The effect of sevelamer on the pharmacokinetics of cyclosporin A and mycophenolate mofetil after renal transplantation.

BACKGROUND: After renal transplantation, patients with insufficient graft function may require phosphate binders. It is still unknown if sevelamer, a new calcium-free phosphate binder, interferes with the uptake of immunosuppressants. We studied its effects on the pharmacokinetics of cyclosporin A (CsA) and mycophenolate mofetil. METHODS: We examined 10 adults and eight children with stable renal graft function and stable CsA trough levels. A 12 h pharmacokinetic profile (10 observation points) was conducted without sevelamer, after a single dose and after 4 days of treatment with it. CsA levels were measured with both a monoclonal antibody assay (CEDIA) and a polyclonal antibody assay (FPIA), mycophenolic acid (MPA) levels by EMIT assay and CsA metabolites AM1, AM9 and AM4N by a modified HPLC method. RESULTS: Sevelamer had no significant effect on CsA kinetics [area under the curve (AUC), peak concentration (C(max)), time of C(max)]. The AUC of AM1 was decreased by 30% and C(max) by 25% after 4 days of sevelamer intake. MPA levels were significantly reduced by a mean of 25% of the AUC (P<0.05) and by 30% of the C(max) after a single dose of sevelamer. CONCLUSIONS: A single sevelamer dose reduces the C(max) and the AUC of MPA. Its intake for several days does not significantly influence CsA kinetics.     

Testosterone Concentrations and Sirolimus in Male Renal Transplant Patients

Sirolimus damages the testes in animals; however, human data are sparse. We conducted a case-control study to obtain further insight into this issue and compared testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin concentrations in matched renal transplant patients who did or did not receive sirolimus. We found that testosterone values were lower (11.2 +/- 6.3 nmol/L vs. 15.5 +/- 7.7 nmol/L, p < 0.05), in 28 sirolimus-treated patients, compared to 28 non-sirolimus-treated controls. Furthermore, these patients more commonly had testosterone concentrations that were below our reference value for normal men. In contrast, FSH and LH concentrations were higher while prolactin levels were not different. These data are consistent with sirolimus-related testosterone suppression and suggest a need for further studies.     

Relationships between toxicopathic hepatic lesions and exposure to chemical contaminants in English sole (Pleuronectes vetulus), starry flounder (Platichthys stellatus), and white croaker (Genyonemus lineatus) from selected marine sites on the Pacific Coast,USA.

Relationships between hepatic lesions and chemical contaminant concentrations in sediments, stomach contents, liver tissue, and bile were statistically evaluated in three species of bottomfish, English sole (Pleuronectes vetulus), starry flounder (Platichthys stellatus), and white croaker (Genyonemus lineatus), captured from 27 urban and nonurban sites on the Pacific Coast from Alaska to southern California. Lesions detected were neoplasms, preneoplastic foci of cellular alteration, nonneoplastic proliferative lesions, unique or specific degenerative/necrotic lesions, nonspecific degenerative/necrotic lesions, and hydropic vacuolation of biliary epithelial cells and hepatocytes. In general, lesion prevalences were significantly higher in all three species captured at chemically contaminated urban sites, and certain lesions had significantly higher relative risks of occurrence at urban sites in Puget Sound, San Francisco Bay, the vicinity of Los Angeles, and San Diego Bay. Concentrations of polycyclic aromatic hydrocarbons, polychlorinated biphenyls, DDT and its derivatives, and chlordanes and dieldrin in sediment, stomach contents, liver, and fluorescent aromatic compounds in bile were significant risk factors for the occurrence of neoplastic, preneoplastic, nonneoplastic proliferative, and specific degenerative/necrotic lesions, as well as hydropic vacuolation. Fish age also had a significant influence on occurrence of several hepatic lesions, but gender was rarely a significant risk factor. These relationships provide strong evidence for the involvement of environmental contaminants in the etiology of hepatic lesions in several marine bottomfish species and clearly indicate the utility of these lesions as biomarkers of contaminant-induced effects in wild fish.     

