Phenotyping of CYP 4501A2 Activity by Total Overnight Salivary Caffeine Assessment (TOSCA) in Patients on Warfarin Treatment: A Cross-Sectional Study.

Warfarin is an oral anticoagulant, commonly used for primary and secondary prevention of venous and arterial thromboembolic events. The drug is characterized by narrow therapeutic index, widespread individual variability in clinical response, and high rates of adverse events, particularly bleeding complications. For these reasons, a close monitoring of the dosage, using the frequent assessment of coagulation status by means of International Normalized Ratio value, is mandatory. Warfarin is metabolized by hepatic cytochrome P-450. High CYP 450 activity may lead to low drug concentration and requires high warfarin doses to reach efficacy; conversely, low CYP 450 activity is responsible for high drug concentration and needs for low doses to avoid potential toxicity risks. The major isoforms of CYP involved in the metabolism of warfarin sodium are CYP1A2 (for the R-warfarin) and CYP2C9 (for the S-warfarin). The probes for testing CYP1A2 are phenacetin and caffeine while for CYP2C9 tolbutamide. Although S-warfarin has major activity, it was decided to exclude its phenotyping for ethical issues, being mandatory to use a drug (tolbutamide). Instead, it was chosen to test the 1A2 isoform, as the activity of the latter isoform could be investigated by using caffeine contained in the caffeinated beverages. Specifically, a single-point concentration of salivary caffeine (total overnight salivary caffeine assessment [TOSCA]) after an overnight period of the caffeinated beverages abstinence was utilized. In the present study, 75 nonsmoker patients regularly receiving warfarin sodium were enrolled. The results have showed a significant association of the warfarin dose with TOSCA values (coefficient = -0.15, standard error = 0.04, 95% confidence interval = -0.24 to -0.06, t = -3.23, P = .002). In conclusion, the phenotyping of CYP1A2 by TOSCA could be useful, if further proven, to help manage patients on warfarin in order to lessen severe adverse events.

Evaluation of effectiveness and safety of a herbal compound in primary insomnia symptoms and sleep disturbances not related to medical or psychiatric causes.

BACKGROUND AND PURPOSE: Sleep disturbances and related daytime activities impairment are common diseases nowadays. General practitioners are often the first health care professional asked to alleviate sleep disturbances and primary insomnia symptoms. Beyond a wide class of hypnotic drugs, botanicals can represent an alternative treatment for those kinds of symptoms. The scope of the present study is to evaluate safety and effectiveness of a herbal compound composed of valerian, hop, and jujube (Vagonotte®) on primary insomnia symptoms and sleep disturbances not related to medical or psychiatric causes. PATIENTS AND METHODS: One hundred and twenty subjects with sleep disturbances symptoms were randomized in two branches of 60 persons each, receiving the herbal compound or placebo at dosage of two pills per day 30 minutes before their scheduled bedtime. All subjects were screened for precise items related to sleep quality and daytime activity at the beginning, after 10 days, and after 20 days of consecutive dietary supplement (or placebo) consumption. The participants remained blind to group assignment until all of them completed the trial. RESULTS: Sleep onset, numbers of nocturnal awakenings, and overall nocturnal slept time were assessed. A statistically significant difference between the two groups emerged. The group receiving the herbal compound showed a lower time of sleep onset compared to placebo group, the same result was obtained for total slept time and night awakenings frequency (p<0.001). Daily symptom improvement in subjects receiving the herbal compound showed significant reduction in tension and irritability, difficulty in concentration, and fatigue intensity, if compared to placebo scores (p<0.001). None of the 60 subjects in the verum group reported adverse reaction related to the herbal compound, and 98% of subjects judged the product as having from good to excellent safety and tolerability. CONCLUSION: Botanicals dietary supplement with relaxing and soothing properties can help practitioner to treat primary insomnia, especially when the risk/benefit profile of a patient does not sustain hypnotic drugs prescription. This clinical investigation on safety and effectiveness of a herbal compound made of valerian, hop, and jujube opens interesting perspectives on usage of herbal compound to manage primary insomnia. Further investigations could help in understanding herbal compounds' effectiveness on sleep disturbances.

Oral anticoagulant drugs and the risk of osteoporosis: new anticoagulants better than old?

Several drugs have been associated with an increased risk of osteoporosis when used chronically. Coumarins (warfarin, acenocoumarol, phenprocoumon, and fluindione) are oral anticoagulants widely used for the prevention and treatment of arterial and venous thromboembolic diseases. These drugs are vitamin K antagonists that interfere with γ-carboxyglutamate formation, and consequently inhibit the carboxylation of glutamate residues of proteins that are synthesized in the bone. These effects on bone turnover and dietary restrictions in patients on anticoagulation are possible mechanisms inducing osteoporosis in coumarin users. However, conflicting evidence is available concerning the risk of osteoporosis and bone fractures in patients on treatment with these drugs. This risk is likely to be clinically relevant in long-term (more than 1 year) coumarin users. Novel direct oral anticoagulants, recently introduced in clinical practice, exert reduced interference on bone metabolism; however, limited in vitro and animal data are currently available, and their long-term effects will only become apparent in time.