK/PD endpoints and PK/PDco values in order to predict the optimal dose regimen of cephalothin for antimicrobial prophylaxis in dogs. Anesthesia/surgery significantly reduced cephalothin clearance by 18.78%. Based on the results of this study, a cephalothin dose regimen of 25 mg/kg q6h by intravenous administration showed to be effective against Staphylococcus spp. isolates with MIC values ≤2 µg/mL and could be recommended for antimicrobial prophylaxis for clean surgery in healthy dogs.

Prevalence, causes, and clinical course of patients with surgical reintervention due to complications during cesarean section.

OBJECTIVE: The objective of the study is to identify the prevalence, causes, and clinical evolution of patients with surgical reintervention due to complications during cesarean section. MATERIALS AND METHODS: The file of the Toco-Surgical Unit of the Gynecological Obstetrics Hospital No. 3 of the National Medical Center "La Raza" Mexican Institute of Social Security was reviewed to know the total number of patients undergoing cesarean section from January to December 2019 and cases with reintervention due to complications during cesarean section were selected. Their general data, the cause of reintervention, stay in the intensive care unit (ICU), hospital stay, and mortality were studied. The data were analyzed with descriptive statistics using the statistical program SPSS version 20. RESULTS: It was found that 3371 patients underwent cesarean section, of which 1.60% (54 cases) underwent reoperation for the following reasons: Unpacking 27.79%, obstetric hemorrhage 20.37%, bleeding due to uterine atony 20.37%, hysterotomy commissure hematoma 18.52%, uterine infiltration 3.70%, vascular injury 3.70%, bladder injury 3.70%, and colonic injury 1.85%. The ICU stay was 3.79 ± 2.03 days, hospital stay was 13.67 ± 11.16 days, and mortality was 1.85%. CONCLUSION: The prevalence of reintervention was reduced, bleeding was the main cause, and the clinical evolution was satisfactory with low mortality.

OBJETIVO: Identificar la prevalencia, causas y evolución clínica de las pacientes con reintervención quirúrgica por complicaciones durante la cesárea. MATERIAL Y MÉTODOS: Se revisó el archivo de la Unidad de Toco-Quirúrgica del Hospital Ginecobstetricia No. 3 del Centro Médico Nacional "La Raza" Instituto Mexicano del Seguro Social para conocer el total de pacientes sometidas a cesárea desde enero hasta diciembre de 2019 y se seleccionaron los casos con reintervención por complicaciones durante la cesárea. Se estudiaron sus datos generales, la causa de reintervención, estancia en la Unidad de Cuidados Intensivos (UCI), estancia en hospital y la mortalidad. Los datos se analizaron con estadística descriptiva utilizando el programa estadístico SPSS versión 20. RESULTADOS: Se encontró que 3371 pacientes fueron sometidas a cesárea de las cuales 1.60% (54 casos) se reintervinieron por las siguientes causas: desempaquetamiento 27.79%, hemorragia obstétrica 20.37%, sangrado por atonía uterina 20.37%, hematoma de la comisura de histerotomía 18.52%, infiltración uterina 3.70%, lesión vascular 3.70%, lesión vesical 3.70% y lesión colónica 1.85%. La estancia en UCI fue 3.79 ± 2.03 días, estancia en hospital 13.67 ± 11.16 días y mortalidad 1.85%. CONCLUSIÓN: La prevalencia de reintervención fue reducida, el sangrado fue la principal causa y la evolución clínica resultó satisfactoria con baja mortalidad.

Population pharmacokinetics and pharmacokinetic/pharmacodynamic evaluation of marbofloxacin against Coagulase-negative staphylococci, Staphylococcus aureus and Mycoplasma agalactiae pathogens in goats.

Marbofloxacin is a broad-spectrum fluoroquinolone, and an extra-label use has been reported in horse, sheep and goat. However, extrapolation of dosage regimens from cattle to horse and small ruminants could lead to incorrect dosing due to pharmacokinetic differences among species, increasing the risk of antimicrobial resistance or toxicity. Pharmacokinetic properties of marbofloxacin, including PK/PD analysis, have been studied by intravenous, intramuscular and subcutaneous administration in lactating and non-lactating goats. A population pharmacokinetic model of marbofloxacin in goats was built using 10 pharmacokinetic studies after intravenous, intramuscular, and subcutaneous administration at a dose of 2, 5 and 10 mg/kg. Serum or plasma and milk concentration-time profiles were simultaneously fitted with a non-linear mixed effect model with Monolix software. Level of milk production (lactating and non-lactating) and health status (healthy and un-healthy) were retained as covariates on volume of distribution and clearance. Marbofloxacin concentrations were well described in plasma/serum and milk by the population model. Simulated dose regimens of marbofloxacin administered at 2, 5 and 10 mg/kg by intramuscular route for five days were evaluated (n = 5000 per group). Steady-state fAUCs for each dose regimen were obtained. Probability of target attainment of fAUC/MIC ratios were determined and PK/PDco values (highest MIC for which 90% of individuals can achieve a prior numerical value of the fAUC/MIC index) were established using Monte Carlo simulations (n = 50,000). MIC values for wild type isolates of Staphylococcus aureus, coagulase negative staphylococci, and Mycoplasma agalactiae were determined and tentative epidemiological cutoff (TECOFF) were obtained at 1.0, 0.5 and 0.5 mg/L, respectively. The PK/PDco for the dose regimen of 2 mg/kg/24 h and 5 mg/kg/24 h (0.125 and 0.25 mg/L) were lower than TECOFF (0.5 and 1 mg/L). The dosage regimen of 10 mg/kg/24 h was adequate for intermediate MIC values of 0.125-0.50 mg/L and could be effective for a population with a target fAUC/MIC ratio ˂ 48 for Coagulase negative staphylococci and Mycoplasma agalactiae, but not for Staphylococcus aureus. Results obtained in this study could be taken as a starting point by committees that set the clinical breakpoints and justifies expert rules to optimize marbofloxacin dose regimens.

