(E)-5-(2-bromovinyl)-2'-desoxyuridine--a new nucleoside analog with selective inhibitory action against herpesviruses. Studies in cell culture and animal experiments

(E)-5-(2-Bromovinyl)-2'-deoxyuridine (1; BrVUdR) inhibits the replication of herpes simplex virus type 1 (HSV-1) and of varicella-zoster virus (VZV) in vitro at concentrations of 0.01 to 0.23 mumol/l, whereas herpes simplex virus type 2 (HSV-2) is influenced only at 5.5 to 27 mumol/l. In comparison to some classical and newly developed antiherpetics, i. e. 5-iodo-2'-desoxyuridine (2; idoxuridine, IDU), 9-beta-D-arabinofuranosyladenine (4; vidarabine Ara-A), 9-(2-hydroxyethoxymethyl) guanine (5; acyclovir, ACV) and 2'-fluoro-5-iodo-1-beta-D-aracytosine (6;FIAC) the following order of decreasing activity was found:1 greater than 6 greater than 5 greater than 2 greater than 4 (against HSV-1) and 6 greater than 2 greater than 5 greater than 1 greater than 4 (against HSV-2). The high selectivity of the antiviral effect of BrVUdR towards HSV-1 and TZV is based on the fact, that proliferation of different mammalian cell lines is inhibited by 50% only at concentrations as high as 90 to 170 mumol/l, resulting in a therapeutical index of 1000 to 10,000. Successful treatment of an HSV-1 encephalitis in mice as well as an HSV-1 keratitis of rabbits confirmed the efficiency of 1 in experimental animal infections. No toxic side effects in both local and systemic applications were observed. Promising data from cell culture and animal experiments recommend 1 as a potential candidate for the local and systemic treatment of HSV-1 and VZV infections in man.     

经内镜注射硬化剂治疗食管静脉曲张(附15例报告)

经内镜注射5％鱼肝油酸钠治疗食管静脉曲张15例,共注射45次。其肝功能按Child分级,A级1例,B级8例,C级6例。曾经作过脾切除,分流或断流术者7例。8例急症出血患者经用硬化疗法获得了止血成功。1例急症患者死亡。6例作了择期预防出血的注射,治疗后均得到改善。治疗出血方面,硬化疗法在15例患者中14例有效,随访6～12月无再出血。     

Postextrasystolic regulation patterns of blood pressure and heart rate in patients with idiopathic dilated cardiomyopathy

Assessment of fluctuations in heart rate (HR) following a premature ventricular complex (PVC) is valuable for identifying patients at high risk of sudden cardiac death. We hypothesised that postextrasystolic potentiation is the main determinant of the regulation patterns of blood pressure (BP) and HR following a PVC. Twelve patients with idiopathic dilated cardiomyopathy (IDC) and 13 control subjects with single PVCs (comparable coupling intervals) were investigated. Non-invasive finger arterial BP and ECGs were analysed. Regulation patterns following a single PVC were quantified using the indices postextrasystolic amplitude potentiation (PEAP) and maximum turbulence slope of five consecutive mean BP values (MBP-TS), and compared with the HR turbulence parameters turbulence slope (HR-TS) and turbulence onset (HR-TO). PEAP was significantly higher in IDC patients compared to controls (48.7 ± 32.6 vs. 9.8 ± 5.4 %, P < 0.01), whereas MBP-TS was lower (0.97 ± 0.60 vs. 2.07 ± 1.04 mmHg BBI⁻¹ (BBI, beat-to-beat interval), P < 0.05), as was HR-TS (8.46 ± 7.90 vs. 30.73 ± 22.90 ms BBI⁻¹, P < 0.01). HR-TO was significantly higher in IDC patients (−0.56 ± 2.19 vs. −5.52 ± 4.13 %, P < 0.01). In addition, the regulation patterns of BP and HR following a single PVC differed significantly between IDC patients and controls. Specifically, we observed pronounced PEAPs in IDC patients. The baroreflex response initiated by the low pressure amplitude of the PVC was suppressed in IDC patients due to the augmented potentiation of the first postextrasystolic blood pressure. Furthermore, IDC patients displayed impressive postextrasystolic pulsus alternans phenomena, whereas healthy subjects exhibited a typical baroreflex pattern. The pulsus alternans phenomenon seems to be triggered by a PVC.     

Correlation Between In Vivo Antipyrine Metabolite Formation and Theophylline Metabolism in Rats

