Dihydroergotamine protects against ischemic stroke by modulating microglial/macrophage polarization and inhibiting inflammation in mice.

OBJECTIVES: The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke. METHODS: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting. RESULTS: From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1ß in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype. CONCLUSION: This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.

Dihydroergotamine mesylate enhances the anti-tumor effect of sorafenib in liver cancer cells.

Liver cancer is the most common and frequentlyoccurring cancer. In addition to radiotherapy, chemotherapy and surgery are recommended as part of liver cancer treatment. The efficacy of sorafenib and sorafenib-based combination treatment against tumors has been verified. Although, clinical trials have revealed that some individuals are not sensitive to sorafenib therapy, and current therapeutic approaches are ineffective. Consequently, it is urgent to explore effective drug combinations and innovative techniques for increasing the effectiveness of sorafenib in the curing of liver tumor. Herein, we show that dihydroergotamine mesylate (DHE), an anti-migraine agent, could effectively suppress liver cancer cells proliferation by inhibiting STAT3 activation. However, DHE can enhance the protein stability of Mcl-1 by activating ERK, making DHE less effective in apoptosis induction. Specifically, DHE enhances the effects of sorafenib on liver cancer cells, such as decreased viability and increased apoptosis. Furthermore, the mixture of sorafenib and DHE could enhance DHE-triggered STAT3 suppression and inhibit DHE-mediated ERK-Mcl-1 pathway activation. In vivo, the combination of sorafenib with DHE produced a substantial synergy in suppressing tumour growth and causing apoptosis, ERK inhibition and Mcl-1 degradation. These findings suggest that DHE can effectively inhibit cell proliferation and enhance sorafenib anti-cancer activity in liver cancer cells. The current study provides some new insights that DHE asa novel anti-liver cancer therapeutic agent has been shown to improve treatment outcomes of sorafenib, which might be helpful in order to advance sorafenib in liver cancer therapeutics.

Identification of FDA approved drugs against SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and 3-chymotrypsin-like protease (3CLpro), drug repurposing approach.

The RNA-dependent RNA polymerase (RdRp) and 3C-like protease (3CLpro) from SARS-CoV-2 play crucial roles in the viral life cycle and are considered the most promising targets for drug discovery against SARS-CoV-2. In this study, FDA-approved drugs were screened to identify the probable anti-RdRp and 3CLpro inhibitors by molecular docking approach. The number of ligands selected from the PubChem database of NCBI for screening was 1760. Ligands were energy minimized using Open Babel. The RdRp and 3CLpro protein sequences were retrieved from the NCBI database. For Homology Modeling predictions, we used the Swiss model server. Their structure was then energetically minimized using SPDB viewer software and visualized in the CHIMERA UCSF software. Molecular dockings were performed using AutoDock Vina, and candidate drugs were selected based on binding affinity (∆G). Hydrogen bonding and hydrophobic interactions between ligands and proteins were visualized using Ligplot and the Discovery Studio Visualizer v3.0 software. Our results showed 58 drugs against RdRp, which had binding energy of - 8.5 or less, and 69 drugs to inhibit the 3CLpro enzyme with a binding energy of - 8.1 or less. Six drugs based on binding energy and number of hydrogen bonds were chosen for the next step of molecular dynamics (MD) simulations to investigate drug-protein interactions (including Nilotinib, Imatinib and dihydroergotamine for 3clpro and Lapatinib, Dexasone and Relategravir for RdRp). Except for Lapatinib, other drugs-complexes were stable during MD simulation. Raltegravir, an anti-HIV drug, was observed to be the best compound against RdRp based on docking binding energy (-9.5 kcal/mole) and MD results. According to the MD results and binding energy, dihydroergotamine is a suitable candidate for 3clpro inhibition (-9.6 kcal/mol). These drugs were classified into several categories, including antiviral, antibacterial, anti-inflammatory, anti-allergic, cardiovascular, anticoagulant, BPH and impotence, antipsychotic, antimigraine, anticancer, and so on. The common prescription-indications for some of these medication categories appeared somewhat in line with manifestations of COVID-19. We hope that they can be beneficial for patients with certain specific symptoms of SARS-CoV-2 infection, but they can also probably inhibit viral enzymes. We recommend further experimental evaluations in vitro and in vivo on these FDA-approved drugs to assess their potential antiviral effect on SARS-CoV-2.

Dihydroergotamine-induced vasospastic angina in a patient taking a calcium channel blocker.