Pharmacokinetics and oral bioavailability of cannabidiol in horses after intravenous and oral administration with oil and micellar formulations.

BACKGROUND: Intravenous pharmacokinetics and oral bioavailability of cannabidiol (CBD) with different formulations have not been investigated in horses and may represent a starting point for clinical studies. OBJECTIVES: To describe pharmacokinetics after intravenous and oral administrations with oil and micellar formulations and simulate different treatments. STUDY DESIGN: Single intravenous experiment and two-way randomised oral experiments, Latin-square design. METHODS: Eight healthy horses received intravenous CBD at 1.00 mg/kg dose, oral CBD in sesame oil and in micellar formulation, both at 10.00 mg/kg. Concentrations were measured using LC-MS/MS and fitted by nonlinear mixed effect modelling. Parameters obtained were used to simulate single and multiple treatments at steady state. RESULTS: Intravenous and oral concentrations were simultaneously fitted using a three-compartment model. Final estimates indicate that CBD has a volume of distribution of 36 L/kg associated with a systemic clearance of 1.46 L/h/kg and half-lives ranged between 24 and 34 h. Oral bioavailability was close to 14% for both oral administrations. Simulated dose regimen of CBD every 12 and 24 h predicted similar percentages to reach effective plasma concentration with both oral formulation at 10.00 mg/kg. MAIN LIMITATIONS: A small horse population was used (8 horses per trial). CONCLUSIONS AND CLINICAL IMPORTANCE: Oral bioavailability was low at the doses studied but fell within the range described for horse and other species. CBD had a high steady-state volume of distribution, a high clearance and long half-lives. No adverse reactions were detected at any dose or route. The micellar formulation showed a faster absorption and higher concentration peak, while the oil formulation presented lower levels, but more maintained over time. Simulations predicted that both could be useful in multiple oral dose treatments. These results indicated that CBD could be of interest, but further studies are needed to evaluate its clinical use in horses.

Valores de la gasometría arterial en pacientes embarazadas con preeclampsia severa / Arterial blood gas parameters in pregnant patients with severe preeclampsia

Resumen OBJETIVO: Determinar e interpretar los valores de la gasometría arterial en pacientes embarazadas con preeclampsia severa. MATERIALES Y MÉTODOS: Estudio observacional, transversal, retrospectivo y descriptivo llevado a cabo en pacientes con más o menos 20 semanas de embarazo y diagnóstico establecido de preeclampsia severa atendidas en la unidad de cuidados intensivos entre el 1 de julio y el 31 de diciembre del 2019. Los datos generales, la condición obstétrica, los estudios de laboratorio clínico y los valores de la gasometría arterial se documentaron conforme a lo registrado en los expedientes clínicos. Se utilizó estadística descriptiva y los datos se procesaron en el programa SPSS versión 20. RESULTADOS: Se estudiaron 30 pacientes con media de edad de 31.6 ± 6.85 años, mediana de paridad 1, todas con feto único de 33.89 ± 3.43 semanas y residencia en la Ciudad de México. Los valores de la gasometría arterial fueron: pH 7.41 ± 0.08, presión parcial de dióxido de carbono 25.51 ± 6.12 mmHg, presión parcial de oxígeno 85.24 ± 41.81 mmHg, hematocrito 33.86 ± 7.51%, ión carbonato 16.95 ± 5.13 mmol/L, patrón de bicarbonato estandarizado 19.04 ± 2.50 mmol/L, gases de efecto invernadero 16.94 ± 2.51 mmHg, exceso de base del fluido extracelular -7.72 ± 5.60 mmol/L, BE (B) -7.36 ± 3.07 mmol/L, porcentaje de saturación de oxígeno 93 ± 8.29, hemoglobina total en la gasometría arterial 10.64 ± 2.36 g/dL, gradiente alvéolo-arterial de oxígeno 49.43 ± 10.98 mmHg, presión parcial de oxígeno 140.43 ± 106.93 mmHg, concentraciones de dióxido de carbono 0.79 ± 0.28 mmHg e Índice respiratorio 0.95 ± 2.57. CONCLUSIONES: Los resultados corresponden a un patrón gasométrico de acidosis metabólica compensada.

