ABSTRACT
BACKGROUND: Acute kidney injury (AKI) is a serious and common complication of cardiac surgery, for which reduced kidney perfusion is a key contributing factor. Intravenous amino acids increase kidney perfusion and recruit renal functional reserve. However, the efficacy of amino acids in reducing the occurrence of AKI after cardiac surgery is uncertain. METHODS: In a multinational, double-blind trial, we randomly assigned adult patients who were scheduled to undergo cardiac surgery with cardiopulmonary bypass to receive an intravenous infusion of either a balanced mixture of amino acids, at a dose of 2 g per kilogram of ideal body weight per day, or placebo (Ringer's solution) for up to 3 days. The primary outcome was the occurrence of AKI, defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria. Secondary outcomes included the severity of AKI, the use and duration of kidney-replacement therapy, and all-cause 30-day mortality. RESULTS: We recruited 3511 patients at 22 centers in three countries and assigned 1759 patients to the amino acid group and 1752 to the placebo group. AKI occurred in 474 patients (26.9%) in the amino acid group and in 555 (31.7%) in the placebo group (relative risk, 0.85; 95% confidence interval [CI], 0.77 to 0.94; P = 0.002). Stage 3 AKI occurred in 29 patients (1.6%) and 52 patients (3.0%), respectively (relative risk, 0.56; 95% CI, 0.35 to 0.87). Kidney-replacement therapy was used in 24 patients (1.4%) in the amino acid group and in 33 patients (1.9%) in the placebo group. There were no substantial differences between the two groups in other secondary outcomes or in adverse events. CONCLUSIONS: Among adult patients undergoing cardiac surgery, infusion of amino acids reduced the occurrence of AKI. (Funded by the Italian Ministry of Health; PROTECTION ClinicalTrials.gov number, NCT03709264.).
Subject(s)
Acute Kidney Injury , Amino Acids , Cardiac Surgical Procedures , Cardiopulmonary Bypass , Postoperative Complications , Aged , Female , Humans , Male , Middle Aged , Acute Kidney Injury/diagnosis , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Acute Kidney Injury/prevention & control , Amino Acids/administration & dosage , Amino Acids/adverse effects , Cardiac Surgical Procedures/adverse effects , Cardiopulmonary Bypass/adverse effects , Creatinine/blood , Double-Blind Method , Infusions, Intravenous , Kidney/drug effects , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/prevention & control , Renal Replacement TherapyABSTRACT
BACKGROUND: Minimizing the use of blood component can reduce known and unknown blood transfusion risks, preserve blood bank resources, and decrease healthcare costs. Red Blood Cell (RBC) transfusion is common after cardiac surgery and associated with adverse perioperative outcomes, including mortality. Acute normovolemic hemodilution (ANH) may reduce bleeding and the need for blood product transfusion after cardiac surgery. However, its blood-saving effect and impact on major outcomes remain uncertain. METHODS: This is a single-blinded, multinational, pragmatic, randomized controlled trial with a 1:1 allocation ratio conducted in Tertiary and University hospitals. The study is designed to enroll patients scheduled for elective cardiac surgery with planned cardiopulmonary bypass (CPB). Patients are randomized to receive ANH before CPB or the best available treatment without ANH. We identified an ANH volume of at least 650 ml as the critical threshold for clinically relevant benefits. Larger ANH volumes, however, are allowed and tailored to the patient's characteristics and clinical conditions. RESULTS: The primary outcome is the percentage of patients receiving RBCs transfusion from randomization until hospital discharge, which we hypothesize will be reduced from 35% to 28% with ANH. Secondary outcomes are all-cause 30-day mortality, acute kidney injury, bleeding complications, and ischemic complications. CONCLUSION: The trial is designed to determine whether ANH can safely reduce RBC transfusion after elective cardiac surgery with CPB. STUDY REGISTRATION: This trial was registered on ClinicalTrials.gov in April 2019 with the trial identification number NCT03913481.
