RESUMEN
OBJECTIVE: The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect. BACKGROUND: Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co-administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co-administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5-HT1B/1D receptor agonist. METHODS: We investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37. RESULTS: Sumatriptan as well as PL37 each produced a dose-dependent inhibition of ISDN-induced cephalic MH. Median effective dose (ED50 ) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04. CONCLUSION: These results suggest that PL37 acts synergistically with sumatriptan to produce an anti-allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine. PLAIN LANGUAGE SUMMARY: There have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model.
Asunto(s)
Trastornos Migrañosos , Sumatriptán , Humanos , Masculino , Ratas , Animales , Neprilisina/efectos adversos , Trastornos Migrañosos/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Dinitrato de Isosorbide/efectos adversosRESUMEN
On March 11, 2020 the World Health Organization (WHO) declared the state of global pandemic caused by the new SARS-CoV-2 (COVID-19). To date, no antivirals directed against SARS-CoV-2 or effective vaccines to combat the viral infection are available. Severe acute respiratory syndrome caused by SARS-CoV-2 is treated empirically with antivirals, anti-inflammatory, anticoagulants. The approval of an effective vaccine still takes time. In this state, it may be useful to find new therapeutic solutions from drugs already on the market. Recent hypotheses suggest that the use of AT-1 receptor antagonists (ARB) in combination with neprilisin inhibitors (NEPi) could indirectly provide clinical benefits to patients with SARS-CoV-2 and cardiac involvement. In this article we investigate and describe a possible innovative pharmacological approach for the treatment of the most severe stages of COVID-19 infection.
Asunto(s)
Aminobutiratos/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Insuficiencia Cardíaca/tratamiento farmacológico , Tetrazoles/administración & dosificación , Valsartán/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina , Antivirales/uso terapéutico , Compuestos de Bifenilo , Síndrome de Liberación de Citoquinas/virología , Citocinas/metabolismo , Combinación de Medicamentos , Insuficiencia Cardíaca/virología , Homeostasis , Humanos , Inflamación , Modelos Teóricos , Péptido Natriurético Encefálico/metabolismo , Neprilisina/efectos adversos , Fragmentos de Péptidos/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Organización Mundial de la SaludRESUMEN
BACKGROUND: Heart failure is a highly prevalent disease with a global prevalence of 37 million, and the prevalence is increasing. Patients with heart failure are at an increased risk of death and morbidity. Traditionally, patients with heart failure have been treated with a beta-blocker in addition to an inhibitor of the renin-angiotensin-aldosterone system. However, new drugs are currently being added to the recommended guideline therapy. The latest drug to be added combines inhibition of the renin-angiotensin-aldosterone system pathway with inhibiting the neprilysin enzyme and is therefore classified as an ARNI. Our objective is to identify the beneficial and harmful effects of ARNIs in the treatment of patient with heart failure. METHODS: This protocol for a systematic review was undertaken using the recommendations of the Cochrane, the Preferred Report Items of Systematic reviews with Meta-Analysis Protocols, and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ARNIs in the treatment of patients with heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS to identify relevant trials. We will also search for grey literature and unpublished trials. Extracted data will be analysed using Review Manager 5, STATA 5, and Trial Sequential Analysis. Our primary outcomes will be all-cause mortality and serious adverse events. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the GRADE assessment. DISCUSSION: The present systematic review will have the potential to aid clinicians in decision-making and thereby, benefit patients with heart failure. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019129336.
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Antagonistas Adrenérgicos beta , Inhibidores de la Enzima Convertidora de Angiotensina , Causas de Muerte , Insuficiencia Cardíaca , Neprilisina , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Neprilisina/efectos adversos , Neprilisina/uso terapéutico , Sistema Renina-Angiotensina , Metaanálisis como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
Heart failure is a disease with a high prevalence and incidence. New therapeutic approaches are needed to prevent the onset of heart failure and to reduce the high morbidity and mortality associated with this disease. An optimized therapy of arterial hypertension in patients with risk factors and the use of the SGLT2 inhibitor empagliflozin in type 2 diabetics are proven strategies to prevent heart failure. The therapeutic options in heart failure with preserved ejection fraction are still insufficient. In heart failure with reduced ejection fraction sacubitril/valsartan, the first approved angiotensin receptor-neprilysin inhibitor, is superior to an angiotensin converting enzyme (ACE) inhibitor. Whether digitalis affects the prognosis in heart failure remains unclear; however, serum concentration should be targeted at the lower therapeutic range. Iron supplementation in heart failure with reduced systolic function and iron deficiency improves symptoms and quality of life.
