First-pass effects of verapamil on the intestinal absorption and liver disposition of fexofenadine in the porcine model.

The aim of this study in pigs was to investigate the local pharmacokinetics of fexofenadine in the intestine and liver by using the pig as a model for drug transport in the entero-hepatobiliary system. A parallel group design included seven pigs (10-12 weeks, 22.2-29.5 kg) in three groups (G1, G2, G3), and a jejunal single-pass perfusion combined with sampling from the bile duct and the portal, hepatic, and superior caval veins was performed. Fexofenadine was perfused through the jejunal segment alone (G1: 120 mg/l, total dose 24 mg) or with two different verapamil doses (G2: 175 mg/l, total dose 35 mg; and G3: 1000 mg/l, total dose 200 mg). The animals were fully anesthetized and monitored throughout the experiment. Fexofenadine had a low liver extraction (E(H); mean +/- S.E.M.), and the given doses of verapamil did not affect the E(H) (0.13 +/- 0.04, 0.16 +/- 0.03, and 0.12 +/- 0.02 for G1, G2, and G3, respectively) or biliary clearance. The E(H) for verapamil and antipyrine agreed well with human in vivo data. Verapamil did not increase the intestinal absorption of fexofenadine, even though the jejunal permeability of fexofenadine, verapamil, and antipyrine showed a tendency to increase in G2. This combined perfusion and hepatobiliary sampling method showed that verapamil did not affect the transport of fexofenadine in the intestine or liver. In this model the E(H) values for both verapamil and antipyrine were similar to the corresponding values in vivo in humans.     

Influence of age and cell number of a tissue culture on its susceptibility to poliovirus

Summary By means of comparative virus titrations it is shown that significantly different titers may be found as a result of experimentally produced variations in the cultures used for titrations. The results were obtained by following the cytopathic changes daily in the microscope. The applied variations concerned the following factors: Age of the cultures used, time for last fluid change before virus inoculation and cell number of cultures of same age.Supported by a grant from the Swedish Association against Polio.     

Strabismus and diplopia as complications after cataract surgery with IOL implantation

Summary In our Department of Orthoptics we have seen an increasing number of patients suffering from diplopia after cataract surgery with IOL implantation. Between 1993 and 1997 the total number of patients with this problem was 24 (2.7 % of all patients, mean age 71 years, age range 38–88). We addressed the question of whether there is a common pattern of motility dysfunction. Methods: After evaluation of the clinical history and the basic ophthalmological findings the following parameters were examined: binocular function (Bagolini test), squint angles (Maddox cross), ocular motility. Results: The 24 patients could be divided up into three groups. Group 1 consisted of 9 patients (mean age 82 years, range 64–88) who complained about diplopia because of strabismus incomitans with vertical deviation and restricted motility on the first day after surgery. In 8 of the 9 patients strabismus surgery was done. Group II consisted of 10 patients (mean age 66 years, range 38–77) who noticed diplopia and strabismus within 7 days after surgery. We found various kinds of heterotropia. Seven of these patients were operated on and two had a prism correction. Group III consisted of 5 patients (mean age 67 years, range 61–78). Their already known strabismus paralyticus or concomitans deteriorated, leading to diplopia in some cases. All patients in this group were operated on. Discussion: For group I we believe that retro-, para- or peribulbar anesthesia caused the motility dysfunction. In groups II and III it is unlikely that local anesthesia had a causative role. The prolonged disruption of binocular vision and the abrupt change in the sensory situation after the cataract operation with lens implantation may be the leading causes for strabismus or deterioration of a preexisting strabism, respectively. Conclusions: These patients need a subtil meticulous diagnostic work-up and follow-up because of the possibility of early surgical therapy, which has a good prognosis. Evaluation of binocular vision and eye movements prior to cataract surgery appears to be helpful for later strabismic surgery.      

