Induction of Ticlike Involuntary Movements in Rats by Striatotomy and Subsequent Neurochemical Sensitization.

OBJECTIVE: It has been proposed that Tourette syndrome is associated with dysfunction in widespread cortical areas and globus pallidus externus hyperactivity secondary to dopaminergic hyperactivity and serotonergic/dynorphinergic hypoactivity. The main objective of this study was to test this hypothesis by developing an animal model of Tourette syndrome via striatotomy, followed by administration of drugs that mimic the neurotransmitter environment, so as to induce globus pallidus externus hyperactivity. METHODS: Rats were assigned to 3 groups: stereotactic striatotomy (STT) and striatal sham -lesion (SHAM) groups, treated with anterior and posterior striatum procedures in both hemispheres, and a group of nonoperated animals (NAIVE). Postoperatively, all rodents were blindly administered 3 drug protocols: levodopa/benserazide; levodopa/benserazide/ergotamine/naloxone (MIX); and saline. The animals were filmed at the peak action of these drugs. The videos were evaluated by a single blinded researcher. RESULTS: Six types of involuntary movements (IMs) were observed: cephalic, trunk jerks, oromandibular, forepaw jerks, dystonic, and locomotive. The number of animals with IM and the mean number of IM after both levodopa/benserazide and MIX was significantly higher in the STT compared with the SHAM and NAIVE groups. In the SHAM and NAIVE, MIX was superior to levodopa/benserazide in the induction of IM. In the STT, MIX was superior to levodopa/benserazide in the induction of trunk jerks. Appendicular IM were more common after posterior than after anterior striatotomy. CONCLUSIONS: These results show that striatotomy, followed by administration of levodopa/benserazide alone or associated with ergotamine and naloxone, is efficacious in inducing IM, supporting the hypothesis that led to this study.

Dynamic in vitro intestinal barrier model coupled to chip-based liquid chromatography mass spectrometry for oral bioavailability studies.

In oral bioavailability studies, evaluation of the absorption and transport of drugs and food components across the intestinal barrier is crucial. Advances in the field of organ-on-a-chip technology have resulted in a dynamic gut-on-a-chip model that better mimics the in vivo microenvironment of the intestine. Despite a few recent integration attempts, ensuring a biologically relevant microenvironment while coupling with a fully online detection system still represents a major challenge. Herein, we designed an online technique to measure drug permeability and analyse unknown product formation across an intestinal epithelial layer of Caco-2 and HT29-MTX cells cultured on a flow-through Transwell system, while ensuring the quality and relevance of the biological model. Chip-based ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was coupled to the dynamic Transwell system via a series of switching valves, thus allowing alternating measurements of the apical and basolateral sides of the in vitro model. Two trap columns were integrated for online sample pre-treatment and compatibility enhancement. Temporal analysis of the intestinal permeability was successfully demonstrated using verapamil as a model drug and ergotamine epimers as a model for natural toxins present in foods. Evidence was obtained that our newly developed dynamic system provided reliable results versus classical static in vitro models, and moreover, for the first time, epimer-specific transport is shown for ergotamine. Finally, initial experiments with the drug granisetron suggest that metabolic activity can be studied as well, thus highlighting the versatility of the bio-integrated online analysis system developed. Graphical abstract.

Development of a model for investigation of perennial ryegrass toxicosis in sheep.

