Search

Objectives: The aim was to adapt a US adverse drug event (ADE) trigger tool for UK use, and to establish its positive predictive value (PPV) and sensitivity in comparison to retrospective health record review for the identification of preventable ADEs, in a pilot study on one hospital ward., Methods: An established US trigger tool was adapted for UK use. We applied it retrospectively to 207 patients' health records, following up positive triggers to identify any ADEs (both preventable and non-preventable). We compared the preventable ADEs to those identified using full health record review., Key Findings: We identified 168 positive triggers in 127 (61%) of 207 patients. Seven ADEs were identified, representing an ADE in 3.4% of patients or 0.7 ADEs per 100 patient days. Five were non-preventable adverse drug reactions and two were due to preventable errors. The prevalence of preventable ADEs was 1.0% of patients, or 0.2 per 100 patient days. The overall PPV was 0.04 for all ADEs, and 0.01 for preventable ADEs. PPVs for individual triggers varied widely. Five preventable ADEs were identified using health record review. The sensitivity of the trigger tool for identifying preventable ADEs was 0.40, when compared to health record review., Conclusions: Although we identified some ADEs using the trigger tool, more work is needed to further refine the trigger tool to reduce the false positives and increase sensitivity. To comprehensively identify preventable ADEs, retrospective health record review remains the gold standard and we found no efficiency gain in using the trigger tool., (© 2010 The Authors. IJPP © 2010 Royal Pharmaceutical Society of Great Britain.)

Background: Activation of macrophages is central to the implantation of endometriosis (EM). We examined the hypothesis that macrophage depletion by intraperitoneal (IP) injection of liposomal alendronate (LA) could result in EM attenuation in a rat model, thus supporting the notion of the pivotal role of macrophages in EM pathology., Methods: In this study, 90 rats were subjected to an EM model and were divided randomly into seven groups: five groups were treated by 4x once-weekly IP injections of LA (0.02, 0.1, 1, 5 or 10 mg/kg) and the other two groups received saline injections (control) or empty liposomes. Sham-operated rats also received empty liposomes. Depletion of circulating monocytes was determined by flow cytometry analyzes of blood specimens. Four weeks after the initial surgery, the number, size and weight of implants were recorded, adhesions were graded, macrophage infiltration was assessed and the peritoneal fluid was analyzed for monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor alpha (TNFalpha)., Results: Monocyte depletion following IP LA administration resulted in an inhibitory effect on the initiation and growth of EM implants, as expressed by implantation rate, adhesion scoring, implants' size and weight (>0.1 mg/kg LA, P < 0.05). Reduced numbers of infiltrating macrophages were observed in implants of the 1 mg/kg LA group. Peritoneal fluid MCP-1 levels were negatively correlated with LA dose (P < 0.001), whereas no significant correlation could be found for TNFalpha., Conclusions: Macrophage depletion using IP LA has been shown to effectively inhibit the initiation and growth of EM implants, in a rat EM model. The clear dose-response effect may be viewed as a confirmation of the validity of the concept and encourages further study.

Informed consent traditionally has been viewed as a safeguard for the protection of patients' decisional autonomy. While informed consent is a critical means for the protection of the patient's dominion over the integrity of his body, exclusive consideration of the doctrine as a safeguard for patients eclipses the doctrine's significant benefits for the therapeutic endeavor. Undertaking a thorough informed consent process helps the physician avoid the unilateral burdens of paternalism; furthers compliance with the doctor's legal obligations, ethical duties, and clinical responsibilities; and, as importantly, enhances the collaborative treatment enterprise. When informed consent is viewed narrowly and solely as a protective device for patients' rights, the physician may be less likely to engage the patient in ongoing discussions. Important opportunities may be missed to elicit additional clinical information, assess psychosocial concerns, and reiterate the commitment to collaboration and patient autonomy.

