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Expert Opinion on Drug Safety Oct 2016To explore the usefulness of number needed to treat to be harmed (NNTH), in benefit-risk assessments, by studying the agreement between NNTH values and withdrawals of... (Meta-Analysis)
Meta-Analysis
Testing the usefulness of the number needed to treat to be harmed (NNTH) in benefit-risk evaluations: case study with medicines withdrawn from the European market due to safety reasons.
OBJECTIVE
To explore the usefulness of number needed to treat to be harmed (NNTH), in benefit-risk assessments, by studying the agreement between NNTH values and withdrawals of medicines from European market due to safety reasons.
METHODS
Medicines with data from longitudinal studies were included. Studies were identified from European Medicines Agency's Reports. Meta-analyses were performed to pool odds ratios (OR) with 95% confidence-intervals (CI). Published control event rates were applied to ORs to calculate NNTHs (95%CI) for selected adverse events.
RESULTS
NNTH (95%CI) decreased from pre- to post-marketing for the eight medicines included: peripheral neuropathy (∞ vs. 12[non-significant; NS] with almitrine; heart valve disease with benfluorex (∞ vs. NNTH ranging from 7[4-13] to 7[5-9]); myopathy (-4096[NS] vs. 797[421-1690]), new-onset diabetes (113[NS] vs. 390[425-778]), bleeding (∞ vs. 517[317-1153]), and infection (∞ vs. 253[164-463]) with niacin-laropiprant; psychiatric disorders (12[7-34] vs. 9[5-24]) with rimonabant; myocardial infarction (MI) [-1305 vs. 270[89-4362]) with rofecoxib; MI (-510 vs. NNTH ranging from 152[55-4003] to 568[344-1350]) with rosiglitazone; cardiovascular events (∞ vs. 245[129-1318]) with sibutramine; and liver injury (∞ vs. 5957[NS]) with ximelagatran.
CONCLUSION
NNTH have potential of use as a supportive tool in benefit-risk re-evaluations of medicines and may help regulators to making decisions on drug safety.
Topics: Adverse Drug Reaction Reporting Systems; Drug-Related Side Effects and Adverse Reactions; Europe; Humans; Numbers Needed To Treat; Product Surveillance, Postmarketing; Risk Assessment; Safety-Based Drug Withdrawals
PubMed: 27467204
DOI: 10.1080/14740338.2016.1217989 -
Minerva Anestesiologica May 2014Lung ultrasound can be used at bedside to assess initial lung morphology in hypoxemic patients. We hypothesized that blood flow in consolidated lung and therefore...
BACKGROUND
Lung ultrasound can be used at bedside to assess initial lung morphology in hypoxemic patients. We hypothesized that blood flow in consolidated lung and therefore effects of inhaled nitric oxide (iNO) and intravenous almitrine could be directly assessed using Doppler transesophageal echocardiography (TEE).
METHODS
We conducted a prospective study including 13 ALI patients with consolidated left lower lobe (LLL). Regional arterial and venous flow signals within the consolidation were recorded with TEE using Doppler at baseline, after iNO (5 ppm), almitrine (4 μg/kg/min) and their combination. Pulmonary shunt (Qs/Qt) was measured using a Swan-Ganz catheter. Arterial and venous velocity time integral (VTI), peak velocity (Vmax) and mean velocity (Vmean) were measured. Patients were responders if PaO2 basal value increased by 20% after iNO or almitrine.
RESULTS
In 7 NO responders, iNO decreased regional arterial VTI (8.1±1.9 vs. 6.7±1.6, P<0.05). In 8 almitrine responders, almitrine decreased regional arterial and venous VTI (from 6.7±2.0 to 4.5±2.3 cm and from 12.3±5.4 to 7.5±3.8 cm, respectively, P<0.05). For all patients, combination of iNO and almitrine decreased regional arterial and venous VTI (from 7.3±0.3 to 4.1±0.3 cm and from 12.6±0.7 to 6.7±0.8 cm, respectively, P<0.05). Arterial and venous Vmean and Vmax significantly decreased. Variations of arterial VTI and venous Vmean were correlated to variations of Qs/Qt (r=.71, P<.001 and r=.62, P<.01, respectively).
