Prophylactic use of ergot alkaloids in the third stage of labour.

BACKGROUND: Previous research has shown that the prophylactic use of uterotonic agents in the third stage of labour reduces postpartum blood loss and moderate to severe postpartum haemorrhage (PPH). PPH is defined as a blood loss of 500 mL or more within 24 hours after birth. This is one of a series of systematic reviews assessing the effects of prophylactic use of uterotonic drugs; in this review prophylactic ergot alkaloids as a whole, and different regimens of administration of ergot alkaloids, are compared with no uterotonic agents. This is an update of a Cochrane Review which was first published in 2007 and last updated in 2011. OBJECTIVES: To determine the effectiveness and safety of prophylactic use of ergot alkaloids in the third stage of labour by any route (intravenous (IV), intramuscular (IM), or oral) compared with no uterotonic agents, for the prevention of PPH. SEARCH METHODS: For this update, we searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (19 September 2017); we also searched reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials or cluster-randomised trials comparing prophylactic ergot alkaloids by any route (IV, IM, or oral) with no uterotonic agents in the third stage of labour among women giving birth vaginally. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data and checked them for accuracy; they also assessed the risk of bias in included studies. Two review authors assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: There were eight included studies: three studies had a low risk of bias and five studies had high risk of bias. The studies compared ergot alkaloids with no uterotonic agents, with a total of 2031 women in the ergot alkaloids group and 1978 women in the placebo or no treatment group. Seven studies used the IV/IM route of administration and one study used the oral route.Ergot alkaloids (any route of administration) versus no uterotonic agentsUse of ergot alkaloids in the third stage of labour decreased mean blood loss (mean difference (MD) -80.52 mL, 95% confidence interval (CI) -96.39 to -64.65 mL; women = 2718; studies = 3; moderate-quality evidence); decreased PPH of at least 500 mL (average risk ratio (RR) 0.52, 95% CI 0.28 to 0.94; women = 3708; studies = 5; I2 = 83%; low-quality evidence); increased maternal haemoglobin concentration (g/dL) at 24 to 48 hours postpartum (MD 0.50 g/dL, 95% CI 0.38 to 0.62; women = 1429; studies = 1; moderate-quality evidence); and decreased the use of therapeutic uterotonics (average RR 0.37, 95% CI 0.15 to 0.90; women = 2698; studies = 3; I2 = 89%; low-quality evidence). There were no clear differences between groups in severe PPH of at least 1000 mL (average RR 0.32, 95% CI 0.04 to 2.59; women = 1718; studies = 2; I2 = 74%; very low-quality evidence). The risk of retained placenta or manual removal of the placenta, or both, were inconsistent with high heterogeneity. Ergot alkaloids increased the risk of elevated blood pressure (average RR 2.60, 95% CI 1.03 to 6.57: women = 2559; studies = 3; low-quality evidence) and pain after birth requiring analgesia (RR 2.53, 95% CI 1.34 to 4.78: women = 1429; studies = 1; moderate-quality evidence) but there were no differences between groups in vomiting, nausea, headache or eclamptic fit.Results for IV/IM ergot alkaloids versus no uterotonic agents were similar to those for the main comparison of ergot alkaloids administered by any route, since most of the studies (seven of eight) used the IV/IM route. Only one small study (289 women) compared oral ergometrine with placebo and it showed no benefit of ergometrine over placebo. No maternal adverse effects were reported.None of the studies reported on any of our prespecified neonatal outcomes AUTHORS' CONCLUSIONS: Prophylactic IM or IV injections of ergot alkaloids may be effective in reducing blood loss, reducing PPH (estimated blood loss of at least 500 mL), and increasing maternal haemoglobin. Ergot alkaloids may also decrease the use of therapeutic uterotonics, but adverse effects may include elevated blood pressure and pain after birth requiring analgesia. There were no differences between groups in terms of other adverse effects (vomiting, nausea, headache or eclamptic fit). There is a lack of evidence on the effects of ergot alkaloids on severe PPH, and retained or manual removal of placenta. There is also a lack of evidence on the oral route of administration of ergot alkaloids.

