PHARMACOKINETICS AND SAFETY OF SINGLE INTRAVENOUS AND ORAL DOSES OF DOLASETRON MESYLATE IN HEALTHY WOMEN

Twenty-four healthy women received 2·4 mg kg⁻¹ dolasetron mesylate (1·8 mg kg⁻¹ dolasetron base) by a 10 min intravenous administration and by oral administration. Pharmacokinetics of dolasetron and of its active reduced metabolite MDL 74 156 were monitored for 48 h in plasma. Urine was collected from 0 to 48 h, blood pressure and heart rate were measured at 0, 0·08, 1, 2, 12, 24, and 36 h, and ECGs were measured at 0, 0·08 (intravenous only), 1, 2, and 36 h after dosing. Dolasetron was widely distributed and rapidly reduced (mean t_1/2=0·23 h) to MDL 74 156 (mean t_1/2=8·05 and 9·12 h after intravenous and oral administration respectively). MDL 74 156 was extensively distributed; between 27 (oral route) and 33% (intravenous route) was eliminated unchanged in urine. Safety assessment showed mild to moderate headache, dizziness, and hot flushes after the intravenous administration and headache, abdominal cramps or pain, and constipation after oral administration. Small and clinically non-significant changes in PR, QRS, and QT_c intervals were observed. We conclude that there is no obvious difference in dolasetron pharmacokinetics between healthy women and men and that dolasetron can be used as safely in women as in men. ©1997 by John Wiley & Sons, Ltd.     

精液质量的正常参考值与男性生育能力

最近的研究表明:如果男性精液中精子密度低于40×106/mL,其生育能力就会随精子密度减少而相应下降。然而最新出版的《世界卫生组织人类精液分析实验室技术手册》第5版将正常精液密度的下限值,从原来的20×106/mL降低到15×106/mL。鉴于这一改动,全世界很大一部分生育能力低下的男性,将被认为"正常"而得不到适当的男科治疗。     

Tetrodotoxins Secretion and Voltage-Gated Sodium Channel Adaptation in the Ribbon Worm Kulikovia alborostrata (Takakura, 1898) (Nemertea)

Nemertea is a phylum of marine worms whose members bear various toxins, including tetrodotoxin (TTX) and its analogues. Despite the more than 30 years of studying TTXs in nemerteans, many questions regarding their functions and the mechanisms ensuring their accumulation and usage remain unclear. In the nemertean Kulikovia alborostrata, we studied TTX and 5,6,11-trideoxyTTX concentrations in body extracts and in released mucus, as well as various aspects of the TTX-positive-cell excretion system and voltage-gated sodium (Nav1) channel subtype 1 mutations contributing to the toxins’ accumulation. For TTX detection, an immunohistological study with an anti-TTX antibody and HPLC-MS/MS were conducted. For Nav1 mutation searching, PCR amplification with specific primers, followed by Sanger sequencing, was used. The investigation revealed that, in response to an external stimulus, subepidermal TTX-positive cells released secretions actively to the body surface. The post-release toxin recovery in these cells was low for TTX and high for 5,6,11-trideoxyTTX in captivity. According to the data obtained, there is low probability of the targeted usage of TTX as a repellent, and targeted 5,6,11-trideoxyTTX secretion by TTX-bearing nemerteans was suggested as a possibility. The Sanger sequencing revealed identical sequences of the P-loop regions of Nav1 domains I–IV in all 17 studied individuals. Mutations comprising amino acid substitutions, probably contributing to nemertean channel resistance to TTX, were shown.     

人内原性逆转录病毒基因表达及在染色体上的分布和功能与I型糖尿病的关系

目的 从病毒形态,基因表达,免疫,遗传及分子生物学角度来自四位新近发病的Ⅰ型糖尿病（ＩＤＤＭ）病人的胰腺等组织标本进行了研究。方法 从电子显微镜下观察糖尿病病人胰腺的ｂｅｔａ细胞胞浆中有Ｃ型病毒颗粒。从这些组织的互补ＤＮＡ基因库里检测内原性逆转录病毒ｐｏｌ基因的表达并分析研究它们的序列。结果 糖尿病病人组的ｐｏｌ基因表达与对照组相比有显著差异,特别是ＥＲＶ９,ＨＥＲＶ－Ｋ－ＭＬＮ,ＨＥＲＶＫ－Ｋ１     

Mitochondrial defects by intracellular calcium overload versus endothelial cold ischemia/reperfusion injury

Abstract Questions as to the critical stress factor and primary targets of cold ischemia/reperfusion (CIR) injury were addressed by comparing mitochondrial defects caused by (1) CIR injury and (2) intracellular Ca²⁺ overload. CIR was simulated in transformed human umbilical vein endothelial cell cultures (tEC) by 8 h cold anoxia in University of Wisconsin solution and reoxygenation at 37°C. Intracellular Ca²⁺ concentrations were changed by permeabilization of suspended cells with digitonin in culture medium (RPMI, 0.4 mM Ca²⁺). Binding of free Ca²⁺ by ethylene glycol‐bis(β‐aminoethylether)‐N,N,N',N'‐tetraacetic acid in RPMI or mitochondrial incubation medium served as controls. Extracellular Ca²⁺ protected the cell membrane against permeabilization. Mitochondrial functions were determined before and after permeabilization of the cell membrane. After CIR, mitochondrial respiratory capacity declined, but oxygen consumption remained coupled to adenosine triphosphate (ATP) production. In contrast, Ca²⁺ overload caused uncoupling of mitochondrial respiration. High intracellular Ca²⁺ overload, therefore, does not reproduce cold ischemia/reperfusion injury in endothelial cells.     

