Neurobiology and systems physiology of the endocannabinoid system.

Endocannabinoids are synthesised from lipid precursors, are released from postsynaptic neurons in an activity-dependent way, and act as retrograde signalling messengers on specific G (i)-protein-coupled cannabinoid (CB (1)) receptors on presynaptic terminals. Hence, endocannabinoids are in a strategic position to regulate transmitter release. CB (1)-receptors are abundant on GABAergic, glutamatergic and dopaminergic synapses and play an essential role in a variety of cognitive processes and in the control of behaviour. The endocannabinoid system is not only the target of the psychoactive components of the hemp plant (tetrahydrocannabinol from hashish and marijuana) but has also been exploited for drugs acting as agonists (e.g. dronabinol) or antagonists (e.g. rimonabant) of the CB (1)-receptor. The former drugs exert orexigenic effects and can be used for the mitigation of anorexia e.g. in cancer patients, but have also been used for the treatment of multiple sclerosis. The latter have been used to treat adipositas. The role of the endocannabinoid system in the development of drug dependence has been discussed controversially, but recent evidence suggests that chronic stimulation of the endocannabinoid system may facilitate drug dependence.

Megestrol acetate for treatment of anorexia and cachexia associated with human immunodeficiency virus infection.

Cachexia is a common problem in persons infected with the human immunodeficiency virus (HIV). Megestrol acetate, an agent used for the treatment of metastatic breast cancer, is associated with appetite stimulation and weight gain. To determine whether this drug might benefit HIV-positive patients, 22 such subjects (14 previously reported) were treated with oral megestrol acetate, beginning at a dose of 80 mg four times daily. All patients had lost at least 10% of their preillness weight prior to treatment; the median loss was 11.4 kg (range, 5.5 to 26.8). Preliminary data from patients observed during therapy from 2 to 72 weeks showed that 21 of the 22 patients gained weight; the average weight gain was 7.3 kg (range, -4.1 to 17.3). Three patients failed to gain weight on 320 mg per day of megestrol acetate; both appetite stimulation and weight gain were achieved with 460 mg per day in one and 640 mg per day in another. One patient continued to lose weight despite 480 mg per day megestrol acetate. The median time to peak weight during megestrol acetate treatment was 14 weeks. Seven patients returned to within 1 kg of their normal body weight. In three of the 22 patients treated, megestrol acetate and zidovudine were started simultaneously. For these three patients, weight gain was potentially due to the recognized weight gain associated with the initiation of zidovudine. For the remaining 18 patients, however, appetite stimulation and weight gain were a result of megestrol acetate. All patients tolerated the drug well. One patient developed a deep vein thrombosis. No patient developed peripheral edema or drug-related impotence. The appetite improvement and weight gain seen in this initial series are encouraging. The true effectiveness of megestrol acetate for HIV-related cachexia and the effects of treatment on quality of life are currently being assessed in a national prospective, randomized, double-blind, placebo-controlled trial.

Heroin spongiform leukoencephalopathy (HSLE).

PURPOSE: An increasing number of heroin addicts-especially young and first-time users-prefer inhaling the drug to intravenous injection. A rare complication of inhaling heroin is the development of a spongiform leukoencephalopathy (HSLE). METHODS: Pathological background, symptoms, imaging, and therapeutical options are discussed on the basis of an example case. RESULTS: Pathophysiologically, a dysfunction of the oligodendrocyte mitochondria is suspected. Three distinct stages based on key symptoms are defined. Patients may remain in one stage, or pass through two, or all three stages. Magnetic resonance imaging (MRI) is necessary for diagnosis. There are few therapeutical options. Antioxidants and coenzyme Q may be beneficial. The disorder is self-limiting in the majority of cases. Complications such as hydrocephalus and diffuse cerebellar swelling may, however, require neurosurgical intervention. CONCLUSIONS: HSLE is a rare occurrence in patients with heroin abuse. The number of undetected cases in drug-related deaths may be high. Clinical appearance may be easily mistaken for withdrawal symptoms.

Acute myocardial infarction and cardiogenic shock: prognostic impact of cytokines: INF-γ, TNF-α, MIP-1ß, G-CSF, and MCP-1ß.

BACKGROUND: The IABP SHOCK trial was designed as a morbidity-based randomized controlled trial to determine the effect of intraaortic balloon pulsation (IABP) in patients with infarct-related cardiogenic shock (CS). The primary endpoint was the change in the APACHE II score over a 4-day period. The prospective hypothesis was that adding IABP therapy to "standard care" would reduce CS-triggered multiorgan dysfunction syndrome (MODS). The primary endpoint showed no difference between conventionally managed cardiogenic shock patients and those with additional IABP support. In an inflammatory marker substudy, we analyzed the prognostic value of the cytokines interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1ß (MIP-1ß), granulocyte-colony stimulating factor (G-CSF), and monocyte chemoattractant protein-1ß (MCP-1ß). We also investigated the influence of IABP support, age, and gender on cytokine levels. DESIGN: The inflammatory marker substudy of the prospective, randomized, controlled, open label IABP SHOCK Trial (ClinicalTrials.gov ID NCT00469248). MATERIALS AND METHODS: A prospective, randomized, single-center study in a 12-bed intensive care unit at a university hospital was performed. A total of 40 consecutive patients were enrolled. The observational period was 96 h. RESULTS: The investigated cytokines showed a significant contribution in the prediction of mortality. Initial (on admission) and maximal cytokine levels during the observational period showed a similar predictive power. Patients with elevated levels of pro- and antiinflammatory cytokines had a higher risk of dying. The maximal level measured over the observation period in the hospital was also suited to identify the survivors. Close correlations between maximal cytokine levels resulted in the choice of only one independent marker (MIP-1ß) into the multivariate model (OR 1.024, 95% CI 1.005-1.043). Initial cytokine levels were also suitable to predict the survivors; the risk of death significantly increases with increasing IFN-γ level (OR 1.119, 95% CI 1.005-1.246). Cytokine levels were not affected by the presence of IABP support. Age (< 75 or > 75 years) and gender did not have a clinically relevant effect on INF-γ, TNF-α, MIP-1ß, G-CSF, and MCP-1 in CS patients. CONCLUSION: The inflammatory response in patients with myocardial infarction complicated by CS, as reflected by the inflammatory markers INF-γ, TNF-α, MIP-1ß, G-CSF, and MCP-1ß, have been shown to be of prognostic value in estimating clinical outcome.