A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK).

BACKGROUND: Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. PATIENTS AND METHODS: Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel-Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1. RESULTS: Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; hazard ratio (HR) 1.18 (0.94-1.48)] or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82), P > 0.05], but not PFS, for CS. CONCLUSIONS: Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers. CLINICALTRIALSGOV: NCT00942877.

Long-acting hormonal contraceptives for women.

Following the development and widespread use of oral hormonal contraceptives, it became evident that alternative long-acting delivery systems would be required to improve contraceptive practice in some cultural settings where injectable or subdermal routes of administration are preferred. Nowadays, long-acting contraceptives constitute an important option in family planning services in many parts of the world. Indeed, two long-acting injectable contraceptives containing just a synthetic progestogen (depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN)) have been in clinical practice for more than 20 years. The World Health Organization's (WHO) Special Programme of Research in Human Reproduction, in collaboration with the U.S. National Institute of Child Health and Human Development (NICHD) and universities primarily in developing countries undertook a synthesis programme aimed at producing an improved injectable preparation by developing new derivatives of known steroids. One such compound (levonorgestrel 17-butanoate) is now at the stage of Phase II clinical testing. In addition, the Special Programme has developed and improved once-a-month injectable formulations and assessed their safety and efficacy in different countries worldwide. After large scale clinical testing, at least two progestogen-estrogen combinations have reached the point of introductory trials.

PIP: A survey of recent trials of new injectable hormonal contraceptives, progestogen-only, levonorgestrel esters, and once monthly injectables, follows a brief review of all the experimental long-acting contraceptive modalities, injectables, implants, vaginal rings, and hormone-releasing IUDs. Currently medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN) are being used by 7 million women. WHO is conducting dose reduction trials and studies of bioavailability in various national populations. Even though a dose of 100 mg DMPA every 3 months has been satisfactory for contraception, 150 mg is still recommended until further pharmacodynamic data are available. Some populations, notably Thais and Mexican women, have higher peaks and more rapid elimination rates of DMPA, while Chinese women show slower elimination and higher blood levels of NET-EN. Extensive studies of new synthetic esters of levonorgestrel have proceeded to Phase II clinical trials with levonorgestrel butanoate. This ester is an effective contraceptive for 3 months at 12.5 mg, or 5-6 months at a dose of 25 or 50 mg. Trials of combined estrogen and progestogen injectables once-monthly have been ongoing for 10 years. The ratio of the 2 components is as important as the amounts. 2328 women from 12 countries participated in trials of DMPA 25 mg-estradiol cypionate 5 mg, and NET-EN 50 mg-estradiol valerate 5 mg. The continuation rate was better than that for 3-monthly progestogen-only injectables, because of less irregular bleeding. A combined injectable called Cyclofem, DMPA 25 mg-estradiol cypionate is being introduced in several countries. The steadily increasing demand for long-acting injectables prompts development of better formulations.

The introduction of Cyclofem into national family planning programmes: experience from studies in Indonesia, Jamaica, Mexico, Thailand and Tunisia. Task Force on Research on Introduction and Transfer of Technologies for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland.

Studies on the introduction of Cyclofem into family planning programmes have been undertaken in Indonesia, Jamaica, Mexico, Thailand and Tunisia. Cyclofem is a once-a-month injectable contraceptive containing 25mg medroxyprogesterone acetate and 5mg estradiol cypionate. A total of 7927 subjects were followed in close to routine service delivery conditions in primary and secondary family planning outlets. The studies confirmed the high efficacy of the method with 12-month pregnancy rates ranging from 0 to 0.7%. Major differences were seen in reasons and rates of discontinuation between countries, the overall 12-month life table discontinuation rates ranging from 33.5% in Indonesia to 71.8% in Tunisia. The reasons for discontinuation in each of the five countries are described, differences between countries contrasted, and service delivery issues which should be addressed further, raised.

