Antibiotics from basidiomycetes. 26. Phlebiakauranol aldehyde an antifungal and cytotoxic metabolite from Punctularia atropurpurascens

Phlebiakauranol aldehyde and the corresponding alcohol were isolated from cultures of Punctularia atropurpurascens. The aldehyde but not the alcohol exhibited strong antifungal activity against several phytopathogens as well as antibacterial and cytotoxic activities. Two acetylated derivatives prepared from the aldehyde showed only very weak antifungal and antibacterial and moderate cytotoxic activities. We therefore assume, that the aldehyde group together with the high number of hydroxyl groups are responsible for the biological activity of the compound.     

Preclinical evaluation of coronary vascular function after cardioplegia with HTK and different antioxidant additives.

OBJECTIVE: Due to limited resources, improvement of preservation solutions is still of great importance in cardiac transplant surgery. New additives with antioxidant properties were tested with respect to coronary function of isolated rat hearts. METHODS: Bretschneider HTK solution containing none or an antioxidant additive (deferoxamine, trolox or LK 616) was used for 8h cold cardioplegia. After reperfusion with Krebs-Henseleit buffer (KHB), we assessed vascular dilator capacity (bradykinin, adenosine triphosphate, reactive hyperemia), myocardial function (left ventricular developed pressure, heart rate, oxygen consumption) and release of biochemical markers (aspartate aminotransferase, creatine kinase, lactate dehydrogenase, troponin, adenosine). RESULTS: Bradykinin- and adenosine triphosphate-induced vasodilations were largely reduced in hearts stored 8h in traditional HTK as compared to unstored controls. Storage in HTK+LK 616 significantly improved bradykinin-induced vasodilation. Vasodilation toward ATP was best preserved in hearts stored in HTK+deferoxamine. Deferoxamine and trolox, both improved reactive hyperaemic response during reperfusion. Left ventricular pressure development was significantly reduced after 8h cardioplegia, but no difference existed between different cardioplegia groups. Release of biochemical markers of tissue injury was similar in all cardioplegia groups. After storage in HTK+LK 616 (100 microM), however, heart marker release was slightly augmented as compared to HTK. CONCLUSIONS: Despite similar myocardial function and marker release, coronary vascular function after cardioplegic storage may profit by addition of iron chelators (or antioxidants) to traditional HTK solution.     

Sumatriptan nasal spray in the acute treatment of migraine in adolescents and children

About 4-10% of children and adolescents suffer from migraine. In the last few years, several studies have been performed to assess the efficacy and safety of triptans for the acute treatment of migraine in children and adolescents. Only sumatriptan nasal spray has been approved for the treatment of acute migraine with or without aura in adolescents aged 12-17 years in Europe. This review describes the results of the studies with sumatriptan nasal spray that have been performed in children and adolescents, including a study performed in the Netherlands.     

In vivo and in vitro pharmacokinetic differences between four structurally closely related anthracyclines in hematopoietic cell subtypes in humans

Minor differences in chemical structure of adriamycin (ADM), 4'-epiadriamycin (E-ADM), daunomycin (DNM), and 4-demethoxydaunomycin (D-DNM) lead to large differences between cellular and plasma pharmacokinetic parameters in vivo, as well as in cellular drug handling. Anthracyclines accumulated in cells to several hundred-fold the plasma concentration. Half-lives, as well as the ratio of parent drug/metabolite, differed markedly. The slopes of the in vivo cellular concentration-time curves after the end of the bolus injection resembled the efflux curves observed after a 5-min exposure in vitro. In vivo, the area under the cellular concentration-time curve (AUCc) for equimolar dosages was largest for ADM and smallest for D-DNM. In vitro however, cellular drug levels and AUCc were highest for D-DNM, followed by DNM, E-ADM, and ADM. Final cellular drug concentrations were 300-2500 times the medium concentration, with clearly higher values observed after the 360-min exposure. Minor structural differences were related to considerable variations in cellular drug handling, with different patterns in vivo and in vitro. These studies point to difficulties occurring in the in vitro experimental studies of in vivo pharmacokinetic properties of anthracyclines and stress the need for direct determination of target cell drug concentrations in vivo, in the search for the understanding of cell drug handling-related mechanisms of action of the anthracyclines.     

