[NOAC: Real-life data and the role of antidotes for the treatment of bleeding]. / NOAK: Real-life-Daten und Therapie von Blutungen mit Antidots.

The non-vitamin K antagonists (NOAC) are an integral component of our antithrombotic prevention and therapy. For four of the NOAC, their non-inferiority or even superiority versus vitamin K antagonists (VKA) has been proven. Thus, the management of special patient cohorts or the management of active bleeding complications is a focus of current discussion.In addition to prospective trials, numerous retrospective analyses of health insurers or public health provider data have been analyzed and published as "real life" or "real-world evidence" data. In almost all data sets the results of the NOAC approval trials were confirmed, demonstrating their non-inferiority or even superiority versus VKA. Attempts to compare the various NOAC with each other must be viewed critically since the real-world evidence (RWE) analysis provides very divergent results depending on the cohorts analyzed. Thus, a substantial prescriber-bias must be taken into account and never be excluded.In order to improve the management of bleeding complications, NOAC antidotes were developed. While the factors Xa antidote, andexanet alpha, a modified coagulation factor deleted of an intrinsic activity, will not be available before 2018, the dabigatran antidote idarucizumab is already in clinical use. Idarucizumab, a monoclonal antibody fragment directed against dabigatran, is able to completely antagonize the effect of dabigatran within minutes. Therefore, the drug has the potential to terminate life-threatening bleeding complications earlier and make emergency surgical or interventional procedures possible without an elevated bleeding risk.

Use of folk tests to detect ciguateric fish: a scientific evaluation of their effectiveness in Raivavae Island (Australes, French Polynesia).

Ciguatera fish poisoning is a seafood intoxication commonly afflicting island communities in the Pacific. These populations, which are strongly dependent on fish resources, have developed over centuries various strategies to decrease the risk of intoxication, including the use of folk tests to detect ciguateric fish. This study aims to evaluate the effectiveness of two folk tests commonly used in Raivavae Island (Australes, French Polynesia): the rigor mortis test (RMT) and the bleeding test (BT). A total of 107 fish were collected in Raivavae Lagoon, among which 80 were tested by five testers using the RMT versus 107 tested by four testers using BT. First, the performance between testers was compared. Second, the efficiency of these tests was compared with toxicity data obtained via the receptor binding assay (RBA) by assessing various parameter's values such as sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). Comparisons of outcomes between folk tests and RBA analyses were considered: tests used separately or in a parallel versus the series approach by each tester. The overall efficiency of the RMT and BT tests was also evaluated when the judgments of all testers were "pooled". The results demonstrate that efficiencies varied between testers with one showing the best scores in detecting toxic fish: 55% with RMT and 69.2% with BT. BT gave the best results in detecting toxic fish as compared with RMT, giving also better agreement between testers. If high NPV and Se values were to be privileged, the data also suggest that the best way to limit cases of intoxication would be to use RMT and BT tests in a parallel approach. The use of traditional knowledge and a good knowledge of risky versus healthy fishing areas may help reduce the risk of intoxication among communities where ciguatera fish poisoning is highly prevalent.

Protective effect of Heliotropium foertherianum (Boraginaceae) folk remedy and its active compound, rosmarinic acid, against a Pacific ciguatoxin.

ETHNOPHARMACOLOGICAL RELEVANCE: Senescent leaves of Heliotropium foertherianum Diane & Hilger (Boraginaceae) are traditionally used in the Pacific region to treat Ciguatera Fish Poisoning. This plant contains rosmarinic acid that is known for its multiple biological activities. In the present study, H. foertherianum aqueous extract, rosmarinic acid and its derivatives were evaluated for their capacity to reduce the effect of ciguatoxins. MATERIALS AND METHODS: Aqueous extract of H. foertherianum leaves was prepared and studied for its effects against a Pacific ciguatoxin (P-CTX-1B) in the neuroblastoma cell assay and the receptor binding assay. Rosmarinic acid and six derivatives were also evaluated by means of these bioassays. For this purpose, we have developed an improved synthetic route for caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE). RESULTS: Both the aqueous extract of H. foertherianum leaves and rosmarinic acid showed inhibitory activities against a Pacific ciguatoxin in the above bioassays. Among all the molecules that were evaluated, rosmarinic acid was the most active compound. CONCLUSION: These results confirm further the potential of H. foertherianum in the treatment of Ciguatera Fish Poisoning.

A review of traditional remedies of ciguatera fish poisoning in the Pacific.

Ciguatera fish poisoning (CFP) is an illness caused by eating tropical coral fish contaminated with ciguatoxins (CTXs). The clinical management of patients with CFP is generally supportive and symptomatic in nature as no antidote exists. Of the many drugs prescribed, several have been claimed to be efficient in small, uncontrolled studies, but the outcomes of treatments with these medicines are often contradictory. In New Caledonia, traditional remedies are commonly employed in the treatment of CFP and of the 90 plant species catalogued as useful in CFP, the most popular herbal remedy by far is a decoction prepared from the leaves of Heliotropium foertherianum Diane & Hilger (Boraginaceae). Other important plants used in the treatment of CFP include Euphorbia hirta L. (Euphorbiaceae) and Vitex L. sp. (Lamiaceae). This review focuses on the evidence for efficacy of these species and pharmacological studies which support their use. Other plants used in CFP and the conventional treatment of CFP are also discussed briefly.

