Development of a comprehensive set of P2 receptor pharmacological research compounds.

Pharmacological manipulation of P2X and P2Y receptors has been critical to the elucidation of the biological roles of these receptors within a multitude of physiological and pathological processes. Initial purinergic signalling research made use of compounds based on pyridoxal phosphate, suramin and nucleotide analogues; recently developed compounds are often derivatives of these early tools. Tocris Bioscience first entered the field of purinergic signalling reagents with the commercial release of the pyridoxal phosphate derivative, iso-PPADS. During the past two decades, Tocris has assembled a collection of over 50 compounds for P2 receptor modulation, including research tools commercialised from both academic and industrial laboratories. Recently, a number of P2X subtype-selective compounds have been generated by pharmaceutical company medicinal chemistry programmes, supplementing our range of P2Y-selective compounds. Here, we detail the current, commercially available agonists and antagonists of P2X(1,2/3,3,4,7) and P2Y(1,6,11,12) receptors; considered together, they form the foundations of a comprehensive P2 receptor pharmacological 'toolkit'.

Hysterectomy, endometrial ablation and Mirena® for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis.

OBJECTIVE: The aim of this project was to determine the clinical effectiveness and cost-effectiveness of hysterectomy, first- and second-generation endometrial ablation (EA), and Mirena® (Bayer Healthcare Pharmaceuticals, Pittsburgh, PA, USA) for the treatment of heavy menstrual bleeding. DESIGN: Individual patient data (IPD) meta-analysis of existing randomised controlled trials to determine the short- to medium-term effects of hysterectomy, EA and Mirena. A population-based retrospective cohort study based on record linkage to investigate the long-term effects of ablative techniques and hysterectomy in terms of failure rates and complications. Cost-effectiveness analysis of hysterectomy versus first- and second-generation ablative techniques and Mirena. SETTING: Data from women treated for heavy menstrual bleeding were obtained from national and international trials. Scottish national data were obtained from the Scottish Information Services Division. PARTICIPANTS: Women who were undergoing treatment for heavy menstrual bleeding were included. INTERVENTIONS: Hysterectomy, first- and second-generation EA, and Mirena. MAIN OUTCOME MEASURES: Satisfaction, recurrence of symptoms, further surgery and costs. RESULTS: Data from randomised trials indicated that at 12 months more women were dissatisfied with first-generation EA than hysterectomy [odds ratio (OR): 2.46, 95% confidence interval (CI) 1.54 to 3.93; p = 0.0002), but hospital stay [WMD (weighted mean difference) 3.0 days, 95% CI 2.9 to 3.1 days; p < 0.00001] and time to resumption of normal activities (WMD 5.2 days, 95% CI 4.7 to 5.7 days; p < 0.00001) were longer for hysterectomy. Unsatisfactory outcomes associated with first- and second-generation techniques were comparable [12.2% (123/1006) vs 10.6% (110/1034); OR 1.20, 95% CI 0.88 to 1.62; p = 0.2). Rates of dissatisfaction with Mirena and second-generation EA were similar [18.1% (17/94) vs 22.5% (23/102); OR 0.76, 95% CI 0.38 to 1.53; p = 0.4]. Indirect estimates suggested that hysterectomy was also preferable to second-generation EA (OR 2.32, 95% CI 1.27 to 4.24; p = 0.006) in terms of patient dissatisfaction. The evidence to suggest that hysterectomy is preferable to Mirena was weaker (OR 2.22, 95% CI 0.94 to 5.29; p = 0.07). In women treated by EA or hysterectomy and followed up for a median [interquartile range (IQR)] duration of 6.2 (2.7-10.8) and 11.6 (7.9-14.8) years, respectively, 962/11,299 (8.5%) women originally treated by EA underwent further gynaecological surgery. While the risk of adnexal surgery was similar in both groups [adjusted hazards ratio 0.80 (95% CI 0.56 to 1.15)], women who had undergone ablation were less likely to need pelvic floor repair [adjusted hazards ratio 0.62 (95% CI 0.50 to 0.77)] and tension-free vaginal tape surgery for stress urinary incontinence [adjusted hazards ratio 0.55 (95% CI 0.41 to 0.74)]. Abdominal hysterectomy led to a lower chance of pelvic floor repair surgery [hazards ratio 0.54 (95% CI 0.45 to 0.64)] than vaginal hysterectomy. The incidence of endometrial cancer following EA was 0.02%. Hysterectomy was the most cost-effective treatment. It dominated first-generation EA and, although more expensive, produced more quality-adjusted life-years (QALYs) than second-generation EA and Mirena. The incremental cost-effectiveness ratios for hysterectomy compared with Mirena and hysterectomy compared with second-generation ablation were £1440 per additional QALY and £970 per additional QALY, respectively. CONCLUSIONS: Despite longer hospital stay and time to resumption of normal activities, more women were satisfied after hysterectomy than after EA. The few data available suggest that Mirena is potentially cheaper and more effective than first-generation ablation techniques, with rates of satisfaction that are similar to second-generation techniques. Owing to a paucity of trials, there is limited evidence to suggest that hysterectomy is preferable to Mirena. The risk of pelvic floor surgery is higher in women treated by hysterectomy than by ablation. Although the most cost-effective strategy, hysterectomy may not be considered an initial option owing to its invasive nature and higher risk of complications. Future research should focus on evaluation of the clinical effectivesness and cost-effectiveness of the best second-generation EA technique under local anaesthetic versus Mirena and types of hysterectomy such as laparoscopic supracervical hysterectomy versus conventional hysterectomy and second-generation EA. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding: systematic review and meta-analysis of data from individual patients.