Abstract OBJECTIVE: To determine and interpret arterial blood gas values in pregnant patients with severe preeclampsia. MATERIALS AND METHODS: study carry out in a series of 30 patients with a pregnancy ≥ 20 weeks and an established diagnosis of SP admitted to the Intensive Care Unit from July 1 to December 31, 2019, in whom arterial blood gases are part of the routine studies upon admission to the ICU. Patients with recurrence of preeclampsia, eclampsia and HELLP syndrome or with metabolic, respiratory, cardiological and renal morbidities affecting arterial blood gas values were excluded. The general data, obstetric condition, clinical laboratory and arterial blood gas values were documented from the clinical records. Statistical analysis: descriptive statistics were used with the statistical package SPSS version 20. RESULTS: Thirty patients were studied, with a mean age of mean age 31.6 ± 6.85 years, median parity 1, all with a single product of 33.89±3.43 weeks and residence in Mexico City 31.37 ± 7 years. Arterial blood gas values were: pH 7.41 ± 0.08, PCO2 25.51 ± 6.12 mmHg, PO2 85.24 ± 41.81 mmHg, Hct 33.86 ± 7.51%, HCO3- 16.95 ± 5.13 mmol/L, HCO3- std 19.04 ± 2.50 mmol/L, TCO2 16.94 ± 2.51 mmHg, BE ecf -7.72 ± 5.60 mmol/L, BE (B) -7.36 ± 3.07 mmol/L, SO2c% 93 ± 8.29%, THbc 10.64 ± 2.36 g/dL, Aa DO2 49.43 ± 10.98 mmHg, pAO2 140.43 ± 106.93 mmHg, PaO2/PAO2 0.79 ± 0.28 mmHg and Respiratory Index 0.95 ± 2.57. CONCLUSIONS: The results correspond to a gasometric pattern of compensated metabolic acidosis.

Effects of Growth Medium and Inoculum Size on Pharmacodynamics Activity of Marbofloxacin against Staphylococcus aureus Isolated from Caprine Clinical Mastitis.

Staphylococcus aureus (S. aureus) is an important pathogen that causes clinical mastitis in goats and produces infections difficult to cure. Different antimicrobials as fluoroquinolones have been used against S. aureus. However, the studies developed to evaluate the bacterial drug interaction only have used the MIC as a single reference point with artificial growth media. The aims of this study were to describe the effect of marbofloxacin on S. aureus isolated from mastitis goats' milk by different approaches as the minimum inhibitory and bactericidal concentrations (MIC and MBC) in cation adjusted Mueller-Hinton broth (CAMHB), serum and milk of goats at two inoculum sizes of 105 and 108 CFU/mL, the determination and analysis of the time kill curves (TKC) by non-linear mixed effect models in each growth medium and inoculum size, as well as the estimation of their pharmacokinetics/pharmacodynamics (PK/PD) cutoff values. The results obtained indicate that MIC values were higher and increases 2,4-fold in serum and 3,6-fold in milk at high inoculum, as well as the EC50 values determined by each pharmacodynamics model. Finally, the PK/PD cutoff values defined as fAUC24/MIC ratios to achieve clinical efficacy were highly dependent on inoculum and growth medium, with median values of 60-180, especially at high inoculum in milk, suggesting that further studies are necessary to evaluate and optimize the best therapeutic strategies for treating S. aureus in lactating goats.

PK/PD Analysis by Nonlinear Mixed-Effects Modeling of a Marbofloxacin Dose Regimen for Treatment of Goat Mastitis Produced by Coagulase-Negative Staphylococci.

Coagulase-negative staphylococci are main pathogens that produce goat mastitis. Marbofloxacin is a third-generation fluoroquinolone approved for treat mastitis in animals. The objectives of this study were: (i) to determine the pharmacokinetics of marbofloxacin (10 mg/kg/24 h) in serum and milk administered intramuscularly for five days in goats with mastitis induced by coagulase-negative staphylococci; (ii) to characterize the concentration-effect relationship of marbofloxacin against coagulase-negative staphylococci in Mueller Hinton broth and goat milk; (iii) to determine AUC/MIC cutoff values of marbofloxacin, and (iv) to perform a PK/PD analysis to evaluate the efficacy of the dose regimen for the treatment of goat mastitis produced by coagulase-negative staphylococci. Marbofloxacin presented context-sensitive pharmacokinetics, influenced by the evolution of the disease, which decreased marbofloxacin disposition in serum and milk. Marbofloxacin showed a median (95% CI) fAUC/MIC values for MIC of 0.4 and 0.8 µg/mL of 26.66 (22.26-36.64) and 32.28 (26.57-48.35) related with -2 log10CFU/mL reduction; and 32.26 (24.81-81.50) and 41.39 (29.38-128.01) for -3 log10CFU/mL reduction in Mueller Hinton broth. For milk, -2 log10CFU/mL reduction was achieved with 41.48 (35.29-58.73) and 51.91 (39.09-131.63), and -3 log10CFU/mL reduction with 51.04 (41.6-82.1) and 65.65 (46.68-210.16). The proposed dose regimen was adequate for the treatment of goat mastitis produced by coagulase-negative staphylococci, resulting in microbiological and clinical cure of all animals. The animal model used in this study provided important pharmacokinetic information about the effect of the infection on the pharmacokinetics of marbofloxacin. Pharmacodynamic modeling showed that fAUC/MIC cutoff values were higher in goat milk compared with Mueller Hinton broth.

