Evaluation of a program of integrated care to reduce recurrent osteoporotic fractures.

PURPOSE: To evaluate the outcomes of patients participating in a program of integrated care for osteoporosis in terms of medication supply, fracture incidence and expenses. METHODS: Outcomes were assessed from secondary data provided by the AOK PLUS health insurance for 2455 participants of the program and the same number of matched controls who were also diagnosed with osteoporosis but did not participate in the program. Supply with Calcium and Vitamin D, antiresorptive agents and analgesics was assessed by defined daily doses. Osteoporotic fractures were identified by hospitalization data. Costs for fracture treatment, medication supply and additional expenses of the program were also included in the dataset. RESULTS: Patients enrolled in the program of integrated care received significantly more medication to treat osteoporosis than controls. There was no significant reduction in fracture incidence among participants of integrated care, but a reduced need of analgesics was noted. Additional costs for patients enrolled in the program were caused by a higher number of drug prescriptions, higher costs for stationary treatment and additional expenses for program related care and diagnostics. CONCLUSIONS: The program of integrated care was not found to be effective in reducing recurrent fractures. Cost effectiveness defined as a reduced rate of fractures in integrated care patients could not be shown by the assessed outcome measures. This missing reduction in fracture incidence may be explained by a non-sufficient improvement - compared to a placebo-controlled clinical trial - in medication supply and non-comparability of our real-world patient population with highly controlled clinical trial participants.

Efficacy and tolerability of oral lactoferrin supplementation in mild to moderate acne vulgaris: an exploratory study.

OBJECTIVE: Lactoferrin, an innate defense iron-binding protein, possesses antimicrobial and anti-inflammatory activities. Beneficial systemic effects on inflammatory diseases have been proposed. The aim of the present study was to explore the efficacy and tolerability of oral bovine lactoferrin supplementation in subjects with mild to moderate facial acne vulgaris. METHODS: In this open-label, single-arm study, 43 adolescents and young adults were enrolled to take a chewable tablet formulation of bovine lactoferrin twice daily for 8 weeks. The primary efficacy endpoint was the improvement in acne lesion counts compared with baseline. Tolerability was evaluated on the basis of adverse event frequencies. RESULTS: Thirty-nine subjects, aged 17.5 ± 3.8 years, completed the study per protocol. At the end of the study (week 8), a mean reduction in inflammatory lesion count of 20.2% (-2.2 ± 7.0, p = 0.054), in non-inflammatory lesion count of 23.5% (-6.2 ± 9.8, p < 0.001), and in total lesion count of 22.5% (-8.4 ± 13.1, p < 0.001) was observed as compared with baseline. At study conclusion, 76.9% (30 of 39) of subjects showed a reduction in total lesion count. The results for inflammatory acne lesions were variable over the study course. None of the subjects experienced a lactoferrin-related adverse event during the trial. CONCLUSION: Despite the limitations of an uncontrolled, open-label study, the results from this study indicate that lactoferrin in mild to moderate acne vulgaris is well tolerated and may lead to an overall improvement in acne lesion counts in the majority of affected adolescents and young adults when administered as a dietary supplement on a twice daily regimen. Further randomized, placebo-controlled trials of longer duration appear warranted.

The effects of lorazepam on skin conductance responses to aversive stimuli in healthy subjects.

BACKGROUND: Autonomic responses to aversive stimuli are widely used to model anxiolytic drug effects in healthy humans. Benzodiazepine anxiolytics dose dependently attenuate autonomic responses to aversive stimuli by their anxiolytic as well as sedative action. The present study aimed to examine the effects of non-sedative doses of lorazepam on skin cutaneous responses to aversive stimuli and subjective mood. METHODS: A randomized, double blind, cross over study of 12 healthy male volunteers aged 24 years (23-32; median; range) was carried out. Subjects received single oral doses of 0.5 and 1.0 mg lorazepam as well as placebo on three different occasions with at least 5 days in-between. Skin conductance responses (SCRs) to unpleasant pictures and noises, pupillary unrest index as well as subjective levels of anxiety were measured repeatedly before and after drug administration. RESULTS: SCRs were found significantly lower 2 hours following ingestion of 0.5 mg lorazepam as well as 1, 2 and 3 hours after 1.0 mg lorazepam were given as compared to baseline conditions. By contrast, administration of placebo did not influence SCRs to a significant extent. Both doses of lorazepam did not change pupillary unrest index nor subjective mood. CONCLUSIONS: Lorazepam may attenuate SCRs to aversive stimuli without affecting vigilance nor subjective mood. Attenuation of autonomic responses to aversive stimuli may not be specific for an anxiolytic effect.