OBJECTIVE: To evaluate the relative effectiveness of hysterectomy, endometrial destruction (both "first generation" hysteroscopic and "second generation" non-hysteroscopic techniques), and the levonorgestrel releasing intrauterine system (Mirena) in the treatment of heavy menstrual bleeding. DESIGN: Meta-analysis of data from individual patients, with direct and indirect comparisons made on the primary outcome measure of patients' dissatisfaction. DATA SOURCES: Data were sought from the 30 randomised controlled trials identified after a comprehensive search of the Cochrane Library, Medline, Embase, and CINAHL databases, reference lists, and contact with experts. Raw data were available from 2814 women randomised into 17 trials (seven trials including 1359 women for first v second generation endometrial destruction; six trials including 1042 women for hysterectomy v first generation endometrial destruction; one trial including 236 women for hysterectomy v Mirena; three trials including 177 women for second generation endometrial destruction v Mirena). Eligibility criteria for selecting studies Randomised controlled trials comparing hysterectomy, first and second generation endometrial destruction, and Mirena for women with heavy menstrual bleeding unresponsive to other medical treatment. RESULTS: At around 12 months, more women were dissatisfied with outcome with first generation hysteroscopic techniques than with hysterectomy (13% v 5%; odds ratio 2.46, 95% confidence interval 1.54 to 3.9, P<0.001), but hospital stay (weighted mean difference 3.0 days, 2.9 to 3.1 days, P<0.001) and time to resumption of normal activities (5.2 days, 4.7 to 5.7 days, P<0.001) were longer for hysterectomy. Unsatisfactory outcomes were comparable with first and second generation techniques (odds ratio 1.2, 0.9 to 1.6, P=0.2), although second generation techniques were quicker (weighted mean difference 14.5 minutes, 13.7 to 15.3 minutes, P<0.001) and women recovered sooner (0.48 days, 0.20 to 0.75 days, P<0.001), with fewer procedural complications. Indirect comparison suggested more unsatisfactory outcomes with second generation techniques than with hysterectomy (11% v 5%; odds ratio 2.3, 1.3 to 4.2, P=0.006). Similar estimates were seen when Mirena was indirectly compared with hysterectomy (17% v 5%; odds ratio 2.2, 0.9 to 5.3, P=0.07), although this comparison lacked power because of the limited amount of data available for analysis. CONCLUSIONS: More women are dissatisfied after endometrial destruction than after hysterectomy. Dissatisfaction rates are low after all treatments, and hysterectomy is associated with increased length of stay in hospital and a longer recovery period. Definitive evidence on effectiveness of Mirena compared with more invasive procedures is lacking.

A pragmatic randomised comparison of transcervical resection of the endometrium with endometrial laser ablation for the treatment of menorrhagia.

