Almitrine Infusion in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Acute Respiratory Distress Syndrome: A Single-Center Observational Study.

OBJECTIVES: Treating acute respiratory failure in patients with coronavirus disease 2019 is challenging due to the lack of knowledge of the underlying pathophysiology. Hypoxemia may be explained in part by the loss of hypoxic pulmonary vasoconstriction. The present study assessed the effect of almitrine, a selective pulmonary vasoconstrictor, on arterial oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome. DESIGN: Single-center retrospective observational study. SETTING: ICU of Lille Teaching Hospital, France, from February 27, 2020, to April 14, 2020. PATIENTS: Patients with coronavirus disease 2019 pneumonia confirmed by positive reverse transcriptase-polymerase chain reaction for severe acute respiratory syndrome-coronavirus 2 and acute respiratory distress syndrome according to Berlin definition. Data focused on clinicobiological features, ventilator settings, therapeutics, outcomes, and almitrine-related adverse events. INTERVENTIONS: Almitrine was considered in patients with severe hypoxemia (Pao2/Fio2 ratio < 150 mm Hg) in addition to the recommended therapies, at an hourly IV delivery of 10 µg/kg/min. Comparative blood gases were done before starting almitrine trial and immediately after the end of the infusion. A positive response to almitrine was defined by an increase of Pao2/Fio2 ratio greater than or equal to 20% at the end of the infusion. MEASUREMENTS AND MAIN RESULTS: A total of 169 patients were enrolled. Thirty-two patients with acute respiratory distress syndrome received an almitrine infusion trial. In most cases, almitrine was infused in combination with inhaled nitric oxide (75%). Twenty-one patients (66%) were responders. The median Pao2/Fio2 ratio improvement was 39% (9-93%) and differs significantly between the responders and nonresponders (67% [39-131%] vs 6% [9-16%], respectively; p < 0.0001). The 28-day mortality rates were 47.6% and 63.6% (p = 0.39) for the responders and nonresponders, respectively. Hemodynamic parameters remained similar before and after the trial, not suggesting acute cor pulmonale. CONCLUSIONS: Almitrine infusion improved oxygenation in severe acute respiratory syndrome coronavirus 2-induced acute respiratory distress syndrome without adverse effects. In a multistep clinical approach to manage severe hypoxemia in this population, almitrine could be an interesting therapeutic option to counteract the loss of hypoxic pulmonary vasoconstriction and redistribute blood flow away from shunting zones.

Repurposing the Medicines for Malaria Venture's COVID Box to discover potent inhibitors of Toxoplasma gondii, and in vivo efficacy evaluation of almitrine bismesylate (MMV1804175) in chronically infected mice.

Toxoplasmosis, caused by the obligate intracellular parasite Toxoplasma gondii, affects about one-third of the world's population and can cause severe congenital, neurological and ocular issues. Current treatment options are limited, and there are no human vaccines available to prevent transmission. Drug repurposing has been effective in identifying anti-T. gondii drugs. In this study, the screening of the COVID Box, a compilation of 160 compounds provided by the "Medicines for Malaria Venture" organization, was conducted to explore its potential for repurposing drugs to combat toxoplasmosis. The objective of the present work was to evaluate the compounds' ability to inhibit T. gondii tachyzoite growth, assess their cytotoxicity against human cells, examine their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and investigate the potential of one candidate drug through an experimental chronic model of toxoplasmosis. Early screening identified 29 compounds that could inhibit T. gondii survival by over 80% while keeping human cell survival up to 50% at a concentration of 1 µM. The Half Effective Concentrations (EC50) of these compounds ranged from 0.04 to 0.92 µM, while the Half Cytotoxic Concentrations (CC50) ranged from 2.48 to over 50 µM. Almitrine was chosen for further evaluation due to its favorable characteristics, including anti-T. gondii activity at nanomolar concentrations, low cytotoxicity, and ADMET properties. Administering almitrine bismesylate (Vectarion®) orally at dose of 25 mg/kg/day for ten consecutive days resulted in a statistically significant (p < 0.001) reduction in parasite burden in the brains of mice chronically infected with T. gondii (ME49 strain). This was determined by quantifying the RNA of living parasites using real-time PCR. The presented results suggest that almitrine may be a promising drug candidate for additional experimental studies on toxoplasmosis and provide further evidence of the potential of the MMV collections as a valuable source of drugs to be repositioned for infectious diseases.