Background: We aimed to examine the efficacy of using an embryo transfer medium enriched with hyaluronan (HA) to improve implantation in a selected group of patients aged <43 years with repeated (>4) implantation failures after IVF-embryo transfer., Methods: About 101 patients, meeting our selection criteria, were randomly allocated to undergo embryo transfer either using our routine embryo transfer medium without HA (control group) or a HA enriched commercial embryo transfer medium (study group). The primary outcome was clinical pregnancy rate., Results: After a similar treatment protocol, the ovarian hormonal response, the mean number of ova retrieved and injected per patient, fertilization and cleavage rates and mean embryo quality were comparable between the study and control groups. Although a similar number of embryos was transferred in both groups (3.1 +/- 0.7 versus 2.9 +/- 0.6, mean +/- SD), a significantly higher implantation rate (16.3% versus 4.8%, P = 0.002) and clinical pregnancy rate (35.2% versus 10.0%, P = 0.004) and delivered or ongoing pregnancy rate (31.3% versus 4.0%, P = 0.0005) were observed in the study group. When mean implantation rate per patient was calculated, the difference between the study (0.148 +/- 0.23) and control (0.04 +/- 0.13) group was significant (P = 0.003)., Conclusions: In this selected group of patients after multiple IVF-embryo transfer failures, the use of HA enriched embryo transfer medium is beneficial.

Background: Poor sperm morphology is statistically associated with an increase in the incidence of chromosome abnormalities. Our aim was to examine the possible correlation between chromosomal aberrations and sperm morphology in the same cell., Methods: 12349 spermatozoa from 7 teratozoospermic and one globozoospermic patients, and from 3 fertile donors were analyzed using a system which scans for cell morphology and chromosomal ploidy in the same cell using digital technology., Results: Chromosomal aberrations were detected in 5.3% of teratozoospermic cases and in 6.7% in the globozoospermic patient compared with 1.6% in donors (P < 0.0001). Chromosomal aberrations were more common in abnormally formed sperm compared with normal spermatozoa: 4.5% vs 1.3% in the teratozoospermic group and 2.0% vs 0.3% in the control group (NS), especially frequent among sperm with two heads or two tails (52.1-77.2%) or extreme head deformations (10.6-11.1%) irrespective of grouping, and in mild amorphous heads in the globozoospermic patients (20.2%). The frequency of chromosomal aberrations in morphologically normal sperm was comparable whether derived from teratozoospermic or normospermic patients., Conclusions: The computerized cell-scanning system demonstrated the relationship between chromosomal aberrations and sperm morphology in the same spermatozoon. The incidence of chromosomal aberrations was positively linked to abnormal sperm morphology, the more severe the abnormality, the higher the incidence of aneuploidy.

Controlling nuclear maturation during oocyte culture might improve nuclear-cytoplasmic maturation synchrony. We aimed to evaluate the quality of in vitro-matured, germinal vesicle (GV)-stage human oocytes following a prematuration culture (PMC) with a meiotic arrester, phosphodiesterase 3-inhibitor (PDE3-I). Follicles (diameter, 6-12 mm) were retrieved 34-36 h post-hCG administration from informed, consenting patients who had undergone controlled ovarian stimulation. Cumulus-enclosed oocytes (CEOs) presenting moderate expansion or full compaction were placed in PMC with the PDE3-I, Org9935, for 24 or 48 h. Subsequently, oocytes were removed from PMC, denuded of cumulus cells, matured in vitro, and fertilized, and the resulting embryos were cultured. In the presence of PDE3-I, approximately 98% of the oocytes were arrested at the GV stage. Following PDE3-I removal, oocytes acquired a higher maturation rate than oocytes that were immediately denuded of cumulus cells after retrieval and in vitro matured (67% vs. 46%, P = 0.01). In controls, immature CEOs retrieved with moderate expansion reached higher maturation rates compared to fully compacted CEOs, but in PMC groups, high values of maturation were achieved for both morphological classes of CEOs. No effect of PMC on fertilization was observed. A 24-h PMC period proved to be the most effective in preserving embryonic integrity. Similar proportions of nuclear abnormalities were observed in embryos of all in vitro groups. In summary, PMC with the specific PDE3-I had a beneficial effect on human CEOs by enhancing maturation, benefiting mainly the fully compacted CEOs. This resulted in an increased yield of mature oocytes available for insemination without compromising embryonic development. These results suggest that applying an inhibitor to control the rate of nuclear maturity by regulating intraoocyte PDE3 activity may allow the synchronization of nuclear and ooplasmic maturation.