OBJECTIVE: To compare endometrial laser ablation (ELA) with transcervical resection of the endometrium (TCRE) in the treatment of menorrhagia. DESIGN: Randomised controlled trial. SETTING: Gynaecology department of a large teaching hospital. PARTICIPANTS: Women with menorrhagia due to dysfunctional uterine bleeding (n = 372) were randomly allocated to ELA (n = 188) or TCRE (n = 184). MAIN OUTCOME MEASURES: Operative complications, post-operative recovery, relief of menstrual and other symptoms, need for further surgical treatment, satisfaction with treatment after 6 and 12 months, and differential resource use. RESULTS: TCRE was significantly quicker, with lower rates of fluid overload. Perioperative morbidity was low and similar in both groups. Outcome at 12 months was also similar: 72 women (45%) had either amenorrhoea or brown discharge in the ELA group compared with 71 (49%) in the TCRE group; 79 (49%) versus 68 (46%) had lighter periods. Thirty (16%) versus 36 (20%) had received further surgical treatment: 9 (5%) compared with 25 (14%) had had a hysterectomy and 21 (11%) versus 11 (6%) had received repeat ablation. Anxiety and depression, dysmenorrhoea and pre-menstrual symptoms were improved by both procedures and bladder symptoms were affected by neither. At 12 months 148 (90%) women in the ELA group and 140 (91%) women in the TCRE group were satisfied with their treatment. The estimated additional cost of ELA was Pound 145 per procedure. CONCLUSIONS: At one year there was no clear difference in clinical outcome between ELA and TCRE. Both procedures were associated with low morbidity. ELA was the more costly procedure. Despite the need for further surgery for about one in six women, satisfaction rates were high following both ELA and TCRE.

A cost comparison of hysterectomy and hysteroscopic surgery for the treatment of menorrhagia.

OBJECTIVES: To estimate and compare the costs of treating women with menorrhagia by hysterectomy or hysteroscopic surgery, in the form of transcervical resection of the endometrium (TCRE) or endometrial laser ablation (ELA). STUDY DESIGN: Randomised controlled trial set in the gynaecological department of a large British teaching hospital. Under usual circumstances, 204 women who would have undergone hysterectomy for menorrhagia were randomly allocated to either hysterectomy (n = 99) or hysteroscopic surgery in the form of TCRE (n = 52) or ELA (n = 53). National Health Service (NHS) costs and costs to patients per patient occurring up to 1 year following surgery were estimated. Theatre times and length of hospital stay were recorded during the trial. Costs were obtained from the health board finance department and relevant suppliers of technical equipment. One year after treatment patients completed questionnaires on personal costs incurred. RESULTS: The NHS costs of treating women with hysteroscopic surgery were 24% (TCRE) or 20% (ELA) less than treating women by hysterectomy (1001 pounds/1046 pounds vs. 1315 pounds). On average, women undergoing hysteroscopic surgery incurred 71% less costs to themselves than those who underwent hysterectomy (21 pounds vs. 73.40 pounds). CONCLUSIONS: Hysteroscopic endometrial ablation incurs less costs than hysterectomy both to the National Health Service and to women alike, up to 1 year after surgery.

A comparison of bladder and ovarian function two years following hysterectomy or endometrial ablation.

