Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients.

Topiramate belongs to the second generation of antiepileptic drugs (AEDs) and has been approved for treatment of adults and children with different kinds of epilepsy as mono or as adjunctive therapy.1,2) The exact mechanism of topiramate action is unknown; however, it is considered that antiepileptic effects are exerted by modulation of voltage-dependent sodium channels, enhancement of g-aminobutyrate (GABA)ergic inhibition on the GABA A receptor, inhibition of carbonic anhydrase isoenzymes, and possibly, through the activity at non-N-methyl-D-aspartate receptors. 1,3,4) The effectiveness of topiramate in adults and children with partial onset and primary generalized seizures was established as initial monotherapy as well as adjunctive treatment. 5)Following oral administration of topiramate, absorption is rapid and almost complete with bioavailability ranging from 81 to 95%. 4,6) Peak plasma concentrations of the drug are reached within 1-4 h after administration. 4,6) Food delays topiramate absorption by approximately 2 h, but the extent of absorption remains unaffected.4) Plasma protein-bound fraction of topiramate varies from 9 to 17%. 4,6) In the dose range 100 to 1200 mg the mean apparent volume of distribution is between 0.6 and 1.0 l/kg. 4,6) In women the volume of distribution is about 50% less than in men, which is attributed to a higher percentage of body fat in women.6) This difference is not considered to be clinically relevant. Over 80% of topiramate is eliminated via the kidneys, predominantly as unchanged drug.6) To date, six trace metabolites formed by glucuronidation, hydroxylation and hydrolysis have been identified in humans. In animal seizure models the metabolites have little or no anticonvulsant activity. 4,6) At steadystate the renal clearance of topiramate is 1.02 l/h 6) and its elimination half-life (t 1/2 ) varies from 20 to 30 h. 1,4) Consequently, the steady-state is being reached in 4 to 8 d.2) Over the dose range 100-800 mg the relationship between topiramate dose and serum concentration is linear in both adults and children. 3,7,8) With the commonly used dosage regimen, serum topiramate concentrations in the range between 16 and 60 mmol/l have been reported.3) A wide range of doses and serum concentrations have been associated with optimal clinical response.3) Topiramate serum concentration was found to correlate with the time to the first seizure, 9) while in the majority of studies no clear relationship between average plasma concentration of topiramate and seizure reduction was found. 6,8,10) Based on these findings, clinical response, rather than blood concentrations is used to guide topiramate dosage adjustments. 1,6) Topiramate pharmacokinetic data mostly come from single dose studies with frequent blood sampling in healthy volunteers as well as from studies with sparse sampling in epileptic patients. However, both types of studies provide little information on inter-and intraindividual variability in pharmacokinetics of topiramate. So far there is no published study with a ...

Chitosan in 0.5% w/v concentration enhanced the permeability of the isolated pig urinary bladder wall by desquamation of the urothelium as ascertained in our previous study. The aim of the present work was to determine the time and concentration dependence of chitosan's effect on the permeation of a model drug into the bladder wall and to establish if the mechanism of permeation enhancement depends on the concentration of chitosan used. In the permeability studies performed by the use of diffusion cells, transport of a model drug moxifloxacin into the isolated pig urinary bladder wall was determined. For morphological observations of the urothelium in response to chitosan treatment scanning and transmission electron microscopy were applied. Within 90 min the effect of chitosan on the tissue amounts of moxifloxacin gradually increased and approached its plateau. In one hour even 0.0005% w/v dispersion of chitosan significantly enhanced the permeability of the pig urinary bladder wall for the model drug and at 0.001% w/v concentration the maximal effect on the tissue permeability was achieved. All concentrations of chitosan that significantly enhanced the permeability of the bladder wall triggered necrosis of superficial cells or desquamation of the urothelium. However, at lower concentrations and shorter exposure times the damage of the urothelium was limited to the changes in tight junctions. Chitosan was ascertained to increase the permeation of moxifloxacin into the urinary bladder wall in a time and concentration dependent manner.

High transepithelial electrical resistance (TEER) demonstrates a functional permeability barrier of the normal urothelium, which is maintained by a layer of highly differentiated superficial cells. When the barrier is challenged, a quick regeneration is induced. We used side-by-side diffusion chambers as an ex vivo system to determine the time course of functional and structural urothelial regeneration after chitosan-induced injury. The exposure of the urothelium to chitosan caused a 60 % decrease in TEER, the exposure of undifferentiated urothelial cells to the luminal surface and leaky tight junctions. During the regeneration period (350 min), TEER recovered to control values after approximately 200 min, while structural regeneration continued until 350 min after injury. The tight junctions are the earliest and predominant component of the barrier to appear, while complete barrier regeneration is achieved by delayed superficial cell terminal differentiation. The barrier function and the structure of untreated urothelium were unaffected in side-by-side diffusion chambers for at least 6 h. The urinary bladder tissue excised from an animal thus retains the ability to maintain and restore the transepithelial barrier and cellular ultrastructure for a sufficient period to allow for studies of regeneration in ex vivo conditions.

What is known and objectives Gentamicin is often used for the treatment of Gram‐negative infections. Due to pharmacokinetic variability in paediatric patients, appropriate dosing of gentamicin in the paediatric population is challenging. This article reviews published population pharmacokinetic models of gentamicin in paediatric patients, identifies covariates that significantly influence gentamicin pharmacokinetics, and determines whether there is a consensus on proposed dosing for intravenous gentamicin in this population. Methods The PubMed database was searched for articles published until the end of 2017. If the articles described population pharmacokinetic models of gentamicin in the paediatric population (after intravenous administration of gentamicin), the following data were extracted: type of study, year of publication, population characteristics and number of patients, gentamicin dosing, total number of gentamicin (serum and/or plasma) concentrations, type of population modelling approach, developed model with pharmacokinetic parameters and covariates included. Results and discussion In most of the studies, one‐ or two‐compartment modelling was applied. The mean estimated gentamicin clearance for newborns, infants and the complete paediatric population was 0.048, 0.13 and 0.067 L/h/kg, respectively, and the mean predicted volume of distribution was 0.475, 0.35 and 0.33 L/kg, respectively. The values reflect differences in body composition and kidney maturation within the different paediatric populations. Gentamicin pharmacokinetics were most influenced by age, body size and renal function. What is new and conclusion Based on our review, the authors agree on a prolonged dosing interval for preterm and term newborns (up to 48 hours). However, there was no agreement on proposed dosing with respect to gestational age. In general, the proposed daily doses were lower compared to those initially applied for preterm newborns and comparable to those for term newborns. For infants and children, the dosing interval remained unchanged (24 hours), but the proposed daily doses were higher than actually applied. When differences in the paediatric population are considered and an appropriate population PK model with applicable covariates is applied, dosing can be individualized. In the future, studies of gentamicin pharmacokinetics in paediatric patients should focus on currently underestimated covariates, such as fat‐free mass, concomitantly administered drugs, body temperature and critical illness because these can change gentamicin PK considerably. Consequently, different dosing is required and TDM becomes even more important.