Fumigaclavine C ameliorates dextran sulfate sodium-induced murine experimental colitis via NLRP3 inflammasome inhibition.

In the present study, the effect of Fumigaclavine C, a fungal metabolite, on murine experimental colitis induced by dextran sulfate sodium (DSS) and its possible mechanism were examined in vivo and vitro. Oral administration of Fumigaclavine C dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. The disease activity index, histopathologic scores of musco was also significantly reduced by Fumigaclavine C treatment. Protein and mRNA levels of DSS-induced pro-inflammatory cytokines in colon, including TNF-α, IL-1ß and IL-17A, were markedly suppressed by Fumigaclavine C. At the same time, decreased activation of caspase-1 in peritoneal macrophages was detected in Fumigaclavine C -treated mice which suggested that the NLRP3 inflammasome activation was suppressed. Furthermore, in the LPS plus ATP cell model, we found that Fumigaclavine C dose-dependent inhibited IL-1ß release and caspase-1 activation. Taken together, our results demonstrate the ability of Fumigaclavine C to inhibit NLRP3 inflammasome activation and give some evidence for its potential use in the treatment of inflammatory bowel diseases.

[Current pharmacotherapy in migraine]. / A migrén korszeru farmakoterápiája.

The exact pathomechanism of migraine is still unknown, currently there are no biomarkers for migraine diagnosis, and current animal models reflect only one aspect of migraine, therefore future migraine studies are necessary. The current treatment of migraine (both acute and preventive) is suboptimal. There are no specific preventive drugs for migraine, and current preventatives may become inefficient during long-term use. Triptans are useful abortive drugs, but not effective in some of the patients; severe cardio-or cerebrovascular side effects may occur. Triptans and ergot alkaloids (and also non-specific abortive agents) can cause medication overuse headache. A number of newly synthesized experimental drugs seem to be effective and promising for migraine therapy, but at present our experience with these is limited, therefore further studies are essential.

Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage.