Efficacy and safety of the six-dose regimen of artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in adolescents and adults: a pooled analysis of individual patient data from randomized clinical trials.

To demonstrate the superiority of the six-dose over the four-dose regimen of artemether-lumefantrine (co-artemether, Coartem) in patients >12 years, data from 11 randomized clinical trials were pooled and analyzed. A total of 1368 patients with uncomplicated Plasmodium falciparum malaria (six-dose: 598; four-dose: 770) were included in the analysis, together with 717 patients treated with comparators. Analysis of the 28-day cure rate based on the ITT and evaluable populations yielded corrected cure rates for the six-dose regimen of 87% and 97% compared with 74% and 87%, respectively, with the four-dose regimen (P<0.0001, for both comparisons). For mefloquine/artesunate, the most frequently used comparator, cure rates were 87% and 99%, respectively. The six-dose regimen was well tolerated and not markedly different to the four-dose regimen. The main finding of our analysis is that the six-dose regimen of co-artemether is more effective than the four-dose regimen in adolescents and adults without compromising safety.

Pharmacokinetics and pharmacodynamics in clinical use of scopolamine.

The alkaloid L-(-)-scopolamine [L-(-)-hyoscine] competitively inhibits muscarinic receptors for acetylcholine and acts as a nonselective muscarinic antagonist, producing both peripheral antimuscarinic properties and central sedative, antiemetic, and amnestic effects. The parasympatholytic scopolamine, structurally very similar to atropine (racemate of hyoscyamine), is used in conditions requiring decreased parasympathetic activity, primarily for its effect on the eye, gastrointestinal tract, heart, and salivary and bronchial secretion glands, and in special circumstances for a CNS action. Therefore, scopolamine is most suitable for premedication before anesthesia and for antiemetic effects. This alkaloid is the most effective single agent to prevent motion sickness. Scopolamine was the first drug to be made commercially available in a transdermal therapeutic system (TTS-patch) delivering alkaloid. Recently, pharmacokinetic data on scopolamine in different biozlogic matrices were obtained most efficiently using liquid chromatographic-tandem mass spectrometric (LC-MS/MS) or gas chromatography online coupled to mass spectrometry. Pharmacokinetic parameters are dependent on the dosage form (oral dose, tablets; parenteral application; IV infusion; SC and IM injection). Scopolamine has a limited bioavailability if orally administered. The maximum drug concentration occurs approximately 0.5 hours after oral administration. Because only 2.6% of nonmetabolized L-(-)-scopolamine is excreted in urine, a first-pass metabolism is suggested to occur after oral administration of scopolamine. Because of its short half-life in plasma and dose-dependent adverse effects (in particular hallucinations and the less serious reactions, eg, vertigo, dry mouth, drowsiness), the clinical use of scopolamine administered orally or parenterally is limited. To minimize the relatively high incidence of side effects, the transdermal dosage form has been developed. The commercially available TTS-patch contains a 1.5-mg drug reservoir and a priming dose (140 microg) to reach the steady-state concentration of scopolamine quickly. The patch releases 0.5 mg alkaloid over a period of 3 days (releasing rate 5 microg/h). Following the transdermal application of scopolamine, the plasma concentrations of the drug indicate major interindividual variations. Peak plasma concentrations (Cmax) of approximately 100 pg/mL (range 11-240 pg/mL) of the alkaloid are reached after about 8 hours and achieve steady state. During a period of 72 hours the plaster releases scopolamine, so constantly high plasma levels (concentration range 56-245 pg/mL) are obtained, followed by a plateau of urinary scopolamine excretion. Although scopolamine has been used in clinical practice for many years, data concerning its metabolism and the renal excretion in man are limited. After incubation with beta-glucuronidase and sulfatase, the recovery of scopolamine in human urine increased from 3% to approximately 30% of the drug dose (intravenously administered). According to these results from enzymatic hydrolysis of scopolamine metabolites, the glucuronide conjugation of scopolamine could be the relevant pathway in healthy volunteers. However, scopolamine metabolism in man has not been verified stringently. An elucidation of the chemical structures of the metabolites extracted from human urine is still lacking. Scopolamine has been shown to undergo an oxidative demethylation during incubation with CYP3A (cytochrome P-450 subfamily). To inhibit the CYP3A located in the intestinal mucosa, components of grapefruit juice are very suitable. When scopolamine was administered together with 150 mL grapefruit juice, the alkaloid concentrations continued to increase, resulting in an evident prolongation of tmax (59.5 +/- 25.0 minutes; P < 0.001). The AUC0-24h values of scopolamine were higher during the grapefruit juice period. They reached approximately 142% of the values associated with the control group (P < 0.005). Consequently, the related absolute bioavailabilities (range 6% to 37%) were significantly higher than the corresponding values of the drug orally administered together with water (range 3% to 27%). The effect of the alkaloid on quantitative electroencephalogram (qEEG) and cognitive performance correlated with pharmacokinetics was shown in studies with healthy volunteers. From pharmacokinetic-pharmacodynamic modeling techniques, a direct correlation between serum concentrations of scopolamine and changes in total power in alpha-frequency band (EEG) in healthy volunteers was provided. The alkaloid readily crosses the placenta. Therefore, scopolamine should be administered to pregnant women only under observation. The drug is compatible with nursing and is considered to be nonteratogenic. In conclusion, scopolamine is used for premedication in anesthesia and for the prevention of nausea and vomiting associated with motion sickness. Pharmacokinetics and pharmacodynamics of scopolamine depend on the dosage form. Effects on different cognitive functions have been extensively documented.