Subject(s)
Cardiac Surgical Procedures , Cardiopulmonary Bypass , Hemodilution , Humans , Hemodilution/methods , Cardiac Surgical Procedures/methods , Single-Blind Method , Cardiopulmonary Bypass/methods , Erythrocyte Transfusion/methods , Male , Blood Loss, Surgical/prevention & control , FemaleABSTRACT
BACKGROUND: Minimizing the use of blood component can reduce known and unknown blood transfusion risks, preserve blood bank resources, and decrease healthcare costs. Red Blood Cell (RBC) transfusion is common after cardiac surgery and associated with adverse perioperative outcomes, including mortality. Acute normovolemic hemodilution (ANH) may reduce bleeding and the need for blood product transfusion after cardiac surgery. However, its blood-saving effect and impact on major outcomes remain uncertain. METHODS: This is a single-blinded, multinational, pragmatic, randomized controlled trial with a 1:1 allocation ratio conducted in Tertiary and University hospitals. The study is designed to enroll patients scheduled for elective cardiac surgery with planned cardiopulmonary bypass (CPB). Patients are randomized to receive ANH before CPB or the best available treatment without ANH. We identified an ANH volume of at least 650 mL as the critical threshold for clinically relevant benefits. Larger ANH volumes, however, are allowed and tailored to the patient's characteristics and clinical conditions. RESULTS: The primary outcome is the percentage of patients receiving RBCs transfusion from randomization until hospital discharge, which we hypothesize will be reduced from 35% to 28% with ANH. Secondary outcomes are all-cause 30-day mortality, acute kidney injury, bleeding complications, and ischemic complications. CONCLUSION: The trial is designed to determine whether ANH can safely reduce RBC transfusion after elective cardiac surgery with CPB. STUDY Registration: This trial was registered on ClinicalTrials.gov in April 2019 with the trial identification number NCT03913481.
Subject(s)
Cardiopulmonary Bypass , Randomized Controlled Trial , Critical CareABSTRACT
BACKGROUND: Sepsis is caused by dysregulated immune responses due to infection and still presents high mortality rate and limited efficacious therapies, apart from antibiotics. Recent evidence suggests that very high dose proton pump inhibitors might regulate major sepsis mediators' secretion by monocytes, which might attenuate excessive host reactions and improve clinical outcomes. This effect is obtained with doses which are approximately 50 times higher than prophylactic esomeprazole single daily administration and 17 times higher than the cumulative dose of a three day prophylaxis. We aim to perform a randomized trial to investigate if high dose esomeprazole reduces organ dysfunction in patients with sepsis or septic shock. METHODS: This study, called PPI-SEPSIS, is a multicenter, randomized, double blind, placebo-controlled clinical trial on critically ill septic patients admitted to the emergency department or intensive care unit. A total of 300 patients will be randomized to receive high dose esomeprazole (80 mg bolus followed by 12 mg/h for 72 h and a second 80 mg bolus 12 h after the first one) or equivolume placebo (sodium chloride 0.9%), with 1:1 allocation. The primary endpoint of the study will be mean daily Sequential Organ Failure Assessment (SOFA) score over 10 days. Secondary outcomes will include antibiotic-free days, single organ failure severity, intensive care unit-free days at day 28, and mortality. DISCUSSION: This trial aims to test the efficacy of high dose esomeprazole to reduce acute organ dysfunction in patients with septic shock. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov with the trial identification NCT03452865 in March 2018.
