Why portal hypertensive varices bleed and bleed: a hypothesis.

Continued bleeding or early rebleeding is associated with a poor prognosis in patients with variceal haemorrhage. It is not clear why bleeding stops in some patients and continues or restarts in others. It is suggested that secondary haemodynamic changes in the splanchnic circulation after a bleed may contribute to the risk of further bleeding. These changes include the effects of hypotension on portocollateral resistance, the effects of blood in the gut on splanchnic blood flow, and the effects of blood volume expansion on portal venous pressure during resuscitation. These factors, working in concert, cause a secondary rise in portal venous pressure, which may precipitate further bleeding. Treatment aimed at preventing these secondary haemodynamic changes may be beneficial. It is probable that somatostatin and octreotide could act in this way, which may explain their therapeutic efficacy.     

The Riluzole Derivative 2-Amino-6-trifluoromethylthio-benzothiazole (SKA-19), a Mixed KCa2 Activator and NaV Blocker,is a Potent Novel Anticonvulsant

Inhibitors of voltage-gated sodium channels (Na_v) have been used as anticonvulsants since the 1940s, while potassium channel activators have only been investigated more recently. We here describe the discovery of 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a thioanalog of riluzole, as a potent, novel anticonvulsant, which combines the two mechanisms. SKA-19 is a use-dependent Na_V channel blocker and an activator of small-conductance Ca²⁺-activated K⁺ channels. SKA-19 reduces action potential firing and increases medium afterhyperpolarization in CA1 pyramidal neurons in hippocampal slices. SKA-19 is orally bioavailable and shows activity in a broad range of rodent seizure models. SKA-19 protects against maximal electroshock-induced seizures in both rats (ED₅₀ 1.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED₅₀ 4.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED₅₀ 12.2 mg/kg), Frings audiogenic seizure-susceptible mice (ED₅₀ 2.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED₅₀ 5.5 mg/kg). Toxicity tests for abnormal neurological status revealed a therapeutic index (TD₅₀/ED₅₀) of 6–9 following intraperitoneal and of 33 following oral administration. SKA-19 further reduced acute pain in the formalin pain model and raised allodynic threshold in a sciatic nerve ligation model. The anticonvulsant profile of SKA-19 is comparable to riluzole, which similarly affects Na_V and KCa2 channels, except that SKA-19 has a ~4-fold greater duration of action owing to more prolonged brain levels. Based on these findings we propose that compounds combining KCa2 channel-activating and Na_v channel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-014-0305-y) contains supplementary material, which is available to authorized users.     

Drug use and initiation in prison: results from a national prison survey in England and Wales

Aims  To investigate heroin and cocaine use in a sample of British prisoners, and to explore the characteristics of inmates who use these drugs for the first time while in prison.
Design, participants  A cross-sectional survey of all prisons in England and Wales conducted as part of a major national study of psychiatric morbidity. A total of 3142 prisoners (88.2% of those selected) completed a structured interviewer-administered questionnaire.
Measurements  Interview measures of personal demographics, social history, psychiatric morbidity and drug use. Personality disorders were diagnosed via the Structured Clinical Interview for DSM-IV (SCID-II) and neurotic symptoms were assessed using the revised Clinical Interview Schedule (CIS-R).
Findings  More than 60% of the heroin users and cannabis users reported that they had used these drugs in prison compared with less than a quarter of the life-time cocaine users. More than a quarter of the heroin users reported that they had initiated use of this drug in prison. The extent of an individual's experience of prison was related more consistently to heroin and/or cocaine use in and out of prison than other personal background, social history or psychiatric variables assessed.
Conclusions  The findings indicate that prisons are a high-risk environment for heroin and other drug initiation and use. Although related to drug use, psychiatric variables were not generally associated with initiation in prison, which was dominated by prison exposure. There is a need to explore ways of reducing heroin initiation in prison as part of a broader risk-prevention strategy.