BACKGROUND: Active management of the third stage of labour has been shown to reduce the risk of postpartum haemorrhage (PPH) greater than 1000 mL. One aspect of the active management protocol is the administration of prophylactic uterotonics, however, the type of uterotonic, dose, and route of administration vary across the globe and may have an impact on maternal outcomes. OBJECTIVES: To determine the effectiveness of prophylactic oxytocin at any dose to prevent PPH and other adverse maternal outcomes related to the third stage of labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013). SELECTION CRITERIA: Randomised or quasi-randomised controlled trials including pregnant women anticipating a vaginal delivery where prophylactic oxytocin was given during management of the third stage of labour. The primary outcomes were blood loss > 500 mL and the use of therapeutic uterotonics. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, assessed trial quality and extracted data. Data were checked for accuracy. MAIN RESULTS: This updated review included 20 trials (involving 10,806 women). Prophylactic oxytocin versus placebo Prophylactic oxytocin compared with placebo reduced the risk of PPH greater than 500 mL, (risk ratio (RR) 0.53; 95% confidence interval (CI) 0.38 to 0.74; six trials, 4203 women; T² = 0.11, I² = 78%) and the need for therapeutic uterotonics (RR 0.56; 95% CI 0.36 to 0.87, four trials, 3174 women; T² = 0.10, I² = 58%). The benefit of prophylactic oxytocin to prevent PPH greater than 500 mL was seen in all subgroups. Decreased use of therapeutic uterotonics was only seen in the following subgroups: randomised trials with low risk of bias (RR 0.58; 95% CI 0.36 to 0.92; three trials, 3122 women; T² = 0.11, I² = 69%); trials that performed active management of the third stage (RR 0.39; 95% CI 0.26 to 0.58; one trial, 1901 women; heterogeneity not applicable); trials that delivered oxytocin as an IV bolus (RR 0.57; 95% CI 0.39 to 0.82; one trial, 1000 women; heterogeneity not applicable); and in trials that gave oxytocin at a dose of 10 IU (RR 0.48; 95% CI 0.33 to 0.68; two trials, 2901 women; T² = 0.02, I² = 27%). Prophylactic oxytocin versus ergot alkaloids. Prophylactic oxytocin was superior to ergot alkaloids in preventing PPH greater than 500 mL (RR 0.76; 95% CI 0.61 to 0.94; five trials, 2226 women; T² = 0.00, I² = 0%). The benefit of oxytocin over ergot alkaloids to prevent PPH greater than 500 mL only persisted in the subgroups of quasi-randomised trials (RR 0.71, 95% CI 0.53 to 0.96; three trials, 1402 women; T² = 0.00, I² = 0%) and in trials that performed active management of the third stage of labour (RR 0.58; 95% CI 0.38 to 0.89; two trials, 943 women; T² = 0.00, I² = 0%). Use of prophylactic oxytocin was associated with fewer side effects compared with use of ergot alkaloids; including decreased nausea between delivery of the baby and discharge from the labour ward (RR 0.18; 95% CI 0.06 to 0.53; three trials, 1091 women; T² = 0.41, I² = 41%) and vomiting between delivery of the baby and discharge from the labour ward (RR 0.07; 95% CI 0.02 to 0.25; three trials, 1091 women; T² = 0.45, I² = 30%). Prophylactic oxytocin + ergometrine versus ergot alkaloids: There was no benefit seen in the combination of oxytocin and ergometrine versus ergometrine alone in preventing PPH greater than 500 mL (RR 0.90; 95% CI 0.34 to 2.41; five trials, 2891 women; T² = 0.89, I² = 80%). The use of oxytocin and ergometrine was associated with increased mean blood loss (MD 61.0 mL; 95% CI 6.00 to 116.00 mL; fixed-effect analysis; one trial, 34 women; heterogeneity not applicable).In all three comparisons, there was no difference in mean length of the third stage or need for manual removal of the placenta between treatment arms. AUTHORS' CONCLUSIONS: Prophylactic oxytocin at any dose decreases both PPH greater than 500 mL and the need for therapeutic uterotonics compared to placebo alone. Taking into account the subgroup analyses from both primary outcomes, to achieve maximal benefit providers may opt to implement a practice of giving prophylactic oxytocin as part of the active management of the third stage of labour at a dose of 10 IU given as an IV bolus. If IV delivery is not possible, IM delivery may be used as this route of delivery did show a benefit to prevent PPH greater than 500 mL and there was a trend to decrease the need for therapeutic uterotonics, albeit not statistically significant.Prophylactic oxytocin was superior to ergot alkaloids in preventing PPH greater than 500 mL; however, in subgroup analysis this benefit did not persist when only randomised trials with low risk of methodologic bias were analysed. Based on this, there is limited high-quality evidence supporting a benefit of prophylactic oxytocin over ergot alkaloids. However, the use of prophylactic oxytocin was associated with fewer side effects, specifically nausea and vomiting, making oxytocin the more desirable option for routine use to prevent PPH.There is no evidence of benefit when adding oxytocin to ergometrine compared to ergot alkaloids alone, and there may even be increased harm as one study showed evidence that using the combination was associated with increased mean blood loss compared to ergot alkaloids alone.Importantly, there is no evidence to suggest that prophylactic oxytocin increases the risk of retained placenta when compared to placebo or ergot alkaloids.More placebo-controlled, randomised, and double-blinded trials are needed to improve the quality of data used to evaluate the effective dose, timing, and route of administration of prophylactic oxytocin to prevent PPH. In addition, more trials are needed especially, but not only, in low- and middle-income countries to evaluate these interventions in the birth centres that shoulder the majority of the burden of PPH in order to improve maternal morbidity and mortality worldwide.

The endocrine disruptive effects of ergopeptine alkaloids on pregnant mares.

During equine gestation, ergopeptine alkaloid exposure is not uncommon, and pregnant mares are particularly sensitive to the endocrine disruptive effects of these compounds on lactogenesis and steroidogenesis. Agalactia, prolonged gestation, abortion, dystocia, and placental and fetal abnormalities are all clinical manifestations of changes in the endocrine milieu induced by the ingestion of ergopeptine alkaloid-contaminated feedstuffs by mares during late gestation. An understanding of the endocrine disruptive effects of gestational exposure to ergopeptine alkaloids is necessary for the diagnosis of potential exposures to these compounds and for effective prophylaxis and therapy.