AIMS To develop a clinical model of perennial ryegrass toxicosis (PRGT) based on feeding a known dose of lolitrem B and ergotamine, and to produce a consistent clinical presentation for assessment of disease pathophysiology, neurological changes and neurohistopathology. METHODS Male lambs, aged between 10-12 months, were randomly assigned to either Treatment (n=9) or Control (n=9) groups. Lambs in the Treatment group received feed containing a novel endophyte-infested perennial ryegrass seed, commencing on Day 0 of the Feeding phase with a low induction dose, then increasing after 3 days to provide 0.16 mg/kg live bodywight (LBW)/day of lolitrem B and 0.054 mg/kg LBW/day ergotamine. Lambs were examined daily and when defined signs of PRGT were observed they were transferred to the Testing phase. Neurological examinations, assessment of gait, surface electromyography (EMG) and mechanosensory nociceptive threshold testing were carried out and blood samples collected during both phases of the trial, with a full necropsy, histopathological examination and measurement of faecal cortisol metabolites (FCM) performed on Day 2 of the Testing phase. RESULTS Typical clinical signs of PRGT, including ataxia of vestibulocerebellar origin leading to stumbling, were observed in all Treatment lambs. The median interval from the start of the Feeding phase to entry into the Testing phase was 21 (min 18, max 34) days. Histopathological characterisation of neurological lesions included the presence of Purkinje cell vacuolation, pyknotic granular layer neurons and proximal axonal Purkinje cell spheroids. Lesions were most apparent within the vestibulocerebellum. Mean root-mean-square voltages from triceps EMG increased in Treatment lambs between Feeding phase Day 0 and Testing phase Day 2 (p<0.001). Daily water intake during the Testing phase for the Treatment group was less than in Control group lambs (p=0.002), and concentrations of FCM at necropsy were higher in Treatment compared to Control lambs (p=0.02). CONCLUSIONS AND CLINICAL RELEVANCE Lolitrem B and ergotamine dosing in feed on a live weight basis combined with neurological/gait assessment provides an effective model for investigation of PRGT and potential therapeutics. Assessment of gait changes using defined criteria and RMS voltages from EMG appear to be useful tools for the assessment of the severity of neurological changes.

Ergotismo y VIH: el riesgo de la automedicación / Ergotism and HIV: the risk of self-medication

El ergotismo es una complicación bien conocida, aunque poco fre-cuente, asociada a la ingesta de derivados de la ergotamina en dosis habitualmente más altas de las recomendadas. No obstante, también puede presentarse luego del uso de bajas dosis cuando se adminis-tran concomitantemente drogas que inhiben su metabolismo, entre ellas los inhibidores de proteasa (IP), ampliamente utilizados en el tra-tamiento de pacientes con infección por el virus de la inmunodeficien-cia humana (VIH). A pesar de esta interacción predecible se siguen observando en la práctica clínica diaria casos de ergotismo, probable-mente debido a que se trata de una droga de uso frecuente, bajo cos-to y que no requiere prescripción médica, sumado a la falta de conoci-miento del paciente de las potenciales interacciones. Se describen las características, diagnóstico, tratamiento y evolución de cuatro pacien-tes con infección por VIH en tratamiento antirretroviral (TARV), basa-do en IP, que presentaron un cuadro de ergotismo

Ergotism is a well-known but rare complication associated with the intake of ergotamine derivatives at doses usually higher than recommended. However, it may also occur after low doses of ergotamine when it is co-administered with drugs that inhibit its metabolism, such as protease inhibitors (PIs), widely used in the treatment of patients with human immunodeficiency virus. Despite this predictable interaction, cases of ergotism are still being observed in daily clinical practice, probably because it is a frequently used, low cost drug that does not require medical prescription, in addition to the patient's lack of knowledge of the potential interactions. We describe here the characteristics, diagnosis, treatment and evolution of four HIV-infected patients on PI-based antiretroviral treatment who presented a clinical picture of ergotism

Acute leg ischaemia in an HIV-infected patient receiving antiretroviral treatment.

An HIV-infected patient treated with tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat developed severe acute ischaemia of both legs during a migraine episode. After being interrogated he admitted taking an ergotamine-containing preparation. Ergotism due to interaction between ergotics and cobicistat was diagnosed. We describe the first reported case of this interaction.

Use of lopinavir/ritonavir associated with ergotamine resulting in foot amputation: brief communication.

A 32-year-old female, was diagnosed in 2004 with a C1 HIV1 infection, using zidovudine/lamivudine 300/150 mg BID and lopinavir/ritonavir 400/100 mg BID, in addition to prophylaxis with trimethoprim-sulfamethoxazole 800/160 mg QD, but no prophylaxis with macrolide antibiotics. The patient presented with a severe headache and was prescribed two capsules of the anti-migraine drug Ormigrein™, which contained ergotamine tartrate 1 mg, caffeine 100 mg, paracetamol 220 mg, hyoscyamine sulfate 87.5 mcg, and atropine sulfate 12.5 mcg. Afterwards she was prescribed one capsule of Ormigrein every 30 minutes for a total of six capsules a day. The patient took the medication as prescribed but developed a pain in her left ankle three days later, which evolved to the need for amputation.

