O2 consumption, aerobic glycolysis and tissue phosphagen content during activation of the Na+/K+ pump in rat portal vein

Oxygen consumption, lactate production and tissue contents of ATP, phosphocreatine (PCr) and lactate were measured following readdition of K+ to K+-depleted rat portal veins, in order to study the energy turnover associated with Na+/K+ pumping. During incubation in K+-free medium at 37 degrees C spontaneous contractions disappeared in 10-20 min. Readdition of K+ (5.9 mM) after 40 min K+-free incubation caused hyperpolarization of the cell membrane for the first 5-10 min and then gradual depolarization with return of spontaneous action potentials and contractions by 10-20 min. During the first 4-6 min after K+ readdition aerobic lactate production was about doubled and then gradually returned to the original level (0.17 mumol/min g) at about 20 min. The increase in glycolytic rate was prevented by 1 mM ouabain. In contrast, O2 consumption (in K+-free medium, 0.38 mumol/min g) rose by about 10% when K+ was added and this increase lasted about 5 min. By 8 min after K+ addition the increased glycolysis and oxidative phosphorylation had accounted for each about the same amount of extra ATP generation over that extrapolated from the steady rate before K+ addition. The average total increase in ATP turnover in the first 8 min was 15%. During this period there was no change in the cellular content of ATP, PCr, or extractable ADP. The results indicate that Na+/K+ pumping utilizes a relatively small share of the total energy turnover in the vascular smooth muscle but is to a large extent dependent on aerobic glycolysis and therefore a major site of carbohydrate usage

Local and systemic effects of inhaled AZD9164 compared with tiotropium in patients with COPD.

There is still a need for new agents which improve upon the therapeutic index of tiotropium, the current standard of care for many patients with chronic obstructive pulmonary disease (COPD). We examined in patients with COPD the efficacy of single doses of AZD9164, an M(3)-selective muscarinic antagonist, to identify an appropriate dose-range for future studies. COPD patients (n = 28) inhaled AZD9164 (100, 400 and 1200 μg), tiotropium (18 μg) and placebo at 5 study centre visits (Clinicaltrials.gov identifier NCT00939211). The effects of these test drugs on average (E(av)), peak (E(max)) and trough (E(22-26)) forced expiratory volume in one second (FEV(1)) were assessed, as were systemically-mediated effects and the safety and exposure of single doses of AZD9164. AZD9164 100, 400 and 1200 μg caused increases in FEV(1) to peak effects of 12, 17 and 12% above baseline respectively, following an initial transient and dose-related fall in FEV(1) and associated increase in mild respiratory symptoms such as cough. Bronchodilation was maintained overnight, with minimal FEV(1) decline. AZD9164 400 and 1200 μg produced larger effects than tiotropium on E(22-26) (p < 0.05; both doses) while AZD9164 400 μg also had larger effects on E(max) (p = 0.001) and E(av) (p < 0.05). There were no serious adverse events and statistically significant systemic effects were observed only with AZD9164 1200 μg. AZD9164 may improve upon the therapeutic index of tiotropium, increasing the magnitude and duration of lung function improvements without increasing systemically-mediated adverse events. The initial bronchoconstrictor effect of AZD9164 requires further investigation

Transient paradoxical bronchospasm associated with inhalation of the LAMA AZD9164: analysis of two Phase I, randomised, double-blind, placebo-controlled studies

BACKGROUND: AZD9164 has demonstrated potential as an inhaled, long-acting, muscarinic antagonist (LAMA) bronchodilator. However, in patients with COPD, but not in healthy subjects, a transient initial drop in FEV(1) was observed following inhalation of nebulised doses of AZD9164 in citrate buffer. Two additional studies were conducted to further assess the safety and tolerability of multiple ascending doses of AZD9164 in 27 white and 18 Japanese healthy subjects and in 4 patients with COPD. In these studies, AZD9164 was inhaled via Turbuhaler™. METHODS: These were Phase I, randomised, double-blind, placebo-controlled, multiple ascending dose (MAD) studies conducted in Sweden and UK. Healthy subjects (mean age 25.9 yrs) and patients with COPD (mean age 66 yrs, mean post-bronchodilator FEV(1) 60.1% predicted normal value) were randomised 2:1 to active treatment (400, 1000 or 2800 μg delivered doses of AZD9164) or placebo. RESULTS: No safety or tolerability concerns were identified in the healthy subjects at doses up to and including 2800 μg and both studies confirmed the bronchodilator effect of AZD9164. However, the first 3 patients in the COPD cohort who received AZD9164 (1000 μg) experienced a transient fall in FEV(1) 5 to 15 minutes after inhalation of AZD9164 while the patient receiving placebo did not. The study safety review process then resulted in cessation of further activities on AZD9164. Retrospective analysis showed that two healthy subjects had also had transient falls in FEV(1) shortly after inhalation of AZD9164 400 and 2800 μg respectively, although neither reported any related respiratory symptoms or other AEs. CONCLUSIONS: These results show that transient paradoxical bronchoconstriction can occur in some healthy subjects, in addition to patients with COPD, following inhalation of AZD9164 and that the citrate buffer used in the nebulised formulation cannot have been the only cause of the drop in FEV(1) in previous studies. As preclinical data do not provide an explanation, the reasons for this brief post-dose drop in FEV(1) remain unclear. However, these results highlight the importance of monitoring lung function immediately post-dose when investigating novel inhaled treatments, even when a rapid onset of effect is not expected. TRIAL REGISTRATION: Clinicaltrials.gov NCT01016951 and NCT01096563

Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting β2-adrenoreceptor agonist (uLABA).