Background: The use of immature oocytes is limited to cases where these are the only available oocytes, and they are usually only microinjected with sperm after having undergone maturation in vitro. This study compares the outcome of injection of sperm into metaphase I oocytes immediately after their denudation (MI) performed 2 h after their retrieval, with the outcome of injection of sperm into rescued in vitro matured metaphase II (IVM MII) oocytes after their short incubation in routine laboratory conditions., Methods: ICSI was performed on MI oocytes, rescued IVM MII oocytes and on MI oocytes that were incubated but failed to extrude their first polar body (arrested IVM MI). Fertilization and cleavage rates were compared with those achieved in mature metaphase II oocytes (MII)., Results: ICSI of MI oocytes showed impaired performance compared with ICSI of rescued IVM MII oocytes and MII oocytes, in terms of oocyte degeneration rate (11 versus 6 versus 4%; P < 0.0001), fertilization rate (28 versus 44 versus 68%; P < 0.0001) and multipronucleated fertilization (10 versus 4 versus 4%; P < 0.01). The cleavage rate was lower in rescued IVM MII oocytes compared with MII oocytes (86 versus 95%; P < 0.01). Arrested IVM MI oocytes showed similar results to those of MI oocytes but had a lower cleavage rate (72 versus 96%; P < 0.01)., Conclusions: The injection of rescued IVM MII oocytes is preferred to the injection of MI oocytes.

Coasting is a method to decrease the incidence of ovarian hyperstimulation syndrome (OHSS), which involves withdrawing exogenous gonadotrophins until the serum estradiol (E(2)) level decreases. The application of this strategy, as it appears in the literature, has been variable, with heterogeneous criteria for initiating and ending the coasting process and as a result, reports of efficacy are inconsistent. In attempt to establish a recommended protocol for coasting we reviewed and analysed 10 relevant studies, found by a Medline search. Based on the data collected, coasting should be initiated when the serum E(2) concentration exceeds 3000 pg/ml, but not unless the leading follicles reach a diameter of 15-18 mm. Its duration should be limited to <4 days, thus, preventing the decrease in implantation and pregnancy rates that occur after longer periods of coasting. Administration of hCG should be withheld until serum E(2) falls below 3000 pg/ml. Based on the published data, these suggested guidelines result in an acceptably low incidence of severe OHSS (<2%) and provide satisfactory fertilization and pregnancy rates (55-71% and 36.5-63% respectively). A multicentre randomized prospective study would help to confirm the effectiveness of this approach.