Preperitoneal ropivacaine infusion versus epidural ropivacaine-morphine for postoperative analgesia in dogs undergoing ovariohysterectomy: a randomized clinical trial.

OBJECTIVE: To assess the effect of continuous wound infusion (CWI) with preperitoneal ropivacaine on postoperative analgesia and compare it with the epidural administration of ropivacaine and morphine in bitches undergoing ovariohysterectomy. STUDY DESIGN: A parallel, randomized, clinical, prospective and nonblinded study. ANIMALS: A group of 38 Greyhound bitches. METHODS: In the catheter group (CathG), CWI with ropivacaine 1% (1 mg kg-1 + 0.8 mg kg-1 hour-1) was applied to the preperitoneal space over the surgical incision. In the epidural group (EpiG), ropivacaine 0.5% (1.3 mg kg-1) and morphine (0.1 mg kg-1) were epidurally administered. Occipital-coccygeal length was used to calculate the volume for the epidural. Pain was scored using a dynamic interactive visual analogue scale (DIVAS) and Glasgow composite measure pain scale-short form (CMPS-SF) before anaesthesia and at 2, 4, 6, 18, 21 and 24 hours after extubation. Incisional sensitivity using a dynamometer (MWTs-incision) was evaluated simultaneously. Plasma ropivacaine and cortisol concentrations, degree of sedation, motor blockade and response to interdigital clamping were measured or assessed. A two-way mixed analysis of variance and a Mann-Whitney U test were used to analyse data; p < 0.05. RESULTS: No differences were detected in the DIVAS (p = 0.301), CMPS-SF (p = 0.600) scores, MWTs-incision measurements (p = 0.257) and cortisol values (p = 0.878) between the groups. Rescue analgesia was required in two dogs, one in each group, at 2 hours. Sedation, motor blockade and negative response to interdigital clamping were detected in EpiG at 2, 4 and 6 hours. Mean plasma ropivacaine values were higher in CathG (0.475 ± 0.164 ng mL-1) than in EpiG (0.184 ± 0.213 ng mL-1; p = 0.001). CONCLUSION AND CLINICAL RELEVANCE: Compared with epidural ropivacaine and morphine, CWI with preperitoneal ropivacaine is an effective analgesic technique for postoperative pain management in bitches undergoing ovariohysterectomy without motor blockade.

Influence of general anaesthesia on the intravenous acetaminophen pharmacokinetics in Beagle dogs.

OBJECTIVE: To determine if general anaesthesia influences the intravenous (IV) pharmacokinetics (PK) of acetaminophen in dogs. STUDY DESIGN: Prospective, crossover, randomized experimental study. ANIMALS: A group of nine healthy Beagle dogs. METHODS: Acetaminophen PK were determined in conscious and anaesthetized dogs on two separate occasions. Blood samples were collected before, and at 5, 10, 15, 30, 45, 60 and 90 minutes and 2, 3, 4, 6, 8, 12 and 24 hours after 20 mg kg-1 IV acetaminophen administration. Haematocrit, total proteins, albumin, alanine aminotransferase, aspartate aminotransferase, urea and creatinine were determined at baseline and 24 hours after acetaminophen. The anaesthetized group underwent general anaesthesia (90 minutes) for dental cleaning. After the administration of dexmedetomidine (3 µg kg-1) intramuscularly, anaesthesia was induced with propofol (2-3 mg kg-1) IV, followed by acetaminophen administration. Anaesthesia was maintained with isoflurane in 50% oxygen (Fe'Iso 1.3-1.5%). Dogs were mechanically ventilated. Plasma concentrations were analysed with high-performance liquid chromatography. PK analysis was undertaken using compartmental modelling. A Wilcoxon test was used to compare PK data between groups, and clinical laboratory values between groups, and before versus 24 hours after acetaminophen administration. Data are presented as median and range (p < 0.05). RESULTS: A two-compartmental model best described time-concentration profiles of acetaminophen. No significant differences were found for volume of distribution values 1.41 (0.94-3.65) and 1.72 (0.89-2.60) L kg-1, clearance values 1.52 (0.71-2.30) and 1.60 (0.91-1.78) L kg-1 hour-1 or terminal elimination half-life values 2.45 (1.45-8.71) and 3.57 (1.96-6.35) hours between conscious and anaesthetized dogs, respectively. Clinical laboratory variables were within normal range. No adverse effects were recorded. CONCLUSIONS AND CLINICAL RELEVANCE: IV acetaminophen PK in healthy Beagle dogs were unaffected by general anaesthesia under the study conditions. Further studies are necessary to evaluate the PK in different clinical contexts.