Use of lopinavi//ritonavir associated with ergoamine resulting in foot amputattion: brief communicatoon / Uso de lopinavir/ritonavir associado com ergotamina resultando em amputação de pé: comunicação breve

A 32-year-old female, was diagnosed in 2004 with a C1 HIV1 infection, using zidovudine/lamivudine 300/150 mg BID and lopinavir/ritonavir 400/100 mg BID, in addition to prophylaxis with trimethoprim-sulfamethoxazole 800/160 mg QD, but no prophylaxis with macrolide antibiotics. The patient presented with a severe headache and was prescribed two capsules of the anti-migraine drug Ormigrein™, which contained ergotamine tartrate 1 mg, caffeine 100 mg, paracetamol 220 mg, hyoscyamine sulfate 87.5 mcg, and atropine sulfate 12.5 mcg. Afterwards she was prescribed one capsule of Ormigrein every 30 minutes for a total of six capsules a day. The patient took the medication as prescribed but developed a pain in her left ankle three days later, which evolved to the need for amputation.

Mulher de 32 anos infectada pelo HIV 1, vinha utilizando zidovudina/lamivudina 300/150 mg um comprimido duas vezes ao dia e lopinavir/ritonavir 200/50 mg dois comprimidos duas vezes ao dia e profilaxia com sulfametoxazol-trimetoprim 800/160 mg uma vez ao dia, sem profilaxia com macrolídeos. A paciente apresentou enxaqueca severa com prescrição da associação tartarato de ergotamina 1 mg, cafeína 100 mg, paracetamol 220 mg, sulfato de hiosciamina 87,5 mcg, sulfato de atropina 12,5 mcg, dois comprimidos na crise, seguido de um comprimido a cada 30 minutos, com no máximo seis comprimidos ao dia. A paciente ingeriu seis comprimidos em um dia, surgindo uma dor em tornozelo esquerdo três dias depois, que evoluiu para ergotismo e amputação do pé.

Ergotamine-induced acute tubulo-interstitial nephritis.

Ergotamine has been used for the treatment of migraine for many years, and its use in adults is considered to be safe and effective. In this report, we present a 22-year-old female patient, a known case of migraine, who was on ergotamine tartrate and presented with hypertension and renal failure. Renal biopsy indicated features of acute tubulo-interstitital nephritis.

Combined effects of fungal alkaloids on intestinal motility in an in vitro rat model.

Diarrhea is caused by factors that alter absorption and secretion of water and ions across the intestinal epithelium and disrupt motility. Parasitic infection, stress, poor nutrition, and exposure to plant or fungal toxins predispose livestock to noninfectious diarrhea. This is more prevalent in sheep that graze pastures infected with wild-type endophytic fungus, suggesting the involvement of fungal alkaloids. These increase smooth muscle contraction: ergovaline/ergotamine (ergot alkaloid) activates serotonin (5-HT) receptors, and lolitrem B (indole diterpene) inhibits large-conductance Ca2+-activated K+ (BK) channels. Because of their separate mechanisms of action the objective of this study was to investigate whether they act synergistically to increase smooth muscle contraction. Effects of ergotamine (1 µM) and lolitrem B (0.1 µM) on the tension and frequency of spontaneous contractions were investigated in a longitudinal preparation of isolated distal colon. The compounds were dissolved in 0.1% dimethyl sulfoxide (DMSO) and applied separately or together for 1 h. Ergotamine increased contractile tension compared to the pretreatment control (P<0.01) and produced a short-lived increase in frequency (P<0.001). Lolitrem B increased contractile tension (P<0.05) but had no effect on frequency. When applied together, the contractile tension was greater than the sum of the compounds applied separately (P<0.05). The frequency of contractions was increased (P<0.05) but was not significantly different from that for ergotamine alone. The increased contractile tension when both compounds were applied together indicates that ergotamine and lolitrem B acted synergistically to increase smooth muscle contraction, suggesting that they would alter motility in vivo.