OBJECTIVE: To test the hypothesis that at two years bladder and ovarian function function are no different following either simple hysterectomy or endometrial ablation (transcervical resection/laser ablation). DESIGN: Randomised controlled trial comparing hysterectomy with endometrial ablation. Two years after trial entry bladder and ovarian function were evaluated subjectively by means of questionnaires and objectively by means of cystometry and estimation of serum follicle stimulating hormone respectively. SETTING: Aberdeen Royal Infirmary. PARTICIPANTS: Tow hundred and four women with dysfunctional uterine bleeding who, when recruited to the initial study two years previously, were aged less than 50 years, weighed less than 100 kg, and who would otherwise have undergone hysterectomy. RESULTS: Of the 204 women originally recruited, 101 re-attended the clinic and underwent cystometry and follicle stimulating hormone estimation. These, together with a further 59 women, completed postal questionnaires (79% of original cohort). Rates of stress incontinence (44% vs 44%, 95% CI of difference -16% to +15%), urge incontinence (21% vs 19% 95% CI of difference -11% to +14%), and hot flushes (30% vs 44%, 95% CI of difference -25% to +7%) were similar in the hysterectomy and endometrial ablation groups, respectively. Cystometry revealed 14 (31%) cases of bladder dysfunction after hysterectomy and 17 (35%) after hysteroscopic surgery (95% CI of difference -23% to +15%). Serum follicle stimulating hormone levels > 40 IU/L [corrected] were found in three (6%) women following hysterectomy and five (10%) of women after endometrial ablation. CONCLUSION: This study suggests that in comparison with endometrial ablation, simple hysterectomy for dysfunctional uterine bleeding does not compromise bladder or ovarian function, at least at two years after the operation. Due to lack of power the estimates of any differences are imprecise, and clinically significant effects cannot be ruled out.

Randomised trial comparing hysterectomy with endometrial ablation for dysfunctional uterine bleeding: psychiatric and psychosocial aspects.

OBJECTIVE: To compare in psychiatric and psychosocial terms the outcome of hysterectomy and endometrial ablation for the treatment of dysfunctional uterine bleeding. DESIGN: Prospective randomised controlled trial. SETTING--Obstetrics and gynaecology department of a large teaching hospital. SUBJECTS: 204 women with dysfunctional bleeding for whom hysterectomy would have been the preferred treatment were recruited over 24 months and randomly allocated to hysterectomy (99 women) or to hysteroscopic surgery (transcervical resection (52 women) or laser ablation (53 women). MAIN OUTCOME MEASURES: Mental state, martial relationship, psychosocial and sexual adjustment in assessments conducted before the operation and one month, six months, and 12 months later. RESULTS: Both treatments significantly reduced the anxiety and depression present before the operation, and there were no differences in mental health between the groups at 12 months. Hysterectomy did not lead to postoperative psychiatric illness. Sexual interest after the operation did not vary with treatment. Overall, 46 out of 185 (25%) women reported a loss sexual interest and 50 out of 185 (27%) reported increased sexual interest. Marital relationships were unaffected by surgery. Personality and duration of dysfunctional uterine bleeding played no significant part in determining outcome. CONCLUSIONS: Hysteroscopic surgery and hysterectomy have a similar effect on psychiatric and psychosocial outcomes. There is no evidence that hysterectomy leads to postoperative psychiatric illness.

Blood rheology and albumin excretion in diabetic pregnancy.

Blood rheology is altered in diabetes and also in non-diabetic pregnant women. The cumulative effect of hyperfiltration, abnormal rheology of pregnancy, and diabetes could be one mechanism contributing to increased intraglomerular pressure and albuminuria in diabetic pregnancy. We conducted a prospective study of 22 Type 1 (insulin-dependent) diabetic patients and 22 non-diabetic women to determine if there was an association of altered blood rheology on glomerular function in diabetic pregnancy. Albumin excretion showed no increment with increasing gestation and was similar in diabetic and non-diabetic women throughout pregnancy (first trimester: 5.0 (3.0-14.0) vs 5.8 (3.7-10.7) mg l-1, p = 0.89; second trimester: 6.0 (5.0-12.0) vs 5.1 (3.6-10.4) mg l-1, p = 0.25; third trimester: 7.5 (3.5-16.0) vs 4.9 (2.9-7.3) mg l-1, p = 0.18). Red cell aggregation index increased in both groups between the first and third trimesters (diabetic patients: mean difference 2.0; Cl: 1.0-2.9, p = 0.003, and control patients: mean difference 2.3, Cl: 1.0-3.5, p = 0.002). Fibrinogen levels were significantly higher between the third and first trimesters in diabetic patients (mean difference 0.7, Cl: 0.2-1.3 g l-1, p = 0.006). Pregnancy, therefore, was associated with increased red cell aggregation, related in part to increased fibrinogen levels but the extent of change was similar in diabetic and nondiabetic women and appeared to have no adverse effect on glomerular function in pregnant insulin-dependent diabetic women.

Randomised trial of hysterectomy, endometrial laser ablation, and transcervical endometrial resection for dysfunctional uterine bleeding.

