ABSTRACT
BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.
Subject(s)
Tuberculosis , Humans , Biological Specimen Banks , Tuberculosis/drug therapy , Clinical Trials as TopicABSTRACT
The drug-resistant tuberculosis (DR-TB) cascade-from estimated or incident cases to numbers successfully treated or disease-free survival-has long been characterised by sharp declines at each step in the cascade. The losses along the cascade vary across different settings, and the reasons why some countries have a higher burden of DR-TB are complex and multifactorial; broadly, weak health systems, inadequate financing and poverty all impact differential access to DR-TB care. Within a human rights framework that mandates the right to health and the right to benefit from scientific progress, the aim of this review is to focus on describing inequities in access to DR-TB care at critical points in the cascade.
Subject(s)
Global Health , Health Services Accessibility , Tuberculosis, Multidrug-Resistant/therapy , Antitubercular Agents/administration & dosage , Delivery of Health Care/economics , Delivery of Health Care/statistics & numerical data , Healthcare Disparities/statistics & numerical data , Humans , Poverty , Right to Health , Tuberculosis, Multidrug-Resistant/diagnosis , Tuberculosis, Multidrug-Resistant/epidemiologyABSTRACT
The international community has committed to end the tuberculosis (TB) epidemic by 2030. To facilitate the meeting of the global incidence and mortality indicators set by the World Health Organization's End TB Strategy, the Stop TB Partnership launched the three 90-(90)-90 diagnostic and treatment targets in 2014. In this paper, we argue that a 'fourth 90'-Ensuring that 90% of all people successfully completing treatment for TB can have a good health-related quality of life'-should be considered. Many individuals who successfully complete anti-TB treatment are burdened with lifelong comorbidities-human immunodeficiency virus (HIV) and diabetes mellitus, obstructive and restrictive lung disease, involving lung destruction, cavitation, fibrosis and bronchiectasis, that either pre-existed or developed as a result of TB (e.g., chronic pulmonary aspergillosis), permanent disabilities such as hearing loss resulting from second-line anti-TB drugs, and mental health disorders. These need to be identified during TB treatment and appropriate care and support provided after anti-TB treatment is successfully completed. A 'fourth 90' has also been proposed for the UNAIDS 90-90-90 targets similar in scope to what is being suggested here for TB. Adoption by both HIV and TB control programmes would highlight the current focus on integrated person- and family-centred services.
Subject(s)
Health Promotion , Tuberculosis, Pulmonary/epidemiology , Global Health , Humans , Tuberculosis, Pulmonary/prevention & controlABSTRACT
SETTING: The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens. DESIGN: A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use. RESULTS: A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them. CONCLUSION: While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.
Subject(s)
Antitubercular Agents/therapeutic use , Diarylquinolines/therapeutic use , Nitroimidazoles/therapeutic use , Oxazoles/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapy , Antitubercular Agents/supply & distribution , Diarylquinolines/supply & distribution , Humans , Internationality , Nitroimidazoles/supply & distribution , Oxazoles/supply & distributionSubject(s)
COVID-19 , Coinfection , Tuberculosis , Humans , Risk Factors , SARS-CoV-2 , Treatment Outcome , Tuberculosis/drug therapy , Tuberculosis/epidemiologyABSTRACT
The large and growing access gap between the number of children who become sick with drug-resistant tuberculosis (DR-TB) and those who are treated for the disease each year represents a significant health systems failure. While there are multiple reasons why children with DR-TB are not diagnosed and treated, a serious challenge is the medications used to treat the disease. This paper presents three child DR-TB cases who were treated incorrectly; the cases are used to illustrate some of the problems with existing second-line medications. Challenges, including the perception that the drugs are more dangerous than the disease, lack of proper dosing recommendations and formulations, and the high cost of current treatment, all contribute to a perverse situation in which the most vulnerable pediatric patients are provided with a lower standard of care. This situation can be reversed with novel partnerships and training models, pharmacokinetic studies of the relevant drugs, increased collaboration, and dedicated funding, grounded in a rights-based approach to DR-TB in children.