Progesterone-releasing vaginal rings for use in postpartum contraception. I. In vitro release rates of progesterone from core-loaded rings.

Vaginal rings of Dow Corning 382 Silastic polymer, having identical outside dimensions, were fabricated to contain cores of different diameters loaded with 25% w/w progesterone. Elution of rings was carried out in continuously flowing baths of isotonic saline at 37 degrees C and quantities of progesterone released in 24 h periods measured for up to 128 days. Release of the steroid was shown to be a membrane diffusion-controlled process, modified by the development of a gradually increasing zone of depletion at the core surface. Rings of a suitable core diameter were selected to give initial release of 5 mg/24 h progesterone and sterile batches of these rings, prepared for WHO-sponsored clinical studies in post-partum, lactating women, were shown to give highly consistent and reproducible rates of in vitro drug delivery. A comparison was made with the in vitro release rates of rings containing a homogeneous dispersion of progesterone.

PIP: Chemists from London, England and a chemist from WHO in Geneva, Switzerland compared release rates of progesterone from vaginal rings with cores of different diameters (4, 5, 6, 6.7, and 7.24 mm). The manufacturer loaded each core with 25% w/w progesterone. The technique used to dissolve the progesterone from the silicone rubber core consisted of placing the rings in continuously flowing baths of isotonic saline at 37 degrees Celsius. The learned that a membrane diffusion controlled process, modified by the development of a gradually increasing zone of depletion at the core surface, did indeed release the progesterone. The used the UV absorption method to measure the amount of progesterone released in 24 hour periods for as much as 128 days. The vaginal ring with the 6 mm core released 3.6-5.5 mg progesterone/day in a 90 day period. The daily range of maximum and minimum values for each set of rings demonstrated good reproducibility. Progesterone release was inversely related to diffusion distance (between core surface and ring surface) for each day. Since, in their clinical trials in postpartum women, WHO wanted to use vaginal rings which initially released 5 mg progesterone/day and declines by about 0.5 mg/month under conditions of membrane limited diffusion as the depletion zone grew thicker, the study showed that the rings with a 6 mm core met the criteria. The chemists found that these rings and 4 sterile batches of these rings have highly consistent and reproducible rates in vitro drug delivery. They also compared the vaginal rings with a 6 mm core with rings with at homogeneous dispersion of progesterone throughout the polymer. The homogenous rings 1st released much progesterone then fell quickly from 10-20 mg/day during the 1st week to a gradual release of about 6 mg/day during the end of the 90 days.

Progesterone-releasing vaginal rings for use in postpartum contraception. II. Pharmacokinetic profiles in women.

Vaginal rings releasing progesterone with 3 different initial release rates (5, 8 and 20 mg/day) were used by 11, 10 and 10 women, respectively. The period of insertion was 90 days. The 5 and 8 mg/day rings consisted of a core loaded with progesterone, the 20 mg/day ring contained progesterone homogeneously distributed throughout the mass of the ring. Notwithstanding these differences, the total progesterone levels (areas under curve) were directly related to the release rates. So were the rates of decrease of progesterone levels during the 90 days of insertion of the ring. They were 25, 31 and 47% for the rings releasing 5, 8 and 20 mg/day, respectively.

PIP: Physicians from Karolinska Hospital in Stockholm, Sweden and a scientist form WHO in Geneva, Switzerland examined the pharmacokinetic behavior of progesterone released from vaginal rings over 90 days in 31 women who took a combined oral contraceptive (OC) each day. The OC suppressed ovarian function. The physicians inserted a vaginal ring with a core which released 5 mg progesterone/day in 11 women and a 8 mg/day ring in 10 women. The inserted a 20 mg/day vaginal ring with progesterone homogeneously distributed throughout the mass of the ring in 10 women. Total circulating progesterone levels were significantly correlated with initial release rates of the 3 vaginal rings (p.001). Further, at the end of 90 days, progesterone levels decreased significant from initial levels in all women (25% for the 5 mg/day vaginal ring, 31% for the 8 mg/day ring, and 47% for the 20 mg/day ring). These results matched those of earlier in vitro studies with the same vaginal rings. Researchers next need to determine which type of vaginal ring and release rate optimally protects against pregnancy and induces an acceptable bleeding pattern. WHO promotes research in vaginal rings saturated with progesterone as a possible contraception for postpartum mother since progesterone does not adversely affect breast fed infants. Furthermore progesterone suppresses ovulation.