PK/PD Analysis of Marbofloxacin by Monte Carlo Simulation against Mycoplasmaagalactiae in Plasma and Milk of Lactating Goats after IV, SC and SC-Long Acting Formulations Administration.

Contagious agalactia is a mycoplasmosis affecting small ruminants that have become an important issue in many countries. However, PK/PD studies of antibiotics to treat this problem in lactating goats affected by Mycoplasma (M.) agalactiae, the main CA-causing mycoplasma are almost non-existent. The aims of this study were to evaluate the plasma and milk disposition of marbofloxacin in lactating goats after intravenous (IV), subcutaneous (SC) and subcutaneous poloxamer P407 formulations with and without carboxy-methylcellulose (SC-P407-CMC and SC-P407) administration. Marbofloxacin concentrations were analysed by the High Performance Liquid Chromatography (HPLC) method. Minimum inhibitory concentrations (MIC) of M. agalactiae field isolates from mastitic goat's milk were used to calculate surrogate markers of efficacy. Terminal half-lives of marbofloxacin after IV, SC, SC-P407 and SC-P407-CMC administration were 7.12, 6.57, 13.92 and 12.19 h in plasma, and the half-lives of elimination of marbofloxacin in milk were 7.22, 7.16, 9.30 and 7.74 h after IV, SC, SC-P407 and SC-P407-CMC administration, respectively. Marbofloxacin penetration from the blood into the milk was extensive, with Area Under the Curve (AUCmilk/AUCplasma) ratios ranged 1.04-1.23, and maximum concentrations (Cmax-milk/Cmax-plasma) ratios ranged 0.72-1.20. The PK/PD surrogate markers of efficacy fAUC24/MIC and the Monte Carlo simulation show that marbofloxacin ratio (fAUC24/MIC > 125) using a 90% of target attainment rate (TAR) need a dose regimen between 8.4 mg/kg (SC) and 11.57 mg/kg (P407CMC) and should be adequate to treat contagious agalactia in lactating goats.

Comparative pharmacokinetics and pharmacokinetic/pharmacodynamic analysis by nonlinear mixed-effects modeling of cefquinome in nonpregnant, pregnant, and lactating goats after intravenous and intramuscular administration.

Cefquinome is a fourth-generation cephalosporin that is used empirically in goats. Different physiologic factors like pregnancy or lactation could determine the pharmacokinetic behavior of drugs in the organism. The objectives of this study are to (a) compare the pharmacokinetics of cefquinome after intravenous and intramuscular administration in adult nonpregnant (n = 6), pregnant (n = 6), and lactating goats (n = 6), at a dose of 2 mg/kg, with rich sampling by nonlinear mixed-effects modeling, (b) conduct a pharmacokinetic/pharmacodynamic analysis to evaluate the efficacy of the recommended posology in goats with different physiological states, and (c) determine the optimal posology that achieve a PTA value ≥ 90%, taking into account a T > MIC ≥ 60% of a MIC value ≤ 0.25 µg/ml, in the different subpopulations of goats for both routes. Gestation significantly increased Ka and V1, while reduced F0, Cl, and Q. On the other hand, lactation significantly increased V1 and reduced Tk0. Cefquinome concentrations achieved in placental cotyledon, amniotic fluid, and fetal serum indicate a minimal penetration across the placental barrier. Moreover, milk penetration of cefquinome was minimal. The total body clearance of cefquinome for goats was 0.29 L kg-1  hr-1 , that is apparently higher than the reported for cows (0.13 L kg-1  hr-1 ) and pigs (0.16 L kg-1  hr-1 ). So, the optimal dose regimen for cefquinome after intravenous and intramuscular administration required higher dose and frequency of administration compared with recommendations for cows or pigs. Therefore, 2 mg kg-1  8 hr-1 and 5 mg kg-1  12 hr-1 could be used for IV and IM routes, respectively, for the treatment of respiratory infections caused by P. multocida and M. haemolytica, but only 5 mg kg-1  12 hr-1 by both routes should be recommended for Escherichia coli infections.

Age and APOE genotype affect the relationship between objectively measured physical activity and power in the alpha band, a marker of brain disease.

BACKGROUND: Electrophysiological studies show that reductions in power within the alpha band are associated with the Alzheimer's disease (AD) continuum. Physical activity (PA) is a protective factor that has proved to reduce AD risk and pathological brain burden. Previous research has confirmed that exercise increases power in the alpha range. However, little is known regarding whether other non-modifiable risk factors for AD, such as increased age or APOE ε4 carriage, alter the association between PA and power in the alpha band. METHODS: The relationship between PA and alpha band power was examined in a sample of 113 healthy adults using magnetoencephalography. Additionally, we explored whether ε4 carriage and age modulate this association. The correlations between alpha power and gray matter volumes and cognition were also investigated. RESULTS: We detected a parieto-occipital cluster in which PA positively correlated with alpha power. The association between PA and alpha power remained following stratification of the cohort by genotype. Younger and older adults were investigated separately, and only younger adults exhibited a positive relationship between PA and alpha power. Interestingly, when four groups were created based on age (younger-older adult) and APOE (E3/E3-E3/E4), only younger E3/E3 (least predicted risk) and older E3/E4 (greatest predicted risk) had associations between greater alpha power and higher PA. Among older E3/E4, greater alpha power in these regions was associated with improved memory and preserved brain structure. CONCLUSION: PA could protect against the slowing of brain activity that characterizes the AD continuum, where it is of benefit for all individuals, especially E3/E4 older adults.

