Single-Ascending-Dose Pharmacokinetic Study of Tribendimidine in Opisthorchis viverrini-Infected Patients

Praziquantel is the only drug available for the treatment of Opisthorchis viverrini infections. Tribendimidine has emerged as a potential treatment alternative; however, its pharmacokinetic (PK) properties have not been sufficiently studied to date. Via two phase IIa dose-finding studies, 68 O. viverrini patients were treated with 25- to 600-mg doses of tribendimidine using 50- and 200-mg tablet formulations. Plasma, blood, and dried blood spots (DBS) were sampled at selected time points. The two main metabolites of tribendimidine, active deacetylated amidantel (dADT) and acetylated dADT (adADT), were analyzed in plasma, blood, and DBS. PK parameters were estimated by noncompartmental analysis. An acceptable agreement among plasma and DBS concentrations was observed, with a mean bias of ≤10%, and 60% dADT and 74% adADT concentrations being within ±20% margins. We found that 200-mg tribendimidine tablets possess immediate floating characteristics, which led to variable time to maximal concentration of drug (T_max) values (2 to 24 h) between individuals. Dose proportionality was observed for dADT from 25 to 200 mg using 50-mg tablets, but at higher dosages (200 to 600 mg), saturation occurred. The median ratio of the area under the plasma concentration-time curve from 0 to 24 h (AUC_0–24) of dADT to the AUC_0–24 of adADT ranged from 0.8 to 26.4, suggesting substantial differences in acetylation rates. Cure rates ranged from 11% (25-mg dose) to 100% (400-mg dose). Cured patients showed significantly higher dADT maximal serum concentrations (C_max) and AUC_0–24 values than uncured patients. Tribendimidine is a promising drug for the treatment of opisthorchiasis. However, the tablet formulation should be optimized to achieve consistent absorption among patients. Further studies are warranted to assess the large differences between individuals in the rate of metabolic turnover of dADT to adADT. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.)     

Cutaneous ganglioneuroma within a giant congenital nevus

Cutaneous ganglioneuroma has only occasionally been reported in the literature. Cutaneous ganglioneuroma is seen even more rarely in association with a giant congenital nevus. Differential diagnosis includes malignancies, especially melanoma and metastatic neuroblastoma.It is essential to rule out malignancy in a solid lesion within a congenital nevus. The present report is possibly the first relating ganglioneuroma and a congenital nevus to a cervical mass detected during routine prenatal ultrasound.     

Replantation of digits or hands followed by destructive joint disease

The clinical records and radiographs of 45 patients who had undergone replantation of a total hand, or a part thereof, were reviewed in order to determine the prevalence and the type of articular changes occurring distal to the site of anastomoses. In three patients, destructive joint changes were observed, consisting of bony fragmentation, spiculation, and cystic or erosive lesions. These changes, which developed between five and ten months after replantation, are most likely neuropathic or osteonecrotic in pathogenesis.     

Neuroimaging and spectroscopy in children with epileptic encephalopathies

AIMS: To investigate the nature of the unifocal cortical abnormalities on FDG positron emission tomography (PET) in children with an epileptic encephalopathy but no focal abnormality on electroencephalogram or standard magnetic resonance imaging (MRI). METHODS: Repeat FDG PET, surface rendered high resolution MRI, and single voxel magnetic resonance proton spectroscopy of the areas of abnormal metabolism compared to the contralateral side in 11 children aged 2 to 12 years. Imaging was repeated after a median of 13 months. RESULTS: Visual analysis of repeat FDG PET revealed similar abnormalities in 10 of 11 children. Semiquantitative analysis revealed similar sited abnormalities in eight children. One child with ictal hypermetabolism initially had an inconsistent second scan. Magnetic resonance spectra in three children showed the N-acetyl-aspartate/choline ratio was lower in the hypometabolic focus than in the reciprocal area on the opposite side, in two children it was higher, and in one child it was equal. Surface rendered MRI was normal in seven of eight children, and showed temporal lobe asymmetry in one. CONCLUSION: In children with established epileptic encephalopathies most hypometabolic areas on FDG PET are stable over time. While focal neuronal loss is likely in these areas in some children, microdysplasias or other focal cortical dysplasias are probable in others.     

Mycoplasma pneumoniae infection and neurological disease

The cases are reported of 13 children seen over a 22 month period who presented with a variety of acute neurological illnesses associated with Mycoplasma pneumoniae infection. Although presentation with a decreased level of consciousness or seizures was common, psychosis, hemiparesis, cranial nerve palsies, and Guillain-Barré syndrome were also seen. In contrast with published reports, only one child had an associated chest infection. Although some children have been left with residual disability, most have made a complete recovery. In this recent experience, M pneumoniae is a not rare cause of neurological illness in childhood and may present in unusual ways.     

Removal of anti-Galalpha1,3Gal xenoantibodies with an injectable polymer

Preformed and elicited Ab's against the Galalpha1,3Gal terminating carbohydrate chains (alphaGal Ab's) are the primary cause of hyperacute and acute vascular xenograft rejection in pig-to-primate transplantation. alphaGal Ab's are produced by long-lived Ab-producing cells that are not susceptible to pharmacological immunosuppression. We reasoned that antigen-specific elimination of alphaGal Ab's might be achieved in vivo by systemic administration of nonimmunogenic polyvalent alphaGal structures with high avidity for alphaGal Ab's. We devised GAS914, a soluble trisaccharide-polylysine conjugate of approximately 500 kDa that effectively competes for alphaGal binding by alphaGal IgM (IC(50), 43 nM) and IgG (IC(50), 28 nM) in vitro. Injections of GAS914 in cynomolgus monkeys, at the dose of 1 mg/kg, resulted in the immediate decrease of more than 90% of circulating alphaGal Ab's and serum anti-pig cytotoxicity. In baboons, repeated injections of GAS914 effectively reduced both circulating alphaGal Ab's and cytotoxicity over several months. Studies with [(14)C]GAS914 in rhesus monkeys and Gal(-/-) mice indicate that GAS914 binds to circulating alphaGal Ab's and that the complex is quickly metabolized by the liver and excreted by the kidney. Remarkably, posttreatment alphaGal Ab titers never exceeded pretreatment levels and no sensitization to either alphaGal or the polylysine backbone has been observed. Furthermore there was no apparent acute or chronic toxicity associated with GAS914 treatment in primates. We conclude that GAS914 may be used therapeutically for the specific removal of alphaGal Ab's.