11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) has been proposed as a new target for type 2 diabetes drugs. The aim of the present study was to assess the effects of inhibition of 11 beta-HSD1 on blood glucose levels, glucose tolerance, and insulin sensitivity in mouse models of type 2 diabetes. BVT.2733 is an isoform-selective inhibitor of mouse 11 beta-HSD1. Hyperglycemic and hyperinsulinemic ob/ob, db/db, KKAy, and normal C57BL/6J mice were orally administered BVT.2733 (200 mg/kg.d, twice daily). In hyperglycemic, but not in normal mice, BVT.2733 lowered circulating glucose (to 50-88% of control) and insulin (52-65%) levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT.2733 treatment, and in KKAy mice insulin concentrations were decreased (62-74%). Euglycemic, hyperinsulinemic clamps demonstrated decreased endogenous glucose production (21-61%). Analysis of hepatic mRNA in KKAy mice showed reduced phosphoenolpyruvate carboxykinase mRNA (71%). A slight reduction in food intake was observed in ob/ob and KKAy mice. Cholesterol, triglycerides, and free fatty acid levels were decreased to 81-86% in KKAy mice after a 4-h fast. The results support previous suggestions that selective 11 beta-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.

Oncolytic viruses are a fast-developing cancer treatment field. Numerous viruses have been tested in clinical trials and three are approved. The first, Rigvir, is an immunomodulator with anti-tumour effect for treatment of melanoma, local treatment of skin and subcutaneous metastases of melanoma, for prevention of relapse and metastasis after radical surgery registered in Latvia, Georgia, Armenia and Uzbekistan. The aim of the present review is to summarize the development of Rigvir. Approximately 60 viruses were screened preclinically. Clinical safety and efficacy trials were with 5 oncolytic enteroviruses. Safety of the selected and melanoma-adapted ECHO-7 virus Rigvir was tested in over 180 patients with no severe adverse events observed. Pre-registration efficacy studies involved over 700 cancer patients: over 540 melanoma patients, and patients with late stage stomach (ca. 90), colorectal cancer (ca. 60), and other cancers. Patients were treated with Rigvir for 3 years after surgery and compared to immunotherapy: 3- and 5-year overall survival appeared to be increased in Rigvir treated patients. In post-marketing retrospective studies, Rigvir-treated stage II melanoma patients showed a 6.67-fold decreased risk for disease progression in comparison to those that had been observed according to guidelines, and stage IB and stage II melanoma patients that had received Rigvir therapy had 4.39-6.57-fold lower mortality. The results are confirmed and extended by case reports. Several immunological markers have been measured. In conclusion, Rigvir is an oncotropic and oncolytic virus for treatment of melanoma; the results will be confirmed and updated by modern clinical studies.

An oncolytic, nonpathogenic ECHO-7 virus adapted for melanoma that has not been genetically modified (Rigvir) is approved and registered for virotherapy, an active and specific immunotherapy, in Latvia since 2004. The present retrospective study was carried out to determine the effectiveness of Rigvir in substage IB, IIA, IIB and IIC melanoma patients on time to progression and overall survival. White patients (N=79) who had undergone surgical excision of the primary melanoma tumour were included in this study. All patients were free from disease after surgery and classified into substages IB, IIA, IIB and IIC. Circulating levels of clinical chemistry parameters were recorded. Survival was analysed by Cox regression. Rigvir significantly (P<0.05) prolonged survival in substage IB–IIC melanoma patients following surgery compared with patients who were under observation (according to current guidelines). The hazard ratio for patients under observation versus treated with Rigvir was statistically significantly different: hazard ratio 6.27 for all, 4.39 for substage IIA–IIB–IIC and 6.57 for substage IIB–IIC patients. The follow-up period was not statistically different between both treatment groups. These results indicate that the patients treated with Rigvir had a 4.39–6.57-fold lower mortality than those under observation. In this study, there was no untoward side effect or discontinuation of Rigvir treatment. Safety assessment of adverse events graded according to NCI CTCAE did not show any value above grade 2 in Rigvir-treated patients. In conclusion, Rigvir significantly prolongs survival in early-stage melanoma patients without any side effect.

