Transdermal penetration of zalcitabine, lamivudine and synthesised N-acyl lamivudine esters

The objective of this study was to determine the in vitro transdermal permeation through human epidermis of zalcitabine, lamivudine and the synthesised N-acyl lamivudine esters, with and without the use of Pheroid as delivery system and to establish a correlation, if any, with selected physicochemical properties. Six N-acyl lamivudine esters were prepared by acylation of lamivudine with six different acid chlorides. The experimental aqueous solubility, log D and in vitro transdermal flux values were determined for these compounds. There was an inverse correlation between the aqueous solubility and the log D values. The median flux of zalcitabine (0.442 micromol/cm2 h) in PBS was lower than that of lamivudine (4.289 micromol/cm2 h), but in Pheroid, lamivudine (0.011 micromol/cm2 h) had a slightly lower median flux than zalcitabine (0.015 micromol/cm2 h). Entrapment of compounds in Pheroid was confirmed by confocal laser scanning microscopy.     

A PCV2 vaccine based on genotype 2b is more effective than a 2a-based vaccine to protect against PCV2b or combined PCV2a/2b viremia in pigs with concurrent PCV2, PRRSV and PPV infection

The predominant genotype of porcine circovirus (PCV) in the pig population today is PCV2b yet PCV2a-based commercial vaccines are considered effective in protecting against porcine circovirus associated disease. The objective of this study was to compare the ability of PCV2a- and PCV2b-based vaccines to control PCV2b viremia in a challenge model that mimics the U.S. field situation. Sixty-three pigs were randomly assigned to one of eight groups. Sixteen pigs were vaccinated with an experimental live-attenuated chimeric PCV1-2a vaccine based on genotype 2a and another 16 pigs with a chimeric PCV1-2b vaccine based on genotype 2b. Challenge was done 28 days post vaccination (dpv) using PCV2b (or a combination of PCV2a and PCV2b), porcine reproductive and respiratory syndrome virus (PRRSV), and porcine parvovirus (PPV) to mimic what commonly occurs in the field. The experiment was terminated 21 days post challenge (dpc) or 49 dpv. Pigs vaccinated with the chimeric PCV1-2b vaccine had significantly higher levels of PCV1-2b viremia and shedding of the PCV1-2b vaccine virus in feces and nasal secretions but also a more robust humoral immune response as evidenced by significantly higher ELISA S/P ratios compared to the PCV1-2a vaccination. Regardless of challenge, the PCV1-2b vaccination significantly reduced the prevalence and amount of PCV2 viremia compared to the PCV1-2a vaccination. Interestingly, in the non-vaccinated pigs concurrent PCV2a infection resulted in clinical disease and increased macroscopic lung lesions compared to pigs challenged with PCV2b alone, further supporting the idea that concurrent PCV2a/PCV2b infection is necessary for optimal PCV2 replication.     

Inactivated Schmallenberg virus prototype vaccines

Schmallenberg virus (SBV), a novel Orthobunyavirus, is an insect-transmitted pathogen and was first described in Europe in 2011. SBV causes a mild transient disease in adult ruminants, but severe foetal malformation and stillbirth were observed after an infection of naive cows and ewes, which is responsible for considerable economic losses. The virus is now widely distributed in Europe, and no vaccines were available to stop transmission and spread.     

Limited and excess protein intake of pregnant gilts differently affects body composition and cellularity of skeletal muscle and subcutaneous adipose tissue of newborn and weanling piglets

Aim  

This study investigated whether dietary protein intake less (50%) or greater (250%) than requirements throughout gestation differently affects offspring body composition and cellular properties of skeletal muscle and subcutaneous adipose tissue (SCAT).     