CONCLUSION
Doppler of consolidated LLL allows assessment of regional pulmonary circulation in ICU settings. It detects changes in flow profiles resulting from the administration of NO and/or almitrine. Further applicability remains to be determined.
Topics: Acute Lung Injury; Administration, Inhalation; Aged; Almitrine; Bronchodilator Agents; Echocardiography, Transesophageal; Female; Humans; Injections, Intravenous; Male; Middle Aged; Nitric Oxide; Pulmonary Circulation; Respiratory Distress Syndrome; Respiratory System Agents
PubMed: 24299918
DOI: No ID Found -
Minerva Anestesiologica May 2014
Topics: Acute Lung Injury; Almitrine; Bronchodilator Agents; Female; Humans; Male; Nitric Oxide; Pulmonary Circulation; Respiratory System Agents
PubMed: 24280828
DOI: No ID Found -
Journal of Cardiothoracic and Vascular... Aug 2014Almitrine enhances hypoxic pulmonary vasoconstriction (HPV) and can improve hypoxemia related to one-lung ventilation (OLV). Studies using almitrine have been conducted... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Almitrine enhances hypoxic pulmonary vasoconstriction (HPV) and can improve hypoxemia related to one-lung ventilation (OLV). Studies using almitrine have been conducted without inhaled anesthetics because they could inhibit HPV, counteracting the effect of almitrine. This hypothesis, however, has not been confirmed. This study's aim was to evaluate whether almitrine could improve oxygenation when administered during OLV with sevoflurane anesthesia.
DESIGN
A prospective, randomized, double-blind, placebo-controlled trial.
SETTING
A tertiary care, university teaching hospital.
PARTICIPANTS
Thirty adult patients undergoing open-chest thoracic surgery.
INTERVENTIONS
Patients were assigned randomly to receive almitrine or placebo during OLV. Respiratory and hemodynamic variables were recorded continuously. Anesthesia was maintained with sevoflurane and remifentanil. Intraoperative techniques and medical teams were the same all over the study.
MEASUREMENTS AND MAIN RESULTS
Respiratory and hemodynamic variables were measured during two-lung ventilation and during open-chest OLV. Two-way repeated-measures analysis of variance was used to compare the effects of almitrine and placebo. During OLV, PaO2 and shunt fraction worsened in all patients without significant differences between groups. At 30-minutes of OLV, PaO2 was 184±67 mmHg in the almitrine group and 145±56 mmHg in the placebo group, while shunt fraction were 31%±6% and 36%±13%, respectively. Mean pulmonary artery pressure was higher in the almitrine group (31±5 v 24±5 mmHg, p<0.001).
CONCLUSIONS
During anesthesia with sevoflurane for open-chest OLV, almitrine failed to improve oxygenation and increased pulmonary artery pressure. The combination of sevoflurane and almitrine should, therefore, be avoided.
Topics: Adolescent; Adult; Aged; Almitrine; Anesthesia, General; Anesthetics, Inhalation; Blood Gas Analysis; Double-Blind Method; Female; Hemodynamics; Humans; Hypoxia; Lung; Male; Methyl Ethers; Middle Aged; Monitoring, Intraoperative; One-Lung Ventilation; Oxygen Consumption; Prospective Studies; Respiratory System Agents; Sevoflurane; Thoracic Surgical Procedures; Young Adult
PubMed: 24016684
DOI: 10.1053/j.jvca.2013.03.019 -
Respiratory Physiology & Neurobiology Nov 2013Drug-induced respiratory depression (DIRD) is a common problem encountered post-operatively and can persist for days after surgery. It is not always possible to predict... (Review)
Review
Drug-induced respiratory depression (DIRD) is a common problem encountered post-operatively and can persist for days after surgery. It is not always possible to predict the timing or severity of DIRD due to the number of contributing factors. A safe and effective respiratory stimulant could improve patient care by avoiding the use of reversal agents (e.g., naloxone, which reverses analgesia as well as respiratory depression) thereby permitting better pain management by enabling the use of higher doses of analgesics, facilitate weaning from prolonged ventilation, and ameliorate sleep-disordered breathing peri-operatively. The purpose of this review is to discuss the current pharmaceutical armamentarium of drugs (doxapram and almitrine) that are licensed for use in humans as respiratory stimulants and that could be used to reverse drug-induced respiratory depression in the post-operative period. We also discuss new chemical entities (AMPAkines and GAL-021) that have been recently evaluated in Phase 1 clinical trials and where the initial regulatory registration would be as a respiratory stimulant.