OBJECTIVE: To report a probable case of vasospastic angina after administration of dihydroergotamine mesylate in a patient without coronary artery disease. CASE SUMMARY: A 49-year-old woman with relapsing/remitting multiple sclerosis was admitted for severe headache and pain crisis. She received a single dose of intravenous dihydroergotamine and, within 30 minutes, experienced chest pain, nausea, and vomiting. No changes on electrocardiogram were noted, but cardiac enzyme levels were elevated. Brief episodes of chest pain persisted for several days and resolved spontaneously before the woman's discharge. She had several cardiac risk factors, including cigarette smoking, hypertension, and a family history of coronary artery disease, but cardiac catheterization on hospital day 5 revealed no underlying coronary artery disease. DISCUSSION: Although cardiovascular adverse reactions have been reported with ergotamine tartrate, dihydroergotamine has rarely been linked with such reactions, including coronary vasospasm and myocardial infarction. Prescribing information for dihydroergotamine cautions against its use in patients with coronary artery disease or risk factors for underlying coronary artery disease without a cardiac workup before initiation of therapy. This patient had several cardiac risk factors, but cardiac catheterization revealed no underlying coronary artery disease. Concomitant verapamil therapy for hypertension did not prevent the vasospastic effects of dihydroergotamine. The Naranjo probability scale revealed a probable adverse reaction of vasospastic angina associated with dihydroergotamine. CONCLUSIONS: Health-care professionals should be aware of the possibility for vasospastic angina in patients receiving dihydroergotamine who have no underlying coronary artery disease. Prescribing information should be closely followed.

Deep vein thrombosis: risk factors and prevention in surgical patients.

BACKGROUND: Deep vein thrombosis (DVT) is a cause of preventable morbidity and mortality in hospitalized surgical patients. The occurrence of the disease is related to presence of risk factors, which are related primarily to trauma, venous stasis and hyper-coagulability. DVT seems not to be taken seriously by many surgeons in Nigeria. This is despite comprehensive studies that show no real differences in racial demography of the disease. OBJECTIVE: To highlight the importance of physician awareness about DVT especially its risks and prevention methods. METHODS: A detailed literature search was completed to extrapolate articles that described DVT risks and prevention. This involved hand and online searches. Specific search terms used included DVT/risk factors/prevention. The searches generated 468 papers. Of these 57 papers were included in the review. RESULTS: Predominant risk factors for DVT include middle or old age, prolonged surgery, trauma, confinement, presence of malignancy and insertion of deep venous catheters. In women, contraceptive use, hormone replacement therapy, pregnancy and the puepernum are a additional risk factors. Prophylactic measures include those directed at eliminating venous stasis and those directed at changes in blood coagulability. CONCLUSION: Deep Venous Thrombosis is a common disease with fatal and serious long term burdensome complications. We must target primary and secondary prophylaxis to improve survival and reduce morbidity from this preventable disease.

Pharmacological management of postoperative ileus.

The duration of postoperative ileus following abdominal surgery is quite variable, and prolonged postoperative ileus is an iatrogenic phenomenon with important influence on patient morbidity, hospital costs and length of stay in hospital. Adequate treatment for prolonged postoperative ileus is important to improve patient morbidity and clinical efficiency. Both clinical and pharmacological management strategies have improved rapidly over the last decade, and appropriate and timely management using multimodal techniques should be used for optimal care. In this review, we define postoperative ileus, describe the pathogenesis and briefly discuss clinical management before detailing potential pharmacologic management options.

Diagnosis and management of the primary headache disorders in the emergency department setting.

Headache continues to be a frequent cause of emergency department (ED) use, accounting for 2% of all visits. Most of these headaches prove to be benign but painful exacerbations of chronic headache disorders, such as migraine, tension-type, and cluster. The goal of ED management is to provide rapid and quick relief of benign headache, without causing undue side effects, and to recognize headaches with malignant course. Although these headaches have distinct epidemiologies and clinical phenotypes, there is overlapping response to therapy; nonsteroidals, triptans, dihydroergotamine, and the antiemetic dopamine antagonists may play a therapeutic role for each of these acute headaches. This article reviews the diagnostic criteria and management strategies for the primary headache disorders.

Variations among emergency departments in the treatment of benign headache.