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration

Communication between leukocytes and endothelial cells is crucial for inflammatory reactions. Paracrine cross-talk and outside-in signaling (via adhesion molecules) have been characterized as communication pathways to date. As leukocytes and endothelial cells express connexins, we considered intercellular communication via gap junctions an intriguing additional concept. We found that gap-junctional coupling between neutrophils and endothelium occurred in a time-dependent, bidirectional manner and was facilitated by adhesion. After blockade of connexins, transmigration of neutrophils through the endothelial layer was enhanced, and the barrier function of cell monolayers was reduced during transmigration. Tumor necrosis factor alpha decreased coupling. In the presence of connexins, transmigration of neutrophils did not alter permeability. Thus, neutrophils couple to endothelium via gap junctions, functionally modulating transmigration and leakiness. Gap-junctional coupling may be a novel way of leukocyte-endothelial communication.     

Head circumference of children with Williams-Beuren syndrome

Head circumference is considered an important parameter of brain growth and development. Syndrome-specific standards for head circumference in Williams-Beuren syndrome (WBS) are not available to date, although mental retardation is a leading manifestation in the syndrome. Therefore, we investigated head growth in 63 girls (251 measurements) and 88 boys (298 measurements) with WBS between birth and adulthood. Most measurements in both sexes were from the first 4 years of life (n = 162 in girls and n = 189 in boys). Mean (±SD) head circumference at birth was 33.39 ± 1.38 cm and 34.02 ± 1.44 cm for term girls and boys, respectively. Although head growth in WBS girls and boys was at a slower velocity, the pattern of head circumference was similar to that in the normal population. After the age of 3 months, head circumference started to fall below the normal mean in girls (0.5–2 cm). In boys, mean head circumference was below the normal mean already at 1 month of age (2 cm). The deficit increased to 3 cm from 6 months to 4 years. Adult OFC was 52.85 ± 1.75 cm (n = 16) compared to 55.70 ± 1.83 cm (n = 46; P < 0.00001) in WBS women and 55.51 ± 1.68 cm (n = 30) compared to 57.87 ± 1.29 cm (n = 31; P < 0.00001) in WBS men. During development, microcephaly is only seen in about one third of WBS patients. © 1994 Wiley-Liss, Inc.     

Microdissection genotyping of mixed glial and primitive neuroectodermal central nervous system neoplasm

A 22-year-old man with previous radiation treatment for childhood astrocytoma underwent resection of a right parietooccipital lesion. Histopathology revealed a malignant neoplasm with areas of astrocytic and primitive neuroectodermal components. To resolve the relationship and cellular origin, representative tissue was microdissected from several targets, obtaining a balanced mixture of each element. Nonneoplastic brain parenchyma was separately microdissected to determine polymorphic marker informativeness and to serve as an internal negative control. Despite the relatively small quantity of tissue removed for each microdissection target, sufficient material was available for reliable, balanced, polymerase chain reaction-format genotyping encompassing a panel of tumor suppressor genes and genetic loci associated with these forms of neoplasia. The findings revealed distinct discordant genotypic profiles for each of the neoplastic components. The efficacy of the approach used for molecular analysis of this complex neoplasm and the implication of the genotypic findings are discussed.     

No evidence for involvement of the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus in early onset obesity

In light of evidence of linkage of obesity to chromosome 2q31-q37, we hypothesized that the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus (NIDDM) is involved in early onset obesity. We screened the NIDDM 'high-risk'-haplotype combination formed by the alleles 112 and 121 of the polymorphisms UCSNP-43, -19, and -63 in 166 families consisting of an extremely obese child or adolescent (mean BMI percentile: 99.3+/-1.38), one or more obese sibs (mean BMI percentile: 97.42+/-2.88), and both of their parents. Genotyping for three calpain-10 gene polymorphisms was performed by polymerase chain reaction (PCR) with (a) length polymorphism detection (UCSNP-19) or (b) allele-specific PCR (UCSNP-43 and -63). To allow for correct haplotype assignment all individuals were additionally genotyped for two microsatellite markers (D2S125 and D2S2338). We followed a hierarchical test procedure. As the first step, model-free linkage analysis was performed using maximum likelihood binomial statistics. The second stage consisted of a one-sided asymptotic pedigree disequilibrium test for the UCSNP-43 and on an exploratory level for the other SNP-markers and all haplotypes formed by the three SNPs. The final stage investigated the reported haplotype combination. We failed to detect an initial linkage of obesity to this region (LOD score <0.4). All subsequent exploratory analyses were negative. Our analysis of the relationship between the NIDDM 'high-risk' haplotype combination and extreme early onset obesity revealed no evidence for linkage and association.