Topics: Humans; Postoperative Complications; Pulmonary Ventilation; Respiratory Insufficiency; Respiratory System Agents
PubMed: 23791825
DOI: 10.1016/j.resp.2013.06.010 -
Anesthesiology Aug 2011
Topics: Almitrine; Humans; Hypoxia; Intraoperative Complications; Nitric Oxide; Respiration, Artificial
PubMed: 21792000
DOI: 10.1097/ALN.0b013e318223bbc0 -
The Cochrane Database of Systematic... Mar 2011Almitrine-raubasine combination (brand name Duxil), has been considered as an alternative treatment for dementia. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Almitrine-raubasine combination (brand name Duxil), has been considered as an alternative treatment for dementia.
OBJECTIVES
To determine the clinical efficacy and safety of Duxil in the treatment of patients with dementia.
SEARCH STRATEGY
We searched the Cochrane Dementia and Cognitive Improvement Group Specialised Register (now known as ALOIS) (September 2009), the China Biological Medicine Database (CBM-disc 1979 to December 2009), the Chinese National Knowledge Infrastructure (www.cnki.net 1979 to December 2009), the Stroke Trials Registry at www.strokecentre.org/trials/index.aspx. We searched identified citations for additional trials, contacted the first author of identified trials for additional references and unpublished data. We also contacted the pharmaceutical company manufacturing Duxil (Servier Pharmaceutical Co Ltd) for additional unpublished data.
SELECTION CRITERIA
Randomised controlled trials studying the efficacy and safety of Duxil for dementia were included, irrespective of blinding, publication status, or language. If the trial was cross-over in nature, only data from the first period were included.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials for inclusion, assessed trial quality and extracted the data.
MAIN RESULTS
Three trials involving a total of 206 participants were included, all patients with vascular dementia. All three included studies were assessed as being at high risk of bias. When analysing these trials together, there was significant beneficial effect of Duxil on the improvement of cognitive function measured by MMSE (WMD 2.04, 95% CI 1.43 to 2.66). No data on behaviour and death at the end of treatment and follow-up were available from the included trials. Two trials failed to show an improvement of functional performance measured by ADL (WMD -1.68; 95% CI -3.70 to 0.35). Of the three included trials, all described the adverse events in detail, there were no statistically significant differences across the trials (OR 4.84, 95%CI 0.55 to 42.67). Behaviour disturbance, quality of life, caregiver burden were not undertaken in the included trials.
AUTHORS' CONCLUSIONS
Due to the low methodological quality of included trials, small number of trials and probable publication bias, this review did not provide sufficient evidence to support the routine use of Duxil for the treatment of patients with dementia. High-quality and large-scale randomised controlled trials are needed to confirm or refute these results.
Topics: Aged; Almitrine; Dementia; Drug Combinations; Humans; Middle Aged; Neuroprotective Agents; Yohimbine
PubMed: 21412915
DOI: 10.1002/14651858.CD008068.pub2 -
Talanta Jan 2011Stability-indicative determination of raubasine (RAB) in the presence of its degradate and its binary mixture with almitrine dismesylate (ALM) was investigated. The...