Triptans reduce the inflammatory response in bacterial meningitis.

Severe headache and meningism provide clear evidence for the activation of trigeminal neurotransmission in meningitis. The authors assessed the antiinflammatory potential of 5HT1B/D/F receptor agonists (triptans), which inhibit the release of proinflammatory neuropeptides from perivascular nerve fibers. In a 6-hour rat model of pneumococcal meningitis, zolmitriptan and naratriptan reduced the influx of leukocytes into the cerebrospinal fluid, and attenuated the increase of regional cerebral blood flow. Elevated intracranial pressure as well as the brain water content at 6 hours was reduced by triptans. These effects were partially reversed by a specific 5HT1D as well as by a specific 5HT1B receptor antagonist. Meningitis caused a depletion of calcitonin gene-related peptide (CGRP) and substance P from meningeal nerve fibers, which was prevented by zolmitriptan and naratriptan. In line with these findings, patients with bacterial meningitis had significantly elevated CGRP levels in the cerebrospinal fluid. In a mouse model of pneumococcal meningitis, survival and clinical score at 24 hours were significantly improved by triptan treatment. The findings suggest that, besides mediating meningeal nociception, meningeal nerve fibers contribute to the inflammatory cascade in the early phase of bacterial meningitis. Adjunctive treatment with triptans may open a new therapeutic approach in the acute phase of bacterial meningitis.     

Enteric-coated mycophenolate sodium immunosuppression in renal transplant patients: efficacy and dosing

Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) formulation, has improved both short- and long-term outcomes following renal transplantation, but is often associated with gastrointestinal (GI) complications that can lead to dose reduction or discontinuation, potentially jeopardizing patient outcomes. Enteric-coated mycophenolate sodium (EC-MPS) delivers equivalent MPA exposure to MMF and offers the potential to reduce GI burden (while maintaining patient safety). Here we review the efficacy of EC-MPS compared with MMF in renal transplant patients in terms of biopsy-proven acute rejection and graft loss, and examine the use of EC-MPS in newer regimens such as intensified dosing and calcineurin inhibitor minimization.     

The influence of age on changes in health-related quality of life over three years in a cohort undergoing hemodialysis

OBJECTIVES: To assess the extent to which persons aged 70 and older undergoing hemodialysis (HD) had greater changes in health‐related quality of life (HRQOL) over 3 years than younger patients undergoing HD. DESIGN: Longitudinal. SETTING: The Hemodialysis Study (HEMO Study) was a randomized, clinical trial of the effects of HD dose and membrane flux on mortality and morbidity in patients undergoing chronic dialysis. PARTICIPANTS: Secondary analysis of the HEMO Study. MEASUREMENTS: Participants completed the Index of Well‐Being (IWB) and the Kidney Disease Quality of Life—Long Form (KDQOL‐LF), which also includes the Medical Outcomes Study 36‐item Short Form Questionnaire (SF‐36) annually. Changes in subjects those aged 70 and older were compared with changes in subjects aged 55 to 69 and 18 to 54. RESULTS: At baseline, 1,813 (98%) of HEMO participants completed HRQOL surveys. Their mean age was 58, 56% were female, 64% were black, and mean duration of dialysis was 3.8 years. In subjects with HRQOL data at the first three annual assessments, there were no substantial mean declines in the SF‐36 Physical or Mental Component Summary scales over 3 years. In models incorporating effects of attrition, the differences in average change over 3 years between patients undergoing HD aged 70 and older and the younger cohorts were small in magnitude. There were high rates of adverse HRQOL events in all age groups and significantly higher composite event rates of death or clinically significant decline in HRQOL over 3 years was found in subjects aged 70 and older. CONCLUSION: Although HRQOL was impaired in the population undergoing HD, HRQOL scores at baseline reflect a better‐preserved multidimensional quality of life in respondents in the HEMO Study aged 70 and older than in younger patients undergoing HD. There was no substantial relationship between age and average decline in HRQOL score over 3 years in participants in the HEMO Study.