[Cannabis and cannabinoids-easier access, hype and disappointment : What has been confirmed in therapy?] / Cannabis und Cannabinoide ­ erleichterter Zugang, Hype und Enttäuschung : Was ist gesichert in der Therapie?

BACKGROUND: Cannabis products are being increasingly liberalized all over the world and there is a huge interest in cannabis-based medicine. OBJECTIVES: Presentation of current studies on the efficacy of different cannabis-based medicine for the treatment of various diseases CURRENT DATA: In German pharmaceutical legislation, nabiximols is approved for the treatment of moderate to severe therapy-resistant spasticity in multiple sclerosis and nabilone is approved for the treatment of therapy-resistant chemotherapy-associated nausea and vomiting. In case of therapy failure cannabinoids, as part of an individual therapeutic attempt, may be considered for the treatment of chronic pain (neuropathic pain, cancer pain, non-neuropathic noncancer pain), cachexia in human immunodeficiency virus as well as for Dravet and Lennox-Gastaut syndrome. From the authors' perspective there is not enough evidence for the use in chemotherapy-associated nausea and vomiting and chronic non-neuropathic pain. CONCLUSIONS: Currently, a wide use of cannabinoids does not seem probable in the near future. Further studies involving more patients and evaluating long-term effects are necessary.

[Cannabinoid therapy in practice]. / Cannabinoidtherapie in der Praxis.

BACKGROUND: In recent years, the media and scientists have shown increased interest in cannabis-based drugs. OBJECTIVES: Background information about cannabis-based drugs and their mechanism of action as well as discussion of possible applications as supportive therapy or in palliative medicine, respectively, are presented. MATERIALS AND METHODS: The recent literature was examined and evaluated. RESULTS: In many medical fields, we do not have sufficient evidence for the efficacy of cannabinoids. In German pharmaceutical legislation, the use of nabiximols for the treatment of intermediate to severe, therapy-resistant spasticity in multiple sclerosis is the only approved indication for cannabis-based drugs. Furthermore, in view of the current evidence cannabinoids, combined with established treatments and as part of an individual therapeutic attempt, can be used for neuropathic pain, cancer-associated pain and human immunodeficiency virus (HIV)-related cachexia. CONCLUSIONS: In most cases, today's assessment of cannabinoids relies on studies that are classified as low evidence. Therefore, further studies which involve more participants and evaluate long-term effects are needed.

[Drug-induced angioedema : Focus on bradykinin]. / Arzneimittelassoziierte Angioödeme : Bradykinin im Fokus.

On a pathophysiological level, angioedema can be differentiated into histamine- and bradykinin-mediated types. The prototype drug-associated, bradykinin-mediated form of angioedema is angiotensin-converting enzyme (ACE) inhibitor-induced angioedema. The hypothesized cause is a decrease in bradykinin degradation via ACE inhibition. In this scenario, other bradykinin-degrading enzymes assume major importance. When the effect of these enzymes is also diminished, e. g., due to genetic variants or external factors, compensation for the inhibition of ACE may be insufficient. An increased risk of angioedema has also been reported for other drugs, particularly when prescribed in combination with ACE inhibitors. Here, the suspected cause also relates to the degradation of bradykinin. When angioedema arises within the context of concomitant ACE inhibitor use, additive bradykinin degradation effects may be implicated.

Homozygosity for a factor XII mutation in one female and one male patient with hereditary angio-oedema.

Hereditary angio-oedema (HAE) with normal C1 inhibitor is associated with heterozygous mutations in the factor XII gene (FXII-HAE). We report two Brazilian FXII-HAE families segregating the mutation c.983 C>A (p.Thr328Lys). In each family, one patient with a homozygous mutation was found. The homozygous female patient in family 1 displayed a severe phenotype. However, this falls within the clinical phenotype spectrum reported for heterozygous female mutation carriers. The homozygous male patient in family 2 also showed a severe phenotype. This finding is intriguing, as to our knowledge, it is the first such report for a male FXII-HAE mutation carrier. In the rare instances in which male mutation carriers are affected, a mild phenotype is typical. The present findings therefore suggest that homozygous FXII-HAE mutation status leads to a severe phenotype in females and males, and to an increased risk of manifest symptoms in the latter.

Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients.

