Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation Nuclear receptors such as the estrogen receptors (ERα and ERβ) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised
[Sterility from hormonal causes and unexplained sterility. Treatment with cyclofenil. Double-blind controlled study]. We treated 213 women during 3 cycles by cyclofenil versus placebo in a double-blind study. These women had infertility caused by ovulatory deficiencies, a cervical factor or idiopathic infertility. Twenty-six of the 114 women receiving cyclofenil became pregnant and 21 of the 99
Cyclofenil versus placebo in progressive systemic sclerosis. A one-year double-blind crossover study of 27 patients. Cyclofenil was evaluated versus placebo in the treatment of progressive systemic sclerosis (PSS, scleroderma) in a 2 x 6-month double-blind crossover study. The mean duration of disease was six years. Of 38 patients entering the study, 27 completed both periods. Reasons for drop -outs were very high liver transaminases in three cases, cardiac death in two, and drug allergy, alcoholic problems, suspected congestive heart failure, reactivation of tuberculosis, arteriosclerotic heart disease, and lethal progression of PSS in one case each. No fatality was attributed to cyclofenil. Liver enzyme abnormalities were seen in 13 of 35 active drug periods and in 5 of 30 placebo periods
Cyclofenil treatment of scleroderma--a controlled study. A double-blind cross-over study of cyclofenil and placebo treatments was conducted in 11 scleroderma patients. Each treatment period was for four months. A range of subjective and objective measurements failed to reveal any consistent or obvious response to cyclofenil. One patient died of his disease during active treatment. Four were withdrawn because of liver dysfunction which was attributed to cyclofenil. It remains to be seen whether treatment over longer periods will exert a clinically significant effect.
Plasma FSH, LH and prolactin levels in postmenopausal women undergoing cyclofenil treatment. Ten postmenopausal women were studied in an attempt to identify the mechanism of action of cyclofenil, a non-steroidal anti-estrogen which has proved to be effective in the climacteric syndrome. A double-blind inter-patient clinical investigation was undertaken, with patients assigned randomly to treatment for 10 days with cyclofenil, 400 mg/day, or else conjugated estrogens, 1.25 mg/day, always given orally at 8 a.m. Serum FSH, LH and PRL levels were determined daily 2 days before, during and for 2 days after treatment. On the first and tenth day of treatment, five blood samples were drawn between 8 a.m. and 4 p.m. to ascertain if there was any drug-induced variation in the hormonal secretory
The effect of three anti-oestrogen drugs on cervical mucus quality and in-vitro sperm-cervical mucus interaction in ovulatory women. The anti-oestrogens, clomiphene citrate, tamoxifen and cyclofenil are commonly used in the treatment of female infertility. Their role in the management of anovulation is well established but there is continuing controversy about their relevance to other areas , and follicle scanning was also undertaken. Cervical mucus quality and sperm-cervical mucus interaction were studied on the day of onset of the LH surge. The use of clomiphene and tamoxifen resulted in a significant reduction in cervical mucus score and sperm-cervical mucus interaction as judged by the distance travelled by the vanguard spermatozoa. Cyclofenil had no effect on these parameters.
Effect of cyclofenil on hormonal dynamics, follicular development and cervical mucus in normal and oligomenorrhoeic women. Cyclofenil is a triphenylethylene derivative, similar in structure to clomiphene citrate, which is used to induce ovulation in anovulatory women. The effects of cyclofenil on a group of 10 normal cyclic and 10 oligomenorrhoeic subjects were examined in a double blind controlled cross-over study. Both groups of women were administered either cyclofenil or, following a washout cycle, a placebo in two treatment cycles. Urinary oestrone and pregnanediol excretion were measured daily and ultrasound scans performed to assess follicular development. Frequent sampling of blood was performed on day 6 to study luteinizing hormone (LH) and follicle stimulating hormone (FSH
Long-term evaluation of penicillamine or cyclofenil in systemic sclerosis. Results from a two-year randomized study. In a two-year prospective therapeutic trial 13 patients with systemic sclerosis (SSc) were treated with penicillamine, 9 with cyclofenil, and 7 with neither. At entry skin involvement and esophageal, lung, heart, and kidney function did not differ significantly between the groups . Reevaluation after one and two years did not show any significant changes in skin, esophageal, heart, and kidney manifestations, while lung function had slightly improved in both drug-treatment groups. This study thus shows little overall effect of penicillamine and cyclofenil, although both drugs may arrest worsening of pulmonary dysfunction.