Two model substrates for oxidative hepatic enzyme activity, viz. antipyrine (A) and theophylline (T), were given simultaneously to rats by iv administration. Blood concentrations of A and T were measured by a high-performance liquid chromatographic (HPLC) method. Urinary excretions of A, T, and the major metabolites arising from A—4-hydroxyantipyrine (OHA), norantipyrine (NORA), 3-hydroxymethylantipyrine (HMA), and 4,4-dihydroxyantipyrine (DOHA)—and from T—1-methyluric acid (1-MU) and 1,3-dimethyluric acid (1,3-DMU)—were also determined by HPLC. It was found that the pharmacokinetic parameters obtained after the simultaneous administration of A and T at relatively low dose levels (A, 5.0 mg; and T, 1.3 mg) were not different from those obtained after the separate administration of A or T at the same dose level. In order to investigate whether the metabolic pathways of A and T are mediated by the same or closely related forms of the cytochrome P-450 system, metabolic clearances of A (CL_A,M) and T (CL_T,M) and the clearances for production of their various metabolites, obtained in untreated rats and in rats pretreated with 3-methylcholanthrene (MC) or with MC followed by 9-hydroxyellipticine (E), were correlated. These two compounds are a selective cytochrome P-448 inducer and inhibitor, respectively. Strong correlations were found between CL_T,M and the clearances for production of OHA, NORA, and DOHA but not HMA. The best correlation, however, was observed between CL_T,M and CL_OHA, not only when all data points were taken into account (r = 0.99), but also in separate pretreatment groups (r ranging from 0.87 to 0.92). Moreover, the slopes of these correlation lines varied only slightly among groups, while the intercepts were not significantly different from zero. In the separate pretreatment groups, the correlation coefficients for the correlations between CL_T,M and the clearance for production of the other metabolites of A were considerably lower, while the slopes of the correlation lines varied substantially. Clearances for production of the metabolites of T were strongly correlated with each other (r = 0.99) and with CL_OHA (r = 0.95). It can be concluded that theophylline metabolism and formation of OHA are mediated by the same or very similar forms of cytochrome P-450, whereas formation of the other major metabolites of A is not or only partly. The study of the various pathways of metabolism after simultaneous administration of drugs is a powerful tool in the study of correlations in drug metabolism in vivo.     

Continuous infusion of low-dose doxorubicin, epirubicin and mitoxantrone in cancer chemotherapy: A review

With the recent development of reliable portable pumps and safe venous access systems, continuous infusion of chemotherapeutic agents on an out-patient basis has become feasible. Advantages of continuous infusion are the long-term exposure of tumour cells to the drug and the fact that most toxic effects are reduced for doxorubicin, epirubicin and mitoxantrone due to elimination of the high peak plasma levels. Preliminary data for doxorubicin suggest that its antitumour activity is maintained. Pharmacokinetic studies with epirubicin and mitoxantrone showed a linear relationship between drug dose infused and the steady-state plasma level for these drugs. The area under the curve for leukocytes drug level was higher during continuous infusion than after an equitoxic bolus injection of epirubicin and mitoxantrone. Well-randomized clinical trials will be necessary to investigate the role of continuous infusion of antracyclines and mitoxantrone in cancer chemotherapy in the future.     

Experiences,considerations and emotions relating to cardiogenetic evaluation in relatives of young sudden cardiac death victims

Relatives of young sudden cardiac death (SCD) victims are at increased risk of carrying a potentially fatal inherited cardiac disease. Hence, it is recommended to perform an autopsy on the victim and to refer his or her relatives to a cardiogenetics clinic for a full evaluation to identify those at risk and allow preventive measures to be taken. However, at present, the number of families attending a cardiogenetics clinic after the SCD of a young relative is low in the Netherlands. We performed a qualitative study and report on the experiences and attitudes of first-degree relatives who attended a cardiogenetics clinic for evaluation. In total, we interviewed nine first-degree relatives and one spouse of seven SCD victims about their experiences, considerations and emotions before attendance and at the first stage of the cardiogenetic evaluation before DNA results were available. Interviews were transcribed verbatim and analysed. Medical professionals did not have an important role in informing or referring relatives to a cardiogenetics clinic. Importantly, all participants indicated that they would have appreciated a more directive approach from medical professionals, because their mourning process hampered their own search for information and decision-making. A need to understand the cause of death and wanting to prevent another SCD event occurring in the family were the most important reasons for attending a clinic. There are possibilities to improve the information process and better support their decision-making. The multidisciplinary cardiogenetic evaluation was appreciated, but could be improved by minor changes in the way it is implemented.     

Effects of arginine-vasopression on regional blood volume distribution in supine humans

Summary In healthy humans, the increase in arterial blood pressure seen in patients with autonomic dysfunction in response to exogenous vasopressin (AVP) is abolished. We tested the hypothesis that redistribution of blood from the intra- to the extrathoracic vascular compartment might contribute to this buffer response. Regional distribution of^99mTc labeled autologous red cells was assessed in healthy supine volunteers (n=7) during arginine-vasopressin administration (1 ng·kg^–1 bolus i.v. followed by a 14-min infusion of 3 ng·kg^–1·min^–1), along with arterial and central venous pressures, and heart rate. Exogenous vasopressin increased plasma vasopressin concentration from 4.0±1.4 SEM to 91 pg·ml^–1±12. Thoracic counts increased slightly but significantly by 2.2%±0.9, while global abdominal counts remained unchanged. Most surprisingly, counts in the liver markedly increased (+8.1%±1.8, p=0.02), but significantly decreased in the spleen (–3.1%±1.4). Intestinal (–2.5%±2.4) and limb counts did not change significantly. Consistent with the increase in thoracic counts centralvenous pressure increased from 3.6 mm Hg±1 to 4.7±1 (p=0.02), while arterial pressure and heart rate did not change. All changes reversed towards baseline when vasopressin administration ceased. Thus, in humans with an intact autonomic system, vasopressin, at concentrations observed during hypotension, increases liver and, albeit to a small extent, also thoracic blood volume, but decreases splenic blood content. These results 1) are incompatible with the hypothesis that AVP induces a shift of blood from intra- to extrathoracic capacitance vessels, and 2) show that AVP increases rather than decreases central blood volume.