ABSTRACT
BACKGROUND: Postoperative acute kidney injury (AKI) is frequent in cardiac surgery patients. Its pathophysiology is complex and involves decreased renal perfusion. Preliminary clinical evidence in critically ill patients shows that amino acids infusion increases renal blood flow and may decrease the incidence and severity of AKI. We designed a study to evaluate the effectiveness of perioperative continuous infusion of amino acids in decreasing AKI. METHODS: This is a phase III, multi-center, randomized, double-blind, placebo-controlled trial. Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) are included. Patients are randomly assigned to receive either continuous infusion of a balanced mixture of amino acids in a dose of 2 g/kg ideal body weight/day or placebo (balanced crystalloid solution) from the operating room up to start of renal replacement therapy (RRT), or ICU discharge, or 72 h after the first dose. The primary outcome is the incidence of AKI during hospital stay defined by KDIGO (Kidney Disease: Improving Global Outcomes). Secondary outcomes include the need for, and duration of, RRT, mechanical ventilation; ICU and hospital length of stay; all-cause mortality at ICU, hospital discharge, 30, 90, and 180 days after randomization; quality of life at 180 days. Data will be analyzed in 3500 patients on an intention-to-treat basis. DISCUSSION: The trial is ongoing and currently recruiting. It will be one of the first randomized controlled studies to assess the relationship between amino acids use and kidney injury in cardiac surgery. If our hypothesis is confirmed, this practice could reduce morbidity in the studied population. STUDY REGISTRATION: This trial was registered on ClinicalTrials.gov with the trial identification NCT03709264 in October 2018.
Subject(s)
Acute Kidney Injury , Cardiac Surgical Procedures , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Acute Kidney Injury/prevention & control , Adult , Amino Acids , Clinical Trials, Phase III as Topic , Crystalloid Solutions , Humans , Kidney , Multicenter Studies as Topic , Quality of Life , Randomized Controlled Trials as TopicABSTRACT
OBJECTIVE: Meropenem is a ß-lactam, carbapenem antibacterial agent with antimicrobial activity against gram-negative, gram-positive and anaerobic micro-organisms and is important in the empirical treatment of serious infections in Intensive Care Unit (ICU) patients. Multi-drug resistant gram-negative organisms, coupled with scarcity of new antibiotic classes, forced healthcare community to optimize the therapeutic potential of available antibiotics. Our aim is to investigate the effect of continuous infusion of meropenem against bolus administration, as indicated by a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens in a population of ICU patients. DESIGN: Double blind, double dummy, multicenter randomized controlled trial (1:1 allocation ratio). SETTING: Tertiary and University hospitals. INTERVENTIONS: 600 ICU patients with sepsis or septic shock, needing by clinical judgment antibiotic therapy with meropenem, will be randomized to receive a continuous infusion of meropenem 3â¯g/24â¯h or an equal dose divided into three daily boluses (i.e. 1g q8h). MEASUREMENTS: The primary endpoint will be a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens. Secondary endpoints will be death from any cause at day 90, antibiotic-free days at day 28, ICU-free days at day 28, cumulative SOFA-free (Sequential Organ Failure Assessment) score from randomization to day 28 and the two, separate, components of the primary endpoint. We expect a primary outcome reduction from 52 to 40% in the continuous infusion group. CONCLUSIONS: The trial will provide evidence for choosing intermittent or continuous infusion of meropenem for critically ill patients with multi-drug resistant gram-negative infections.
Subject(s)
Critical Illness , Sepsis , Anti-Bacterial Agents/therapeutic use , Critical Care , Humans , Meropenem , Sepsis/drug therapyABSTRACT
BACKGROUND: Bleeding and transfusions affect mortality in aortic surgery. Although tranexamic acid significantly reduced bleeding in multiple settings, its role in major vascular surgery was never studied. The aim of this study was to determine if tranexamic acid reduces blood loss in open abdominal aortic aneurysm (AAA) surgery. METHODS: A total of 100 patients undergoing elective open AAA repair were randomised to receive tranexamic acid (a loading dose of 500 mg and a continuous infusion of 250 mg h-1) or placebo. The primary outcome was intraoperative blood loss, and the secondary outcomes were the number of patients receiving red blood cells, occurrence of thromboembolic events, and mortality. Data were analysed using the intention-to-treat principle. RESULTS: Fifty patients were randomised into each group. Median (inter-quartile range) intraoperative blood loss was 400 (300-1050) ml in the tranexamic acid group vs 500 (360-1000) ml in the placebo group (P=0.44). Transfusion rate was seven/50 (14%) in the tranexamic group vs 12/50 (24%) in the placebo group (P=0.20). No thrombosis was recorded. In a post hoc analysis, postoperative blood loss was reduced in the tranexamic group both at 4 h (60 [40-80] ml vs 100 [60-140] ml, P<0.001) and 24 h (180 [120-275] vs 275 [190-395] ml, P=0.003) after surgery. At 1 yr, three patients were dead, all in the placebo group (P=0.24) and all after 28 days. CONCLUSIONS: Tranexamic acid did not reduce intraoperative blood loss or blood transfusions in open AAA repair, although it may reduce postoperative blood loss without increasing adverse effects. CLINICAL TRIAL REGISTRATION: NCT02335359.