Feeding yearling Angus bulls low-level ergot daily for 9 weeks decreased serum prolactin concentrations and had subtle effects on sperm end points.

Our objective was to determine whether feeding yearling bulls with the higher recommended Canadian limit of ergot alkaloids (∼3 mg/kg dry matter intake, DMI) would affect sperm characteristics and plasma prolactin concentrations. Aberdeen Angus bulls (12-13 mo old, n = 7/group) allocated by blocking for sperm concentration and body weight, were fed placebo or ergot alkaloids in gelatin capsules (60 µg/kg body weight daily, 3.4 mg/kg of DMI) for 9 wk. Semen samples were collected weekly by electroejaculation and examined with a computer assisted semen analyzer (CASA) and flow cytometry, for the intervals 5 wk before (Pre-exposure period), 9 wk during (Exposure period) and 9 wk after (Post-exposure period) treatment. Weekly plasma samples were analyzed for prolactin by radioimmunoassay. Plasma prolactin concentrations decreased markedly (mean ± SEM, 16.74 ± 3.70 in Exposure and 33.42 ± 3.08 ng/mL in Post-Exposure periods; P < 0.01) compared to Control (67.54 ± 21.47 and 42.59 ± 15.06 ng/mL). Treatment did not affect (P ≥ 0.17) body weight gain, sperm concentration, sperm count/ejaculate, motility or percent live sperm. Averaged over the exposure and post-exposure durations, the scrotal circumference was smaller (P = 0.02) by 2.7% in the Ergot group. Progressive motility remained unchanged from 59.92 ± 2.31% in Exposure to 59.61 ± 2.59% in Post-Exposure periods, compared to marked increase in Control (61.42 ± 1.60% to 67.52 ± 1.47%; P = 0.02). Straight-line sperm velocity decreased (-3.15 ± 1.53 µm/s) from exposure to post-exposure periods in Ergot group (P = 0.04) versus an increase (2.96 ± 2.17 µm/s) in Control. Midpiece defects decreased from Exposure to Post-exposure periods in Control group but remained unchanged in Ergot group (trt∗age, P < 0.01). Ergot feeding resulted in a smaller proportion of sperm with medium mitochondrial potential (Ergot: 22.65 ± 0.98%, Control: 24.35 ± 1.05%, P = 0.04). In conclusion, feeding ergot at Canadian permissible limit for 9-wk resulted in a 4-fold decrease in plasma prolactin concentrations. Semen end points were not significantly affected, although there were subtle effects on progressive motility, midpiece defects and mitochondrial membrane potential. Clinical relevance of observed changes requires further evaluation. Results supported our hypothesis that prolonged low-level ergot will adversely affect plasma prolactin. However, semen parameters were partially affected, supporting similar work on fescue toxicosis.

Postpartum hemorrhage: evidence-based medical interventions for prevention and treatment.

Postpartum hemorrhage (PPH) remains a significant contributor to maternal morbidity and mortality throughout the world. The majority of research on this topic has focused on efforts to prevent PPH. Sound data exist that active management of the third stage of labor can reduce the occurrence of PPH. Although there remains debate regarding the optimal protocol for active management, it appears at this time that oxytocin is the preferable uterotonic to use. Misoprostol may be a reasonable option where parenteral administration of an uterotonic is not feasible. There is little evidence to guide treatment decisions should PPH occur.

Prophylactic use of ergot alkaloids in the third stage of labour.