Lipid and biochemical changes after low-dose oral contraception.

A randomized double-blind study of the metabolic effects of 2 low-dose combined oral contraceptives was carried out in Singaporean women. The subjects comprised 58 women randomly allocated to two treatment groups (29 each): norethisterone 1 mg/ethinyl estradiol 35 micrograms (NET/EE) or levonorgestrel 150 micrograms/ethinyl estradiol 30 micrograms (LNG/EE) and a control group of 23 women using intra-uterine devices (IUD). Blood samples were taken on admission and at 3 and 12 months after pills or insertion of IUDs. Fasting glucose levels were decreased while 2h glucose and triglyceride were increased throughout the treatment period in NET/EE group [corrected]. LNG/EE group only showed significant increase of 2h glucose at 12 months and decrease of LDL cholesterol at 3 months while total cholesterol was significantly suppressed at 3 and 12 months [corrected]. The atherogenic index, LDL/HDL cholesterol was significantly reduced by 12 months. Both groups had no change in hemoglobin, hematocrit and total protein levels but alkaline phosphatase, bilirubin and aspartate transaminase (SGOT) were suppressed. While NET/EE suppressed albumin significantly, this was not observed with LNG/EE group. However, these differences observed with use of each pill preparations, were not so obvious between treatment groups and control. Changes in total, HDL and LDL cholesterol and SGOT were not significantly different than the IUD group. Furthermore, except for 2h glucose, there was no increase in the number of abnormal parameters after treatment. On the contrary, there was a reduction of abnormal values in most liver function parameters. Thus, except for glucose intolerance, the observed changes in metabolic parameters may not constitute any clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: This randomized double-blind study of the metabolic effects of two low-dose oral contraceptives was conducted in 58 randomly selected Singaporean women. Study subjects were divided into two treatment groups: 1) norethisterone 1 mg/ethinyl estradiol 35 mcg (NET/EE) or levonorgestrel 150 mcg/ethinyl estradiol 30 mcg (LNG/EE) were given to 35 women; 2) a control group of 23 women using IUDs. Blood samples were taken on admission and at 3 and 12 months after pills or insertion of IUDs. Findings demonstrate a significant decrease in mean fasting glucose and in 2-hour glucose loading, while triglycerides were increased throughout the treatment period in the NET/EE group. The LNG/EE group only showed significant suppression of the 2-hour glucose loading at 12 months and low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol was significantly reduced by 12 months. Both groups had no change in hemoglobin, hematocrit and total protein levels, but alkaline phosphatase, bilirubin and aspartate transaminase (SGOT) were decreased. Decreased albumin was observed in the NET/EE group, but not in the LNG/EE group. Changes in total HDL and LDL cholesterol and SGOT were not significantly different in the treatment group compared to the IUD group, except for the 2-hour glucose loading. There was no increase in the number of abnormal parameters after treatment. On the contrary, there was a reduction of abnormal values in most liver function parameters. Thus, except for glucose intolerance, the observed changes in metabolic parameters may not be of any clinical significance.

A multicentered pharmacokinetic, pharmacodynamic study of once-a-month injectable contraceptives. I. Different doses of HRP112 and of DepoProvera. World Health Organization Task Force on Long-acting Systemic Agents for Fertility Regulation.