Background: Elevated levels of plasma homocysteine have recently been implicated as a significant risk factor for cardiovascular disease, pre-eclampsia, and recurrent pregnancy loss, and have been found to be associated with insulin resistance in a number of clinical situations. We examined the relationship between plasma homocysteine and insulin resistance in patients with polycystic ovary syndrome (PCOS)., Methods: A total of 155 infertile patients with PCOS as defined by clinical, biochemical and ultrasound criteria were screened for insulin resistance utilizing single-sample fasting insulin and glucose measurement, calculated by glucose:insulin ratio or homeostasis model assessment (HOMA) index. Total plasma homocysteine was measured by fluorescence polarization immunoassay. One hundred normo-ovulatory women with normal ovaries being treated for other infertility diagnoses served as a control group., Results: Insulin resistance was found in the majority of PCOS patients: -53.5% (83/155), 60.6% (94/155) and 65.8% (102/155), when defined by fasting insulin, glucose:insulin ratio, or logHOMA respectively. Mean plasma homocysteine in the PCOS group was significantly higher than in the normal ovary group (11.5 +/- 7.4 versus 7.4 +/- 2.1 micromol/l, P < 0.001). Insulin-resistant PCOS patients had significantly higher plasma homocysteine (12.4 +/- 8.4 micromol/l) than non-insulin-resistant PCOS patients (9.6 +/- 4.4 micromol/l) regardless of body mass index (P = 0.003 by groups, P = 0.005 by correlation of single samples). Thirty-four per cent (53/155) of the PCO patients had homocysteine values >95th percentile of the controls (11.0 micromol/l, P < 0.0001). Statistically significant correlations were found between all insulin resistance indices and homocysteine levels. Multiple logistic regression defined insulin resistance as the major factor examined that influenced homocysteine levels., Conclusions: Insulin resistance and hyperinsulinaemia in patients with PCOS is associated with elevated plasma homocysteine, regardless of body weight. This finding may have important implications in the short term regarding reproductive performance, and in the long term regarding cardiovascular complications associated with insulin-resistant PCOS.

Background: Factors influencing success of sperm retrieval in azoospermic patients and outcome of ICSI were evaluated., Methods and Results: Uni- and multifactorial analysis were performed using logistic and stepwise analysis, following surgical sperm retrieval by percutaneous epididymal sperm aspiration (55 cycles) or testicular sperm extraction (142 cycles) in 52 and 123 patients with obstructive azoospermia (OA) and non-obstructive azoospermia (NOA) respectively. ICSI cycles using fresh or cryopreserved-thawed sperm were included. Sperm were retrieved to allow ICSI in 100 and 41% of OA and NOA patients, with no significant correlation with patients' age or FSH level. Occurrence of pregnancy was significantly correlated with female age (90th quantile: 38 years), number of oocytes retrieved (10th quantile: five oocytes) and number of oocytes injected (10th quantile: four oocytes). Sperm origin (epididymal versus testicular), status (fresh or thawed), male partner's age, and serum FSH had no significant effect upon implantation rate, pregnancy rate per embryo transfer or spontaneous miscarriage rate., Conclusions: In OA patients ICSI should be planned in conjunction with surgical sperm retrieval. In contrast, the lack of efficient non-invasive parameters to predict sperm retrieval in NOA suggests that elective surgical sperm retrieval may be offered to these patients prior to ovarian stimulation of their partners, especially when donor back-up is not an alternative. Female factors such as age and ovarian reserve have significant impact upon clinical success rates.

Background: It is unclear whether or not testicular sperm extraction (TESE) should be repeated for patients in whom no sperm were found during their first TESE attempt., Methods and Results: The outcome of repeated TESE was evaluated in patients with non-obstructive azoospermia (NOA) after failing to obtain sperm in their first extraction attempt, or having used all available cryopreserved testicular tissue. Out of 83 patients with NOA, patients repeated TESE two (n = 22), three (n = 8), four (n = 6) and five (n = 3) times. Distribution of main testicular histology included germ cell aplasia (55%), maturation arrest (29%) and germ cell hypoplasia (16%). The first TESE yielded mature sperm for ICSI in 39% of patients (sp+), and failed in the remaining 61% (sp-). A second TESE yielded mature sperm in 1/4 from the sp- group and in 16/18 from the sp+ group. At the third, fourth and fifth trials, 8/8, 5/6 and 3/3 of the original sp+ patients were sp+ again respectively. Compared with the outcome of the first trial, all further trials did not differ statistically in the rate of fertilization (54 versus 49%), implantation (9.5 versus 5.4%), or clinical pregnancy/cycle (19 versus 15%). No pregnancies were achieved among the three patients after their fifth TESE. Pregnancies occurred in all histological groups, except maturation arrest., Conclusions: The outcome of repeated TESE cycles, up to the fourth trial, justifies the procedure.