Systemic and local effects of lidocaine or mepivacaine when used for intravenous regional anaesthesia of the distal limb in standing sedated horses.

BACKGROUND: Local anaesthetics are being combined clinically with amikacin in intravenous regional limb perfusion (IVRLP), with limited knowledge on the analgesia provided and its onset and duration of action after tourniquet application and release. OBJECTIVE: To evaluate the systemic clinical effect, limb withdrawal to nociceptive stimulation, and plasma and synovial fluid concentrations after IVRLP with lidocaine or mepivacaine in standing sedated horses. STUDY DESIGN: Prospective, controlled, randomised, cross-over study. METHODS: Six healthy adult horses were sedated and received IVRLP with lidocaine, mepivacaine or saline (negative control), or perineural anaesthesia of the medial and lateral palmar and palmar metacarpal nerves (positive control) in one forelimb with a 3-week washout period between trials. Electrical and mechanical stimuli were used to test nociceptive threshold of the limb before and after IVRLP/perineural anaesthesia. For lidocaine and mepivacaine trials, blood was collected from the jugular vein and synovial fluid from the radiocarpal joint before, during and out to 24 hours after IVRLP. Drug concentrations were measured using high-performance liquid chromatography. RESULTS: Nociceptive thresholds for lidocaine, mepivacaine and perineural anaesthesia trials were significantly increased compared with saline and baseline values at 10, 20 and 30 minutes, with no differences between anaesthetic trials. During this time, horses had lower heart rates than IVRLP with saline. After tourniquet release at 30 minutes, nociceptive thresholds for lidocaine and mepivacaine trials gradually returned to baselines, whereas perineural anaesthesia trial remained unchanged out to an hour. Plasma lidocaine and mepivacaine concentrations were ≤50 ng/mL while the tourniquet was in place, significantly increasing 10 minutes after tourniquet release. Maximal lidocaine and mepivacaine concentrations in synovial fluid were reached 25 minutes after IVRLP injection. MAIN LIMITATIONS: Amikacin was not included in the perfusate. CONCLUSION: Similar to perineural anaesthesia, IVRLP with lidocaine or mepivacaine provides anti-nociception to the distal limb in standing sedated horses while a tourniquet is applied with concentrations remaining below toxic levels in plasma and synovial fluid.

Pharmacokinetics of meloxicam after oral administration of a granule formulation to healthy horses.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are administered in horses for several systemic diseases. Selective cyclooxygenase-2 inhibitors are preferred because of lower risk of adverse effects. Several meloxicam formulations have been tested in horses, but a recently marketed granule oral formulation has not been studied. OBJECTIVE: To characterize the pharmacokinetics of a novel granule meloxicam formulation in fasted and fed horses, and to compare pharmacokinetic features with oral suspension and tablets. ANIMALS: Seven healthy adult horses. METHODS: Meloxicam was administered at 0.6 mg/kg in fasted or fed horses. Blood samples were collected for pharmacokinetic analysis, and vital signs, hematology, and biochemistry variables were monitored for 72 hours. RESULTS: No adverse effects were detected. Volume of distribution and clearance after intravenous administration of meloxicam were 0.36 L/kg and 29.12 mL/h/kg, respectively, with a 12.39 hours of terminal half-life. Protein binding was of 97%. Bioavailability was high for every oral formulation, ranging 70%-110%, without feed effect. Because of a slower absorption, meloxicam after administration of granules had a longer half-life (24 and 34 hours, fasted and fed, respectively) and mean residence time (31 and 47 hours), than suspension and tablets (ranging 10-13 and 13-15 hours, respectively). In addition, the time above therapeutic concentration was higher for the granule formulation than other formulations. CONCLUSIONS AND CLINICAL IMPORTANCE: Granule formulation has different PK parameters compared to other oral formulations, which could enable this formulation to be used for different dosage regimens in order to reach a desired clinical effect or decrease the risk of adverse effects.

Comparative pharmacokinetics and a clinical laboratory evaluation of intravenous acetaminophen in Beagle and Galgo Español dogs.

