Serum cystatin C concentration as a marker of acute renal dysfunction in critically ill patients

The second part of this review addresses the treatment and prognosis of the vasculitides Wegener's granulomatosis, microscopic polyangiitis, Churg–Strauss syndrome and polyarteritis nodosa. Treatment regimens consist of an initial remission phase with aggressive immunosuppression, followed by a more prolonged maintenance phase using less toxic agents and doses. This review focuses on the initial treatment of fulminant vasculitis, the mainstay of which remains immunosuppression with steroids and cyclophosphamide. For Wegener's granulomatosis and microscopic polyangiitis plasma exchange can be considered for first-line therapy in patients with acute renal failure and/or pulmonary haemorrhage. Refractory disease is rare and is usually due to inadequate treatment. The vasculitides provide a particular challenge for the critical care team. Particular aspects of major organ support related to these conditions are discussed. Effective treatment has revolutionized the prognosis of these conditions. However, mortality is still approximately 50% for those requiring admission to intensive care unit. Furthermore, there is a high morbidity associated with both the diseases themselves and the treatment.     

Effects of sulindac on myeloid precursors growth in vitro

We have studied the effects of sulindac and its main active metabolites on human bone marrow progenitors. Granulocytic-macrophagic colony forming units (CFU-GM) techniques were used for assessment. As in vitro inhibitory action of this drug or its metabolites on CFU-GM growth could not be demonstrated. These results refute the clinically presumed toxicity of sulindac on human bone marrow progenitors at pharmacological doses.     

Levels of insulin in the brains of rats modified by chronic administration of amphetamine, haloperidol and sulpiride

Rats treated with two classic neuroleptic drugs at therapeutic doses, haloperidol (0.05 mg/kg/day i.p.) and sulpiride (3 mg/kg/day i.p.) showed a marked decline in cerebral levels of insulin (0.085 +/- 0.02 ng/g and 0.120 +/- 0.04 ng/g wet weight respectively) compared to the control group (0.383 +/- 0.05 ng/g wet weight), while rats given D-amphetamine bitartrate chronically (20 mg/kg/day p.o.) showed an increase in cerebral insulin (0.55 +/- 0.04 ng/g wet weight). Combining treatment with each neuroleptic drug and amphetamine, at the same doses, produced a significant decrease in cerebral levels of insulin (P less than 0.001) as in the amphetamine animals. In the groups of rats treated with haloperidol, sulpiride and both of these drugs combined with amphetamine, there was a slight increase in levels of serum insulin, more so in the neuroleptic groups. Serum glucose values did not vary.     

Characterization of opioid receptor-mediated regulation of incertohypothalamic dopamine neurons: lack of evidence for a role of 5-hydroxytryptaminergic neurons in mediating the stimulatory effects of morphine.

The purpose of the present study was to characterize opioid receptor-mediated regulation of incertohypothalamic dopaminergic (DA) neurons in the rat brain by examining the acute effects of selective mu or kappa opioid receptor agonists and antagonists on concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the medial zona incerta (MZI) and the dorsomedial hypothalamic nucleus (DMN) which contain cell bodies and terminals, respectively, of these neurons. Morphine caused a dose- and time-related increase in concentrations of DOPAC in MZI and DMN; this stimulatory effect was blocked by the mu opioid receptor antagonist naltrexone. In contrast, activation or blockade of kappa opioid receptors following administration of U-50,488 or nor-binaltorphimine, respectively, had no effect on DOPAC concentrations in either the MZI or DMN. The basal activity of incertohypothalamic DA neurons and their response to morphine was similar in male and female rats. Morphine also increased the concentrations of 5-hydroxyindoleacetic acid in MZI and DMN, indicating that morphine increases the activity of 5-hydroxytryptamine (5HT) neurons projecting to these regions. This might suggest that morphine-induced activation of incertohypothalamic DA neurons is mediated by 5HT neurons; but 5,7-dihydroxytryptamine-induced lesions of 5HT neurons did not alter the ability of morphine to increase DOPAC concentrations in MZI and DMN. These results indicate that the stimulatory effects of mu opioid receptor activation on incertohypothalamic DA neurons is not dependent upon the presence of 5HT neurons.     

Synthesis and preliminary pharmacological study of thiophene analogues of the antipyretic and analgesic agent ethenzamide.

A preliminary pharmacological study of a thiophene analogue 1b of the analgesic and antipyretic agent Ethenzamide and of a closely related compound 1a showed that a great similarity exists among Ethenzamide and the thiophenic compounds for analgesic, antipyretic, ulcerogenic, hypothermic, and sedative effects. However, the acute toxicity in mice for the thiophenic compounds is notably higher than that of Ethenzamide.     

