The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate – a randomised controlled trial

Background

Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI.

Methods/Design

We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI.Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included.Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total).An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm).

Discussion

The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women.

Trial registration number

Netherlands Trial register NTR1449

     

Structure-activity relationship studies of CNS agents. Part 29. N-Methylpiperazino-substituted derivatives of quinazoline, phthalazine and quinoline as novel α1, 5-HT1A and 5-HT2A receptor ligands

New N-methylpiperazino-substituted quinazolines 8 and 9, phthalazine 13, and quinoline 19 have been synthesized. The receptor binding profiles (α₁, 5-HT_1A, 5-HT_2A) of these compounds and their analogs (7–22) have been determined. It has been demonstrated that orientation of a local dipole moment of the heteroaromatic ring system affects both the α₁ and 5-HT_2A affinity of the investigated class of ligands. Distortion of the coplanar unfused heteroaromatic ring system results in a decreased 5-HT_2A affinity. 4-(4-Methylpiperazino)-2-(2-thienyl)quinoline 18 is the most active and selective α₁ ligand (K_i = 4.9 nM) with a much lower affinity for 5-HT_1A (K_i = 3420 nM) and 5-HT_2A (K_i = 211 nM) receptors.     

Discriminating between 5-HT3A and 5-HT3AB receptors

The 5-HT3B subunit was first cloned in 1999, and co-expression with the 5-HT3A subunit results in heteromeric 5-HT₃AB receptors that are functionally distinct from homomeric 5-HT₃A receptors. The affinities of competitive ligands at the two receptor subtypes are usually similar, but those of non-competitive antagonists that bind in the pore often differ. A competitive ligand and allosteric modulator that distinguishes 5-HT₃A from 5-HT₃AB receptors has recently been described, and the number of non-competitive antagonists identified with this ability has increased in recent years. In this review, we discuss the differences between 5-HT₃A and 5-HT₃AB receptors and describe the possible sites of action of compounds that can distinguish between them.     

The Aging Males' Symptoms (AMS) scale: Update and compilation of international versions

Background

The interest of clinical research in aging males increased in recent years and thereby the interest to measure health-related quality of life (HRQoL) and symptoms of aging men. The Aging Males' Symptoms scale (AMS) became the most commonly used scale to measure HRQoL and symptoms in aging males in many countries worldwide. The aim of this paper is to review the current state of the instrument particularly concerning versions of the scale in different languages in the light of the quality of the translation process.

AMS versions available

Most of the translations were performed following international methodological recommendations for linguistic & cultural adaptation of HRQoL instruments. Mainly the English version was used as source language for the translation into Dutch, Spanish, Portuguese, Italian, Swedish, and Japanese (attached as additional PDF-files). Preliminary versions that were derived only from forward translations are of secondary quality and available in Finnish, Flemish, and Russian. It is recommended to complete the translation process for the latter languages before using them in international studies.

Translations in process

The AMS scale is in the process of consensus finding of two existing French versions, and the versions in the Korean, Thai, and Indonesian languages have not yet been completed in the translation process.

Conclusion

The AMS scale is obviously a valuable tool for assessing health related quality of life in aging men, because it is used worldwide. It is a standardized scale according to psychometric norms. Most of the currently available language versions were translated following international standards for linguistic and cultural translation of quality of life scales. Assistance is offered to help interested parties in the translation process.     

More potential organ donors than actual donations in 52 intensive-care units in the Netherlands, 2001-2004

OBJECTIVE: To assess the number of potential organ donors and the main reasons why organ donation is not performed. DESIGN: Retrospective. METHOD: The number of potential heart-beating (HB) and non-heart-beating (NHB) donors was assessed by reviewing the medical records of 588o patients who died between 2001 and 2004 in 52 intensive-care units (ICUs) in 30 hospitals. The number of actual donations was also assessed. RESULTS: The potential of HB donors was 2.5 to possibly 6.6% of all ICU deaths and HB donation was performed in 1.9% of all ICU deaths. The potential of NHB donors of category III was at least 4.2% of all ICU deaths and NHB donation was performed in 1.0% of all ICU deaths. The main difficulty in the donation process was objection from family members, which was reported in 45% of all potential HB and NHB donors and in 59% of all donation requests to relatives. Of the potential HB and NHB donors 7.3% were not identified as potential donors. CONCLUSION: These results confirm that organ-donor potential is greater than the number of actual donations. Objection from family members is the main limiting factor.     

Triamterene Increases Lithium Excretion in Healthy Subjects: Evidence for Lithium Transport in the Cortical Collecting Tubule

The possible presence of lithium transport beyond the proximaltubule was examined by measuring lithium excretion after administrationof triamterene, a potassium-sparing diuretic, exclusively actingin the cortical collecting tubule. Eight young and healthy volunteerswere studied on two occasions during maximal water diuresis.After obtaining baseline values triamterene (100mg orally) orplacebo was administered, and measurements continued for 4 hours.Creatinine clearance was used as a marker of glomerular filtrationrate, and phosphate excretion was used as an additional markerof proximal sodium transport. Compared to placebo (P), triamterene(T) caused a significant increase in fractional excretion ofsodium (P, 0.74±0.08%; T, 1.73±0.24%, mean±SEM;P<0.01), and lithium (P, 21.2±1.3%; T, 27.5±1.5%;P<0.01), whereas fractional excretion of phosphate remainedunchanged (P, 9.8±1.3%; T, 9.4±1.5%; P=NS). Theseresults indicate that lithium is transported in the corticalcollecting tubule, and provide further evidence that the useof lithium as a marker of purely proximal tubular sodium transportis of limited value.     

A prosthetic contact lens in the treatment of ocular manifestations of albinism

A patient with severe ocular albinism was fitted with a prosthetic soft contact lens which improved both photophobic symptoms and facial cosmesis.     

Assessment of hemodynamic changes in human kidney grafts induced by cyclosporin infusion

Abstract. Cyclosporin A (CyA) nephrotoxicity is at least partly caused by the vasoconstrictive action of the drug. In this study we set out to assess this hemodynamic effect of CyA on Doppler spectra obtained in arteries of human renal allografts. Doppler spectra of renal arteries were obtained shortly before and after the start of CyA infusion in renal transplant recipients. Doppler spectrum analysis revealed a significant change in several spectrum-derived parameters. T_max (acceleration time of the systolic frequency peak), in particular, showed a decrease after 4 h of CyA administration (106 ± 58 ms vs 76 ± 36 ms in segmental arteries; P <0.05). On day 2 the T_max returned to its original value (117 ± 57 ms). Thus, Doppler spectrum analysis enables one to detect temporary hemodynamic changes in the transplanted kidney following CyA administration. These observations may be useful in differentiating causes of renal dysfunction by Doppler spectrum analysis in clinical transplantation.