Determinants of hepato- and spleno-megaly in Hunan, China: cross-sectional survey data from areas endemic for schistosomiasis

In order to understand the determinants of schistosome-related hepato- and spleno-megaly better, 14 002 subjects aged 3-60 years (59% male; mean age =32 years) were randomly selected from 43 villages, all in Hunan province, China, where schistosomiasis caused by Schistosoma japonicum is endemic. The abdomen of each subject was examined along the mid-sternal (MSL) and mid-clavicular lines, for evidence of current hepato- and/or spleno-megaly, and a questionnaire was used to collect information on the medical history of each individual. Current infections with S. japonicum were detected by stool examination. Almost all (99.8%) of the subjects were ethnically Han by descent and most (77%) were engaged in farming. Although schistosomiasis appeared common (42% of the subjects claiming to have had the disease), only 45% of the subjects said they had received anti-schistosomiasis drugs. Overall, 1982 (14%) of the subjects had S. japonicum infections (as revealed by miracidium-hatching tests and/or Katon Katz smears) when examined and 22% had palpable hepatomegaly (i.e. enlargement of at least 3 cm along the MSL), although only 2.5% had any form of detectable splenomegaly (i.e. a Hackett's grade of at least 1). Multiple logistic regression revealed that male subjects, fishermen, farmers, subjects aged greater than or equal to 25 years, subjects with a history of schistosomiasis, and subjects who had had bloody stools in the previous 2 weeks were all at relatively high risk of hepato- and/or spleno-megaly. In areas moderately endemic for Schistosoma japonicum, occupational exposure and disease history appear to be good predictors of current disease status among older residents. These results reconfirm those reported earlier in the same region.

Structure-hepatic disposition relationships for cationic drugs in isolated perfused rat livers: Transmembrane exchange and cytoplasmic binding process

This work studied the structure-hepatic disposition relationships for cationic drugs of varying lipophilicity using a single-pass, in situ rat liver preparation. The lipophilicity among the cationic drugs studied in this work is in the following order: diltiazem. propranolol. labetalol. prazosin. antipyrine. atenolol. Parameters characterizing the hepatic distribution and elimination kinetics of the drugs were estimated using the multiple indicator dilution method. The kinetic model used to describe drug transport (the two-phase stochastic model) integrated cytoplasmic binding kinetics and belongs to the class of barrier-limited and space-distributed liver models. Hepatic extraction ratio (E) (0.30-0.92) increased with lipophilicity. The intracellular binding rate constant (k(on)) and the equilibrium amount ratios characterizing the slowly and rapidly equilibrating binding sites (K-S and K-R) increase with the lipophilicity of drug (k(on) : 0.05-0.35 s(-1); K-S : 0.61-16.67; K-R : 0.36-0.95), whereas the intracellular unbinding rate constant (k(off)) decreases with the lipophilicity of drug (0.081-0.021 s(-1)). The partition ratio of influx (k(in)) and efflux rate constant (k(out)), k(in)/k(out), increases with increasing pK(a) value of the drug [from 1.72 for antipyrine (pK(a) = 1.45) to 9.76 for propranolol (pK(a) = 9.45)], the differences in k(in/kout) for the different drugs mainly arising from ion trapping in the mitochondria and lysosomes. The value of intrinsic elimination clearance (CLint), permeation clearance (CLpT), and permeability-surface area product (PS) all increase with the lipophilicity of drug [CLint (ml . min(-1) . g(-1) of liver): 10.08-67.41; CLpT (ml . min(-1) . g(-1) of liver): 10.80-5.35; PS (ml . min(-1) . g(-1) of liver): 14.59-90.54]. It is concluded that cationic drug kinetics in the liver can be modeled using models that integrate the presence of cytoplasmic binding, a hepatocyte barrier, and a vascular transit density function.

Diffusion modeling of percutaneous absorption kinetics: 2. Finite vehicle volume and solvent deposited solids

The diffusion model for percutaneous absorption is developed for the specific case of delivery to the skin being limited by the application of a finite amount of solute. Two cases are considered; in the first, there is an application of a finite donor (vehicle) volume, and in the second, there are solvent-deposited solids and a thin vehicle with a high partition coefficient. In both cases, the potential effect of an interfacial resistance at the stratum corneum surface is also considered. As in the previous paper, which was concerned with the application of a constant donor concentration, clearance limitations due to the viable eqidermis, the in vitro sampling rate, or perfusion rate in vivo are included. Numerical inversion of the Laplace domain solutions was used for simulations of solute flux and cumulative amount absorbed and to model specific examples of percutaneous absorption of solvent-deposited solids. It was concluded that numerical inversions of the Laplace domain solutions for a diffusion model of the percutaneous absorption, using standard scientific software (such as SCIENTIST, MicroMath Scientific software) on modern personal computers, is a practical alternative to computation of infinite series solutions. Limits of the Laplace domain solutions were used to define the moments of the flux-time profiles for finite donor volumes and the slope of the terminal log flux-time profile. The mean transit time could be related to the diffusion time through stratum corneum, viable epidermal, and donor diffusion layer resistances and clearance from the receptor phase. Approximate expressions for the time to reach maximum flux (peak time) and maximum flux were also derived. The model was then validated using reported amount-time and flux-time profiles for finite doses applied to the skin. It was concluded that for very small donor phase volume or for very large stratum corneum-vehicle partitioning coefficients (e.g., for solvent deposited solids), the flux and amount of solute absorbed are affected by receptor conditions to a lesser extent than is obvious for a constant donor constant donor concentrations. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:504-520, 2001.