Potential role of flavonoids in the prevention of intestinal neoplasia: a review of their mode of action and their clinical perspectives.

Intestinal neoplasia (adenomas and carcinomas) can possibly be prevented by a diet rich in vegetables and fruits, treatment with aspirin and other nonsteroidal antiinflammatory drugs, and early colonoscopic removal of adenomas. Ballast, fiber, and secondary plant products could play a major role in colon cancer prevention. Recently there has been much experimental work in vitro and in vivo about flavonoids as inducers of bioprevention. Flavonoids are secondary plant products with a wide variety of beneficial biological properties, and they possess anticarcinogenic, antimutagenic, and antioxidative modes of actions. Flavonoids are the main components of a healthy diet containing fruits and vegetables and are concentrated especially in tea, apples, and onions. We will focus this review on flavonoids which are derived from tea products such as proanthocyanidins (green tea) and flavons (camomille tea). Oral supplementation with bioflavonoids derived from tea could be used in humans to prevent growth of intestinal neoplasia such as adenomatous polyps of the colon. Flavonoids are a large group of natural compounds of which only a few have been used in animal models, cell cultures, and enzyme studies to inhibit mutagenic and carcinogenic events. Their clinical mode of action was evaluated by epidemiological studies, but no intervention studies in humans have been performed so far. In vitro flavonoids can bind electrophils, inactivate oxygen radicals, prevent lipid peroxidation, and inhibit DNA oxidation. In cell cultures they increase the rate of apoptosis, inhibit cell proliferation, and angiogenesis. In vivo they can induce the activities of protective enzymes (conjugating enzymes such as glutathione transferases and glucuronosyl transferases) of the intestine and the liver. In models of intestinal polyposis, flavonoids suppress polyp formation. Some epidemiological studies show a protective effect of flavonoids contained in fruits, vegetables, and tea. Flavonoid mixtures of tea origin supplied as nutritional supplements could be studied as a new way of bioprevention of intestinal neoplasia (colon adenomas and cancer). Therefore, a controlled, randomized clinical study should be performed to evaluate the efficacy of flavonoids.

The effects of St. John's wort extract and amitriptyline on autonomic responses of blood vessels and sweat glands in healthy volunteers.

St. John's wort extract is widely used and advertised as a "natural antidepressant" lacking autonomic side effects. This randomized, double-blind, placebo-controlled study compared the effects of St. John's wort extract on autonomic responses of blood vessels and sweat glands with those of amitriptyline and placebo. A randomized, double-blind, crossover study was performed in healthy male volunteers aged 22 to 31 years (25 +/- 3 years; mean +/- SD) years. Subjects orally received capsules with 255 to 285 mg St. John's wort extract (900 microg hypericin content), 25 mg amitriptyline, and placebo 3 times daily for periods of 14 days each with at least 14 days between. Vasoconstrictory response of cutaneous blood flow (VR) and skin conductance response (SR) following a single deep inspiration were employed as parameters of autonomic function. St. John's wort extract had no effect on VR and SR. In contrast, SR was diminished and the dilation phase of VR was prolonged following multiple dosing with amitriptyline (P < 0.05). Decreased electrodermal reactivity observed with amitriptyline reflects inhibition of acetylcholine at peripheral m3-cholinoreceptors, whereas prolongation of VR induced by the tricyclic drug may be due to sustained activation of central and/or peripheral sympathetic neurons.