Ergotamina e inhibidores de la proteasa: impacto clínico de las interacciones farmacológicas: presentación de dos casos / Ergotamine and protease inhibitors: clinical impact of drugs interactions: report of two cases

Las interacciones medicamentosas constituyen un factor relevante en lo que a la alteración de la terapéutica se refiere. Dicha importancia debería ser valorada de forma permanente y su detección y prevención deberían constituir dos de los ejes centrales de la actuación del equipo de salud en su ejercicio profesional. La polifarmacia y la automedicación son dos puntos a supervisar. A su vez, la subnotificación al ente regulatorio es una constante que impide la toma de medidas correctivas por parte del mismo. La difusión de alertas y la educación del paciente son medidas fundamentales en este aspecto. Se presentan dos casos que describen el impacto clínico de las interacciones en pacientes ambulatorios.

Drug interactions are a relevant factor as far as the alteration of therapy is concerned. Such an importance should be assessed on an ongoing basis and its detection and prevention should be two of the cornerstones of the health team's performance inpractice. Polypharmacy and self-medication are two points to be monitored. At the same time, the underreporting to the Regulating Entity is a constant that prevents it from taking corrective actions. Warnings dissemination and patient education are key steps at this point. Two cases are presented describing the clinical impact of the interactions on outpatients.

Ergotamina e inhibidores de la proteasa: impacto clínico de las interacciones farmacológicas: presentación de dos casos / Ergotamine and protease inhibitors: clinical impact of drugs interactions: report of two cases

Las interacciones medicamentosas constituyen un factor relevante en lo que a la alteración de la terapéutica se refiere. Dicha importancia debería ser valorada de forma permanente y su detección y prevención deberían constituir dos de los ejes centrales de la actuación del equipo de salud en su ejercicio profesional. La polifarmacia y la automedicación son dos puntos a supervisar. A su vez, la subnotificación al ente regulatorio es una constante que impide la toma de medidas correctivas por parte del mismo. La difusión de alertas y la educación del paciente son medidas fundamentales en este aspecto. Se presentan dos casos que describen el impacto clínico de las interacciones en pacientes ambulatorios.(AU)

Drug interactions are a relevant factor as far as the alteration of therapy is concerned. Such an importance should be assessed on an ongoing basis and its detection and prevention should be two of the cornerstones of the health teams performance inpractice. Polypharmacy and self-medication are two points to be monitored. At the same time, the underreporting to the Regulating Entity is a constant that prevents it from taking corrective actions. Warnings dissemination and patient education are key steps at this point. Two cases are presented describing the clinical impact of the interactions on outpatients.(AU)

Ergotamina e inhibidores de la proteasa: impacto clínico de las interacciones farmacológicas: presentación de dos casos / Ergotamine and protease inhibitors: clinical impact of drugs interactions: report of two cases

Las interacciones medicamentosas constituyen un factor relevante en lo que a la alteración de la terapéutica se refiere. Dicha importancia debería ser valorada de forma permanente y su detección y prevención deberían constituir dos de los ejes centrales de la actuación del equipo de salud en su ejercicio profesional. La polifarmacia y la automedicación son dos puntos a supervisar. A su vez, la subnotificación al ente regulatorio es una constante que impide la toma de medidas correctivas por parte del mismo. La difusión de alertas y la educación del paciente son medidas fundamentales en este aspecto. Se presentan dos casos que describen el impacto clínico de las interacciones en pacientes ambulatorios.(AU)

Drug interactions are a relevant factor as far as the alteration of therapy is concerned. Such an importance should be assessed on an ongoing basis and its detection and prevention should be two of the cornerstones of the health teams performance inpractice. Polypharmacy and self-medication are two points to be monitored. At the same time, the underreporting to the Regulating Entity is a constant that prevents it from taking corrective actions. Warnings dissemination and patient education are key steps at this point. Two cases are presented describing the clinical impact of the interactions on outpatients.(AU)

Influence of dihydroergotoxine, bromocriptine, and ergotamine on penile erection in Wistar rats.