Subject(s)
Antitubercular Agents/administration & dosage , Tuberculosis, Multidrug-Resistant/drug therapy , Child, Preschool , Female , Humans , Male , Mycobacterium tuberculosis/drug effects , Treatment FailureABSTRACT
The relationship between ambulatory intra-arterial blood pressure and left ventricular ejection fraction was examined in a group of 23 untreated hypertensive subjects who underwent concurrent radionuclide ventriculography. All patients had a normal ejection fraction at rest (range, 50-80%), and no significant correlation was found between blood pressure and resting ejection fraction. Sixty-one percent of patients failed to increase their ejection fraction by 5% on exercise; the mean daytime systolic pressure (168 +/- 15 mm Hg) was lower in this group than in those who had a normal exercise response (188 +/- 17 mm Hg; p less than 0.005). Thirty percent of patients had left ventricular hypertrophy based on electrocardiographic criteria; this group had a higher mean blood pressure (189 +/- 20 mm Hg) than the remainder (170 +/- 15 mm Hg; p less than 0.05). A closer correlation was demonstrated between blood pressure and ejection fraction response to exercise in the group with left ventricular hypertrophy (r = 0.8) than in the group without hypertrophy (r = 0.3). These results failed to demonstrate a linear relationship between blood pressure and ejection fraction. However, a relationship between the height of blood pressure and the development of left ventricular hypertrophy was shown, and myocardial response to exercise was increased in patients with left ventricular hypertrophy.
Subject(s)
Blood Pressure , Heart/physiopathology , Hypertension/physiopathology , Aged , Circadian Rhythm , Female , Humans , Hypertension/diagnostic imaging , Male , Middle Aged , Monitoring, Physiologic , Posture , Radionuclide Angiography , Stroke VolumeABSTRACT
Ambulatory intra-arterial blood pressure was monitored in 15 obese hypertensive and 10 obese normotensive subjects weighing more than 30% of their ideal body weight. Measurements were taken before and after 1 month in hospital on a diet of 330kCal/day designed to ensure 34 g protein and 65 mmol sodium. Mean +/- s.d. body mass index in the whole group fell from 40.8 +/- 7.6 to 37.2 +/- 7.4 kg/m2 (P less than 0.0001). Daytime intra-arterial blood pressure fell from 176 +/- 19/102 +/- 14 to 162 +/- 16/95 +/- 14 mmHg (P less than 0.0005 and P less than 0.002) in the hypertensive group and from 141 +/- 15/82 +/- 5 to 131 +/- 13/79 +/- 4 mmHg (P less than 0.005 for systolic pressure) in the normotensive group. Circadian variation of systolic intra-arterial blood pressure comparing the mean daytime with the mean night-time blood pressure recordings showed a day-night difference of 27 +/- 10 mmHg in the normotensive group compared with 12 +/- 13 mmHg in the hypertensive group (P less than 0.01). This trend was reversed after weight loss, when the normotensive group showed a day-night difference of 20 +/- 13 mmHg compared with 18 +/- 17 mmHg in the hypertensive group. Thus, circadian variation of systolic intra-arterial blood pressure in the hypertensive group was significantly (P less than 0.01) reduced compared with the normotensive group prior to, but not after, weight loss. These data show that, in obese subjects, weight loss produced a significant reduction in ambulatory intra-arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Blood Pressure/physiology , Circadian Rhythm/physiology , Obesity/diet therapy , Obesity/physiopathology , Weight Loss/physiology , Adult , Aged , Body Mass Index , Diet, Reducing , Diet, Sodium-Restricted , Electrocardiography, Ambulatory , Female , Heart Rate/physiology , Humans , Hypertension/complications , Hypertension/physiopathology , Male , Middle Aged , Obesity/complicationsABSTRACT
The efficacy of the new once-daily dihydropyridine calcium antagonist, lacidipine, in reducing ambulatory intraarterial blood pressure (BP) was examined in 12 untreated hypertensive patients. The intraarterial recording was commenced 24 hours before the first 4-mg dose and was continued for a further 24 hours thereafter. After dose titration and chronic therapy, a second 24-hour ambulatory BP recording was made. There was a steady onset of drug action, maximal at 2 hours, but with reflex tachycardia after the first dose. Chronic administration reduced BP throughout the 24-hour period, without tachycardia. Mean daytime reduction in BP was 20 mm Hg systolic (p less than 0.005) and 12 mm Hg diastolic (p less than 0.02). Mean nighttime reduction was 8-mm Hg systolic (p less than 0.05) and 6-mm Hg diastolic (difference not significant). There was no postural decrease in BP on 60 degrees head-up tilting and hypotensive action was maintained during isometric exercise (reduction at peak of 32/18 mm Hg, p less than 0.05) and throughout dynamic exercise (reduction at peak of 23/14 mm Hg, p less than 0.05). Lacidipine is an effective once-daily antihypertensive agent, with good control of stress response.