A multicentered study was undertaken at three institutions in Hungary, Mexico and Thailand in women of reproductive age to evaluate the effects of full and half doses of HRP112 (depot-medroxyprogesterone acetate (DMPA) plus estradiol cypionate) and DMPA alone on ovarian function, bleeding patterns and HDL-cholesterol levels. Full dose HRP112 contained 25mg DMPA plus 5mg, of estradiol cypionate and the half dose, 12.5mg DMPA plus 2.5mg of estradiol cypionate. The full and half dose DMPA were 25 and 12.5mg respectively. In all, 88 women were recruited in the study and randomized within each centre, to the four treatment groups. Subjects were studied for a control cycle, three one-month injection intervals and followed-up for a further two months. Serum concentrations of estradiol, progesterone and medroxyprogesterone acetate were determined three times a week during the third injection interval and during the two months of follow-up. While the results from all centres indicated that the four preparations were all effective in inhibiting ovulation for at least one month, there were marked between centre differences in pharmacokinetic profiles. More regular bleeding patterns were observed in women who received the estrogen-progestogen combination preparations than in those who received DMPA alone.

A randomized, double-blind study of two combined and two progestogen-only oral contraceptives.

A randomized double-blind study of two combined oral contraceptives and two progestogen-only oral contraceptives was conducted using the same protocol at WHO Collaborating Centres for Clinical Research in Human Reproduction in Bombay and Ljubljana of the 518 women admitted to the trial, 123 received mestranol 50 micrograms + norethisterone 1mg (MES 50 + NET 1); 137 received ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms (EE 30 + LNG 150); 130 received norethisterone 350 micrograms/NET 350); and 128 received levonorgestrel 30 micrograms (LNG 30). At one year, between 52.6 and 61.0 percent of those recruited had discontinued oral contraceptive use for all reasons, and by two years, between 70.5 and 76.5 percent had discontinued the treatment. These rates did not differ between the four treatment groups. However, discontinuation rates for all medical reasons at one and two years, and at two years pregnancy rates and discontinuation rates for bleeding disturbances, were significantly lower in the EE/LNG preparation. The groups receiving the MES/NET, LNG and NET had similar pregnancy rates, discontinuation rates for all medical reasons and all bleeding disturbances. There were two ectopic pregnancies among the 22 pregnancies in the progestogen-only groups. Discontinuation because of headache, dizziness and other central nervous system symptoms were significantly more common in those receiving MES/NET compared to EE/LNG. In contrast, discontinuation for gastro-intestinal disturbances were significantly higher in the EE/LNG combined preparation. Bleeding disturbances in the first few cycles tended to be higher in NET than in the LNG group. The data suggest that greater consideration be given to the benefits and risks of including progestogen-only oral contraceptives in the family planning programmes of some countries.

New once-a-month injectable contraceptives, with particular reference to Cyclofem/Cyclo-Provera.

Once-a-month injectable contraceptives containing a progestogen and an estrogen have been developed that disrupt vaginal bleeding patterns less than the widely used progestogen-only preparations. Pharmacokinetic studies were undertaken of dosages and ratios of the progestogens and the respective estrogens. In Phase III clinical trials, annual pregnancy rates were below 0.4% for Mesigyna (norethisterone enanthate/estradiol valerate, Schering AG, Berlin, Germany) and below 0.2% for Cyclofem (MPA/E2C) (medroxyprogesterone acetate/estradiol cypionate, Aplicaciones Farmaceuticas, SA, Mexico and PT Tunggal, Indonesia). More than two-thirds of women had predictable, regular cycles, and discontinuation due to bleeding-related problems occurred less than half as often as with progestogen-only injectables. With MPA/E2C, return to fertility is similar to that observed with other hormonal or intrauterine methods, and both products have little effect on lipids or hemostasis. Introductory trials of MPA/E2C in 12000 women with 100000 woman-months of experience confirmed the high efficacy of the product in routine use. The use of MPA/E2C in a non-reusable injection device, Uniject (Becton Dickinson, Franklin Lakes, NJ) is discussed. Once-a-month hormonal contraceptives have been shown to provide a safe contraceptive option for all women and an alternative for women who wish to use injectable formulations that cause less disruption in vaginal bleeding and minimal side effects.