The pilot study presented was conducted to determine as to whether ergot alkaloids (alpha-adrenergic blockers) have a potential effect on penile erectile function. The influence of dihydroergotoxine, bromocriptine, and ergotamine was studied on the erection ability in intact, two-grade outbred male Wistar albino rats that were out of their estrous phase. The experimental animals were injected intrapenially with the substances under examination: dihydroergotoxine mesylate (0.1 mg/0.1 mL, 0.3 mg/0.1 mL, and 1 mg/0.1 mL), bromocriptine mesylate (0.3 mg/0.1 mL, 1 mg/0.1 mL, and 3 mg/0.1 mL), and ergotamine tartrate (0.1 mg/0.1 mL, 0.3 mg/0.1 mL, and 1mg/0.1 mL). Every dose was tested on a pattern of 30 rats. These mentioned substances were injected in the amount of 1 mm to the left of the proximal part of the superficial dorsal vein of the penis, in the region of the penis root. After injection, the animals were then observed within the next 90 minutes. In the trial, the following was observed: the number of rats with an erection achieved, the period of time from intrapenial application to the appearance of the first erection, and the duration of the erection. Ultimately, the research results confirm the efficiency of dihydroergotoxine and bromocriptine as erectogenic agents, as well as ergotamine as a detumescent compared with saline solutions.

Unilateral renal agenesis and urethral atresia associated with ergotamine intake during pregnancy.

Ergotamine, an ergot alkaloid, used for the treatment and prevention of migraine attacks, is considered as a teratogenic drug and, therefore, should be avoided in pregnancy. Here, we report a newborn infant with unilateral renal agenesis, urethral atresia, and pulmonary hypoplasia associated with the use of ergotamine for the treatment of migraine attacks at early pregnancy. Genitourinary anomalies in association with ergotamine usage were rarely reported and this was the third case of renal agenesia in association with ergotamine usage in literature. We suggest that ergotamine teratogenicity may be dose dependent and should be avoided in pregnancy for the possibility of genitourinary anomalies.

Sumatriptan (rectal route of administration) for acute migraine attacks in adults.

BACKGROUND: Migraine is a highly disabling condition for the individual and also has wide-reaching implications for society, healthcare services, and the economy. Sumatriptan is an abortive medication for migraine attacks, belonging to the triptan family. Rectal administration may be preferable to oral for individuals experiencing nausea and/or vomiting. OBJECTIVES: To determine the efficacy and tolerability of rectal sumatriptan compared to placebo and other active interventions in the treatment of acute migraine attacks in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, online databases, and reference lists for studies through 13 October 2011. SELECTION CRITERIA: We included randomised, double-blind, placebo- and/or active-controlled studies using rectally administered sumatriptan to treat a migraine headache episode, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or 'risk ratio') and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment. MAIN RESULTS: Three studies (866 participants) compared rectally administered sumatriptan with placebo or an active comparator. Most of the data were for the 12.5 mg and 25 mg doses. For the majority of efficacy outcomes, sumatriptan surpassed placebo. For sumatriptan 12.5 mg versus placebo the NNTs were 5.2 and 3.2 for headache relief at one and two hours, respectively. Results for the 25 mg dose were similar to the 12.5 mg dose, and there were no significant differences between the two doses for any of the outcomes analysed. The NNTs for sumatriptan 25 mg versus placebo were 4.2, 3.2, and 2.4 for pain-free at two hours, headache relief at one hour, and headache relief at two hours, respectively.Relief of functional disability was greater with sumatriptan than with placebo, with NNTs of 8.0 and 4.0 for the 12.5 mg and 25 mg doses, respectively. For the most part, adverse events were transient and mild and were more common with sumatriptan than with placebo, but there were insufficient data to perform any analyses.Direct comparison of sumatriptan with active treatments was limited to one study comparing sumatriptan 25 mg with ergotamine tartrate 2 mg + caffeine 100 mg. AUTHORS' CONCLUSIONS: Based on limited amounts of data, sumatriptan 25 mg, administered rectally, is an effective treatment for acute migraine attacks, with participants in these studies experiencing a significant reduction in headache pain and functional disability within two hours of treatment. The lack of data on relief of headache-associated symptoms or incidence of adverse events limits any conclusions that can be drawn.

