Pearl Index study with levonorgestrel-releasing intravaginal rings: using pharmacokinetic results to investigate treatment compliance as a potential contributor for contraceptive failure.

STUDY QUESTION: What is the reason for insufficient contraceptive efficacy of levonorgestrel (LNG) delivered by intravaginal ring (IVR) releasing comparable amounts of LNG as approved progestogen-only pills (POPs)? SUMMARY ANSWER: The pharmacokinetic (PK) evaluation in a subpopulation indicated that the steady-state concentration of plasma LNG was markedly lower in the participants in the USA compared to those in Japan suggesting non-compliance in the US participants which may explain a clearly higher Pearl Index (PI) in USA (8.2, unadjusted PI) compared to Japan (1.4, unadjusted PI). WHAT IS KNOWN ALREADY: Contraceptive efficacy of LNG in POPs has been demonstrated following different routes of administration (e.g. orally, implants, intrauterine systems), and the PK is well-characterized including a target exposure needed for contraception. Exposure above this target concentration was reached in Phase 1 studies using IVR delivering 40 µg LNG per day. STUDY DESIGN, SIZE, DURATION: The primary objective of this multicenter, open-label, single-arm study conducted in the USA and in Japan was to assess the contraceptive efficacy of an LNG-containing IVR during a planned treatment period of 1 year in healthy women 18-35 years of age. The study was planned to be conducted in 1600 participants (1300 in the USA, 300 in Japan). The study was prematurely terminated after approximately one-third of the planned exposure was reached due to a high number of pregnancies (28) in the US study population. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1471 participants were treated (1166 participants in the USA and 305 participants in Japan). The PI as a measure of contraceptive efficacy was calculated from the frequency of unintended pregnancies during treatment. LNG exposure in the systemic circulation was assessed during treatment in 136 participants (PK subgroups: 106 in the USA and 30 in Japan). MAIN RESULTS AND THE ROLE OF CHANCE: The PK evaluation in the PK subgroups indicated that the steady-state concentration of plasma LNG after 6 months was markedly lower in the participants in the USA (geometric mean 91.2 ng/l) compared to those in Japan (263.8 ng/l). This PK finding cannot be explained by the regional differences in body weight observed between the PK subgroups, thus suggesting non-compliance in the US participants. In 15.7% of the samples collected in the USA and 3.5% samples in Japan, the LNG concentration at steady state was below the lower limit of quantification (10 ng/l), which is not expected with the required continuous use of the IVR documented in most of the eDiaries. LIMITATIONS, REASONS FOR CAUTION: The planned duration of treatment was 12 months, but due to the premature termination of the study none of the participants completed the 12-month treatment. All data collected until the study termination were considered, but it is to be noted that the amount of missing data limits the conclusions that can be drawn from the data. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study triggered the termination of the project, because the objective to show sufficient contraceptive efficacy of the LNG IVR was not met. The choice of a user-dependent contraceptive method with an LNG dose that is not inhibiting ovulation is not advisable for women who may have compliance issues. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Bayer AG and all authors are employees of Bayer AG. TRIAL REGISTRATION NUMBER: NCT02403401.

DBH*444G/A polymorphism of the dopamine-beta-hydroxylase gene is associated with alcoholism but not with severe alcohol withdrawal symptoms.

As the enzyme dopamine-beta-hydroxylase (DbetaH) converts dopamine to norepinephrine and both transmitters seem to be involved in the pathology of alcoholism and severe alcohol withdrawal symptoms, the gene encoding DbetaH (DBH) was applied to explore the genetic background of alcoholism and severe withdrawal symptoms. 102 healthy control subjects and 208 alcoholics, including 97 patients with a history of mild withdrawal symptoms, 57 with a history of alcohol withdrawal seizure (AWS) and 82 with a history of delirium tremens (DT) were genotyped for the DBH*444G/A polymorphism revealing a significantly elevated frequency of genotypes carrying the A-allele (p = 0.02; after Bonferroni adjustment for multiple tests) in alcoholics compared to healthy controls. Frequencies of alleles and genotypes of individuals with mild withdrawal symptoms did not differ significantly from those of patients with DT or AWS.

Impact of vertebral artery disease on dynamic cerebral autoregulation.

OBJECTIVES: This study applied dynamic cerebral autoregulation (DCA) testing distally to severe bilateral vertebral artery disease (BVAD). METHODS: Using continuous monitoring of beat-to-beat blood pressure and transcranial Doppler of the posterior cerebral arteries (PCA) were examined in 20 patients with BVAD and 22 controls. DCA testing was based on the 'high-pass filter model', which predicts a positive phase relationship between spontaneous oscillations (M-waves 3-9 cpm and R-waves 9-20 cpm) in blood pressure and cerebral blood flow velocity. RESULTS: In patients with BVAD, DCA testing detected autoregulatory deficits of different degrees. The lowest M-wave phase shift angles were found in the PCA territory distally to intracranial BVAD. CONCLUSION: This study suggests that DCA testing of the PCA could help to quantify the hemodynamic impact of BVAD. It highlights the relevance of functional TCD sonography as a useful diagnostic tool for the hemodynamic evaluation of vertebrobasilar disease.

[In vitro investigations of the effect of morphine and its metabolites on the phagocytosis of peripheral mononuclear cells]. / Effekte von Morphin auf die Phagozytosefähigkeit peripher mononukleärer Zellen.

INTRODUCTION: Reports about an increased incidence of infection with facultative intracellular microorganisms suggest a depression of the macrophage/monocyte system. This explosive increase in oxidative metabolism can be measured by chemiluminescence. The aim of the present study was to investigate the influence of morphine and its metabolites morphine-3 (M-3-G) and 6-glucuronide (M-6-G) on the respiratory burst of the peripheral mononuclear cells (PCM). To explain the mechanism of the effect of morphine the antagonist naloxone was used. Furthermore, the effect was compared with that of bupivacaine and propranolol, known as drugs that stabilize the cell membranes. METHODS: PMC were isolated from the blood of healthy young men by Ficol hypaque centrifugation. Four samples of 2 x 10(5) cells were incubated for at 37 degrees C and 10% CO(2) with either morphine, naloxone, bupivacaine, propranolol, M-3-G or M-6-G. After stimulation with oponised zymosan A, the lucigenin-dependent chemiluminescence was measured (n=8) in a biolumat (Berthold). STATISTICS: Wilcoxon matched pairs (significance level p<0.05). RESULTS: Morphine inhibited the phagocytic activity of PMC only in concentrations >10(-7) mol/l. The metabolites M-3-G and M-6-G were considered to be similar based on tests using n=3. Naloxone itself significantly influences the emission of light solely in the high concentration of 10(-4) mol/l. Naloxone (10(-4) mol/l)+morphine(10(-5) mol/l) caused a greater inhibition than either of the substances alone. In comparison, the decreased chemiluminescence of morphine (10(-6) mol/l) was antagonized by naloxone (10(-5) mol/l). Naloxone in the same concentration was ineffective. The membrane stabilization caused by bupivacaine and propranolol did not change the chemiluminescence activity. CONCLUSION: Morphine had a decreasing effect on the respiratory burst of PCM only in concentrations that the human body reaches where renal clearance is reduced. In this situation the metabolites of morphine accumulate more than morphine itself and seem to have a similar effect. The weakening of phagocytosis might possibly be a direct effect of morphine and its metabolites. These investigations suggest that this phenomenon may be receptor dependent: the effect could be antagonized by naloxone, but naloxone itself caused a depression in high concentrations. In comparison the nonspecific stabilization of the membranes showed no such effect.