Studies on Propafenone-type Modulators of Multidrug-Resistance IV: Synthesis and Pharmacological Activity of 5-Hydroxy and 5-Benzyloxy Derivatives

A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3 . Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a–d . Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a–d . Structure activity relationship studies showed, that the 5-hydroxy derivates 6a–d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a–d showed almost identical EC₅₀ values, independent of their log P value.     

Electro-encephalographic disturbances due to chronic toxin abuse in young people, with special reference to glue-sniffing

A study was carried out in order to document any abnormalities in the electro-encephalogram (EEG) that might appear in young adolescents who have deliberately inhaled the range of volatile substances loosely referred to as 'glue'. The EEGs of a group of 'street children' being assisted in a Johannesburg shelter were examined. The records were analysed for any clinical abnormalities and also subjected to spectral analysis in order to examine the overall characteristics of frequency, power and spatial distribution. The EEGs clearly revealed that, although at the time of the examination the subjects were ostensibly abstinent, both clinical and normative evidence of continuing brain disturbance was present. It was concluded that glue sniffing is likely to have long term electrocerebral sequelae.     

Activation-induced changes in evoked and slow brain potentials: effect of cocaine in rabbits previously subchronically treated by cocaine

To study the type of adaptive modification (tolerance vs. sensitization) in different organism's indices following intermittent cocaine (COC) administrations, acute COC (2 mg/kg, SC)-induced changes in heart and breathing rate, response to increasing noxious stimulation, spontaneous EEG and event-related evoked and slow brain potentials (ERP) registered from the occipital cortex and hippocampal CA1 region were investigated in naive rabbits and one subchronically treated with COC (6 injections at a same dose). Tolerance developed for bradycardia, depression of noxious responsiveness, cortical desynchronization and increase of main components of cortical ERP, typical to acute COC, while the changes in breathing and hippocampal ERP were stable. These changes as well as a significant increase due to COC administrations of the basal values of an animal's noxious responsiveness and increase in relative changes in main component of cortical ERP (N205) are considered as a consequence of adaptive changes in neurophysiological/neurochemical substrate accepting COC action and mediating phenomena tolerance-sensitization and dependence typical to the drug.     

Alternaria alternata NADP-dependent mannitol dehydrogenase is an important fungal allergen.

BACKGROUND: Alternaria alternata is one of the most important allergenic fungi worldwide. Mannitol dehydrogenase (MtDH) has previously been shown to be a major allergen of Cladosporium herbarum and cross-reactivity has been demonstrated for several fungal allergens. OBJECTIVE: The present study's objective was to clone the MtDH from an A. alternata cDNA library, express and purify the recombinant non-fusion protein and test its IgE-binding properties. Methods A cDNA library prepared from A. alternata hyphae and spores was screened for mannitol dehydrogenase by DNA hybridization with the radioactively labelled C. herbarum homologue as a probe. The resulting clone was sequenced and heterologously expressed in Escherichia coli as a recombinant non-fusion protein, which was purified to homogeneity and analysed for its IgE-binding capacity. RESULTS: The coding sequence of the full-length cDNA clone comprises 798 bp encoding a protein with a molecular mass of 28.6 kDa and a predicted pI of 5.88. Protein sequence analysis revealed an identity of 75% and a homology of 86% between the MtDHs of A. alternata and C. herbarum. The functional mannitol dehydrogenase was expressed in the E. coli strain BL21(DE3) transformed with the vector pMW172 and purified to homogeneity. The enzyme catalyses the NADPH-dependent conversion of d-fructose to d-mannitol. In IgE-ELISA and immunoblots, MtDH is recognized by 41% of A. alternata-allergic patients. In vivo immunoreactivity of the recombinant MtDH was verified by skin prick testing. Finally, inhibition-ELISA experiments confirmed cross-reactivity between the MtDHs of A. alternata and C. herbarum. CONCLUSION: Mannitol dehydrogenase (Alt a 8) represents an important new allergen of the ascomycete A. alternata that might be suitable for improving diagnostic and therapeutic procedures.     