[Retroperitoneal fibrosis associated with chronic use of ergotamine: report of one case]. / Fibrosis retroperitoneal asociada a uso crónico de ergotamina. Tratamiento con colchicina y esteroides: Caso clínico.

Retroperitoneal fibrosis (RPF) associated with chronic use of ergotamine is a very rare disorder. We report a 45-year-old woman who presented with a RPf after using, almost daily for 23 years, ergotamine tartrate for migraine relief. FRP presented as a chronic inflammatory state, anemia, abdominal and lumbosacral pain and a hypogastric mass. A CT-Scan showed a periaortic mass and left hydronephrosis. A percutaneous biopsy was obtained and the patient was subjected to a surgical ureterolysis and tissue resection. The biopsy confirmed the presence of RPf. Due to persistent symptoms and increase in the volume of periaortic tissue, treatment with colchicine 1 mg/day and defazacort 30 mg/day was started, resulting in a rapid disappearance of symptoms, disappearance of inflammation and a significant reduction in the volume of the periaortic tissue. The patient remains in complete remission after 29 months of follow up.

Fibrosis retroperitoneal asociada a uso crónico de ergotamina. Tratamiento con colchicina y esteroides: Caso clínico / Retroperitoneal fibrosis associated with chronic use of ergotamine: Report of one case

Retroperitoneal fibrosis (RPF) associated with chronic use of ergotamine is a very rare disorder. We report a 45-year-old woman who presented with a RPf after using, almost daily for 23 years, ergotamine tartrate for migraine relief. FRP presented as a chronicinflammatory state, anemia, abdominal and lumbosacral pain and a hypogastric mass. A CT-Scan showed a periaortic mass and left hydronephrosis. A percutaneous biopsy was obtained and the patient was subjected to a surgical ureterolysis and tissue resection. The biopsy confirmed the presence of RPf. Due to persistent symptoms and increase in the volume of periaortic tissue, treatment with colchicine 1 mg/day and defazacort 30 mg/day was started, resulting in a rapid di-sappearance of symptoms, disappearance ofinflammation and a significant reduction in the volume of the periaortic tissue. The patient remains in complete remission after 29 months of follow up.

Oclusão arterial aguda por derivados da ergotamina / Acute arterial occlusion caused by ergotamine derivatives

Os derivados da ergotamina compõem diversas drogas amplamente utilizadas no tratamento de ataques agudos de migrânea. A intoxicação por estas substâncias resulta geralmente de sua administração crônica, promovendo sintomas secundários ao espasmo arterial e à consequente isquemia distal. Neste artigo, é relatado o caso de uma paciente de 47 anos com diagnóstico de oclusão arterial aguda em membros inferiores secundária ao uso de derivados da ergotamina. Após a suspensão da droga e a prescrição de anticoagulantes, vasodilatadores e antiagregante plaquetário, a paciente evoluiu com melhora da dor, da parestesia e com o retorno da coloração normal e dos pulsos distais em membros inferiores.

Ergotamine derivatives include several drugs widely used in the treatment of acute migraine attacks. Intoxication by these substances generally results from chronic administration, promoting symptoms secondary to arterial spasm and the consequent distal ischemia. The authors report the case of a 47-year old patient with acute arterial occlusion in lower limbs secondary to the use of ergotamine derivatives. After drugs were suspended and anticoagulants, vasodilators and antiplatelet drugs were prescribed, the patient progressed with improvement of pain, paresthesia and return of normal skin color and distal pulses in lower limbs.

[Cluster headache]. / Sarjoittainen päänsärky.

Cluster headache is a condition of extremely intense unilateral pain in the ocular or temporal region. Most patients are male. The condition occurs in clusters lasting from weeks to months. In some patients the clusters occur in seasonal periods. Prophylaxis of the bouts is based on verapamil and therapy is based on subcutaneous sumatriptan, intranasally sprayable zolmitriptan, or oxygen. In addition, corticosteroids and a short course of treatment with an ergotamine product can be used, if the bouts cannot be otherwise treated.