Subject(s)
Antifibrinolytic Agents/therapeutic use , Aortic Aneurysm/surgery , Blood Loss, Surgical/prevention & control , Cardiac Surgical Procedures/methods , Tranexamic Acid/therapeutic use , Aged , Antifibrinolytic Agents/adverse effects , Aortic Aneurysm/mortality , Blood Loss, Surgical/statistics & numerical data , Blood Transfusion/statistics & numerical data , Cardiac Surgical Procedures/mortality , Double-Blind Method , Erythrocyte Transfusion , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Thromboembolism/epidemiology , Thromboembolism/prevention & control , Tranexamic Acid/adverse effectsABSTRACT
OBJECTIVE: Few randomized trials have evaluated the use of non-invasive ventilation (NIV) for early acute respiratory failure (ARF) in non-intensive care unit (ICU) wards. The aim of this study is to test the hypothesis that early NIV for mild-moderate ARF in non-ICU wards can prevent development of severe ARF. DESIGN: Pragmatic, parallel group, randomized, controlled, multicenter trial. SETTING: Non-intensive care wards of tertiary centers. PATIENTS: Non-ICU ward patients with mild to moderate ARF without an established indication for NIV. INTERVENTIONS: Patients will be randomized to receive or not receive NIV in addition to best available care. MEASUREMENTS AND MAIN RESULTS: We will enroll 520 patients, 260 in each group. The primary endpoint of the study will be the development of severe ARF. Secondary endpoints will be 28-day mortality, length of hospital stay, safety of NIV in non-ICU environments, and a composite endpoint of all in-hospital respiratory complications. CONCLUSIONS: This trial will help determine whether the early use of NIV in non-ICU wards can prevent progression from mild-moderate ARF to severe ARF.
Subject(s)
Noninvasive Ventilation/methods , Respiratory Insufficiency/therapy , Acute Disease , Adolescent , Adult , Age Factors , Aged , Comorbidity , Disease Progression , Female , Hospital Mortality , Humans , Length of Stay , Male , Middle Aged , Research Design , Sex Factors , Tertiary Care Centers , Young AdultABSTRACT
PURPOSE: This study was done to investigate the correlation between the apparent diffusion coefficient (ADC) and prognostic factors of breast cancer. MATERIALS AND METHODS: From January 2008 to June 2011, all consecutive patients with breast cancer who underwent breast magnetic resonance imaging (MRI) and subsequent surgery in our hospital were enrolled in our study. The MRI protocol included a diffusion-weighted imaging sequence with b values of 0 and 1,000 s/mm(2). For each target lesion in the breast, the ADC value was compared with regard to major prognostic factors: histology, tumour grade, tumour size, lymph node status, and age. RESULTS: A total of 289 patients with a mean age of 53.49 years were included in the study. The mean ADC value of malignant lesions was 1.02 × 10(-3) mm(2)/s. In situ carcinomas, grade 1 lesions, and tumours without lymph nodal involvement had mean ADC values that were significantly higher than those of invasive carcinomas (p = 0.009), grade 2/3 lesions (p < 0.001), and tumours with nodal metastases (p = 0.001). No significant differences were observed in ADC values among tumours of different sizes or among patient age groups. CONCLUSIONS: ADC values appear to correlate with tumour grade and some major prognostic factors.