1. Mechanisms controlling the secretion of [³H]noradrenaline from the noradrenergic nerves of guinea‐pig isolated vas deferens, prelabelled by incubation with [³H]noradrenaline, were studied using (a) different modes of (extramural or transmural) electrical nerve stimulation (a total of 300 shocks of varying strength, and a duration of 2 msec) at 1‐30 Hz, or (b) depolarizing concentrations of K⁺ (60‐110 m m).2. The fractional rise in efflux of ³H‐labelled material (Δt) was used to measure the secretion of [³H]noradrenaline.3. The dependence of [³H]noradrenaline secretion on the external Ca²⁺ concentration (1‐8 m m) was essentially hyperbolic. Double reciprocal plot analysis (1/Δt vs. 1/Ca²⁺) of the data yields that blockade of α‐autoinhibition (phentolamine 1 μ m) does not increase the maximal secretory velocity, but does enhance the apparent affinity of the secretory mechanism for external Ca²⁺. Exogenous noradrenaline has (qualitatively) opposite effects. The interaction between α‐autoinhibition and external Ca²⁺ thus shows a ‘competitive’ pattern, indicating that restriction of the utilization of external Ca²⁺ is a major mechanism in α‐autoinhibition of noradrenaline secretion, in this system.4. Phenoxybenzamine (10 μ m) and phentolamine (1 μ m) increased the secretion of [³H]noradrenaline evoked by depolarization with K⁺ much less than that caused by electrical nerve stimulation (frequencies up to 10 Hz). Exogenous noradrenaline (1‐5 μ m) depressed the secretion evoked by both modes of stimulation. The results indicate that α‐autoinhibition of [³H]noradrenaline secretion is mainly operative when the secretory stimulus requires conduction of nerve impulses between varicosities.5. The frequency dependence of [³H]noradrenaline secretion was hyperbolic, both in the presence and in the absence of α‐autoinhibition; at each frequency the secretion (Δt per shock) increased with the Ca²⁺ concentration in the medium (0·6‐8 m m). Double reciprocal plot analysis (1/Δt vs. 1/frequency) of the data yields that the pattern of interaction between external Ca²⁺ and facilitation depends on the presence or absence of α‐autoinhibition (phentolamine 1 μ m); in the former case it is ‘non‐competitive’, in the latter ‘competitive’. Similar analysis of the effect of facilitation by increasing the length of stimulus trains (from 5 to 300 pulses) at a constant frequency (5 Hz), on the Ca²⁺ dependence of Δt (1/Δt vs. 1/Ca²⁺) in the absence of α‐autoinhibition also yields that facilitation promotes utilization of external Ca²⁺. These results apparently imply that a rise in external Ca²⁺, in the presence of α‐autoinhibition, augments the secretory response to electrical nerve stimulation mainly by promoting recruitment of active units (varicosities?), without markedly altering their ‘affinity’ for facilitation. In the absence of autoinhibition (when all units are already recruited?), the results seem to imply that facilitation promotes depolarization‐secretion coupling in each, by more efficient utilization of external Ca²⁺.6. The pattern of interaction between α‐autoinhibition and facilitation depends on the Ca²⁺ concentration in the medium. At or below the physiological level of Ca²⁺ in extracellular fluid (1·2 m m) it is ‘non‐competitive’, indicating that α‐autoinhibition and facilitation act, at least in part, at separate targets under these conditions. At high (5·4 m m) external Ca²⁺ the pattern becomes almost purely ‘competitive’, indicating that facilitation can, under suitable conditions, overcome all manifestations of α‐autoinhibition.7. The secretion evoked by electrical nerve stimulation (Δt per shock, at 1 or 10 Hz) increased with the strength of applied shocks, both when applied extra‐ or transmurally, in the presence or absence of α‐autoinhibition. In the former case the rise in (Δt per shock) vs. (current strength) was hyperbolic, in the latter it followed a biphasic pattern. Double reciprocal plot analysis (1/Δt vs. 1/current) of the data yields a ‘non‐competitive’ pattern of interaction between facilitation or α‐autoinhibition, and exogenous current, when stimulation was extramural. When it was transmural the pattern is ‘competitive’. The results seem to imply that hyperpolarization, or depolarization, of nerve terminals are major mechanisms whereby α‐autoinhibition and facilitation, respectively, exert their effects on the secretory response to electrical nerve stimulation.8. Neither activation of Na⁺, K⁺‐ATPase, nor promotion of G_Cl appear to be critically involved in α‐autoinhibition. Experiments with known blockers of G_K (tetraethylammonium, 4‐aminopyridine and Rb⁺) did not give support to the notion that promotion of K⁺ efflux is a mechanism whereby prejunctional α‐adrenoceptors cause (hyperpolarization of nerve terminals and) autoinhibition of secretion. If α‐autoinhibition does involve K⁺ channels in the nerve terminal membrane, then these must be different from the (voltage‐sensitive) K⁺ channels blocked by the above mentioned inhibitors of K⁺ efflux.9. The results are discussed in the context of a model that assumes that local control of noradrenaline secretion from noradrenergic nerves may be exerted both by control of invasion of terminals, and by control of depolarization—secretion coupling in each invaded varicosity. Under suitable conditions facilitation and α‐autoinhibition may interact at both levels. It proposed that utilization of external Ca²⁺ plays a pivotal role for both, and that restriction of invasion of nerve terminal varicosities is the main effect of α‐autoinhibition, while promotion of depolarization—secretion coupling is the main effect of facilitation, at physiological concentrations of Ca²⁺ in the medium. For the nerve the role of this dual control system is proposed to be to ensure ‘rotational’ activation of varicosities, and for the effector cell of noradrenergic junctions, to increase the signal/noise ratio.