Stability-indicative determination of raubasine (RAB) in the presence of its degradate and its binary mixture with almitrine dismesylate (ALM) was investigated. The degradation product had been isolated, via acid-degradation, characterized and confirmed. Selective quantification of RAB and ALM in bulk form, pharmaceutical formulations and/or in the presence of RAB degradate was demonstrated. The analytical technique adopted for quantification was high performance liquid chromatography (HPLC). Separation was performed using a ZORBAX ODS column with a mobile phase consisting of acetonitrile+phosphate buffer pH 3.4 80:20 (v/v) with UV detection at 254 nm. The method showed high sensitivity with good linearity over the concentration range of 5-120 and 5-60 μg mL(-1) for RAB and ALM respectively. The HPLC method was used to study the kinetics of RAB acid degradation that was found to follow a first-order reaction. The activation energy could be estimated from the Arrhenius plot and it was found to be 18.152 kcal mol(-1).
Topics: Chromatography, High Pressure Liquid; Drug Stability; Esters; Hydrogen-Ion Concentration; Kinetics; Reproducibility of Results; Secologanin Tryptamine Alkaloids; Vasodilator Agents
PubMed: 21147311
DOI: 10.1016/j.talanta.2010.10.012 -
Drug Testing and Analysis Jun 2009A second-derivative spectrophotometric method ((2)D) and a derivative ratio spectrum zero crossing ((1)DD) method were used to determine raubasine and almitrine...
A second-derivative spectrophotometric method ((2)D) and a derivative ratio spectrum zero crossing ((1)DD) method were used to determine raubasine and almitrine dismesylate in the presence of raubasine degradation product, using methanol as a solvent. Linear relationships were obtained in the range from 6-20 microg ml(-1) raubasine for the ((2)D) method and 12-24 microg ml(-1) almitrine dismesylate for the ((1)DD) method. By applying these methods it was possible to determine raubasine in its pure powdered form with an accuracy of 99.93 +/- 1.116 (n = 8) for the ((2)D) method and almitrine dismesylate with an accuracy of 99.98 +/- 0.602 (n = 7) for the ((1)DD) method.Laboratory-prepared mixtures containing different ratios of raubasine, almitrine dismesylate and raubasine degradation product were analysed and the proposed methods were valid up to 50% of raubasine degradation product. They were found to be suitable stability-indicating assay methods for raubasine and almitrine dismesylate in pharmaceutical formulations.
Topics: Almitrine; Drug Combinations; Drug Stability; Methanol; Respiratory System Agents; Secologanin Tryptamine Alkaloids; Solvents; Spectrophotometry; Vasodilator Agents
PubMed: 20355207
DOI: 10.1002/dta.48 -
Terapevticheskii Arkhiv 2008To elucidate efficacy of a combination almitrine+thiotropium bromide (TB)+pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) of stage II-III... (Comparative Study)
Comparative Study Randomized Controlled Trial
AIM
To elucidate efficacy of a combination almitrine+thiotropium bromide (TB)+pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) of stage II-III complicated with chronic respiratory failure (CRF).
MATERIAL AND METHODS
Efficacy of therapy was compared in two groups of patients: group 1 (n = 22) received TB in a dose 18 mcg/day for one year, almitrine in a dose 10 mg/kg/day for 3 months, an 8 week course of PR, group 2 (n = 17) received TB and PR. The treatment efficacy was determined by spirometric parameters of external respiration function, blood gases, dyspnea indices, exercise tolerance assessed by 6-min walk test, quality of life (St. George Hospital Respiratory Questionnaire).
RESULTS
Group 1 patients walked longer distance after a course of PR and 1 year later (by 90.5 +/- 25.4 and 44.5 +/- 10.2 m, respectively, p < 0.05), had reduced desaturation measured by pulsoxym-etry at the end of 6-min walk test, increased PaO2 in baseline under 70 mmHg (by 5.8 +/- 1.2 mmHg, p > 0.05), decreased exacerbation rate per 1 patient a year (by 25%).
CONCLUSION
Combination treatment with TB, almitrine and PR is indicated for COPD patients with moderate hypoxemia.
Topics: Administration, Inhalation; Almitrine; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exercise Therapy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome
PubMed: 18441680
DOI: No ID Found