Background: Since severe ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproduction, the focus of attention in such cases is placed firmly upon the health of the patient, with the endeavour to achieve a pregnancy being considered of secondary importance. The aim of this study was to focus on the pregnancy rate and pregnancy outcome in IVF patients hospitalized for severe or critical OHSS, in one centre, during a period of 6 years., Methods: We compared the characteristics of patients with severe OHSS: those who conceived with the ones who did not conceive, and among pregnant IVF patients, those with ongoing pregnancies with those that miscarried., Results: Pregnancy was achieved in 60 of 104 (58%) patients with severe OHSS. Pregnancy continued until delivery in 37 of these 60 patients (62%), whereas the remaining 23 (38%) aborted. The pregnancy and abortion rates in patients with severe OHSS were significantly higher than those of IVF patients without OHSS, during the same time period [23% (1138/4922) and 15% (169/1138) respectively, P < 0.001]. The mean duration of hospitalization for OHSS was significantly shorter in those who delivered compared with those who aborted (5.9 +/- 3.2 versus 10.5 +/- 9.6 days, P < 0.01) and in the non-pregnant patients compared with the pregnant patients (5.2 +/- 3.2 versus 7.6 +/- 6.6 days, P < 0.02)., Conclusions: The clinical pregnancy rate of IVF patients with severe OHSS was significantly higher than that of patients without the syndrome. A longer stay in hospital-reflecting a more severe form of OHSS-was correlated with a higher frequency of abortions. OHSS, necessitating hospitalization, is a detrimental clinical situation not only for the mother but also for the developing pregnancy.

Background: Recently, intracytoplasmic sperm injection (ICSI) of testicular spermatozoa retrieved surgically from patients with non-mosaic Klinefelter's syndrome resulted in several deliveries. The aim of this study was to evaluate the outcome of ICSI using fresh and cryopreserved-thawed testicular spermatozoa in these patients., Methods and Results: Following informed consent regarding the genetic risks of their potential offspring, mature testicular spermatozoa were found in five out of 12 (42%) patients who underwent testicular sperm extraction, and ICSI was performed while excess tissue was cryopreserved. The mean age of the patients was 28.7 +/- 3.6 (range 23-36 years). Their baseline FSH was elevated (mean 38.3 +/- 11.4; range 22-58 mIU/ml). All patients had small testicles of 2-4 ml in volume. The outcome of ICSI using fresh or cryopreserved-thawed testicular spermatozoa during five cycles in each group, was compared. No statistical significant difference was found in the two pronuclear fertilization rate (66 versus 58%), embryo cleavage rate (98 versus 90%) and embryo implantation rate (33.3 versus 21.4%) for fresh or cryopreserved sperm accordingly. The clinical outcome after using fresh testicular sperm included two singleton pregnancies (one delivered and one ongoing) and a triplet pregnancy resulting in a twin delivery (after reduction of an 47,XXY embryo). After using cryopreserved-thawed testicular spermatozoa, two pregnancies were obtained resulting in one delivery of twins and one early spontaneous abortion., Conclusions: Outcome of ICSI using cryopreserved-thawed testicular spermatozoa of patients with non-mosaic Klinefelter's syndrome is comparable with that following the use of fresh spermatozoa. The genetic implications for the future offspring should be explained to the patients.

A 3 year retrospective analysis was conducted of pregnancies achieved after various assisted reproductive treatment modalities in our infertility practice, to calculate and compare the rates of monozygotic twinning (MZT). A total of 731 pregnancies achieved after various assisted reproduction treatments were reviewed. Gonadotrophin therapy for induction of ovulation and controlled ovarian hyperstimulation (COH) yielded 129 clinical pregnancies. Conventional IVF yielded 139 pregnancies. IVF and intracytoplasmic sperm injection (ICSI) with or without assisted hatching (AH) yielded 463 pregnancies, all during the same time period. The rates of multiple pregnancy (monozygotic and dizygotic) twins and triplets were recorded. MZT was found in 1.5% of ovulation induction or COH pregnancies (2/129). The incidence of MZT after conventional IVF was 0.72% (1/139). After IVF-ICSI/AH, MZT was found in 0.86% (4/463). The overall rate of MZT was 0.95% (7/731). Five cases were dizygotic triplets and two cases were monozygotic twins. We found the rate of MZT after assisted reproduction treatment increased more than two-fold over the background rate in the general population. Dizygotic triplets were found more often than monozygotic twins. The rate of MZT was consistently increased, irrespective of treatment modality or micromanipulation. This may signify that the aetiology of increased MZT after assisted reproduction is the gonadotrophin treatment rather than in-vitro conditions, micromanipulation, or multiple embryo transfer.