Once-a-month injectable contraceptives.

PIP: Within the past 25 years, steroidal preparations have become available that allow the user contraceptive protection over extended periods of time. There are only 2 injectable preparations presently used at all widely within family planning programs throughout the world: 1) depot medroxyprogesterone acetate (DMPA), and 2) norethisterone enanthate (NET-EN). 1 of the major side effects of progestagen-only contraception has been disruption of normal menstrual bleeding, giving rise to both irregular bleeding and amenorrhea. Several extensive reports on the clinical use of monthly injectables appeared in 1970, but few studies have been reported subsequently. In response to the demand from certain populations to have safe, well-investigated, once-a-month injectable contraceptives with high efficacy and little menstrual bleeding disturbance, the World Health Organization's (WHO) Special Programme of Research in Human Reproduction developed a strategy for the development of a once-a-month contraceptive which involves: 1) the assessment of use-effectiveness and side-effects of HRP102 (NET-EN, 50 mg., plus oestradiol valerate, 5 mg) and Clyloprovera (DMPA, 25 mg., plus estradiol cypionate, 5 mg.); and 2) the optimum improvement of these 2 combined formulas by reduction of the progestagen content. Results from a pharmacokinetic/pharmacodynamic study show that many of the women receiving reduced progestagen dose preparations ovulated during the 3rd treatment month; thus the 2 original preparations, Cycloprovera and HRP102 appear to be the optimal formulations for these combinations of steroids. Plans are being developed to make 1 or both of these available for introduction into certain family planning programs in developing countries early in 1988.^ieng

Cortical blindness as a complication of eclampsia.

Presented is a case of an eclamptic patient whose primary clinical presentation was cortical blindness. The patient was not known to be preeclamptic during her prenatal course, but she was lost to follow up one month prior to her presentation. Computed tomographic scan of the head was consistent with hypertensive encephalopathy. She was treated as an eclamptic patient. Her blood pressure was controlled with hydralazine, and she was given magnesium sulfate intravenously and intramuscularly. Labor was induced with a pitocin infusion. After delivery of a term infant, her vision returned and all other symptoms resolved without sequelae. The etiology and pathophysiology of cortical blindness as a symptom of eclampsia are discussed.

The effect of propranolol on the rise in plasma ammonia during modest exercise.

Changes in plasma ammonia in response to exercise with and without pretreatment with propranolol have been studied. A standardised submaximal treadmill exercise test was used to assess the effects of placebo or propranolol 40 mg, 80 mg, or 160 mg twice daily given in random order for 3 days, the last dose being taken 90 min before exercise. After placebo the mean incremental rise in plasma ammonia in response to exercise was 16 mumol X 1(-1). The corresponding rise after propranolol 40 mg was 56 mumol X 1(-1) (p less than 0.01). All three doses of propranolol produced similar effects on plasma ammonia and exercise heart rates.

The effects of four beta-adrenoceptor antagonists during modest exercise on plasma ammonia and heart rate.

Plasma ammonia and heart rate were measured in normal volunteers before, during and after an exercise test following administration of placebo, propranolol, pindolol, metoprolol and nadolol. Small changes in plasma ammonia occurred during exercise after placebo. However, all four beta-adrenoceptor antagonists produced considerably greater rises. This effect was most marked after propranolol with the response to pindolol, metoprolol and nadolol being similar and intermediate between placebo and propranolol. Resting heart rate was reduced by all the beta-adrenoceptor antagonists except pindolol. Exercise induced changes in heart rate were significantly reduced to a similar degree by all the beta-adrenoceptor antagonists.

A review of "once-a-month" combined injectable contraceptives.