OBJECTIVE: To evaluate the effectiveness and safety of endometrial laser ablation and transcervical resection of the endometrium compared with hysterectomy in the surgical treatment of women with dysfunctional uterine bleeding. DESIGN: Prospective randomised controlled trial. SETTING: Gynaecology department of a large teaching hospital. SUBJECTS: 204 women who would otherwise have been undergoing hysterectomy for menorrhagia were recruited between August 1990 and March 1992 and randomly allocated to hysterectomy (n = 99) or conservative (hysteroscopic) surgery (transcervical resection (n = 52) and laser ablation (n = 53)). MAIN OUTCOME MEASURES: Operative complications, postoperative recovery, relief of menstrual and other symptoms, patient satisfaction with treatment after six and 12 months. RESULTS: Women treated by hysteroscopic surgery had less early morbidity and a significantly shorter recovery period than those treated by hysterectomy (median time to full recovery 2-4 weeks v 2-3 months, P < 0.001). Twelve months later 17 women in the hysteroscopy group had had a hysterectomy, 11 for continuing symptoms; 11 women had had a repeat hysteroscopic procedure; 45 were amenorrhoeic or had only a brown discharge; and 35 had light periods. Dysmenorrhoea and premenstrual symptoms improved in most women in both groups. After 12 months 89% (79/89) in the hysterectomy group and 78% (75/96) in the hysteroscopy group were very satisfied with the effect of surgery (P < 0.05); 95% (85/89) and 90% (86/96) thought that there had been an acceptable improvement in symptoms, and 72% (64/89) and 71% (68/96) would recommend the same operation to others. CONCLUSIONS: Hysteroscopic endometrial ablation was superior to hysterectomy in terms of operative complications and postoperative recovery. Satisfaction after hysterectomy was significantly higher, but between 70% and 90% of the women were satisfied with the outcome of hysteroscopic surgery. Hysteroscopic surgery can be recommended as an alternative to hysterectomy for dysfunctional uterine bleeding.

The incidence of persistent functioning endometrial tissue following successful radiotherapy for cervical carcinoma.

Sixty-three patients under the age of 50 years who were long-term survivors following radiotherapy for cervical cancer and had been placed on hormone replacement therapy (HRT) were identified. The median age at treatment was 37 years and the mean delay from treatment to the initiation of HRT was over 15 months. Fifteen of the 63 patients had experienced vaginal bleeding attributable to the effects of HRT on persisting endometrial tissue. The significance of this is discussed.

Oncogene expression in cervical intraepithelial neoplasia and invasive cancer of cervix.

Expression of the oncogenes Ha-RAS, c-MYC, and ERB-2 was investigated with an automated image analysis system in 12 specimens of normal cervix, 10 of cervical intraepithelial neoplasia (CIN) grade 1, 24 of CIN 3, and 10 of invasive cancer of the cervix. There was amplification of all three oncogenes in CIN 3 and invasive cancer compared with normal cervix and CIN 1. The difference was most pronounced with an antibody to the RAS p21 protein, with no overlap between CIN 3 and the normal range. This method might be useful in screening for cervical neoplasia, and for the determination of which CIN lesions require treatment.

Preterm caesarean section.

A retrospective study of 1921 caesarean sections at Rutherglen Maternity Hospital in Glasgow during the years 1979-1983, inclusive, showed that 229 (12%) were performed at less than 37 weeks gestation. Of these 229 preterm caesarean sections 41% were elective, 21% were for antepartum haemorrhage and 38% took place during labour. Of the 254 babies born 18 (7%) died in the neonatal period. These deaths comprised 31% of all neonatal deaths during the study period in this hospital. The neonatal death rate was 70% for babies weighing less than 1000 g (7 of 10) and 23% for babies weighing 1000-1500 g (6 of 26), but only 3% for babies heavier than this (7 of 217). Of the 75 women with a subsequent pregnancy after the preterm caesarean section 56% were again delivered by caesarean section. In view of the maternal morbidity associated with caesarean section and the poor neonatal outcome at birthweights of less than 1500 g, the use of operative delivery for very low birthweight infants deserves further scrutiny.