BACKGROUND: Previous research has shown that the prophylactic use of uterotonic agents in the third stage of labour reduces postpartum blood loss and moderate to severe postpartum haemorrhage. This is one of a series of systematic reviews assessing the effects of prophylactic use of uterotonic drugs - here, prophylactic ergot alkaloids compared with no uterotonic agents, and different regimens of administration of ergot alkaloids. OBJECTIVES: To determine the effectiveness and safety of prophylactic use of ergot alkaloids in the third stage of labour compared with no uterotonic agents, as well as with different routes or timing of administration for prevention of postpartum haemorrhage. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 December 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4) and MEDLINE (1966 to December 2006). SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing prophylactic ergot alkaloids with no uterotonic agents or comparing different routes or timings of administration of ergot alkaloids in the third stage of labour among women giving birth vaginally. DATA COLLECTION AND ANALYSIS: We systematically reviewed the potential studies, considered eligible studies, assessed the validity of each included study and extracted data independently. MAIN RESULTS: We included six studies comparing ergot alkaloids with no uterotonic agents, with a total of 1996 women in ergot alkaloids group and 1945 women in placebo or no treatment group. The use of injected ergot alkaloids in the third stage of labour significantly decreased mean blood loss (weighted mean difference -83.03 ml, 95% confidence interval (CI) -99.39 to -66.66 ml) and postpartum haemorrhage of at least 500 ml (relative risk (RR) 0.38, 95% CI 0.21 to 0.69). The risk of retained placenta or manual removal of the placenta, or both, were inconsistent. Ergot alkaloids increased the risk of vomiting (RR 11.81, 95% CI 1.78 to 78.28), elevation of blood pressure (RR 2.60, 95% CI 1.03 to 6.57) and pain after birth requiring analgesia (RR 2.53, 95% CI 1.34 to 4.78). One study compared oral ergometrine with placebo and showed no significant benefit of ergometrine over placebo. No maternal adverse effects were reported. There were no included trials that compared different administration regimens of ergot alkaloids. AUTHORS' CONCLUSIONS: Prophylactic intramuscular or intravenous injections of ergot alkaloids are effective in reducing blood loss and postpartum haemorrhage, but adverse effects include vomiting, elevation of blood pressure and pain after birth requiring analgesia, particularly with the intravenous route of administration.

Postpartum haemorrhage: prevention and treatment.

INTRODUCTION: Postpartum hemorrhage (PPH) is one of the leading causes of maternal death and severe maternal morbidity worldwide and strategies to prevent and treat PPH vary among international authorities. Areas covered: This review seeks to provide a global overview of PPH (incidence, causes, risk factors), prevention (active management of the third stage of labor and prohemostatic agents), treatment (first, second and third-line measures to control PPH), by also underlining recommendations elaborated by international authorities and using algorithms. Expert commentary: When available, oxytocin is considered the drug of first choice for both prevention and treatment of PPH, while peripartum hysterectomy remains the ultimate life-saving procedure if pharmacological and resuscitation measures fail. Nevertheless, the level of evidence for preventing and treating PPH is globally low. The emergency nature of PPH makes randomized controlled trials (RCT) logistically difficult. Population-based observational studies should be encouraged as they can usefully strengthen the evidence base, particularly for components of PPH treatment that are difficult or impossible to assess through RCT.

Drug safety in acute migraine treatment.

INTRODUCTION: A number of drugs are available for acute migraine treatment, but they are not all effective for all patients and all attacks. The safety profiles of migraine drugs limit their use in patients with certain comorbid conditions, and adverse effects may also reduce the level of patient compliance. AREAS COVERED: The different types of acute migraine drugs are discussed, with particular regard to safety issues and potential adverse effects. The frequent use of analgesics, ergot alkaloids and triptans may result in the development of medication overuse headache (MOH). EXPERT OPINION: The initiation of a migraine attack is not fully understood, and therefore treatment aimed at causative factors is currently not available. The tolerability and adverse effects of the drugs available at present often limit their use. NSAIDs are frequently associated with gastrointestinal, and possibly also cardiovascular side effects. Ergot alkaloids may induce arterial vasoconstriction, while the administration of triptans is contraindicated in cardiovascular, cerebrovascular and peripheral vascular diseases. The frequent use of these drugs poses the risk of the development of MOH. There is a need for pathomechanism-based drugs, and for the future achievement of personalized medicine.

Identification of bovine prolactin in seminal fluid, and expression and localization of the prolactin receptor and prolactin-inducible protein in the testis and epididymis of bulls exposed to ergot alkaloids.