STUDY OBJECTIVE: The practice patterns of US emergency departments in the treatment of patients with isolated benign headache have been recently described. How treatment varies among EDs has not been reported. To assess institutional variability in the pharmacotherapy of patients with benign headache, we describe and analyze the practice patterns of 3 US EDs. METHODS: This health records survey included a cohort sample of consecutive adult patients aged 16 to 65 years treated with parenteral medication for isolated benign headache at 3 nonaffiliated US EDs: a large, group-model health maintenance organization, a tertiary-care academic center, and a rural community hospital. Patients who underwent a diagnostic search for intracranial pathology, who had any nonheadache secondary diagnosis, or who had coexistent trauma, fever (temperature of > or =38.0 degrees C [100.4 degrees F]), or known pregnancy were excluded from study analysis. Demographic, clinical, and pharmacotherapeutic variables were collected for each ED visit. Descriptive analyses were performed; comparisons were made with t tests. RESULTS: Of the 490 eligible patients treated during the 4-month study period, the mean age was 36.4 years, and 374 (76%) were women. During their 629 visits, 364 (58%) received a migraine diagnosis, and 258 (41%) received a nonspecific headache diagnosis. Polypharmacy was common: 515 (82%) received 2 or more medications, and 154 (25%) received 3 or more medications. Pharmacotherapy varied greatly among the EDs. Use of opioid agonists showed the widest variation (16% to 72%), although use of dihydroergotamine (5% to 16%), prochlorperazine (32% to 59%), and adjunct diphenhydramine with prochlorperazine (42% versus 88%) also varied. CONCLUSION: Great institutional variability exists among US EDs in the parenteral treatment of patients with isolated benign headache.

Migraines.

A 26-year-old woman is evaluated for headaches, which began when she was 14 years old. She states that she initially sees bright zig-zag bands, which expand in the shape of a horseshoe in her right visual field. Twenty minutes later, she develops a throbbing headache over the left frontal area, associated with photophobia and nausea. The headaches last 1-3 days and they occur once a month. There is no medical history, and she takes only multivitamin supplements. Her sister has been diagnosed with migraines. Her examination is normal, including equal and reactive pupils, full extraocular movements, and normal strength and sensation. A magnetic resonance scan of the brain shows no abnormalities.

Successful treatment of headache related to intravenous immunoglobulin with antimigraine medications.

In order to investigate headache related to intravenous immunoglobulin, we studied a 36-year-old woman with a history of migraine receiving weekly intravenous immunoglobulin for refractory myasthenia gravis who experienced severe headaches with each treatment. Neurological examination, CT scan of the head, and a lumber puncture after the first headache were normal. Significant therapeutic response was based upon 50% reduction in pain and associated features. Headache features included throbbing pain which worsened with head movement and was associated with severe photophobia and nausea. Sumatriptan, 6 mg subcutaneous, reduced headache significantly with resolution of associated complaints. Treatment prior to intravenous immunoglobulin with dihydroergotamine mesylate resulted in development of only a mild dull ache without further development of severe head pain. Dihydroergotamine mesylate was also abortive in the few instances when the headache worsened. Headaches associated with intravenous immunoglobulin may have features of migraine and may be successfully prevented and/or treated with 5-HT1D receptor agonists.

Coexistence of migraine and idiopathic intracranial hypertension without papilledema.

Eighty-five patients with refractory transformed migraine type of chronic daily headache (CDH) had spinal tap as a part of diagnostic work-up. Twelve had increased intracranial pressure without papilledema, transient visual obscurations, or visual field defects. The headache profile of these 12 patients was not different from that of transformed migraine type of CDH. Acute headache exacerbations responded to specific antimigraine agents such as ergotamine, dihydroergotamine (DHE), and sumatriptan, whereas prophylactic antimigraine medications were only partially helpful. Addition of agents such as acetazolamide and furosemide, after the diagnosis of increased intracranial pressure, resulted in better control of symptoms. These observations suggest a link between migraine and idiopathic intracranial hypertension that needs further research. In refractory CDH with migrainous features, a spinal tap to exclude coexistent idiopathic intracranial hypertension without papilledema may be indicated.

[Prophylaxis of venous thrombosis, yes but...]. / Profilaxis del tromboembolismo venoso, sí pero...

Prevention of venous thromboembolism (VTE) can be achieved through mechanic or pharmacological means. For the latter, unfractionated low dose heparin, low molecular weight heparins and oral anticoagulants are successfully and widely employed. Results of controlled and uncontrolled studies favour the use of prophylactic heparin in different clinical and surgical conditions such as myocardial infarction, stroke, orthopedic or prolonged surgery and surgical interventions in patients older than forty. Useful parameters to evaluate the results of VTE prophylaxis are discussed as well as timing, duration, effectiveness, side effects and costs of therapy. Although the benefits of VTE prophylaxis in high risk patients are clear, it is not routinely employed in Argentina.

The effect of enoxaparin in prevention of deep venous thrombosis in hip and knee surgery--a comparison with the dihydroergotamine-heparin combination.