Gnathodiaphyseal dysplasia: a syndrome of fibro-osseous lesions of jawbones, bone fragility, and long bone bowing.

We report an unusual generalized skeletal syndrome characterized by fibro-osseous lesions of the jawbones with a prominent psammomatoid body component, bone fragility, and bowing/sclerosis of tubular bones. The case fits with the emerging profile of a distinct syndrome with similarities to previously reported cases, some with an autosomal dominant inheritance and others sporadic. We suggest that the syndrome be named gnathodiaphyseal dysplasia. The patient had been diagnosed previously with polyostotic fibrous dysplasia (PFD) elsewhere, but further clinical evaluation, histopathological study, and mutation analysis excluded this diagnosis. In addition to providing a novel observation of an as yet poorly characterized syndrome, the case illustrates the need for stringent diagnostic criteria for FD. The jaw lesions showed fibro-osseous features with the histopathological characteristics of cemento-ossifying fibroma, psammomatoid variant. This case emphasizes that the boundaries between genuine GNAS1 mutation-positive FD and other fibro-osseous lesions occurring in the jawbones should be kept sharply defined, contrary to a prevailing tendency in the literature. A detailed pathological study revealed previously unreported features of cemento-ossifying fibroma, including the participation of myofibroblasts and the occurrence of psammomatoid bodies and aberrant mineralization, within the walls of blood vessels. Transplantation of stromal cells grown from the lesion into immunocompromised mice resulted in a close mimicry of the native lesion, including the sporadic formation of psammomatoid bodies, suggesting an intrinsic abnormality of bone-forming cells.     

Synthesis,Self-Assembly and In Vitro Cellular Uptake Kinetics of Nanosized Drug Carriers Based on Aggregates of Amphiphilic Oligomers of N-Vinyl-2-pyrrolidone

Development of nanocarrier-based drug delivery systems is a major breakthrough in pharmacology, promising targeted delivery and reduction in drug toxicity. On the cellular level, encapsulation of a drug substantially affects the endocytic processes due to nanocarrier–membrane interaction. In this study we synthesized and characterized nanocarriers assembled from amphiphilic oligomers of N-vinyl-2-pyrrolidone with a terminal thiooctadecyl group (PVP-OD). It was found that the dissolution free energy of PVP-OD depends linearly on the molecular mass of its hydrophilic part up to M¯n = 2 × 10⁴, leading to an exponential dependence of critical aggregation concentration (CAC) on the molar mass. A model hydrophobic compound (DiI dye) was loaded into the nanocarriers and exhibited slow release into the aqueous phase on a scale of 18 h. Cellular uptake of the loaded nanocarriers and that of free DiI were compared in vitro using glioblastoma (U87) and fibroblast (CRL2429) cells. While the uptake of both DiI/PVP-OD nanocarriers and free DiI was inhibited by dynasore, indicating a dynamin-dependent endocytic pathway as a major mechanism, a decrease in the uptake rate of free DiI was observed in the presence of wortmannin. This suggests that while macropinocytosis plays a role in the uptake of low-molecular components, this pathway might be circumvented by incorporation of DiI into nanocarriers.     

Influence of volatile organic compounds emitted by Pseudomonas and Serratia strains on Agrobacterium tumefaciens biofilms

The ability to form biofilms plays an important role in bacteria‐host interactions, including plant pathogenicity. In this work, we investigated the action of volatile organic compounds (VOCs) produced by rhizospheric strains of Pseudomonas chlororaphis 449, Pseudomonas fluorescens B‐4117, Serratia plymuthica IC1270, as well as Serratia proteamaculans strain 94, isolated from spoiled meat, on biofilms formation by three strains of Agrobacterium tumefaciens which are causative agents of crown‐gall disease in a wide range of plants. In dual culture assays, the pool of volatiles emitted by the tested Pseudomonas and Serratia strains suppressed the formation of biofilms of A. tumefaciens strains grown on polycarbonate membrane filters and killed Agrobacterium cells in mature biofilms. The individual VOCs produced by the tested Pseudomonas strains, that is, ketones (2‐nonanone, 2‐heptanone, 2‐undecanone), and dimethyl disulfide (DMDS) produced by Serratia strains, were shown to kill A. tumefaciens cells in mature biofilms and suppress their formation. The data obtained in this study suggest an additional potential of some ketones and DMDS as protectors of plants against A. tumefaciens strains, whose virulence is associated with the formation of biofilms on the infected plants.