Subject(s)
Breast Neoplasms/pathology , Carcinoma in Situ/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/pathology , Diffusion Magnetic Resonance Imaging , Adult , Aged , Aged, 80 and over , Algorithms , Breast Neoplasms/surgery , Carcinoma in Situ/surgery , Carcinoma, Ductal, Breast/surgery , Carcinoma, Lobular/surgery , Diffusion Magnetic Resonance Imaging/methods , Female , Humans , Image Enhancement/methods , Image Interpretation, Computer-Assisted , Magnetic Resonance Imaging/methods , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Predictive Value of Tests , Prognosis , Reproducibility of Results , Retrospective Studies , Sensitivity and SpecificityABSTRACT
Patents are clearly one of the main drivers of innovation in pharmaceutical and medical R&D. It is increasingly important for researchers at the sharp end to be familiar with the ins and outs of the patenting process. In this feature a panel of experts from academia and industry discuss their experiences of analyzing the patent landscape and preparing applications. Interview conducted by Gino D'Oca, Managing Commissioning Editor.
Subject(s)
Drug Industry/legislation & jurisprudence , Intellectual Property , Patents as Topic/legislation & jurisprudence , Humans , Research/legislation & jurisprudenceABSTRACT
According to the ß-amyloid (Aß) hypothesis, compounds that inhibit or modulate γ secretase, the pivotal enzyme that generates Aß, are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aß concentrations. However, scanty data are available on the effects of these compounds on brain Aß deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT). γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen and skin in experimental animals and in man. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate γ secretase shifting its cleavage activity from longer to shorter ß-amyloid species without affecting Notch cleavage. Long-term histopathological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on Aß brain pathology and learning depend on their activity on γ-secretase or on other biological targets. The most studied γ-secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of Aß in the cerebrospinal fluid of healthy humans. Unfortunately, two large Phase 3 clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared to those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aß (the carboxy-terminal fragment of APP, or CTFß) resulting from the block of the γ-secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R flurbiprofen), a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notch-sparing γ-secretase inhibitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Animals , Drug Discovery , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/toxicity , HumansSubject(s)
Chemistry, Pharmaceutical , Drug Discovery , Chemistry, Pharmaceutical/instrumentation , Chemistry, Pharmaceutical/methods , Humans , Microwaves , Molecular Structure , Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/chemistry , Polymers/chemistry , Small Molecule LibrariesABSTRACT
Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.
Subject(s)
Imidazolidines/chemical synthesis , Receptor, Muscarinic M3/antagonists & inhibitors , Administration, Oral , Animals , Atrial Function/drug effects , CHO Cells , Caco-2 Cells , Cell Membrane Permeability , Cricetinae , Cricetulus , Female , Humans , Imidazolidines/chemistry , Imidazolidines/pharmacology , In Vitro Techniques , Male , Mice , Microsomes/metabolism , Models, Molecular , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Radioligand Assay , Rats , Receptor, Muscarinic M2/antagonists & inhibitors , Structure-Activity Relationship , Urinary Bladder/drug effects , Urinary Bladder/physiologyABSTRACT
Synthesis and biological activity of a novel class of quaternary ammonium salt muscarinic M3 receptor antagonists, showing high selectivity versus the M2 receptor, are described. Selected compounds exhibited potent anticholinergic properties, in isolated guinea-pig trachea, and good functional selectivity for trachea over atria. In vivo, the same compounds potently inhibited acetylcholine-induced bronchoconstriction after intratracheal administration in the guinea pig.