A randomized study was carried out in order to compare the low-molecular heparin enoxaparin to heparin-dihydroergotamine (HDHE) combination, as prophylactic anti-thrombotic measure in patients undergoing hip replacement or knee replacement surgery or fractures of the femoral neck. A total of 165 patients both female and male were included in the study. The patients were randomized into two treatment groups. One group was treated with heparin-dihydroergotamine 0.5 mg + 5,000 IU twice a day and the other with enoxaparin 40 mg once daily. All patients were examined with Doppler ultrasound on day 3-5 and after the termination of medication which was the end of the study. Positive Doppler ultrasound findings were confirmed either by duplex Doppler or phlebography and clinical signs of pulmonary embolism were confirmed by isotope scintigraphy. The overall incidence of thromboembolic events was low (3%). One deep venous thrombosis (DVT) was seen in the enoxaparin group and two cases of pulmonary embolism in the heparin-dihydroergotamine group. Thus, the two regimens showed comparable efficacy and the overall safety was comparable. However, enoxaparin caused significantly less injection site haematoma. Correspondingly, the size of the injection site haematoma was significantly smaller in the enoxaparin group.

Profilaxis del tromboembolismo venoso, sí pero / Prophylaxis of venous thrombosis, yes but

La prevención del tromboembolismo venoso (TEV) puede efectuarse por medios mecánicos (compresión neumática intermitente y medias de compresión graduada) y por medios farmacológicas (heparina no fraccionada en dosis bajas, heparinas de bajo peso molecular, anticoagulantes orales, etc.). Numerosos trabajos efectuados en los últimos años han demostrado la efectividad de la prevención farmacológica del TEV en pacientes con diversas condiciones clínicas (infarto agudo de miocardio, accidente cerebrovascular isquémico, neumopatías, etc.) y quirúrgicas (cirugía mayor prolongada y/o pacientes mayores de 40 años). Se discuten los diversos parámetros útiles para evaluar los resultados de la profilaxis, tos métodos para adecuar la profilaxis en los pacientes, el momento aconsejabie para su iniciación y su duración, el costo aproximado de este tratamiento, sus efectos secundarias y cual es la efectividad de la profilaxis en diferentes patologías. A pesar de las claras evidencias del beneficio de la prevención del TEV, aun existe en nuestro medio poco entusiasmo en su utilización en la Práctica clínico-quirúrgica.

Dihydroergotamine and metoclopramide in the treatment of organic headache.

Dihydroergotamine and metoclopramide have been used in the treatment of benign headache for many years. The presumed mechanism of action of dihydroergotamine and metoclopramide is related to these drugs' affinity for serotonergic receptors. We present three cases of the use of dihydroergotamine and metoclopramide in patients with organic headache (two patients with viral meningitis and one patient with meningeal carcinomatosis). All three patients had excellent symptomatic relief. Our results demonstrate that dihydroergotamine and metoclopramide can be effective in treating organic headache and, therefore, symptomatic relief can not be assumed to signify benign disease.

Low doses of heparin and heparin dihydergot in postoperative thromboprophylaxis in gynaecological patients.

A prospective study of postoperative thromboembolic prophylaxis involving 500 gynaecological patients was performed to compare the effectiveness and safety of low doses of heparin (LDH) and heparin-dihydergot (HDHE). In the LDH group 255 patients (51%) aged 26-84 were included, in the HDHE group there were 245 patients (49%) aged 34-86. Both groups were well matched with respect to risk factors, duration of surgery, type of operation, volume of blood transfused and duration of prophylaxis. Thromboembolism was detected in 48 patients (9.6%): 26 patients (10.2%) in the LDH group and 22 patients (9%) in the HDHE group. In the LDH group isotopic deep vein thrombosis (DVT) was found in 23 patients (9%), five of them had pulmonary embolism (PE), detected by lung perfusion scanning without clinical signs of PE, three patients developed clinical PE without detected DVT. In the HDHE group, 22 patients (9%) had isotopic DVT and five of them had PE detected by lung perfusion scanning. In the incidence of TE there was no statistically significant difference between the two groups (p > 0.1). Within two months after surgery late clinically manifest TE confirmed by isotopic venography developed in five patients (1.9%) in the LDH group and in one patient (0.4%) in the HDHE group. Wound haematomas appeared in 8 patients (3.1%) in the LDH group and in 9 patients (3.7%) in the HDHE group. There were no ischemic complications (ergotism) in the HDHE group. The HDHE prophylaxis proved no more effective and was ten times more expensive than the usual prevention with LDH.

Perioperative thrombosis prophylaxis with low molecular weight heparins in elective hip surgery. Clinical and economic considerations.