The objectives of this study were to determine (1) the presence and expression levels of bovine prolactin receptor (PRLR) and prolactin-inducible protein (PIP) in bovine testis and epididymis, and (2) the presence and concentrations of prolactin (PRL) present in seminiferous fluid in bulls consuming diets with (E+) or without (E-) ergot alkaloids. Bulls (n = 8) were sacrificed after 126 days (group A) of E+ or E- treatment or 60 days after all bulls (n = 6) were switched to the E- ration (group B). End point and real-time quantitative reverse transcription-polymerase chain reaction and immunohistochemistry were conducted on testis and epididymis samples to establish the presence and relative expression of PRLR and PIP. Seminal fluid samples obtained from bulls consuming E- and E+ diets were subjected to RIA for PRL. Both PIP and PRLR were present in testis and epididymis as determined by reverse transcription-polymerase chain reaction and immunohistochemistry. Prolactin-inducible protein mRNA abundance was affected by time of slaughter in testis and epididymis head, respectively (P < 0.05). Prolactin receptor mRNA expression was affected by time of slaughter in the epididymis (P < 0.05) and differed in testis samples because of treatment (P < 0.05). Radioimmunoassay establishes the presence of PRL in seminal fluid; however, differences in the concentration of PRL over two separate studies were inconsistent, possibly because of differences in diet. The presence and localization of the PRLR are consistent with expression data reported for other species, and the presence of PIP and PRL in seminal fluid is consistent with data generated in humans.

Neuroendocrine dysfunction in galactorrhea-amenorrhea after oral contraceptive use.

Nonpuerperal alactorrhea and amenorrhea have been reported following the use of oral contraceptives. Treatment of this condition with ergot alkaloids has proved to be of great therapeutic value. Pretreatment plasma hLH and hFSH concentrations in 13 women with postqill galactorrhea-amenorrhea (PPGA) were 6.6 plus or minus 0.6 (SE.) and 5.0 plus or minus 0.8 mlU/ml, respectively. The mean prolactin concentration was 80.7 plus or minus 13.2 ng/ml. After complete evaluation in which diagnostic evidence of pituitary tumor was absent, the patients were treated with ergocryptine (CB-154). The mean hPRL concentration at 14 days of therapy was 7.8 p;us or minus 1.9 ng/ml. Cyclic gonadotropin secretion resumed in all but one instance; ovulation was confirmed on the basis of a biphasic temperature chart and in 5 cases, endometrial biopsy. Measurement of serum dopamine-beta-hydroxylase (DBH) activity indicated a significant decline at the end of 8 weeks of CB-154 therapy. The fall in hPRL was not necessarily associated with a fall in DBH. The majority of women in this study exhibited a consistent personality suggesting varying degrees of anxiety unrelated to the PPGA and usually antedating the use of oral contraceptives. PPGA was found in women without hyperprolactinemia, but altered hPRL secretion was evident in all instances. The data suggest that the disorder of cyclic gonadotropin secretion is related to altered hPRL secretion, but the mechanism is possibly related to a catecholamine abnormality. The data support the presence of an inherent cyclic mechanism for the secretion of gonadotropins. CB-154 therapy does not affect conception, and no teratogenic effects were observed in 2 infants born to women who had received CB-154 during the first 40 days of gestation.

Migraine treatment patterns and patient satisfaction with prior therapy: a substudy of a multicenter trial of rizatriptan effectiveness.