Alternative single anticonvulsant drug therapy for refractory epilepsy

Fifty-nine patients with chronic generalized tonic-clonic or partial seizures refractory to the maximally tolerated daily dosage of single-drug therapy with carbamazepine, phenytoin, phenobarbital, or primidone subsequently received single-drug therapy with another one of these primary anticonvulsant drugs. Alternative single-drug therapy resulted in complete seizure control or more than 75% seizure reduction for 18 patients (31%). Side effects disappeared in 16 patients (27%). Patients with a good therapeutic response often had epilepsy of recent onset. Alternative single-drug therapy is beneficial for chronic refractory epilepsy and should be considered before a second drug is permanently added.     

Differential Stripping: Determination of the Amount of Topically Applied Substances Penetrated into the Hair Follicles

The determination of penetration pathways of topically applied substances into the skin is the subject of several investigations. Recently, follicular penetration has become a major focus of interest. To date, a direct, non-invasive quantification of the amount of topically applied substance penetrated into the follicles had not been possible. The development of such a method was the aim of this study. Therefore, the advantages of both stripping techniques, tape stripping and cyanoacrylate skin surface biopsy, were combined and evaluated. Tape stripping was used to remove the part of the stratum corneum that contained the topically applied dye. Subsequently, the follicular contents were ripped off by cyanoacrylate skin surface biopsy. The combined method termed "differential stripping" was evaluated in vitro and in vivo , and the amount of topically applied fluorescent dye penetrated into the hair follicles was quantified after different penetration times. After 30 min, 5% of the recovered concentration of sodium fluorescein was found in the follicular infundibula, where it was still detectable after 48 h. Altogether, the results of this investigation revealed that differential stripping is a new method that can be used to study the penetration of topically applied substances into the follicular infundibula non-invasively and selectively.     

Präimplantationsdiagnostik, Pränataldiagnostik und Schwangerschaftsabbruch

Preimplantation genetic diagnosis (PGD) has been vigorously debated in Germany ever since the Bundesärztekammer (BÄK) published a draft of guidelines for PGD in March 2000. Many stakeholders such as churches, medical societies, and diverse associations have participated in the discussion. However, little is known about the attitudes of experts, directly affected patient groups, and the public in Germany. In several studies that are part of the German research program on ethical implications of the Human Genome Project, representative surveys were undertaken to assess the attitudes of the general population (n=1017), five relevant expert groups (n=879), and couples at high risk for genetic disorders(n=324) towards PGD and prenatal diagnosis (PD). All groups favor legislation for PGD. Differences exist in regard to the extent of their approval. For 17% of the high-risk couples with a persisting desire for a child, PGD performed in a neighboring country is the most probable reproductive option. These results should be carefully considered in the ongoing legislation process on human reproduction in our country.     

Interactions of Mycobacterium fortuitum with solid sterol substrate particles

Mycobacterium fortuitum NRRL B-8119 transformes sterols into 9 alpha-hydroxy-androsta-4-ene-3,17-dione (9OH-AD) at high efficieny. Cells strongly aggregate to the surface of the sterol particles forming stable agglomerates (“substrate immobilized cells”). Substrate uptake and product formation were studied as function of the size of the sterol particles. Using particle sizes comparable with the size of the mycobacterial cells (> 5μm) highest rates were found for both the substrate uptake and the product formation. After mechanical reinforcement of the contact between mycobacterial cells and the sterol substrate by co-grinding of the components, a significantly increased product formation was observed. Associated cells and cell-sterol agglomerates were investigated by freeze-fracture electron microscopy. The micrographs obtained demonstrate that cells of M. fortuitum are growing into the sterol microcrystallite. The uptake of the sterol substrate is assumed to take place via direct contact between cells and the substrate particles. To understand the transport mechanism a model is proposed that includes a flexible multicomponent mesophase (FMCM) which is placed between cells and particles and which mediates the sterol uptake. The putative FMCM is assumed to be composed of mycobacterial glycolipids, extracellular biolipids, synthetical detergents, sterol and water.