Adverse drug reactions in children reported by European consumers from 2007 to 2011

Background Information about medicines safety in children is very limited. Consumer adverse drug reaction (ADR) reports can provide information about serious and unknown ADRs from medicine use in children. Objective To characterize ADRs in children reported by consumers in Europe from 2007 to 2011. Methods We analysed ADRs reported to the European ADR database, EudraVigilance (EV) for individuals from birth to 17 years. Data were characterized with respect to age and sex of the child, type of ADR (system organ class and preferred term), seriousness and suspected medicines (anatomical therapeutic chemical classification system level 1 and 5). Results In total, 240 ADR reports corresponding to 670 ADRs were identified. The relatively largest share of ADRs were reported for infants below 1 year followed by teenagers, and 60 % of all ADRs were reported for girls. The majority of ADRs reported were of the general type (20 %) and nervous system disorders (15 %). The largest share of serious ADRs was of the type nervous system disorders (17 % of all serious). Three cases of death were reported. Vaccines and anti-infectives for systemic use contributed to 30 % of ADRs, antineoplastic and immunomodulating agents for 23 % and sex hormones for 13 %. Conclusion Only few paediatric ADR consumer reports were found in EudraVigilance. Many of these ADRs were serious, and fatal cases were reported, however also nonserious reports were present. The findings indicate that consumer reports may be of value in paediatric ADR signal detection.     

Pentoxifylline and propentofylline prevent proliferation and activation of the mammalian target of rapamycin and mitogen activated protein kinase in cultured spinal astrocytes

Astrocyte activation is an important feature in many disorders of the central nervous system, including chronic pain conditions. Activation of astrocytes is characterized by a change in morphology, including hypertrophy and increased size of processes, proliferation, and an increased production of proinflammatory mediators. The xanthine derivatives pentoxifylline and propentofylline are commonly used experimentally as glial inhibitors. These compounds are generally believed to attenuate glial activity by raising cyclic AMP (cAMP) levels and inhibiting glial tumor necrosis factor (TNF) production. In the present study, we show that these substances inhibit TNF and serum‐induced astrocyte proliferation and signaling through the mammalian target of rapamycin (mTOR) pathway, demonstrated by decreased levels of phosphorylated S6 kinase (S6K), commonly used as a marker of mTOR complex (mTORC) activation. Furthermore, we show that pentoxifylline and propentofylline also inhibit JNK and p38, but not ERK, activation induced by TNF. In addition, the JNK antagonist SP600125, but not the p38 inhibitor SB203580, prevents TNF‐induced activation of S6 kinase, suggesting that pentoxifylline and propentofylline may regulate mTORC activity in spinal astrocytes partially through inhibition of the JNK pathway. Our results suggest that pentoxifylline and propentofylline inhibit astrocyte activity in a broad fashion by attenuating flux through specific pathways. © 2012 Wiley Periodicals, Inc.     

Transcobalamin II deficiency at birth

Transcobalamin II deficiency (# MIM 275350) is a rare, recessively inherited disorder of cobalamin transport that leads to intracellular cobalamin depletion with secondary impairment of methionine synthetase and methyl-malonyl CoA mutase activities. Affected individuals may suffer from long-term neurological sequelae if therapy with intramuscular hydroxocobalamin is not initiated promptly. We report two sisters with complete absence of transcobalamin due to homozygosity for a novel mutation (c.insC110) in the TCN2 gene that leads to a premature stop codon and non-functional protein. The older sister, now 4.5 years old, presented at 6 weeks of age with pancytopenia, protein losing enteropathy and a rapidly declining clinical course. Prompt therapy with 1 mg hydroxocobalamin/day led to full recovery within days. Her now 1.5 year old sister was diagnosed shortly after birth and was started on hydroxocobalamin prior to onset of clinical symptoms. Interestingly, urinary methylmalonic acid excretion was increased significantly during the first days of life suggesting that functional cobalamin deficiency is present also during fetal life, although not giving rise to clinical symptoms until well after birth.