BACKGROUND: Migraine is a common, chronic, often disabling neurologic condition that is underdiagnosed and undertreated. OBJECTIVE: We undertook this questionnaire-based study as a substudy of a multicenter trial of rizatriptan effectiveness. Our goal was to assess the history of acute migraine medication use and the relationship between different migraine medication regimens and patient satisfaction with prior therapy. METHODS: This study was conducted at 85 neurology clinics throughout Spain from March Lo December 2001. It was planned prospectively as part of the screening visit for a multicenter trial of the effectiveness of rizatriptan therapy for migraine. Male and female patients >/=18 years of age were eligible for the primary trial, and hence for this study, if they had a history of migraine attacks and did not have a contraindication for triptan use. At the screening visit for the primary trial, a questionnaire was used by clinicians to record past and current use, and duration and order of use, of analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), ergot derivatives, and triptans; satisfaction with treatment was scored on a 5-point scale ranging from "very dissatisfied" to "very satisfied." RESULTS: Of 712 patients completing the questionnaire (mean [SD] age, 34 [10] years; range, 18-69 years), 75% were women and 94% experienced moderate or severe functional disability during migraine attacks. Analgesics were used by the majority of patients (81%) and for the longest mean [SD] duration (8.8 [7.6] years) but were associated with the least satisfaction (10% of patients "very satisfied" or "somewhat satisfied"). Triptans were used by the fewest patients (32%) and for the shortest mean duration (18 [1.6] years) but were associated with the highest rate of satisfaction (66%) compared with NSAIDs (27%) and ergot derivatives (31%). Regardless of duration or order of drug use, or sex or age of the patient, the likelihood of satisfaction with triptans was significantly greater (P < 0.001) than with nontriptan regimens, with an adjusted odds ratio (95% CI) of 16.8 (11.4-24.9) versus analgesics, 5.1 (3.6-7.1) versus NSAIDs, and 4.1 (2.8-6.0) versus ergot derivatives. CONCLUSIONS: Our results showed that analgesics, NSAIDs, and ergot derivatives were used for long durations but provided low satisfaction among patients. Triptans were rarely used as a first treatment choice; however, patients reported the highest treatment satisfaction scores after triptan therapy compared with ergot derivatives, NSAIDs, or analgesics.

Medicolegal issues: headache.

This article addresses headache-related topics in which medicolegal issues have occurred or in which they are likely to occur. Where possible, an actual case has been presented. Most sections of this article are divided into three parts: principle of care, case history, and discussion and recommendations. When appropriate, American Academy of Neurology guidelines have been noted.

Progress in understanding and treating Parkinson's disease.

This review evaluates the long-term results of Levodopa therapy in Parkinson's disease upon quality of life, prolongation of survival and excess mortality. It also focuses on recent and new therapeutic approaches: Levodopa in combindation with a Dopa-decarboxylase inhibitor or MAO-B inhibitor, dopamine agonists and an active tripeptide: L-prolyl-L-leucylglycine amide (MIF-I). It ends by looking at new avenues of etiological research in Parkinson's disease which may indicate specific accelerated ageing of catecholaminergic (pigmented) neuronal systems.

Neuroimmunomodulation of natural killer (NK) cells by ergot alkaloid derivatives.

Ergot alkaloids (EAs), products of Claviceps spp., are widely used in various fields of clinical medicine (neurology, psychiatry, endocrinology). In the present work we studied the neuroimmunomodulative effect of EAs on activation of NK cells and their signalling pathways. Furthermore, the killing capability of rat NK cells in vitro was examined in the presence of glycosidic derivatives of elymoclavine, agroclavine, and liposome-encapsulated EAs. The engagement of appropriate NK cell membrane receptors by EAs cause an indirect enhancement of adenylyl cyclase system through inhibition of G-protein al,2-subunit (up to 50 % of control values). All of the tested EAs enhanced the rat NK cell-mediated cytotoxic activity in vitro, particularly against target cells of astrocyte origin (C-6 glioma). The present results argue for a possible EA immunomodulatory role of cell-mediated immunity in tumour regression processes.

Effects of topical natural ergot alkaloids on intraocular pressure and aqueous humor dynamics in ocular normotensive rabbits.

Although it has been suggested that ergot derivatives may play a role in antiglaucoma therapy, little attention has been paid to the ocular hypotensive action of these drugs. Having previously reported in our laboratory that topical dihydroergocristine decreases intraocular pressure both in ocular normotensive and alpha-chymotrypsin-induced ocular hypertensive rabbits, the aim of the present work was to assess the effect of natural ergot alkaloids, ergocristine, alpha-ergocryptine and ergocornine, on the intraocular pressure and aqueous humor dynamics in ocular normotensive rabbits in order to further explore the ocular actions of these compounds. Intraocular pressure was measured with a pneumatonometer manometrically calibrated for the rabbit eye. Changes in tonographic facility of aqueous humor outflow and rate of aqueous humor inflow were evaluated in anesthetized rabbits. Natural ergot alkaloids were found to reduce intraocular pressure in ocular normotensive eyes in a dose-related fashion. These compounds decreased both tonographic outflow facility and, to a greater extent, aqueous humor inflow, which explains their final hypotensive effect.