Decision support system for the operating room rescheduling problem

Due to surgery duration variability and arrivals of emergency surgeries, the planned Operating Room (OR) schedule is disrupted throughout the day which may lead to a change in the start time of the elective surgeries. These changes may result in undesirable situations for patients, wards or other involved departments, and therefore, the OR schedule has to be adjusted. In this paper, we develop a decision support system (DSS) which assists the OR manager in this decision by providing the three best adjusted OR schedules. The system considers the preferences of all involved stakeholders and only evaluates the OR schedules that satisfy the imposed resource constraints. The decision rules used for this system are based on a thorough analysis of the OR rescheduling problem. We model this problem as an Integer Linear Program (ILP) which objective is to minimize the deviation from the preferences of the considered stakeholders. By applying this ILP to instances from practice, we determined that the given preferences mainly lead to (i) shifting a surgery and (ii) scheduling a break between two surgeries. By using these changes in the DSS, the performed simulation study shows that less surgeries are canceled and patients and wards are more satisfied, but also that the perceived workload of several departments increases to compensate this. The system can also be used to judge the acceptability of a proposed initial OR schedule.     

Population pharmacokinetics and dose simulation of carvedilol in paediatric patients with congestive heart failure

Aims

To investigate the ontogeny of carvedilol pharmacokinetics and to develop an age-appropriate carvedilol dosing strategy for paediatric patients.

Methods

Data were derived from a prospective, nonplacebo-controlled study of carvedilol for the treatment of paediatric patients with congestive heart failure and analysed using a nonlinear mixed-effects modelling approach (NONMEM, Version V 1.1). The population pharmacokinetic model was further utilized for simulations of different carvedilol dosing strategies.

Results

Four hundred and eighty carvedilol plasma concentrations of 41 patients (0.1–19.3 years; median 3.5) were included in the analysis. A two-compartment model with first-order absorption and absorption lag served as structural model. Weight and age were the most important covariates for carvedilol pharmacokinetics. The weight-adjusted clearance was highest for the younger patients with 2.7 l h⁻¹ kg⁻¹ for a 1-year-old patient compared with 0.7 l h⁻¹ kg⁻¹ for a 19.3-year-old patient. Dose simulations revealed that the area under the plasma concentration–time curve (AUC) as a measure of drug exposure increased with age despite constant doses with respect to body weight. For infants (28 days to 23 months), children (2–11 years) and adolescents (12–15 years) daily doses of 3, 2 and 1 mg kg⁻¹, administered in two or three discrete doses, were necessary to reach an exposure comparable to adults receiving 0.7 mg kg⁻¹ day⁻¹.

Conclusion

The ontogeny of carvedilol pharmacokinetics in paediatric patients depends on age and weight. Dose simulations revealed that younger patients have to be treated with higher doses with respect to body weight to reach the same exposure as adults.

What is already known about this subject

• Applying in silico tools such as population pharmacokinetic analysis and simulation will help to find adequate dosing strategies and increase the probability of success for a randomized controlled trial.
• Up to now, for carvedilol in paediatric patients with congestive heart failure (CHF) the dose has been linearly extrapolated from adults, but the results with this dosing strategy are ambiguous.
• Further trials are necessary to establish carvedilol for paediatric patients with CHF.

What this study adds

• Carvedilol pharmacokinetics in paediatric patients with CHF depends on the weight and age of the patient.
• Therefore, the drug exposure differs substantially between patients of different ages receiving the same dose with respect to body weight.
• Simulations revealed that an age-adjusted carvedilol dosing strategy with higher doses for younger patients with respect to body weight is preferable to a uniform one.

     

Cyclooxygenase inhibition in ischemic brain injury

Neuroinflammation is one of the key pathological events involved in the progression of brain damage caused by cerebral ischemia. Metabolism of arachidonic acid through cyclooxygenase (COX) enzymes is known to be actively involved in the neuroinflammatory events leading to neuronal death after ischemia. Two isoforms of COX, termed COX-1 and COX-2, have been identified. Unlike COX-1, COX-2 expression is dramatically induced by ischemia and appears to be an effector of tissue damage. This review article will focus specifically on the involvement of COX isozymes in brain ischemia. We will discuss issues related to the biochemistry and selective pharmacological inhibition of COX enzymes, and further refer to their expression in the brain under normal conditions and following excitotoxicity and ischemic cerebral injury. We will review present knowledge of the relative contribution of each COX isoform to the brain ischemic pathology, based on data from investigations utilizing selective COX-1/COX-2 inhibitors and genetic knockout mouse models. The mechanisms of neurotoxicity associated with increased COX activity after ischemia will also be examined. Finally, we will provide a critical evaluation of the therapeutic potential of COX inhibitors in cerebral ischemia and discuss new targets downstream of COX with potential neuroprotective ability.     