Subject(s)
Bronchodilator Agents/chemistry , Imidazolidines/chemical synthesis , Quaternary Ammonium Compounds/chemical synthesis , Receptor, Muscarinic M3/antagonists & inhibitors , Animals , Bronchoconstriction/drug effects , Bronchodilator Agents/chemical synthesis , Bronchodilator Agents/pharmacology , CHO Cells , Cricetinae , Cricetulus , Guinea Pigs , Humans , Imidazolidines/chemistry , Imidazolidines/pharmacology , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Myocardial Contraction/drug effects , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/pharmacology , Radioligand Assay , Structure-Activity Relationship , Trachea/drug effects , Trachea/physiologyABSTRACT
(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 K(i) = 0.33 nM), selectivity versus mu-(174-fold), delta-(6391-fold), and kappa (486-fold)-opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED(50) = 0.69 mg/kg, 95% confidence limit (CL) = 0.34-1.21]. SB-62111 administration can also reverse tolerance to morphine in this model, established via repeated morphine administration. In addition, intravenous SB-612111 can antagonize nociceptin-induced thermal hyperalgesia in a dose-dependent manner (ED(50) = 0.62 mg/kg i.v., 95% CL = 0.22-1.89) and is effective per se at reversing thermal hyperalgesia in the rat carrageenan inflammatory pain model. These data show that an ORL-1 receptor antagonist may be a useful adjunct to chronic pain therapy with opioids and can be used to treat conditions in which thermal hyperalgesia is a significant component of the pain response.
Subject(s)
Cycloheptanes/pharmacology , Drug Tolerance/physiology , Morphine/adverse effects , Narcotic Antagonists , Piperidines/pharmacology , Animals , Binding Sites , CHO Cells , Cricetinae , Cycloheptanes/therapeutic use , Humans , Morphine/therapeutic use , Pain/drug therapy , Piperidines/therapeutic use , Receptors, Opioid , Nociceptin ReceptorABSTRACT
This review describes the patent applications and relevant scientific literature published during 2002 in the field of novel neurokinin receptor antagonists, with an emphasis on the medicinal chemistry of recent patent publications. A brief update on the development status of compounds including: the neurokinin-1 receptor antagonists aprepitant (Merck & Co Inc), vofopitant, ezlopitant (Pfizer Inc), R-673 (F Hoffmann-La Roche Ltd); the neurokinin-2 receptor antagonists nepadutant (Menarini Ricerche SpA), saredutant (Sanofi-Synthelabo), SR-144190 (Sanofi-Synthelabo) and UK-290795 (Pfizer Inc); and the neurokinin-3 receptor antagonists osanetant (Sanofi-Synthelabo) and talnetant (GlaxoSmithKline plc) will be given. The review also reports the recent published patent literature in the area of novel therapeutic uses and novel formulations and combinations claimed for neurokinin receptor antagonists.
Subject(s)
Neurokinin-1 Receptor Antagonists , Receptors, Neurokinin-2/antagonists & inhibitors , Receptors, Neurokinin-3/antagonists & inhibitors , Animals , Chemistry, Pharmaceutical , Drug Combinations , Humans , Peptides/pharmacologyABSTRACT
Alkaloids extracted from the Papaverum somniferum are among the most powerfully acting and clinically used drugs for diseases of the central nervous system, in particular for pain. The basic ring system, common to these opiate alkaloids, is the morphinan skeleton, which in the last 50 years has been chemically manipulated to obtain compounds with improved potency and increased selectivity toward different populations of opioid receptors. Despite a huge amount of research, interest surrounding these compounds is still high. This review will discuss the patent applications published from January 2001 to June 2002, focusing on new chemical entities that could become drugs over the next few years, new chemical processes for the production of the morphinans currently used in therapy, novel formulations and combined compositions.
Subject(s)
Morphinans/chemistry , Patents as Topic , Ligands , Molecular Structure , Morphinans/pharmacology , Narcotic Antagonists , Receptors, Opioid/agonists , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, kappa/agonists , Nociceptin ReceptorABSTRACT
In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited (125)I-[MePhe(7)]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K(i) = 2.2 nM and antagonized competitively NKB-induced Ca(2+) mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K(b) = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA(2) = 8.1) and guinea pig ileal circular smooth muscles (pA(2) = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 (K(i) > 100,000 nM) and hNK-2 receptors (K(i) = 209 nM), and was without effect, at 1 microM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED(50) of 0.56 mg/kg). Intraperitoneal SB 235375 (10-30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3-30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system.