We report a rare clinical case of recurrent isolated torsion of the Fallopian tube. An 18 year old woman presented with acute right lower quadrant pain, nausea and vomiting. Torsion of the Fallopian tube was detected by laparoscopy and detorsion was performed. Two years later, a second similar episode of pelvic pain recurred. Having in mind the first episode, diagnosis was facilitated and detorsion was performed in accordance with the patient's wishes. However, the dilemma of ideal management of recurrent cases of torsion of the same tube remains open for discussion. The possibility of torsion of the Fallopian tube and recurrent torsion of the tube, although rare, should be considered in any patient with acute onset of lower abdominal pain.

This study aimed to compare the efficacy of micronized progesterone administered as luteal support following ovulation induction for in-vitro fertilization (IVF)- embryo transfer in cycles using gonadotrophin-releasing hormone agonist, either orally (200 mgx4/day) or vaginally (100 mgx2/day) and to characterize the luteal phase hormonal profile during such treatments. A total of 64 high responder patients requiring intracytoplasmic sperm injection due to male factor infertility were prospectively randomized into two treatment groups. Patients treated orally or vaginally were comparable in age (31.9 +/- 6.1 versus 30.6 +/- 5.2; mean +/- SD), number of oocytes retrieved (17 +/- 8.2 versus 18 +/- 7.0), and number of embryos transferred (3.1 +/- 1.2 versus 2.7 +/- 0.9) per cycle. Following low dose vaginal treatment, a significantly higher implantation rate (30.7 versus 10.7%, P < 0.01), but similar clinical pregnancy rate (47.0 versus 33.3%) and ongoing pregnancy rate (41.1 versus 20.0%) was observed, compared with oral treatment. In conception cycles, luteal serum progesterone and oestrogen concentrations did not differ between the treatment groups. In non-conception cycles, late luteal progesterone concentrations were significantly lower following vaginal treatment. As low dose micronized progesterone administered vaginally is simple, easy and well tolerated, it could be recommended as the method of choice for luteal support, especially for high responder patients at risk for ovarian hyperstimulation syndrome.

Klinefelter's syndrome is one of the known causes of azoospermia or cryptoazoospermia, and it may present in non-mosaic (47,XXY) or mosaic (47,XXY/46,XY) form. The likelihood of finding spermatozoa in the ejaculate or testicular tissue of patients with mosaic Klinefelter's syndrome is low, and with the non-mosaic form, even lower. We describe a patient with non-mosaic Klinefelter in whom initially non-motile spermatozoa were derived from searching the ejaculate. Ten mature oocytes were injected, but none was fertilized. Subsequently, testicular biopsy was undertaken in order to collect spermatozoa for oocyte injection. Fifteen motile sperm cells were found and injected. Nine oocytes were fertilized and cleaved; three embryos were transferred into the uterine cavity. The woman conceived and following a normal pregnancy delivered a healthy child. Genetic analysis of the neonate disclosed a normal 46,XY karyotype. Non-motile spermatozoa in the ejaculate did not prove their fertilization potential, but their presence did not exclude finding motile, fertile spermatozoa in the testicular tissue in a non-mosaic Klinefelter patient. This report is further evidence that normal spermatozoa with fertilization potential are produced in the testes of patients with Klinefelter's syndrome.