OBJECTIVE: To assess the pharmacokinetics (PK) and conduct a clinical laboratory evaluation of acetaminophen in Beagle and Galgo Español (GE) dogs. STUDY DESIGN: Prospective randomized experimental trial. ANIMALS: A total of 20 healthy dogs - 10 Beagles and 10 GE (six males and four females in both groups). METHODS: Acetaminophen (10 and 20 mg kg-1) was administered intravenously (IV) to the dogs on two different occasions. Plasma concentrations were analysed by high-performance liquid chromatography. PK analysis was undertaken using compartmental modelling with ADAPT 5 software. Simulations after multiple IV doses were investigated. Clinical laboratory values such as red blood cell (RBC) count, haemoglobin (Hb), haematocrit (Ht), white blood cell (WBC) count, platelet count, total proteins, alanine aminotransferase (ALT), aspartate aminotransferase, urea and creatinine were measured before and 24 hours after acetaminophen administration in combination with clinical examination to assess side effects resulting from the drug. RESULTS: A two-compartmental model best described time-concentration profiles of acetaminophen. PK parameters were different as a result of a breed effect. For doses of 10 and 20 mg kg-1, respectively, clearance values were 1.70 (1.15-2.27) and 1.62 (1.06-2.86) L kg-1 hour-1 for Beagles and 1.18 (0.70-1.39) and 1.08 (0.67-1.35) L kg-1 hour-1 for GE; elimination half-life values were 2.64 (0.52-4.46) and 2.86 (0.87-4.63) hours for Beagles and 3.49 (1.89-7.80) and 4.57 (2.08-8.90) hours for GE. Significant differences were also found between GE and Beagles in the RBC count, Ht, Hb, WBC count and serum ALT before drug administration, and these differences were maintained 24 hours later, independent of the dosage used. For each breed, no side effects resulting from IV acetaminophen administration were observed at doses of either 10 or 20 mg kg-1. CONCLUSIONS AND CLINICAL RELEVANCE: IV PK of acetaminophen was different between Beagles and GE dogs. Side effects were not detected. Further studies are necessary to evaluate the PK in a clinical context.

Pharmacokinetics of the anti-androgenic drug flutamide in healthy stallions.

Alternatives to surgical castration are necessary for controlling the sexual behaviour of stallions with breeding potential in training and competition. Flutamide is a potent selective non-steroidal androgen receptor competitive antagonist that has been used in human beings as an anti-androgenic drug. In this study, the pharmacokinetics and bioavailability of flutamide and its main active metabolite, 2-hydroflutamide, were determined in seven healthy mature stallions. Single doses of flutamide (1mg/kg intravenously, 1mg/kg orally in fasted horses, 5mg/kg orally in fasted horses and 5mg/kg orally in fed horses) were administered randomly at intervals of 2 weeks. All horses had full physical examinations and blood samples were collected for pharmacokinetics, complete blood counts and biochemistry before and after drug administration. Administration of flutamide did not result in any abnormalities on physical examination or in blood parameters. After intravenous administration of flutamide, the volume of distribution was 0.83L/kg and clearance was 1.20L/h/kg. Flutamide and its metabolite had high protein binding values (93-97%). After oral administration, flutamide was rapidly transformed to 2-hydroxyflutamide, with areas under the concentration-time curve ratios of metabolite:drug ∼7. Oral bioavailability was 6.63% after 1mg/kg flutamide in fasted horses, 6.50% after 5mg/kg flutamide in fasted horses and 6.95% after 5mg/kg in fed horses. Half lives of flutamide were close to 1h after intravenous administration and 2h after oral administration. Half lives of 2-hydroxyflutamide were 4.79-6.84h for all routes and doses. After oral administration, oral flutamide reached plasma concentrations that could be effective as an anti-androgenic agent in horses, but further studies are needed to determine whether flutamide has clinical value as an alternative to castration for controlling sexual behaviour in stallions.

Pharmacokinetic/pharmacodynamic modeling of benazepril and benazeprilat after administration of intravenous and oral doses of benazepril in healthy horses.

Pharmacokinetic and pharmacodynamic (PK/PD) properties of the angiotensin-converting enzyme inhibitor (ACEI) benazeprilat have not been evaluated in horses. This study was designed to establish PK profiles for benazepril and benazeprilat after intravenous (IV) and oral (PO) administration of benazepril using a PK/PD model. This study also aims to determine the effects of benazeprilat on serum angiotensin converting enzyme (ACE), selecting the most appropriate dose that suppresses ACE activity. Six healthy horses in a crossover design received IV benazepril at 0.50mg/kg and PO at doses 0 (placebo), 0.25, 0.50 and 1.00mg/kg. Blood pressures (BP) were measured and blood samples were obtained at different times in order to measure serum drug concentrations and serum ACE activity, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and spectrophotometry, respectively. Systemic bioavailability of benazeprilat after PO benazepril was 3-4%. Maximum ACE inhibitions from baseline were 99.63% (IV benazepril), 6.77% (placebo) and 78.91%, 85.74% and 89.51% (for the three PO benazepril doses). Significant differences in BP were not found. Although oral availability was low, benazeprilat 1.00mg/kg, reached sufficient serum concentrations to induce long lasting serum ACE inhibitions (between 88 and 50%) for the first 48h. Additional research on benazepril administration in equine patients is indicated.

Pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD integration of ceftiofur after a single intravenous, subcutaneous and subcutaneous-LA administration in lactating goats.

