Pharmacokinetics of enteric-coated mycophenolate sodium in stable pediatric renal transplant recipients

This study aims to characterize the pharmacokinetics of mycophenolic acid (MPA) and its glucuronide metabolite (mycophenolic acid 7-O-glucuronide, MPAG) following single oral administration of enteric-coated mycophenolate sodium (EC-MPS, myfortic) at an approximate dose level of 450 mg/m(2) body surface area (BSA) to 25 stable renal transplant recipients (aged 5-16 yr), and to evaluate the safety and tolerability of EC-MPS in this pediatric population. Patients had been maintained on a cyclosporine emulsion, Neoral-based immunosuppressive regimen for at least 3 months and had received their first or second renal transplant more than 6 months prior to entry into the study. After a brief lag phase (t(lag) 0.75 h), MPA was rapidly absorbed (t(max) 2.5 h) and rapidly converted to MPAG (t(max) 3.25 h), with relatively high plasma concentrations of MPAG (C(max) 67.7 microg/mL) compared with MPA (C(max) 36.3 microg/mL). The elimination half-life for MPAG was slightly longer than for MPA (approximately 13 h vs. 8.5 h), and the apparent oral clearance of MPA was approximately 0.2 L/h/kg. The pharmacokinetics of MPA or MPAG were not affected by age, body weight or BSA, within the study population. The pharmacokinetic results for pediatric patients are comparable with those obtained previously in adults, although exposure based on AUC(0-infinity) was approximately 23% higher, and this finding may be a result of dosing on the basis of BSA, rather than body weight. The recommended dose of EC-MPS in pediatric patients is 400-450 mg/m(2) twice daily or, alternatively, approximately 10-14 mg/kg twice daily when used in combination with cyclosporine microemulsion.     

Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses

Molecular characterization of the severe acute respiratory syndrome coronavirus has revealed genetic diversity among isolates. The spike (S) glycoprotein, the major target for vaccine and immune therapy, shows up to 17 substitutions in its 1,255-aa sequence; however, the biologic significance of these changes is unknown. Here, the functional effects of S mutations have been determined by analyzing their affinity for a viral receptor, human angiotensin-converting enzyme 2 (hACE-2), and their sensitivity to Ab neutralization with viral pseudotypes. Although minor differences among eight strains transmitted during human outbreaks in early 2003 were found, substantial functional changes were detected in S derived from a case in late 2003 from Guangdong province [S(GD03T0013)] and from two palm civets, S(SZ3) and S(SZ16). S(GD03T0013) depended less on the hACE-2 receptor and was markedly resistant to Ab inhibition. Unexpectedly, Abs that neutralized most human S glycoproteins enhanced entry mediated by the civet virus S glycoproteins. The mechanism of enhancement involved the interaction of Abs with conformational epitopes in the hACE-2-binding domain. Finally, improved immunogens and mAbs that minimize this complication have been defined. These data show that the entry of severe acute respiratory syndrome coronaviruses can be enhanced by Abs, and they underscore the need to address the evolving diversity of this newly emerged virus for vaccines and immune therapies.     

Animal models of multiple system atrophy

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder presenting with autonomic failure and motor impairment, primarily comprising L-dopa-resistant parkinsonism but occasionally involving cerebellar ataxia. These features result from progressive multisystem neuronal loss that is associated with oligodendroglial alpha-synuclein inclusions. The growing number of animal models for MSA reflects the search for a preclinical test-bed for elucidating MSA pathogenesis and for developing novel therapeutic interventions. Here, the currently available MSA animal models will be reviewed and leads for future research will be identified.     

Correlates of intrusive memories and avoidance of memories of the Holocaust

Although intrusive memories and avoidance of memories are psychological phenomena frequently reported by Holocaust survivors, their correlates have not been systematically researched. The present cross-sectional study examined socio-demographic and health characteristics of elderly Holocaust survivors, as well as the survivors' experiences during the Holocaust. In addition, present distress related to the Holocaust and fear of dying were examined. Results showed that survivors frequently suffered from intrusive memories, but not often from avoidance of memories of the Holocaust. Intrusive memories were strongly associated with present distress from the Holocaust, as well as with self-perceived bad health and fear of dying. These findings suggest that intrusive memories influence survivors' perceptions of life and change the way in which they deal with aging.     

Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery

We investigated the relationship between factor XIII, fibrinogen, blood coagulation screening tests and postoperative bleeding in 98 patients undergoing cardiopulmonary bypass (CPB) surgery. All patients received aprotinin. Blood samples were collected preoperatively (T1),after termination of CPB (T2),12 h (T3) and 24 h (T4) after surgery to determine FXIII activity, fibrinogen, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT) and D-dimers (DD). Laboratory results were correlated with the chest tube drainage 24 h after surgery and compared between patients with 24-hour chest tube drain volumes in the lower (Group 1) with those in the upper tertile (Group 3). Median FXIII and fibrinogen levels dropped by 33.9% and 34.2%, respectively, during CPB. No association between FXIII activity and the extent of postoperative bleeding was found. However, chest tube bleeding was significantly correlated with preoperative and postoperative fibrinogen. This was confirmed by comparing Groups 1 and 3. Group 3 patients had significantly lower fibrinogen levels than Group 1 at T1 - T4, although most fibrinogen values were within or above the reference range (medians, g/l: 3.5 vs. 4.0, p = 0.043 at T1; 2.3 vs. 2.7, p = 0.015 at T2; 2.9 vs. 3.3, p = 0.008 at T3; 4.2 vs. 5.2, p = 0.002 at T4). There was also a significant relationship of platelet count, PT and APTT, as measured after CPB (T2), with postoperative chest tube drainage. In conclusion, plasma FXIII activity does not influence postoperative bleeding in patients undergoing CPB surgery. There is however an inverse association between preoperative or postoperative plasma fibrinogen levels and postoperative bleeding. These findings indicate a modulation of postoperative bleeding by fibrinogen levels.     

Evidence for macrophage-mediated myelin disruption in an animal model for Charcot-Marie-Tooth neuropathy type 1A

Charcot-Marie-Tooth neuropathy type 1A (CMT 1 A) is the most common inherited neuropathy in humans and is mostly caused by a 1.5-Mb tandem duplication of chromosome 17 comprising the gene for the peripheral myelin protein 22-kDa (PMP 22). Although there are numerous studies on the functional role of PMP 22, the mechanisms of myelin degeneration under PMP 22-overexpression conditions have not yet been fully understood. We have shown previously that in mouse mutants hetero- or homozygously deficient for two other myelin components, P0 and C x 32, respectively, immune cells contribute to the demyelinating neuropathy. To test this possibility for PMP 22 overexpression, we investigated a putative mouse model for CMT 1 A, i.e., the mouse strain C 6 1 mildly overexpressing human PMP 22 in peripheral nerves. Electron microscopic and electrophysiologic investigations revealed that this mouse strain develops pathologic features similar to those found in CMT 1 A patients. A novel finding, however, was the upregulation of CD8- and F4/80-positive lymphocytes and macrophages, respectively, in peripheral nerves. The observation that macrophages enter endoneurial tubes of the mutants and obviously phagocytose morphologically normal myelin strongly suggests that the myelin degeneration is mediated at least partially by these phagocytic cells. By gene array technology and quantitative RT-PCR of peripheral nerve homogenates from PMP 22 mutants, monocyte chemoattractant protein-1 (MCP-1; cc l2) could be identified as a putative factor to attract or activate macrophages that attack myelin sheaths in this model of CMT 1 A.     

Safety, tolerability, and efficacy of continuous transdermal dopaminergic stimulation with rotigotine patch in early-stage idiopathic Parkinson disease