Mycophenolate mofetil for treatment of refractory lupus nephritis (Letter to the Editor)

No Abstract

Maintaining clearance in peritoneal dialysis

Numerous studies have now established that there is a strong association between small solute clearance and improved outcomes in peritoneal dialysis (PD) patients. Preservation of both renal and peritoneal clearances is therefore of paramount importance, although very few trials have satisfactorily addressed this critical issue. Observational studies have suggested that the groups most at risk of loss of residual renal function are women, non-whites, diabetic patients, patients with congestive cardiac failure, patients who experience frequent episodes of peritonitis and, possibly, patients treated with automated PD (APD). There have been no controlled trials of renoprotective therapies in PD patients, but reasonable strategies for preventing renal functional decline include avoidance of nephrotoxins and infection, maintenance of adequate blood pressure, abstinence from smoking and possibly administration of angiotensin-converting enzyme inhibitors and/or calcium channel blockers. In contrast, peritoneal small solute removal can be maximized by augmenting fill volume, increasing exchange frequency and using either long-dwell continuous ambulatory PD (CAPD) or short-dwell (APD) therapies to suit individual patients' transport characteristics. Tidal PD may additionally increase solute clearance, although studies have reported conflicting findings. Preservation of membrane function may be achieved by minimizing episodes of peritonitis and avoiding hypertonic glucose exchanges. Newer peritoneal dialysates, such as icodextrin, amino acids, bicarbonate-buffered solutions and aldehyde-poor fluids, are more biocompatible in experimental models of PD, but their long-term clinical safety and efficacy have not yet been established by clinical trials. Moreover, no trials have demonstrated an independent effect of peritoneal clearance on patient outcomes. Further studies determining the relative value of renal and peritoneal clearances are therefore urgently required in order to optimize dialytic adequacy for PD patients.

Epstein-Barr virus encephalitis in a renal allograft recipient diagnosed by polymerase chain reaction on cerebrospinal fluid and successfully treated with ganciclovir

Epstein–Barr virus (EBV) encephalitis has been reported rarely in the context of solid-organ and bone-marrow transplantation [1]. We report a case of a renal transplant recipient who developed EBV encephalitis following OKT3 therapy for acute allograft rejection. The diagnosis was expedited by the detection of EBV DNA in the cerebrospinal fluid (CSF) by nested polymerase chain reaction (PCR). Moreover, clinical recovery and clearance of CSF EBV DNA appeared to follow the institution of parenteral ganciclovir treatment.

Identification of an apolipoprotein(e) variant associated with type III hyperlipoproteinaemia in an indigenous Australian

As a result of testing for lipid and apolipoprotein(e) (apo E) phenotype status of an indigenous Australian community, an apo E variant associated with type III hyperlipoproteinaemia has been identified. Apo E phenotype was determined by analysis of VLDL by isoelectric focusing, and genotype on DNA amplified by polymerase chain reaction, using two different restriction enzyme isotyping assays. Phenotypes and genotypes were discordant in samples from two subjects and an abnormal-sized restriction fragment was also observed in their genotyping gel patterns. DNA sequencing studies revealed this was due to a single nucleotide deletion. 3817delC, at amino acid 136 on apo E. This resulted in a new reading frame and the premature termination of the apo E protein due to a stop codon (TGA) at nucleotide 4105. The variant apo E null allele showed a recessive mode of inheritance and, in combination with the E2 allele, resulted in the type III hyperlipoproteinaemic phenotype but when inherited with the E4 allele had no marked effect on plasma lipids.

Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload

Background Icodextrin is a high molecular weight, starch-derived glucose polymer, which is capable of inducing sustained ultrafiltration over prolonged (12–16 hour) peritoneal dialysis (PD) dwells. The aim of this study was to evaluate the ability of icodextrin to alleviate refractory, symptomatic fluid overload and prolong technique survival in PD patients. Methods A prospective, open-label, pre-test/post-test study was conducted in 17 PD patients (8 females/9 males, mean age 56.8 ± 2.9 years) who were on the verge of being transferred to haemodialysis because of symptomatic fluid retention that was refractory to fluid restriction, loop diuretic therapy, hypertonic glucose exchanges and dwell time optimisation. One icodextrin exchange (2.5 L 7.5%, 12-hour dwell) was substituted for a long-dwell glucose exchange each day. Results Icodextrin significantly increased peritoneal ultrafiltration (885 ± 210 ml to 1454 ± 215 ml, p < 0.05) and reduced mean arterial pressure (106 ± 4 to 96 ± 4 mmHg, p < 0.05), but did not affect weight, plasma albumin concentration, haemoglobin levels or dialysate:plasma creatinine ratio. Diabetic patients (n = 12) also experienced improved glycaemic control (haemoglobin Alc decreased from 8.9 ± 0.7% to 7.9 ± 0.7%, p < 0.05). Overall PD technique survival was prolonged by a mean of 11.6 months (95% CI 6.0–17.3 months). On multivariate Cox proportional hazards analysis, extension of technique survival by icodextrin was only significantly predicted by baseline net daily peritoneal ultrafiltration (adjusted HR 2.52, 95% CI 1.13–5.62, p < 0.05). Conclusions Icodextrin significantly improved peritoneal ultrafiltration and extended technique survival in PD patients with symptomatic fluid overload, especially those who had substantially impaired peritoneal ultrafiltration.