Characterisation of the anti-inflammatory potential of Vitex trifolia L. (Labiatae), a multipurpose plant of the Pacific traditional medicine.

AIM OF THE STUDY: Vitex trifolia L. (Labiatae) is a plant commonly employed against Ciguatera Fish Poisoning (CFP) in the Pacific region. Here, the anti-inflammatory potential of an aqueous extract of Vitex trifolia leaves was evaluated by monitoring its effects on the modulation of cytokines, the mediators of inflammation, as well as on the expression profiles of inducible nitric oxide synthase (iNOS) which produces the free radical nitric oxide (NO). MATERIALS AND METHODS: We prepared an aqueous extract from Vitex trifolia leaves and evaluated its anti-inflammatory potency by monitoring its effect on the lipopolysaccharide (LPS)-induced cytokines and iNOS mRNA over-production in RAW 264.7 macrophages using quantitative Polymerase Chain Reaction (qPCR) and Enzyme-Linked Immunosorbent Assay (ELISA) methods. RESULTS: Aqueous extract of Vitex trifolia leaves showed significant dose- and time-dependent inhibitory activity on interleukin (IL)-1 beta, IL-6 and iNOS mRNA synthesis, but slight effect on tumor necrosis factor (TNF)-alpha, all of which are involved in the inflammatory response. Moreover, the plant extract seemed to induce the LPS-dependent IL-10 anti-inflammatory cytokine. These results were further confirmed by ELISA using specific antibodies to mouse IL-6, IL-10 and TNF-alpha. CONCLUSION: The anti-inflammatory effects of Vitex trifolia could validate its utilization as a traditional remedy against CFP and emphasises its potential therapeutic value against other inflammatory diseases. Therefore, this plant is a promising candidate for further screening of its active compounds through activity-guided fractionation.

Ciguatera risk assessment in two toxic sites of French Polynesia using the receptor-binding assay.

Ciguatera Fish Poisoning (CFP) is a tropical syndrome well known in remote archipelagos where the population is still dependent on fish resources. In order to assess the ciguatera risk in two islands of French Polynesia, Tubuai (Australes) and Nuku Hiva (Marquesas), a study was carried out on both Gambierdiscus populations as well as on various fish species using the receptor-binding assay (RBA) to detect and quantify ciguatoxins. Relationship between RBA data and size or weight of fish was evaluated, and when only few individuals for a particular species were available the trophic level was used to help comparisons between studied areas. According to epidemiological data, toxic versus safe areas were explored and compared in both islands. In Tubuai Island, Gambierdiscus cells were surprisingly absent in the north area, considered as a toxic area, but almost 94% of fishes were classified as RBA+. In contrast, the south area, supposed to be safe, was evolving to be a risky area because of the presence of Gambierdiscus cells and 74% of fishes being RBA+. In Nuku Hiva Island, Gambierdiscus cells were present in the toxic areas, Anaho, Taiohae and Taipivei, with two toxic blooms in Anaho Bay, but none in Terre Déserte, the fishing area of this island. With RBA data, fishes were analyzed to be RBA+ at a high percentage in Anaho and Taiohae, higher than in Taipivei and Terre Déserte areas. In general, our findings were congruent with epidemiological data and the knowledge of local people only for risky fish species.

[Inhibition of platelet aggregation and thromboxane formation by the calcium antagonist nisoldipine following a single oral dose of 10 mg. A double-blind study in healthy probands]. / Hemmung der Plättchenaggregation und Thromboxanbildung durch den Calcium-Antagonisten Nisoldipin nach einer oralen Einmaldosis von 10 mg. Eine Doppelblind-Crossover-Studie bei gesunden Probanden.

The influence of the calcium antagonist nisoldipine on collagen-induced platelet aggregation and platelet thromboxane formation was studied ex vivo in healthy male volunteers in a double-blind, placebo-controlled crossover design. Measurements of general haemodynamics, immunoreactive 6-oxo-prostaglandin F1 alpha and thromboxane B2 ex vivo and collagen-induced (0.6 and 2.5 micrograms/ml) platelet aggregation were performed immediately before (time 0), 0.5 h, 1 h and 2 h after ingestion of 10 mg nisoldipine or an identical placebo tablet. Compared with the control response at time 0, administration of nisoldipine resulted in a significant inhibition of both low-collagen-induced platelet aggregation and formation of immunoreactive thromboxane B2 at time 0.5 h. There were no changes in heart rate or systolic blood pressure but a significant decrease in diastolic blood pressure by nisoldipine at 1 h. No such change was obtained with placebo and there were also no alterations with nisoldipine in platelet aggregation and thromboxane formation after stimulation by high-dose collagen at this or any other time of the study. The data demonstrate a platelet-inhibitory potential of nisoldipine in healthy men which is probably related to an increased resistance of the platelet membrane against foreign stimuli.