BACKGROUND: Bacterial pneumonia in goats is usually caused by Mannheimia haemolytica and Pasteurella multocida. Another important infection disease in lactating goats is intramammary infection producing mastitis, usually associated with coagulase-negative Staphylococcus spp. However, treatment of bacterial pneumonia in goats not affected by mastitis problems should be restricted to antimicrobials with scant penetration to milk in order to avoid long withdrawal times. Ceftiofur is a third-generation cephalosporin antimicrobial with activity against various gram-positive and gram-negative, aerobic and anaerobic bacteria encountered by domestic animals. The objectives of the present study were to establish the serum concentration-time profile for ceftiofur in lactating goats after intravenous, subcutaneous and a SC-long-acting ceftiofur formulation; to determine ceftiofur penetration into milk; to determine in vitro and ex vivo activity of ceftiofur establishing MIC, MBC, MPC and time-kill profiles against field strains of M. haemolytica and finally to calculate the main surrogate markers of efficacy. RESULTS: The pharmacokinetics studies revealed an optimal PK properties for the SC-LA formulation tested. Ceftiofur was well absorbed following SC and SC-LA administration, with absolute bioavailabilities (F) of 85.16 and 84.43 %, respectively. After ceftiofur analysis from milk samples, no concentrations were found at any sampling time. The MIC, MBC and MPC data of ceftiofur against five M. haemolytica strains isolated from goats affected by pneumonia were tested showing excelent sensitivity of ceftiofur against this pathogen. For PK-PD analysis, ratios were calculated suggesting a high level of bacterial kill against the five strains of M. haemolytica tested. CONCLUSIONS: The systemic ceftiofur exposure achieved in lactating goats following IV, SC and especially with the SC-LA administration is consistent with the predicted PK-PD ratios needed for a positive therapeutic outcome for M. haemolytica. Subcutaneous administration of the long-acting formulation showed safety and tolerance for all the animals used. Ceftiofur concentrations exceeded the MIC and MBC for up to 72 h and MPC for up 32 h in serum. Thus, this drug could be effective in treating infectious diseases of goats caused by M. haemolytica at a dose of 6 mg/kg with the SC-LA formulation.

Modulation of acute transient exercise-induced hypertension after oral administration of four angiotensin-converting enzyme inhibitors in normotensive horses.

Changes in blood pressure (BP) during acute hypertension in response to angiotensin-converting enzyme inhibitors (ACEIs) have not been investigated in normotensive horses. In this study, six healthy horses were subjected to five trials, consisting in a treadmill exercise workload of 8 m/s for 1 min, 2 h after oral administration (PO) of placebo (0 mg/kg), enalapril (2.0 mg/kg), quinapril (1.0 mg/kg), ramipril (0.2 mg/kg) or benazepril (0.5 mg/kg). Serum angiotensin converting enzyme (ACE) activity was measured and systolic (SBP) and diastolic (DBP) blood pressures were recorded at rest (R), 2 h after placebo or ACEI administration (pre-E) and within the first 20 s after exercise (post-E). Mean maximum serum ACE inhibition 2 h after PO administration was 4.8% (placebo), 39.4% (enalapril), 46.4% (quinapril), 55.0% (ramipril) and 71.68% (benazepril). There were no significant differences in serum ACE inhibition between enalapril and quinapril. SBP and DBP at times R and pre-E were not different in any of the five trials. In response to exercise, SBP increased by 67.6% (placebo), 52.7% (enalapril), 43.1% (quinapril), 26.6% (ramipril) and 4.2% (benazepril). In response to exercise, DBP increased by 20.6, 13.2, 11.7, 16.6 and 3.7% after placebo, enalapril, quinapril, ramipril and benazepril administration, respectively. Serum ACE activity changed during exercise, but statistical significance was not achieved. In conclusion, administration of PO benazepril at a dose of 0.5 mg/kg modulated physiological hypertension induced by exercise in horses that were otherwise normotensive.

Effectiveness of pre-peritoneal continuous wound infusion with lidocaine for pain control following ovariohysterectomy in dogs.

This study compared the post-operative analgesic efficacy of continuous lidocaine administration with that of intramuscular (IM) methadone in dogs undergoing ovariohysterectomy. Thirty-eight dogs were divided randomly into two groups. Following surgery, the lidocaine group (L) received a continuous lidocaine infusion (2 mg/kg/h) through a wound catheter inserted in the pre-peritoneal space; the control group (C) received methadone (0.2 mg/kg IM). A dynamic and interactive visual analogue scale (DIVAS), the Scale-Form Glasgow Composite Measure Scale (CMPS-SF), mechanical wound thresholds, heart rate, respiratory rate and blood pressure were assessed pre-operatively and 2, 4, 6, 18, and 24 h after surgery. The presence of the wound catheter prevented the evaluator from remaining blinded to group allocations. Plasma lidocaine and cortisol levels were measured 2, 6, 18, and 24 h after surgery. There were no intergroup differences in any pain assessment scale scores at any time point. Stable intravenous lidocaine levels were observed. Four animals in the control group but none in the lidocaine group required rescue analgesia. There were no differences in complication rates between groups. Continuous locoregional lidocaine delivered via a wound catheter between the parietal peritoneum and abdominal muscle offers effective analgesia in dogs during ovariohysterectomy and appears to be a promising analgesic option in veterinary surgery.