Subject(s)
Calcium Channel Blockers/therapeutic use , Dihydropyridines/therapeutic use , Hypertension/drug therapy , Blood Pressure/drug effects , Blood Pressure Determination , Blood Pressure Monitors , Calcium Channel Blockers/administration & dosage , Dihydropyridines/administration & dosage , Drug Administration Schedule , Exercise Test , Female , Heart Rate/drug effects , Humans , Male , Middle AgedABSTRACT
The reduction in blood pressure (BP) after the first dose and after 8 weeks of treatment with a new once-daily angiotensin converting enzyme (ACE) inhibitor, ramipril, was examined in 12 untreated hypertensive patients, using ambulatory intraarterial BP monitoring. The first period of monitoring began 24 hours before the first dose was given, and continued for 24 hours afterwards. A second 24-hour period of monitoring was carried out after 8 weeks of treatment, commencing immediately after the morning dose. Angiotensin II levels and serum drug levels were measured at 0, 2, 6 and 24 hours after the acute dose. BP decreased progressively from the first hour after the first dose, reached a maximum in the fifth hour (p less than 0.001) and then the effect diminished. The maximum reduction of systolic BP in any patient was 64 mm Hg, the minimum 4 mm Hg. Blood pressure was significantly (p less than 0.05) reduced throughout the 24 hours after dosing, with a mean daytime reduction of 13/12 mm Hg, and a mean nighttime reduction of 15/7 mm Hg. Angiotensin II levels were significantly (p less than 0.02) and maximally reduced by 2 hours after administration, but the reduction was no longer significant after 24 hours. Serum drug levels were also maximal 2 hours after administration. The trial population could be clearly divided into groups of good and poor responders on the basis of BP reduction. The angiotensin II levels were higher before treatment, and decreased further, in all patients with a good response than in those with a poor response.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Bridged Bicyclo Compounds/therapeutic use , Bridged-Ring Compounds/therapeutic use , Hypertension/drug therapy , Adult , Aged , Angiotensin II/blood , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Blood Pressure/drug effects , Blood Pressure Determination/methods , Bridged Bicyclo Compounds/administration & dosage , Clinical Trials as Topic , Female , Humans , Male , Middle Aged , Monitoring, Physiologic , Ramipril , Time FactorsABSTRACT
Twenty-four-hour profiles of intraarterial ambulatory blood pressure (BP) and heart rate were significantly reduced by administration of carvedilol, a new beta-blocking drug with vasodilating properties. Twelve patients were given carvedilol, 25 mg twice daily for 2 weeks; the dose was then increased to 50 mg twice daily if the target BP was not achieved. After 4 weeks of therapy, mean daytime reduction in BP was 25 +/- 3 mm Hg systolic and 19 +/- 3 mm Hg diastolic and mean reduction in heart rate was 22 +/- 3 beats/min. BP at the peak of isometric exercise and during dynamic exercise was also significantly reduced. Radionuclide measurements showed that left ventricular ejection fraction was not affected by treatment, but there was a significant reduction in systolic and diastolic volumes. The drug was well tolerated. This clinical trial suggests that carvedilol will be a useful first-line drug for treatment of essential hypertension, and its vasodilating action may have a more favorable effect on left ventricular function than conventional beta-blocking drugs.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Carbazoles/therapeutic use , Hypertension/drug therapy , Propanolamines , Blood Pressure/drug effects , Carvedilol , Clinical Trials as Topic , Depression, Chemical , Female , Heart/diagnostic imaging , Heart Rate/drug effects , Humans , Male , Middle Aged , Myocardial Contraction/drug effects , Physical Exertion , Radionuclide Imaging , Stroke Volume/drug effects , Time FactorsABSTRACT
Ioversol 320, a new nonionic iodinated contrast medium, was injected intravenously into 24 healthy male volunteers using saline as a control. Physical examination, vital signs, electrocardiogram, biochemical and hematological data were recorded before and at intervals after injection. No significant changes were observed. Seventeen volunteers reported no side effects; six volunteers had mild transitory symptoms considered to be related to the contrast medium. The authors conclude that broader clinical trials can be safely conducted to determine safety and tolerability of ioversol.