Rotigotine is a new dopamine agonist with transdermal patch formulation for the treatment of Parkinson disease. The aim of this study was to investigate safety and efficacy of rotigotine in patients with early-stage Parkinson disease. In this open-label, dose-escalation, safety and efficacy study, 31 patients in the early stages of idiopathic Parkinson disease received rotigotine to a maximum of 18.0 mg/day. Of the 29 patients who completed the 28-day treatment phase, 24 were maintained at the maximum dose level. The drug was well tolerated, and skin reactions were mild. A statistically significant improvement in UPDRS I, II, and III scores was observed from baseline to end of treatment for the 29 subjects who completed the trial. Mean improvement (+/- standard deviation) was -0.41 +/- 0.78 on UPDRS I (P = 0.0078), -2.76 +/- 3.31 on UPDRS II (P = 0.0001), and -4.62 +/- 5.32 on UPDRS III (P < 0.0001). When results were stratified by maximum dose achieved, significant improvements were seen on all 3 subscores for patients achieving the maximum dose. These data suggest that rotigotine is a safe, well-tolerated, and effective treatment for early-stage Parkinson disease.     

Value of gradient-echo magnetic resonance imaging in the diagnosis of familial cerebral cavernous malformation

BACKGROUND: Cerebral cavernous malformations (CCMs) are congenital vascular anomalies that can cause seizures, intracranial hemorrhages, focal neurological deficits, and migrainelike headaches. Magnetic resonance (MR) imaging has substantially facilitated diagnosis of CCM. It is now widely accepted that familial clustering with an autosomal dominant inheritance pattern should be suspected in cases of multiple lesions. OBJECTIVE: To determine by MR imaging the penetrance of cavernous malformations in a 3-generation family that included 5 members with typical clinical signs and diagnostic findings. METHODS: All family members underwent routine MR T1-weighted and T2-weighted spin-echo sequences in addition to MR T2-weighted gradient-echo sequences. RESULTS: Four family members had been symptomatic with either brainstem bleeding, headaches, or focal neurological signs. The gradient-echo sequences yielded a dramatically higher sensitivity with regard to lesion number and distribution.As in previous reports of familial CCM, an increase in lesion number with increasing age, changes in lesion characteristics, de novo occurrence in serial MR imaging over time, and the phenomenon of anticipation could be confirmed in this family. CONCLUSION: Magnetic resonance gradient-echo sequences should be considered the method of choice for diagnosis of familial CCM.     

Antiallodynic effects of NMDA glycine(B) antagonists in neuropathic pain: possible peripheral mechanisms

NMDA receptors are implicated in central sensitisation underlying chronic pain, and NMDA antagonists have a potential for the treatment of neuropathic pain. Functional NMDA receptors are also present on primary afferents, where they may play a role in pro-nociceptive plasticity. The importance of this mechanism in neuropathic pain remains unclear. In the present work, we have compared in models of chronic pain the effects of NMDA antagonists at the glycine(B) site with different central access. L-701,324 (the centrally active antagonist) and 5,7-dichlorokynurenic acid (5,7-DCK, known to have limited central access) were tested after systemic administration in rats in the formalin test and in two models of neuropathic pain. The ability of these compounds to exert central actions (sedation, ataxia) was tested in the open field locomotion test; central NMDA antagonism in vivo was tested in anaesthetised rats on responses of spinal cord neurones to iontophoretic NMDA. Both L-701,324 (2.15-21.5 mg/kg i.p.) and 5,7-DCK (10-46.4 mg/kg i.v.) dose-dependently inhibited Phase II of formalin-evoked behaviour. Likewise, both compounds reversed cold allodynia in the chronic constriction injury model and tactile allodynia in animals with spinal nerve ligation. However, only L-701,324 was able to inhibit neuronal responses to NMDA in the antihyperalgesic dose range; 5,7-DCK was inactive on NMDA responses up to 46.4 mg/kg i.v. or 68.1 mg/kg i.p. Consistent with the lack of inhibition of central NMDA-evoked activity, 5,7-DCK did not alter spontaneous behaviour in the open field test, whereas it was significantly inhibited by L-701,324. Thus, peripheral NMDA receptors may substantially contribute to the efficacy of NMDA antagonists in neuropathic pain.     

Drug hypersensitivities: the need for standardization

Owing to differences of opinion, the evaluation of adverse drug reactions in clinical practice is still somewhat arbitrary. In order to obtain reliable results, we need standardized testing procedures, well defined test preparations, and the application of specific algorithms for the different groups of drugs and their reactions. A few milestones have been achieved in this regard; the full accomplishment of these goals still entails a lot of work.