The clinical pharmacokinetics of AZD3199, an ultra-long-acting β2-agonist, were investigated in healthy volunteers and patients with asthma or chronic obstructive pulmonary disease (COPD)

Safety and effectiveness of as-needed formoterol in asthma patients taking inhaled corticosteroid (ICS)-formoterol or ICS-salmeterol maintenance therapy

BACKGROUND: As-needed low-dose inhaled corticosteroid (ICS)-formoterol reliever is recommended in patients with asthma prescribed maintenance ICS-formoterol. Clinicians often ask whether ICS-formoterol reliever can be used with other maintenance ICS-long-acting b2-agonists.OBJECTIVE: To evaluate the safety and effectiveness of as needed formoterol in patients taking maintenance ICSformoterol or ICS-salmeterol from the RELIEF study.METHODS: RELIEF (SD-037-0699) was a 6-month, open-label study that randomized 18,124 patients with asthma to as-needed formoterol 4.5 mg or salbutamol 200 mg on top of maintenance therapy. This post hoc analysis included patients on maintenance ICS-formoterol or ICS-salmeterol (n = 5436). The primary safety outcome was a composite of serious adverse events (SAEs) and/or adverse events leading to discontinuation (DAEs); the primary effectiveness outcome was time-to -first exacerbation. RESULTS: For both maintenance groups and both relievers, similar numbers of patients had & DDAG;1 SAE and/or DAE. In patients taking maintenance ICS-salmeterol, but not ICS-formoterol, significantly more non-asthma-related and nonserious DAEs occurred with as-needed formoterol versus as-needed salbutamol (P = .0066 and P = .0034, respectively). In patients taking maintenance ICS-formoterol, there was a significantly lower risk in time-to -first exacerbation with as-needed formoterol versus as-needed salbutamol (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.70, 0.95; P = .007). In patients taking ICS-salmeterol maintenance, time-to -first exacerbation was not significantly different between treatment arms (HR: 0.95, 95% CI: 0.84, 1.06; P = .35).CONCLUSIONS: As-needed formoterol significantly reduced exacerbation risk compared with as-needed salbutamol when added to maintenance ICS-formoterol, but not to maintenance ICS-salmeterol. More DAEs were seen with ICS-salmeterol maintenance therapy plus as-needed formoterol. Further research is needed to assess whether this is relevant to as-needed combination ICS-formoterol.& COPY; 2023 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). (J Allergy Clin Immunol Pract 2023;11:2104-14

Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study

Trabalho final de mestrado integrado em Medicina, apresentado á Faculdade de Medicina da Universidade de CoimbraA Doença de Huntington é uma afecção neurodegenerativa de transmissão autossómica dominante. A mutação genética responsável por esta doença, identificada pela primeira vez em 1993, está localizada no braço curto do cromossoma quatro, sendo responsável pela síntese de uma proteína (huntingtina) mutada. A Doença de Huntington caracteriza-se pela presença de distúrbios motores, cognitivos e comportamentais. Actualmente a doença é diagnosticada quando surgem sintomas motores evidentes. Contudo, também é sabido que alterações cognitivas e comportamentais podem preceder (em anos) as perturbações motoras. Os indivíduos portadores da mutação genética que ainda não manifestam sintomatologia motora evidente são designados portadores “pré-sintomáticos”. É objectivo deste trabalho efectuar uma exaustiva revisão da literatura existente no que diz respeito às alterações comportamentais na Doença de Huntington e também analisar os estudos originais mais recentes que abordam a sintomatologia comportamental em doentes “pré-sintomáticos”. Concluímos que os sintomas comportamentais são componente importante do espectro clínico da Doença de Huntington. As alterações comportamentais podem preceder os sinais motores da doença e causam impacto substancial no funcionamento diário dos doentes. Uma melhor compreensão da vertente comportamental da Doença de Huntington, nomeadamente em fases “pré-sintomáticas” da doença, permitirá a futura realização de ensaios clínicos de terapêuticas neuroprotectorasHuntington's disease is an autosomal dominant, neurodegenerative disease. The genetic mutation responsible for this disease, first identified in 1993, is located on the short arm of chromosome four. This mutation is responsible for the synthesis of a mutated protein (huntingtin). Huntington’s disease is characterized by the presence of motor disorders, cognitive and behavioral changes. Currently, the disease is diagnosed when evident motor symptoms arise. However, it is also known that the cognitive and behavioral changes may precede (in years) the motor disturbances. Individuals carrying the genetic mutation who do not manifest motor symptoms are called "pre-symptomatic" carriers. The objective of this article is to provide a comprehensive literature review concerning behavioral changes in Huntington’s Disease and also to examine the most recent original research that address behavioral symptoms in “pre-symptomatic” patients. We conclude that behavioral symptoms are important constituents of the clinical spectrum of Huntington’s disease. Behavioral changes may precede motor signs of the disease and cause substantial impact on daily functioning. A further understanding of behavioral aspects, especially in "pre-symptomatic" stages of the disease, will facilitate and improve future neuroprotection trial