Subject(s)
Contrast Media/pharmacology , Iodobenzoates/pharmacology , Triiodobenzoic Acids/pharmacology , Adult , Blood Chemical Analysis , Blood Pressure/drug effects , Contrast Media/administration & dosage , Contrast Media/adverse effects , Contrast Media/pharmacokinetics , Drug Evaluation , Electrocardiography/drug effects , Humans , Male , Random Allocation , Safety , Single-Blind Method , Triiodobenzoic Acids/administration & dosage , Triiodobenzoic Acids/adverse effects , Triiodobenzoic Acids/pharmacokineticsABSTRACT
Previous observations have suggested that pulmonary artery pressure rises during sleep, whereas systemic artery pressure falls. A system has been developed for careful and accurate recording of pulmonary arterial pressure, and applied it to two groups of subjects: patients with heart failure, and patients with chronic stable angina. The results have largely confirmed the nocturnal pressure rise in pulmonary arterial pressure. Detailed analysis strongly suggests that the same physiological mechanisms producing a fall in systemic pressure are responsible for the rise in pulmonary pressure. The precise mechanism remains to be elucidated.
ABSTRACT
Amlodipine is a dihydropyridine calcium antagonist with a long elimination half life making it suitable for once-daily dosing. This study used sphygmomanometric and intra-arterial ambulatory blood pressure (BP) monitoring to confirm the antihypertensive effect of a once-daily dose of amlodipine over the dosing interval. After a 2-week single-blind placebo run in, amlodipine was administered to 11 patients at a starting dose of 5 mg daily for 2 weeks increasing to 10 mg daily for a further 4 weeks if diastolic blood pressure (DBP) measured sphygmomanometrically was not < 90 mmHg or decreased by > 10 mmHg from baseline values. Intra-arterial blood pressure recordings for 24-hour periods were made at the end of the placebo run in and on completion of the active treatment phase. The effects of isometric and dynamic exercise and head-up tilting (60 degrees) on BP and heart rate were measured during ambulatory monitoring. Mean supine cuff BP was 169/104 mmHg (n = 11) at the end of the placebo treatment period and was reduced to 153/95 mmHg (n = 11) after 2 weeks of amlodipine treatment and 146/92 mmHg (n = 11) after 6 weeks of amlodipine treatment. There was no significant change in heart rate. Intra-arterial ambulatory monitoring showed that BP was controlled for the whole dosing interval with once-daily doses of amlodipine. The normal circadian pattern of BP changes was not altered. BP was reduced by amlodipine during exercise and physiological tests, but there was no postural hypotension and the BP and heart rate responses to exercise were not blunted.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Amlodipine/therapeutic use , Antihypertensive Agents/therapeutic use , Blood Pressure Monitors , Hypertension/drug therapy , Amlodipine/administration & dosage , Amlodipine/adverse effects , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Blood Pressure/drug effects , Blood Pressure/physiology , Blood Pressure Determination/instrumentation , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Single-Blind Method , Time FactorsABSTRACT
Five studies were conducted to examine the degree of variability to be expected during the use of the non-imaging nuclear probe (BIOS Inc.) under a variety of clinical conditions. Comparison of the ejection fraction (EF) readings between the nuclear probe and a gamma camera showed good agreement, with the nuclear probe tending to underestimate lower, and overestimate higher camera EF values [mean (S.D.) difference, 0.84% (6.06)]. A comparison of two nuclear probes showed a small mean (S.D.) difference of EF readings of 0.063% (2.26). EF readings obtained in normal subjects 6 weeks apart were reproducible and differed by a mean (S.D.) of 0.23% (4.42). The administration of placebo to 10 normal subjects followed by sequential measurements for 4 h produced EF changes large enough to mimic a clinical effect, the largest hourly change observed being 5.4%, indicating the need for strict placebo control in interventional experiments. Data on four patients with heart failure showed small non-significant EF changes in the 1 h after placebo administration but a wide intra-subject range of ejection time and time to peak filling measurements. This highlights the problem of accurate, reproducible cursor placement in such patients. The nuclear probe is a portable, low cost instrument which produces accurate EF measurements when compared with the gamma camera.