Stress status of gudgeon (Gobio gobio) from rivers in Switzerland with and without input of sewage treatment plant effluent

To assess the importance of sewage treatment plant effluents on fish health, we studied gudgeon in two rivers in the Swiss midlands (Canton Lucerne). Both rivers receive pollution from diffuse sources, while one also receives the effluent of a sewage treatment plant. Male and female gudgeon during and outside of the spawning season were compared with respect to reproductive parameters and health status across both rivers as well as upstream and downstream of the STP. Several biomarkers were studied, including cytochrome P4501A, 7-ethoxyresorufin-O-deethylase, plasma vitellogenin, ovotestis, lipid, liver histology, condition factor, gonadosomatic index, splenosomatic index, parasites of spleen and liver, population structure, and species diversity. Gudgeons of both rivers exhibited signs of a moderately impaired health status. By a stepwise backward analysis, the cytochrome P4501A content, the splenosomatic index, and the incidence of parasites in the liver were found to provide the best discrimination of the three sampling sites. Evidence of a significant elevation in response to the sewage treatment plant effluent was found neither in vitellogenin concentration nor in the ovotestis rate. While population structure was analyzed upstream and downstream of the sewage treatment plant, only gudgeons of the latter site revealed a disturbed population structure, most probably caused by a former nitrite discharge.     

Nutritional status using the Mini Nutritional Assessment questionnaire and its relationship with bone quality in a population of institutionalized elderly women

Malnutrition, a risk factor for osteoporotic fractures, is frequent in elderly people and, is underdiagnosed and undertreated. There are only few studies on the nutritional status of elderly people in Europe. The Mini Nutritional Assessment (MNA) is a non invasive and validated questionnaire to evaluate nutritional status in elderly people, classified in three groups: 1 degree score < 17: malnourished, 2 degrees score >17 and < 24: at risk of malnutrition, 3 degrees score >24: well-nourished, with a maximum of 30 points. Quantitative ultrasound of bone (QUS) is a method for assessing quality of bone which can be easily performed in nursing homes. Therefore, these two tests allowed to study the relationships between nutritional status and ultrasonic parameters of bone in 78 institutionalized women aged 86 +/- 6 years, living in 11 nursing homes around Lausanne (Switzerland). All were assessed by the MNA, had a measurement of the tricipital skin fold and of the grip strength. Functional status was evaluated by the scale "Activity of Daily Living" (ADL), and serum albumin level was measured when permitted. All had QUS of the calcaneus (with an Achilles, GE Lunar). The measured parameters are the Broadband Ultrasound Attenuation (BUA), attenuation of a band of ultrasonic frequencies through the medium, expressed in dB/MHz, and the Speed of Sound (SOS), speed of the ultrasounds through the medium, expressed in m/s. A third parameter, the stiffness index (SI), expressed as a percentage of the values obtained by the manufacturer in a young population and derived from BUA and SOS, was calculated automatically : SI = (0.67xBUA) + (0.28xSOS) - 420, expressed in percent compared to a young adult population (%YA). Fifteen percent of the women were undernourished and 58% were at risk of malnutrition. As expected, compared with the well-nourished minority, undernourished subjects had significant lower body mass index (BMI), tricipital skin fold (TSF), ADL score and albumin level (p < 0,01). The subjects "at risk of malnutrition" had significant lower BMI, ADL score (p < 0.01), tricipital skin fold and serum albumin (p < 0.05). Ultrasound parameters were low independently of the nutritional status. MNA score correlated significantly with tricipital skin fold (r = 0.508, p < 0.01), ADL (r = 0.538, p < 0.01) and albumin serum level (r = 0.409, p = 0.01). There was a trend for a correlation between the MNA and the ultrasound parameter BUA (r = 0.207, p = 0.07), whereas no correlation was found with SOS and SI. A multivariate analysis showed that tricipital skin fold and ADL explained 61% of the variance of the MNA. In conclusion, using simple and non invasive methods, this study showed that malnutrition and osteoporosis are frequent in institutionalized elderly persons in our country, and the ultrasound parameters are influenced by many others factors in addition to nutrition, especially at this age and in elderly residents of nursing homes.