Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration–time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected

Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early

Breast Magnetic Resonance Imaging (MRI) and its impact on the surgical treatment of breast cancer

Breast MRI focuses on the detection of multifocality, multicentricity, and bilaterality of newly diagnosed breast cancer. A retrospective study was carried out on 833 patients that were diagnosed and treated for breast cancer between January 2002 and December 2011. Patients were divided into two groups: those that had a presurgery breast MRI and those that did not. The two groups were compared on the basis of the several parameters. The aim of the study was to determine whether the use of MRI in breast cancer screening changes the initial treatment decision. In 18% of the patients, MRI revealed a multifocal or a multicentric unilateral breast cancer, a bilateral tumour, or a larger cancer than initially diagnosed. Most of these patients underwent a second-look breast ultrasound, with or without an additional biopsy. The percentage of mastectomies did not increase as a result of an MRI exam. Neoadjuvant chemotherapy was used more often and the percentage of reoperations decreased when an MRI was performed.info:eu-repo/semantics/publishe

Isolated medial orbital wall fracture associated with enophthalmos in a paediatric patient: An unusual presentation

Purpose: To report a case of isolated medial orbital wall fracture with enophthalmos in a paediatric patient and describe the clinical presentation and findings by means of computed tomography (CT) of the head and eyes. Methods: We looked at the patient&apos;s medical and ophthalmologic history, and an ophthalmologic examination and a CT of the head were performed at baseline. Results: A 14-year-old boy was admitted to the emergency department of our institution with ecchymosis of his right eyelids secondary to a sport accident. Physical examination revealed a moderate limitation of upgaze without diplopia. CT showed a medial orbital wall fracture without haemorrhage and a gross accumulation of air in the right eyelid with pressure exertion over the right globe and enophthalmos. The patient was treated conservatively with oral antibiotics and steroids showing dramatic improvement within 1 week. Enophthalmos and periorbital emphysema were completely resolved within 3 months after the accident as indicated by CT. Conclusions: We conclude that surgical intervention and intravenous treatment are not warranted in similar cases of medial orbital wall fracture. Medical history, clinical and paraclinical evaluations, and a regular follow-up, including CT, are needed though to avoid complications such as painful abduction, horizontal diplopia, pseudo sixth nerve paresis, or pseudo Duane. © 2018 The Author(s) Published by S. Karger AG, Basel

Noninvasive Two-Photon Microscopy Imaging of Mouse Retina and Retinal Pigment Epithelium

Two-photon excitation microscopy is perfectly suited for imaging deep into the retina due to its use of infrared (IR) wavelengths to excite endogenous fluorophores such as vitamin A-derived retinoids present in this tissue. Furthermore, two-photon excitation occurs only around a small focal volume, and scattered IR photons cannot excite retinal chromophores. These characteristics contribute to subcellular resolution and low noise of images obtained from deep within retinal layers. Here we describe how to customize a two-photon microscope for noninvasive imaging of the retina and retinal pigment epithelium (RPE) in the mouse eye, along with detailed instructions for mouse handling and retinal imaging, and we provide examples of mouse retinal two-photon microscopy data