Evaluation of perennial ryegrass straw as a forage source for ruminants.

Two experiments were conducted to evaluate perennial ryegrass straw as a forage source for ruminants. Experiment 1 evaluated digestion and physiological variables in steers offered perennial ryegrass straw containing increasing levels of ergot alkaloid, lolitrem B. Sixteen ruminally cannulated Angus x Hereford steers (231+/-2 kg BW) were blocked by weight and assigned randomly to one of four treatments. Steers were provided perennial ryegrass straw at 120% of the previous 5-d average intake. Before straw feeding, soybean meal was provided (0.1% BW; CP basis) to meet the estimated requirement for degradable intake protein. Low (L) and high (H) lolitrem B straws (<100 and 1,550 ppb, respectively; DM basis) were used to formulate treatment diets: 100% L; 67% L:33% H; 33% L:67% H; 100% H (DM basis). Intake and digestibility of DM and OM, and ruminal pH, total VFA, and NH3-N were not affected by increasing lolitrem B concentration. Ruminal indigestible ADF (IADF) fill increased linearly (P = 0.01) and IADF passage rate decreased linearly (P = 0.04) as lolitrem B increased. Experiment 2 evaluated performance and production by 72 Angus x Hereford cows (539+/-5 kg BW) consuming perennial ryegrass straw containing increasing lolitrem B during the last third of gestation. Cows were blocked by body condition score and randomly assigned to one of three treatments. Cows were provided perennial ryegrass straw ad libitum and supplemented with soybean meal (0.1% BW; CP basis) to meet the estimated requirement for degradable intake protein. Mixtures of a L and H lolitrem B straw (467 and 2,017 ppb, respectively) were used to formulate treatment diets: 100% L, 50% L:50% H, 100% H (DM basis). Thirteen of 24 cows on the 100% H treatment exhibited signs of ryegrass staggers and were removed from the study; nevertheless, lolitrem B concentration did not influence pre- or postcalving weight or body condition score change. These data suggest that feeding perennial ryegrass straw containing up to 1,550 ppb lolitrem B (DM basis) did not adversely affect nutrient digestion or physiological response variables in steers. However, providing straw with a lolitrem B concentration of approximately 2,000 ppb (DM basis) resulted in 54% of cows exhibiting signs of ryegrass staggers. These data suggest that blending straws with a high (>2,000 ppb) and low (<500 ppb) concentration of lolitrem B can be a successful management practice.

Pharmacokinetics of bromerguride, a new dopamine-antagonistic ergot derivative in rat and dog.

Bromerguride is a novel dopamine antagonistic ergot derivative in which a complete reversed pharmacodynamic profile has been obtained by bromine substitution at position 2 as compared to dopamine agonistic lisuride. The pharmacokinetics of the new drug has been investigated following i.v. and i.g. administration of the 14C-labelled compound to rat (R) and beagle dog (D) with regard to drug registration requirements and to serve other preclinical disciplines (toxicology, pharmacology). Because of incomplete absorption the oral bioavailability was approx. 40% at dose levels of 0.25 mg/kg (R, D) and 4 mg/kg (D) and 20% after i.g. dosing of 5 mg/kg (R). Most of the 14C-label in plasma consisted of unchanged bromerguride apart from small amounts of the N-monodesethyl metabolite, which was also obtained as a biodegradation product in a rat liver perfusion experiment. Bromerguride plasma levels declined with half-lives of 0.7 h and 9 h (R) and 0.2 h and 2.7 h (D) after i.v. treatment. Peak levels in rat brain and plasma were observed within 1-2 h after oral dosing; brain levels accounting for 1/10 of bromerguride plasma levels. Whole body autoradiographs in rat demonstrated that the 14C-label was rapidly distributed into tissues and organs, readily passed the blood-brain and the placental barrier. Bromerguride was excreted to less than 10% unchanged with urine. Excretion was mainly biliary. Most of the 14C-label was recovered in the excreta within 24 h postdose.