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Insuficiencia Cardíaca/tratamiento farmacológico , Aminobutiratos/efectos adversos , Aminobutiratos/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Compuestos de Bifenilo , Enfermedad Crónica , Glicósidos Digitálicos/efectos adversos , Glicósidos Digitálicos/uso terapéutico , Combinación de Medicamentos , Humanos , Neprilisina/efectos adversos , Neprilisina/uso terapéutico , Tetrazoles/efectos adversos , Tetrazoles/uso terapéutico , ValsartánRESUMEN
Neprilysin (NEP) is an endogenous protease that degrades a wide range of peptides including amyloid beta (Aß), the main pathological component of Alzheimer's disease (AD). We have engineered NEP as a potential therapeutic for AD but found in pre-clinical safety testing that this variant increased prothrombin time (PT) and activated partial thromboplastin time (APTT). The objective of the current study was to investigate the effect of wild type NEP and the engineered variant on coagulation and define the mechanism by which this effect is mediated. PT and APTT were measured in cynomolgus monkeys and rats dosed with a human serum albumin fusion with an engineered variant of NEP (HSA-NEPv) as well as in control plasma spiked with wild type or variant enzyme. The coagulation factor targeted by NEP was determined using in vitro prothrombinase, calibrated automated thrombogram (CAT) and fibrin formation assays as well as N-terminal sequencing of fibrinogen treated with the enzyme. We demonstrate that HSA-NEP wild type and HSA-NEPv unexpectedly impaired coagulation, increasing PT and APTT in plasma samples and abolishing fibrin formation from fibrinogen. This effect was mediated through cleavage of the N-termini of the Aα- and Bß-chains of fibrinogen thereby significantly impairing initiation of fibrin formation by thrombin. Fibrinogen has therefore been identified for the first time as a substrate for NEP wild type suggesting that the enzyme may have a role in regulating fibrin formation. Reductions in NEP levels observed in AD and cerebral amyloid angiopathy may contribute to neurovascular degeneration observed in these conditions.
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Enfermedad de Alzheimer/tratamiento farmacológico , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Neprilisina/administración & dosificación , Albúmina Sérica/genética , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Animales , Coagulación Sanguínea/efectos de los fármacos , Angiopatía Amiloide Cerebral/sangre , Angiopatía Amiloide Cerebral/genética , Fibrina/efectos de los fármacos , Fibrina/metabolismo , Fibrinógeno/antagonistas & inhibidores , Humanos , Macaca fascicularis , Neprilisina/efectos adversos , Neprilisina/genética , Tiempo de Tromboplastina Parcial , Proteolisis/efectos de los fármacos , Tiempo de Protrombina , Ratas , Albúmina Sérica/administración & dosificación , Albúmina Sérica/efectos adversos , Tromboplastina/genéticaRESUMEN
Acute diarrhea is a major cause of morbidity and mortality worldwide. Infants and pre-school children are the most vulnerable in whom there are 2-3 million deaths each year as a result of the associated dehydration and acidosis. Although oral rehydration therapy has reduced mortality during the past 30 years ago, the search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce faecal losses in patients with high-volume watery diarrhea has continued for more than 20 years. A variety of potential targets for antisecretory agents have been explored which include loci within the enterocyte (the chloride channel, calcium-calmodulin) and other sites such as enteric nerves and endogenous mediators (such as 5-HT, prostaglandins). Although the potential of calcium-calmodulin inhibition has as yet not been realised, preliminary studies suggest that there are chloride channel blockers under development that will find a place in the management of secretory diarrheas. Recent work has highlighted the importance of neurohumoral mechanisms in the pathogenesis of acute diarrhea. Potentiation of the effects of endogenous enkephalin activity by enkephalinase inhibition has already produced a safe, effective anti-secretory drug, racecadotril. Speculative early work indicates that there may be a role for antagonists of 5-HT, substance P, and VIP receptors. There now seems to be a real possibility that antisecretory therapy will become more widely available in the future.
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Antidiarreicos/uso terapéutico , Diarrea/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Mucosa Intestinal/metabolismo , Antagonistas de la Serotonina/uso terapéutico , Canales de Cloruro/antagonistas & inhibidores , Canales de Cloruro/metabolismo , Humanos , Mucosa Intestinal/efectos de los fármacos , Neprilisina/efectos adversos , Receptores de Péptido Intestinal Vasoactivo/antagonistas & inhibidores , Sustancia P/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
We have studied the metabolism and inactivation of AF1 (KNEFIRF-NH2) by membranes prepared from the locomotory muscle of Ascaris suum. FIRF-NH2 and KNEFIRF were identified as three primary degradation products, resulting from the action of an endopeptidase, aminopeptidase and a deamidase, respectively. The endopeptidase resembled mammalian neprilysin (NEP, endopeptidase 24.11) in that the enzyme activity was inhibited by phosphoramidon and thiorphan and that it cleaved AF1 on the amino side of phenylalanine. The aminopeptidase activity was inhibited by amastatin and bestatin but not by puromycin. The deamidation of AF1 was inhibited by phenylmethylsulfonyl fluoride, p-chloromercuricphenylsulfonate and mercuric chloride, indicating that the deamidase enzyme is a serine protease with a requirement for a free thiol group for activity. AF1 (1 microM) induces an increase in tension and an increase in the frequency and amplitude of spontaneous contractions of an A. suum muscle strip. None of the aforementioned AF1 metabolites (2-20 microM) retained biological activity in this bioassay, indicating that the endopeptidase, aminopeptidase and deamidase have the potential to terminate the action of AF1 on locomotory muscle of A. suum.