Allogeneic bone marrow transplantation versus chemotherapy in the treatment of childhood acute lymphoblastic leukemia in second complete remission

Seventy-six patients between the ages of 2 and 17 years with acute lymphoblastic leukemia (ALL) achieved a second complete remission induced by polychemotherapy. Twenty-one had an HLA-identical donor and underwent allogeneic bone marrow transplantation (BMT) after conditioning with total body irradiation and cyclophosphamide. The remaining 55 patients lacked a suitable donor and received intensive chemotherapy as treatment. Fifteen patients were excluded from the analysis because they relapsed within 3 months after achieving a second complete remission. Three of the 21 BMT patients died of transplant-related complications and seven relapsed between 90 and 480 days after transplantation. Eleven patients are alive and disease free at 5.5-71 months with an actuarial survival of 47.1%; eight patients are on a plateau extending from 22 to 71 months. Thirty-three patients treated with chemotherapy died from relapse and seven are alive and disease free 7.5-99 months from the second remission, with an actuarial survival of 9%. The probability of survival was significantly higher in the BMT group (p less than 0.025). The probability of remaining in complete remission in the BMT group was 58.5% versus 10.9% in the chemotherapy group (p less than 0.005). Our results show that BMT is the best alternative therapy for children affected by ALL who have had a relapse in the marrow.     

High-dose intra-arterial urokinase for the treatment of hepatic artery thrombosis in liver transplantation

Two recipients of orthotopic liver transplants (OLT) underwent intra-arterial thrombolytic treatment for hepatic artery thrombosis. Complete clot lysis was achieved in both using infusion of high-dose urokinase directly into the thrombus for 12 and 3 hours, respectively. Percutaneous transluminal angioplasty (PTA) was later carried out successfully on various strictures. Doppler ultrasonography confirmed arterial permeability one month after treatment. Liver transplantation is now an accepted therapeutic option in some patients with irreversible liver failure. Although the results of this procedure have improved radically since cyclosporine was introduced in 1978, life-threatening postoperative complications still occur. The one with the worst prognosis is hepatic artery thrombosis (HAT), with 64% mortality despite retransplantation. HAT was found in 7.4% of liver transplant recipients in a recent review of the most important group of these patients. Fibrinolytic treatment using an exogenous plasminogen activator, urokinase (UK), is effective and safe in the thrombotic obstruction of acute pulmonary embolism, acute myocardial infarction, and graft or peripheral arterial occlusion. We used intra-arterial thrombolysis in two patients with HAT of the liver graft, to avoid retransplantation and to treat a complication secondary to percutaneous transluminal angioplasty (PTA) of an anastomotic stricture, respectively. To our knowledge, this is the first report of treatment of HAT by direct infusion of urokinase in liver transplantation.     

Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes

Cannabis extracts and synthetic cannabinoids are still widely considered illegal substances. Preclinical and clinical studies have suggested that they may result useful to treat diverse diseases, including those related with acute or chronic pain. The discovery of cannabinoid receptors, their endogenous ligands, and the machinery for the synthesis, transport, and degradation of these retrograde messengers, has equipped us with neurochemical tools for novel drug design. Agonist-activated cannabinoid receptors, modulate nociceptive thresholds, inhibit release of pro-inflammatory molecules, and display synergistic effects with other systems that influence analgesia, especially the endogenous opioid system. Cannabinoid receptor agonists have shown therapeutic value against inflammatory and neuropathic pains, conditions that are often refractory to therapy. Although the psychoactive effects of these substances have limited clinical progress to study cannabinoid actions in pain mechanisms, preclinical research is progressing rapidly. For example, CB(1)mediated suppression of mast cell activation responses, CB(2)-mediated indirect stimulation of opioid receptors located in primary afferent pathways, and the discovery of inhibitors for either the transporters or the enzymes degrading endocannabinoids, are recent findings that suggest new therapeutic approaches to avoid central nervous system side effects. In this review, we will examine promising indications of cannabinoid receptor agonists to alleviate acute and chronic pain episodes. Recently, Cannabis sativa extracts, containing known doses of tetrahydrocannabinol and cannabidiol, have granted approval in Canada for the relief of neuropathic pain in multiple sclerosis. Further double-blind placebo-controlled clinical trials are needed to evaluate the potential therapeutic effectiveness of various cannabinoid agonists-based medications for controlling different types of pain.     

Anxiolytic-like effect of a serotonergic ligand with high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors

S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-alpha]-pyrazine (CSP-2503) is a serotonin (5-HT) receptor ligand with selectivity and high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. CSP-2503 reduced rectal temperature and 5-HT neuronal hypothalamic activity in mice, decreased electrical activity of raphe nuclei cells in rats and blocked the enhancement of adenylate cyclase activity induced by forskolin in HeLa cells transfected with the human 5-HT1A receptor. This compound also blocked head-twitches induced by the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Contractions of guinea pig ileum induced by the 5-HT3 receptor agonist 2-methyl-5-HT were prevented by CSP-2503. Moreover, it reduced the bradycardia reflex induced by 2-methyl-5-HT in anaesthetized rats. In the light/dark box and social interaction tests, CSP-2503 presented anxiolytic activity, an action shared by 5-HT1 agonists and 5-HT3 antagonists. Taken together, these results suggest that CSP-2503 is a new 5-HT1 receptor agonist with 5-HT2A and 5-HT3)receptor antagonist activities that might be useful in a number of conditions associated with anxiety.