BACKGROUND: The first classification of angioedema without wheals was recently reported and comprises different forms of the disease distinguished by aetiology, mediator of oedema and inheritance. METHODS: In total, 1725 consecutive patients with angioedema without wheals were examined at our centre between 1993 and 2012. We excluded from the analysis 667 patients because of incomplete data or because angioedema was related to a specific factor. RESULTS: According to the new classification of angioedema, the 1058 patients included in this analysis were diagnosed with hereditary (HAE; n = 377) or acquired angioedema (AAE; n = 681). The former group included HAE with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE; n = 353) and HAE with normal C1-INH levels (n = 24), of which six had a factor XII mutation (FXII-HAE) and 18 had disease of unknown origin (U-HAE). The AAE group included disease with C1-INH deficiency (C1-INH-AAE; n = 49), AAE related to angiotensin-converting enzyme inhibitor treatment (n = 183), idiopathic histaminergic (IH-AAE; n = 379) and idiopathic nonhistaminergic angioedema (InH-AAE; n = 70). We compared hereditary and AAE with uncertain aetiopathogenesis: the FXII-HAE and U-HAE groups pooled (FXII/U-HAE) versus InH-AAE. The median age at onset of FXII/U-HAE and InH-AAE was 26 and 38 years, respectively. In addition, 56% of patients with FXII/U-HAE and 81% of those with InH-AAE reported more than five attacks per year (median duration of 48 h). The location of angioedema in patients with FXII/U-HAE versus those with InH-AAE was the following: face, 70% versus 86%; tongue, oral cavity or larynx, 55% versus 68%; limbs, 70% versus 56%; and gastrointestinal mucosa, 50% versus 20%. Prophylaxis with tranexamic acid was effective in all six patients with U-HAE and in 37 of 38 with InH-AAE who were started on this treatment. CONCLUSION: Our findings in this cohort of patients with angioedema provide new information on the clinical characteristics, diagnosis and treatment of this disease.

Paramecium--a model system for studying cellular graviperception.

Experiments under varied gravitational accelerations as well as in density-adjusted media showed that sensation of gravity in protists may be linked to the known principles of mechanosensation. Paramecium, a ciliate with clear graviresponses (gravitaxis and gravikinesis) is an ideal model system to prove this hypothesis since the ciliary activity and thus the swimming behaviour is controlled by the membrane potential. It has also been assumed that the cytoplasmic mass causes a distinct stimulation of the bipolarly distributed mechano-sensitive K+ and Ca2+ ion channels in the plasma membrane in dependence of the spatial orientation of the cell. In order to prove this hypothesis, different channel blockers are currently under investigation. Gadolinium did not inhibit gravitaxis in Paramecium, showing that it does not specifically block gravireceptors. Further studies concentrated on the question of whether second messengers are involved in the gravity signal transduction chain. Exposure to 5 g for up to 10 min led to a significant increase in cAMP.

Effect of cyclooxygenase inhibition in a canine model of unilateral pulmonary occlusion and reperfusion.

OBJECTIVE: To assess the effects of the cyclooxygenase inhibitor diclofenac in a canine model of pulmonary occlusion and reperfusion of the left lower lobe (LLL). DESIGN: Twelve adult beagle dogs (13-17 kg) were randomly assigned to a control group (n = 6) and a diclofenac-treated group (n = 6). Animals in the treatment group received 20 mg diclofenac sodium/kg as a single dose both before the experiment and at the end of surgical preparation; six animals served as controls. INTERVENTIONS: In the anesthetized animals, the left upper and middle lobes were resected. Circulation and ventilation of the LLL were selectively blocked by clamping. Complete occlusion of the LLL (30 min) was followed by periods of selective reperfusion (10 min, RP) and combined reperfusion and reventilation (120 min, RP/RV). MEASUREMENTS AND RESULTS: Reperfusion of the LLL resulted in a significant increase in pulmonary arterial pressure (Ppa) in the early RP/RV period as compared to baseline values (25.3 +/- 4.7 vs 15.8 +/- 1.9 mmHg, p < 0.05, paired t-test). This increase was significantly inhibited in the diclofenac-treated animals (17.0 +/- 2.0 mmHg, p < 0.01 vs controls, ANOVA). Gravimetrically determined extravascular lung water (EVLW) showed no significant difference in the continuously ventilated lobes of the right lung between diclofenac-treated animals (3.8 ml/g dry weight) and controls (3.9 +/- 0.9 ml/g dry weight) at the end of the experiment. EVLW, however, increased significantly in the LLL of control animals after 2 h of combined reperfusion and reventilation, whereas this increase was significantly inhibited in the diclofenac-treated animals (4.5 +/- 0.7 ml/g dry weight in the diclofenac group vs 6.5 +/- 1.3 ml/g dry weight in the control group, p < 0.05). CONCLUSIONS: Diclofenac inhibits the increase in both pulmonary arterial pressure and EVLW during reperfusion and reventilation of LLL. Thus, these changes appear to be mediated by cyclooxygenase metabolites.