Background: Thoracoabdominal aortic aneurysm (TAAA) repair is associated with high mortality rates, especially in patients who develop postoperative renal and pulmonary impairment. Organ damage during TAAA repair may be mediated by activated polymorphonuclear neutrophils (PMNs) during a systemic inflammatory response. The association between intraoperative neutrophil activation and postoperative outcome was studied after TAAA surgery., Methods: Perioperative PMN activation (surface CD11b expression by flow cytometry), plasma endotoxin, plasma endotoxin core antibody, tumour necrosis factor (TNF), and interleukin 1 (IL-1) levels were measured in 21 patients undergoing TAAA repair., Results: Intraoperative PMN CD11b expression was significantly greater in the 11 patients who developed pulmonary and renal complications than in those who made an uneventful recovery (P = 0.0009). In addition, CD11b expression during visceral reperfusion was preceded by a rise in plasma endotoxin level and a fall in antibody level (reflecting binding by absorbed endotoxin) which was significantly greater in patients who developed complications (P = 0.031 and P = 0.001 respectively). Plasma endotoxin level correlated with CD11b expression (r = 0.828, P = 0.001). There were no significant differences in intraoperative plasma levels of TNF and IL-1, or aortic cross-clamp times and blood transfusion volumes between the complicated and uncomplicated repairs., Conclusion: Intraoperative neutrophil activation is a marker for the development of postoperative complications after TAAA reconstruction and is associated with endotoxin absorption.

The arterial wall undergoes many changes in hypertension. These changes affect the endothelium, vascular smooth muscle cells and the extracellular matrix of the blood vessel. Current evidence regarding both functional and structural aspects of these changes in the blood vessel wall is reviewed in this article.

In human subcutaneous resistance arteries in-vitro, the relaxation produced by the novel furopyridine compound cicletanine (30 microMs) was inhibited by 51% (P less than 0.0001) in the presence of 20 microMs of the cyclo-oxygenase inhibitor indomethacin. Maximal cicletanine-induced relaxation was reduced by both the cyclo-oxygenase inhibitor mefenamic acid and the relatively specific blocker of prostacyclin synthetase, tranylcypromine by 55% (P less than 0.0005) and 43% (P less than 0.01), respectively. The potassium channel blocker, glibenclamide (100 microMs), did not affect the relaxation produced by cicletanine but did inhibit the relaxation produced by the potassium channel blocker cromakalim (P less than 0.0001). Cromakalim-induced relaxation was inhibited in the presence of indomethacin; relaxation induced by cromakalim (30 microMs) was reduced by 22% (P less than 0.02). The relaxation produced by the hypotensive agonists sodium nitroprusside, hydrochlorothiazide, bumetanide and nicardipine was unaffected by incubation with indomethacin. The results suggest that the vascular eicosanoid system, specifically prostacyclin, may be involved in the mechanism of the acute vasodilator action of cicletanine. Although at high doses, cicletanine is a diuretic, in this model it did not act like either a thiazide or a loop diuretic. The acute vasodilator action of the thiazide diuretic, hydrochlorothiazide was a novel finding of this study. Cromakalim showed a reduced response in the presence of indomethacin suggesting an involvement of the eicosanoid system in its mechanism of action.

Inappropriate platelet activation is thought to have a pathophysiological role in several cardiovascular disorders, including ischaemic heart disease and hypertension. Calcium antagonists are increasingly used in the therapy of these diseases. An inhibitory effect on platelet activation would clearly be a useful component of their therapeutic effect. Since a raised intracellular calcium concentration is crucial for platelet activation, and much of the calcium enters from the extracellular medium, such an effect might be anticipated. In fact, calcium antagonists consistently inhibit platelet activation in vitro, and somewhat less consistently ex vivo. However, many unanswered questions remain. Clinically attained drug concentrations in plasma may be too low to be effective, there appear to be no calcium antagonist receptors on the platelet, and the mechanism of action of the drugs is unclear. More importantly, it is not known whether an anti-platelet effect, if it occurs, is of practical rather than theoretical, value to the patient. These problems will need much more investigation.