A review and meta analysis of randomized prophylaxis studies in total hip arthroplasty (THA) surgery with the low molecular weight heparin (LMWH) compounds presently marketed in Europe. Thromboprophylaxis with recommended dosages of LMWH was significantly more effective than both placebo (no prophylaxis), dextran 70 and low-dose unfractionated heparin (UH) (5,000 IU thrice daily) in terms of protection against objectively diagnosed deep vein thrombosis (DVT), which is the main source of postoperative pulmonary embolism. The efficacy of LMWH was similar to that of adjusted-dose UH but only 2 studies have been conducted with this regimen so far. When combined with 0.5 mg dihydroergotamine (DHE), UH was as effective as LMWH, but DHE bears a definite risk of circulatory disturbances in the lower limbs. In all studies LMWH prophylaxis was safe under the clinical conditions. A cost-effectiveness analysis based on the reported efficacy and safety of LMWH in the European studies showed that, compared with no prophylaxis, dextran 70, and low-dose UH, LMWH prophylaxis used routinely in patients undergoing THA is more profitable for the health care system due to fewer expenses used on treatment of postoperative thromboembolic complications. LMWH therefore leads to better utilization of the economic resources.

Bilateral vocal cord paralysis with Shy-Drager syndrome.

Shy-Drager syndrome consists of progressive autonomic nervous system failure with Parkinson's disease-like symptoms and orthostatic hypotension. It can also result in airway compromise from bilateral vocal cord paralysis. Fewer than 30 cases of severe bilateral vocal cord paresis or paralysis associated with the Shy-Drager syndrome have been reported in the English literature. We present a case of a 72-year-old man who had a 2-year history of orthostatic hypotension, neurogenic bladder, impotence, anhydrosis, and extremity weakness and paresthesias. Hoarseness and dyspnea with stridor developed as a result of bilateral vocal cord paralysis in the median position and required an emergency tracheotomy. This combination of symptoms resulted in the diagnosis of Shy-Drager syndrome. We present the case along with literature review of bilateral vocal cord paralysis with the Shy-Drager syndrome.

Can low molecular weight heparins and heparinoids be safely given to patients with heparin-induced thrombocytopenia syndrome?

BACKGROUND: Low molecular weight heparin (LMWH) and heparinoids have been offered as alternatives to unfractionated heparin (UH) to patients with heparin-associated antiplatelet antibodies (HAAb) and heparin-induced thrombocytopenia syndrome (HIT). Some of these patients have had continued HIT in the presence of the UH substitutes. It would seem important to know whether the heparin substitute is likely to cause patients' platelets to aggregate before administering the substitute to patients with HAAb. METHODS: Patients with HIT were identified as having HAAb by positive platelet aggregometry testing with commercial UH. Plasmas from 51 patients with HAAb were tested for the ability to aggregate platelets in the presence of two LMWHs (Mono-Embolex NM and Fragmin) and one heparinoid (Org 10172). RESULTS: The proportions of plasmas reacting to each UH substitute are Mono-Embolex NM, 60.8%; Fragmin, 25.5%; and Org 10172, 19.6%. Although Fragmin and Org 10172 aggregated platelets in the presence of HAAb significantly less often than Mono-Embolex NM (p < 0.001), a patient with HAAb has a substantial chance of reacting to one of these UH substitutes. CONCLUSIONS: Before giving a LMWH or heparinoid to a patient with HAAb, one should determine with in vitro testing that the patient's HAAb will not cause platelet aggregation in the presence of the heparin substitute.

Prophylaxis of postoperative thromboembolism with low molecular weight heparins.

To evaluate the thromboprophylactic use of low molecular weight heparins (LMWHs), publications from 27 orthopaedic trials and 35 studies of patients undergoing general or gynaecological surgery were scrutinized and subjected to a partial meta-analysis. In orthopaedic surgery, LMWHs were superior to placebo or dextran and at least as efficient as unfractionated heparin in the prevention of deep vein thrombosis (DVT). Compared with unfractionated heparin, one of the LMWH preparations significantly reduced the total incidence of DVT. The rate of non-fatal pulmonary embolism was 0.49 per cent in patients receiving LMWH and 1.22 per cent in controls. Seven orthopaedic patients (0.15 per cent) died from pulmonary embolism, none of whom received LMWH. In general surgery, the LMWHs were at least as efficient as unfractionated heparin, with a trend towards a lower risk of pulmonary embolism with the former. Compared with unfractionated heparin, LMWHs did not reduce the postoperative mortality rate, nor did they cause haemorrhage. LMWHs provide safe and efficient prophylaxis by administration once daily.