Effect on endometrial histology and pharmacokinetics of different dose regimens of progesterone vaginal pessaries, in comparison with progesterone vaginal gel and placebo.

STUDY QUESTION: Which progesterone vaginal pessary dose regimen induces adequate secretory transformation of the endometrium, in comparison with progesterone vaginal gel and placebo? SUMMARY ANSWER: The best secretory transformation of the endometrium was observed during treatment with 400 mg progesterone vaginal pessaries, administered twice daily. WHAT IS KNOWN ALREADY: Vaginally administered progesterone is widely used for luteal phase support (LPS) in assisted reproductive techniques (ART). Although several vaginal formulations using various doses are available, little is known on the impact of formulation and doses at the endometrial level. STUDY DESIGN, SIZE, DURATION: The study had a randomised, observer-blind design and comprised two parts. The participants used study medication during two or three treatment periods, separated by washout periods. Subjects in Part 1 (n = 61 treated) received 200 mg progesterone vaginal pessaries twice daily (bid), 400 mg pessaries bid and the comparator 90 mg progesterone vaginal gel once daily (od) in a 3-way crossover design. Subjects in Part 2 (n = 64 treated) received 100 mg pessaries bid in one period and 400 mg pessaries od in the other period in a 2-way crossover design. A subgroup of these subjects (n = 22 treated) received placebo vaginal pessaries bid in a third period in a non-randomised manner. The study was performed from May 2012 until April 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was performed at a clinical research centre in healthy female volunteers of reproductive age. The subjects used 2 mg estradiol bid for 24 days in each treatment cycle. Progesterone or placebo was administered vaginally from Day 15 onwards during 10 days. In each treatment period, an endometrial biopsy for histological evaluation was performed on Day 23 and pharmacokinetic parameters were determined after the first progesterone dose on Day 15 and after the last dose on Day 24. MAIN RESULTS AND THE ROLE OF CHANCE: Frequencies of (early and late) secretory transformation of the endometrium, i.e. adequate responses, during treatment with 200 mg and 400 mg vaginal pessaries bid were comparable with those during 90 mg vaginal gel treatment (90-94%), whereas lower secretory transformation rates were observed during treatment with 100 mg bid and 400 mg od (64-75%). At the time of the endometrial biopsy in the cycle the late secretory state of the endometrium, which is characteristic of adequate luteal support, was observed more often with 400 mg pessaries bid (90%) than with vaginal gel (82%) and with lower pessary doses (64-78%). Pharmacokinetic parameters after repeated dosing of vaginal pessaries showed a dose-dependent, but not dose-proportional, increase of plasma progesterone levels. The lowest incidence of bleeding and spotting was reported during treatment with 400 mg pessaries bid. LIMITATIONS REASONS FOR CAUTION: The primary outcome parameter, rate of secretory transformation of the endometrium, is a surrogate for endometrial receptivity and for the actual clinical efficacy. WIDER IMPLICATIONS OF THE FINDINGS: Delivery of progestesterone through 400 mg pessaries bid is an effective alternative method for luteal support in ART. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Actavis Group PTC ehf., Iceland, part of Teva Pharmaceuticals, and L.D. Collins. I.D. and C.K. are directors of Dinox, a contract research organisation. I.K. is Managing Director of Pharmaplex and M.W. is Managing Director of M.A.R.C.O., service organisations involved in organisation/supervision and evaluation/reporting of clinical trials. All received funding for the conduct of the study from Actavis. S.H. and Th.M. are employees of Actavis. TRIAL REGISTRATION NUMBER: EudraCT number 2012-001726-95.

Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations.

PURPOSE: To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR). METHODS: In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA. RESULTS: Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0-t(last) and C max were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC0-t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043). CONCLUSIONS: The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.

Evaluation of the bioequivalence of tablet and capsule formulations of granisetron in patients undergoing cytotoxic chemotherapy for malignant disease.

Granisetron is a novel, highly specific 5-hydroxytryptamine receptor antagonist given prophylactically to patients undergoing chemotherapy. An open, randomized, crossover trial was performed with 37 patients (24 females and 13 males) undergoing cytotoxic chemotherapy for malignant disease to compare an oral tablet (1-mg tablet given twice daily) with a clinical-trial capsule (1-mg capsule given twice daily). Complete pharmacokinetic data were determined for 24 patients (14 females and 10 males). The concentration of granisetron in plasma was measured by HPLC; the limit of quantitation was 0.2 ng/mL. The bioavailability evaluation was based mainly on the area under the curve (AUC) (mean values: 52.1 ng.h/mL for the capsule and 54.2 ng.h/mL for the tablet) and the maximum concentration (Cmax) (mean values: 7.42 ng/mL for the capsule and 8.18 ng/mL for the tablet) measured at the steady state after 7 days of continuous therapy. Wide interpatient variability in plasma granisetron levels after oral administration was observed. The 90% standard confidence interval for the geometric mean ratio overlapped the critical range, 0.8-1.25. Point estimates for AUC and Cmax based on two one-sided t tests and log-transformed data showed that the upper limit of the confidence interval was not within 20% of the mean for the capsule; the corresponding power analysis values for AUC and Cmax were 0.89 and 0.81, respectively. Despite bioequivalence not being proven, any differences that exist between the two formulations are likely to be small. There was no difference in efficacy or safety between the two formulations assessed.

[Follow-up of hip endoprostheses following completion of true stress conditions over a 10-year period]. / Verlaufsbeobachtung von Hüftendoprothesen nach Abschluss realer Belastungsbedingungen von 10 Jahren.

Results of a long term followup with total hip-replacement of the Endo-Klinik are presented. The analysed data-material exhibits a relative homogeneity because of a large series of one system of prostheses and homogeneous technique in surgery. Thus, analytic statistical methods (life-tables and regression models) could be used. In this way, prognostic factors on the durability of total hip replacement could be determined. These are essentially: long practical experience of the surgeon with one matured prosthesis-system, type of hip-joint disease, and the age of the patient. It is assumed, that in well organized special centres for joint replacement the failure rate could be reduced generally.

Multiparametric tumor marker (CA 19-9, CEA, AFP, POA) analyses of pancreatic juices and sera in pancreatic diseases.

With respect to their diagnostic utility CA 19-9, CEA, AFP and POA were determined in pancreatic secretions and serum of patients suffering from pancreatic cancer (n = 76/55) or chronic pancreatitis (n = 79/45) and of controls (n = 81/42), respectively. While the determination of AFP and POA both in pancreatic secretions and serum does not permit a differential diagnosis, serum CEA (greater than 10 ng/ml) and CA 19-9 (greater than 50 U/ml) levels were indicative of pancreatic cancer in 30% and 83%, respectively, with a rate of false positive results of 5% and 8.5% confined to the chronic pancreatitis patients. A combination of tumor marker analyses, that is, serum CA 19-9 (greater than 50 U/ml) and pancreatic secretion CEA (greater than 70 ng/ml), proved to be positive in 92.9% of tumor patients with a maximum of 10.5% false positives. Likewise, values of serum CA 19-9 (greater than 50 U/ml) and serum CEA (greater than 10 ng/ml) were found in 85.8% of the pancreatic cancer patients with only 8.8% false positives, which were confined to the chronic pancreatitis patients. These results indicate the superiority of multiparametric tumor marker analyses for the diagnosis of pancreatic cancer, especially when including new monoclonal antibody defined tumor markers.