PIP: The once-a-month combined progestogen and estrogen injectables were developed to overcome menstrual irregularity, a major reason for discontinuation of progestogen-only contraceptives. About 2 million women have already used the combined once-a-month injectables, particularly in Latin America and China. The currently available once-a-month combined injectable contraceptives are Chinese Injectable No. 1 (17 alpha-hydroxyprogesterone caproate, estradiol valerate), another formulation marketed under various brand names in Latin America (dihydroxyprogesterone acetophenide, estradiol enanthate), Cyclofem (medroxyprogesterone acetate [MPA], estradiol cypionate), Mesigyna (norethisterone enanthate, estradiol valerate), and Mego-E (megestrol acetate, 17 beta-estradiol). Cyclofem and Mesigyna are very effective at preventing pregnancy (1-year rate, 99.8-99.6%). The rate for the dihydroxyprogesterone acetophenide/estradiol enanthate formulation is 100%, while that for Chinese Injectable No. 1 is 94%. Even though menstrual disturbances occur less often in once-a-month injectable users, they are the leading medical reason for discontinuation. At 1 year of use, about 70% of Cyclofem and Mesigyna users have regular bleeding patterns compared to 8% of Depo-Provera users. None of the Cyclofem and Mesigyna studies have found them to induce any adverse or clinically relevant metabolic changes. Once-a-month combined estrogen and progestogen injectables do not cause any significant delay in return to ovulation, but researchers should collect more data on conception rates for women who discontinue for planned pregnancy and those who discontinue for bleeding disorders and amenorrhea. Research into service delivery of these injectables is needed to assess managerial requirements or adaptations that would be required should there be more wide scale introduction of a contraceptive into both public and private sectors. Age, contraceptive history, learning about injectables and husbands' attitude, and knowing another user's satisfaction with the service appear to be important determinants of acceptability of once-a-month injectables.^ieng

Transformation of Acetobacter xylinum with plasmid DNA by electroporation.

Genetic analysis of Acetobacter xylinum, a cellulose-synthesizing bacterium, has been limited by lack of a successful transformation method. Transformation of A. xylinum was attempted using two broad-host-range plasmids (pUCD2 and pRK248) and a variety of transformation methods. Methods using CaCl2, freeze/thaw treatments, and polyethylene glycol were unsuccessful. Transformation of a cellulose-negative strain of A. xylinum with plasmid DNA has been achieved with high-voltage electroporation. Electroporation conditions of 25 microF capacitance, 2.5 kV, 400 ohms resistance, and pulse lengths of 6-8 ms were applied to a cell/DNA mixture in a 0.2-cm cuvette. Plasmid pUCD2 transformed at an efficiency of 10(6)-10(7) transformants/micrograms DNA and pRK248 yielded 10(5) transformants/micrograms DNA. The frequency of transformation increased linearly with increasing DNA concentration, while transformation efficiency remained constant. pUCD2 was recovered from transformants following chloramphenicol amplification and observed by agarose gel electrophoresis. Both plasmids could be reisolated from Escherichia coli after back-transformation with alkaline lysis DNA preparations from Acetobacter transformants. Electro-transformation of A. xylinum with plasmid DNA suggests its potential use for analysis of the A. xylinum genome.

The influence of beta-adrenoceptor blockade on the lipolytic response to exercise.

The influence of beta-adrenoceptor blockade on the free fatty acid (FFA) response during and after submaximal exercise was studied in a group of normal volunteers. The study showed that the exercise-induced rise in serum FFA concentrations seen with placebo was reduced after pretreatment with propranolol. Furthermore, the palmitic, stearic, oleic and linoleic acid responses showed progressive attenuation with increasing doses of propranolol. Different beta blockers were studied using comparable doses: metoprolol and nadolol had little effect and produced FFA profiles that were similar to placebo whereas the changes on pindolol were comparable with those on propranolol.