The effects of clomiphene citrate and cyclofenil on cervical mucus volume and receptivity over the periovulatory period. To determine the effects of clomiphene citrate (CC) and cyclofenil on cervical mucus (CM) volume and receptivity sampled serially over the periovulatory period. Using prospective luteinizing hormone (LH) timing CM volume and receptivity were compared in standard CC and cyclofenil-stimulated cycles using normal ovulatory cycles as controls. The Donor Insemination Unit at the University Research Clinic, Sheffield, United Kingdom. Twenty anovulatory patients and 10 normally ovulating patients, all of whom were participating in a treatment cycle of donor insemination. The 20 anovulatory patients were allocated at random into two groups: group 1 was administered 50 mg of CC
A prospective, randomised, cross-over study comparing the effects of clomiphene citrate and cyclofenil on endometrial morphology in the luteal phase of normal, fertile women. To examine the effect of two anti-oestrogens, clomiphene citrate and cyclofenil, on endometrial morphology in the luteal phase. A prospective, randomised, cross-over study. Jessop Hospital for Women, Sheffield, UK. 10 women who were previously fertile and regularly cycling. The administration of clomiphene citrate or cyclofenil in the treatment cycles. A LH timed endometrial biopsy was taken on day LH + 6. Histological dating and morphometric analysis of the endometrial sample. Only one out of 10 subjects had abnormal endometrium. There was no difference in the results between cycles treated with clomiphene citrate
[The sterile woman, the physician and time. Number of spontaneous pregnancies in patients with functional sterility]. We analysed a one to eight year follow-up of the women remaining infertile after a double-blind study of cyclofenil versus placebo to determine the frequency of pregnancy occurring independently of treatment. Pregnancy occurred in 64 women, 25 during treatment, 39 without
The use of cyclofenil in menopausal women. On the basis of some reports, a double-blind experimental trial comparing the activity of cyclofenil, estradiol valerate and placebo in post-menopausal disturbances was carried out. 60 women among those attending the menopausal clinic and affected by climateric disorders have been treated. The objective criterium for the admission had been established a statistically significant difference between the placebo and the active compounds: no significant difference between cyclofenil and estradiol valerate was observed.
Inhibition of lactation by cyclofenil and bromocriptine. In a double blind controlled study of the inhibition of lactation 13 women received 300 mg of cyclofenil and 11 women 2.5 mg of bromocriptine twice daily for 14 days. Lactation was effectively inhibited by both drugs, but with bromocriptine there was a significantly higher frequency of relapse. The plasma concentration of prolactin, which decreased rapidly with bromocriptine, returned to the pretreatment level the day after drug treatment stopped, but with cyclofenil it remained low. Plasma oestradiol followed a similar pattern. Plasma FSH increased more rapidly with bromocriptine than with cyclofenil. There was no significant difference between the treatment groups at any stage for haematology, coagulation or liver function tests
Effects of cyclofenil diphenol, an agent which disrupts Golgi structure, on proteoglycan synthesis in chondrocytes. 1. Cyclofenil diphenol (F6060), a weak non-steroidal oestrogen, was shown previously to inhibit [35S]proteoglycan synthesis [Mason, Lineham, Phillipson & Black (1984) Biochem. J. 223, 401-412] and to induce fragmentation of the Golgi apparatus into small vesicles [Lancaster, Fryer and tamoxiphen are also potent inhibitors of [35S]proteoglycan synthesis. 2. Syntheses of chondroitin 4-[35S]sulphate and chondroitin 6-[35S]sulphate, which are Golgi-mediated events, are inhibited 40-68% and 3-48% respectively by concentrations of cyclofenil between 50 and 70 micrograms/ml. [3H]Hyaluronan synthesis, which occurs by a different mechanism at the plasma membrane, is inhibited by 47-66
Selective inhibition of proteoglycan and hyaluronate synthesis in chondrocyte cultures by cyclofenil diphenol, a non-steroidal weak oestrogen. Cyclofenil diphenol, a weak non-steroidal oestrogen, binds to albumin. In the presence of concentrations of albumin just sufficient to keep cyclofenil diphenol in solution, the compound inhibited the synthesis of [35S]proteoglycans, [3H]glycoproteins, [3H ]hyaluronate and [3H]proteins in primary cultures of chondrocytes from the Swarm rat chondrosarcoma in a dose-dependent manner. When excess albumin was present, conditions were found (90 micrograms of cyclofenil diphenol and 4 mg of albumin per ml of culture medium) which completely inhibited [35S]proteoglycan and [3H]hyaluronate synthesis but had little effect on [3H]protein or [3H]glycoprotein synthesis
Hepatic reactions to cyclofenil Thirty patients with hepatic reactions to cyclofenil, a non-steroidal drug with a stimulating effect on ovulation, are reviewed. The liver damage was probably related to metabolic idiosyncrasy, and was reversible in all patients.
Cyclofenil for Raynaud's phenomenon in progressive systemic sclerosis. To assess the effects and toxicity of Cyclofenil versus placebo for the treatment of Raynaud's phenomenon (RP) in scleroderma. We searched the Cochrane Controlled Trials Register, and Medline up to 1996 using the Cochrane Collaboration search strategy developed by Dickersin et al.(1994). Key words included: Raynaud's or Vasospasm, Scleroderma or Progressive Systematic Sclerosis or Connective Tissue Disease or Autoimmune Disease. Current Contents were searched up to and including April 7, 1997. All bibliographies of articles retrieved were searched and key experts in the area were contacted for additional and unpublished data. The initial search strategy included all languages. All randomized trials comparing cyclofenil