Efficacy of almitrine as a rescue therapy for refractory hypoxemia in COVID and non-COVID acute respiratory distress syndrome. A retrospective monocenter study.

BACKGROUND: Almitrine, a drug enhancing hypoxic pulmonary vasoconstriction, has been proposed as a rescue therapy for refractory hypoxemia in COVID related acute respiratory distress syndrome (C-ARDS). We aimed at investigating the response to almitrine depending on the cause of ARDS (COVID vs. non-COVID). METHODS: Monocenter retrospective study from 2014 to 2021. All patients diagnosed with moderate to severe ARDS and treated with almitrine as rescue therapy for refractory hypoxemia were studied. Factor independently associated with oxygenation response to almitrine infusion were determined. RESULTS: Sixty patients with ARDS and treated with almitrine were analyzed, 36 (60%) due to SARS-CoV-2 infection and 24 (40%) due to other causes. Baseline PaO2/FiO2 was 78 [61-101] mmHg, 76% had at least one prone positioning before the start of almitrine infusion. Median PaO2/FiO2 increased by +38 [7-142] mmHg (+61% [10-151]) after almitrine infusion. PaO2/FiO2 increased by +134 [12-186] mmHg in non-COVID ARDS (NC-ARDS) and by +19 [8-87] mmHg in C-ARDS. The increase in PaO2/FiO2 was lower in C-ARDS than in NC-ARDS (P=0.013). In multivariable analysis, C-ARDS, non-invasive ventilation and concomitant use of norepinephrine were independently associated with a decreased oxygenation response to almitrine infusion. CONCLUSIONS: Our study reports a highly variable response to almitrine infusion in ARDS patients with refractory hypoxemia. Independent factors associated with a reduced oxygenation response to almitrine infusion were: COVID ARDS, concomitant use of norepinephrine, and non-invasive ventilatory strategy.

Almitrine-Raubasine combination for dementia.

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.

[Clinical research of effect of Yishen Yangnao capsule on vascular dementia].

OBJECTIVE: To find a good way to diagnose VD, value the effect of Yishen Yangnao capsule on VD and try to find some rules of changes in Chinese medicine syndromes. METHOD: Patients were randomly divided into treating group and western medicine comparison group. It's the phase III clinical research of Rishen Yangnao capsule curing VD, judging the validity and security of it, using dukexi slice as comparison drug. Some of the patients did the examination of P300. RESULT: The total validity of Yishen Yangnao capsule is 56.3% (contract team is 60.0%). The improve rate of ADL is 0.1069% (contract team is 0.1134%). The scores of Chinese medicine syndrome descend. CONCLUSION: Yishen Yangnao capsule has the same effect as dukexi slice in curing VD at the side of intelligence situation and life ability.

Interest of a therapeutic optimization strategy in severe ARDS.

STUDY OBJECTIVE: Evaluate the interest of the response to a therapeutic optimization as a predictor of prognosis in ARDS. DESIGN: Prospective study. SETTING: ICU of a University Hospital. PATIENTS: Thirty-six consecutive patients with severe ARDS addressed for extracorporeal carbon dioxide removal (ECCO2R). INTERVENTIONS: We studied the response during the first 2 days after arrival to the therapeutic optimization strategy consisting in a combination of the following: (1) decrease in extravascular lung water (diuretics or hemofiltration); (2) selection of the best ventilatory mode; (3) permissive hypercarbia; and (4) correction of hypoxemia by alveolar recruitment, additional continuous oxygen insufflation, body position changes (prone position), inhaled nitric oxide, enhancement of hypoxic pulmonary vasoconstriction with almitrine, and drainage of pleural or mediastinal effusions. In patients remaining severely hypoxemic despite these modalities, ECCO2R was then proposed. MEASUREMENTS AND RESULTS: Thirty-six patients were addressed after 8.3+/-5.5 days of mechanical ventilation. On arrival, mean simplified acute physiologic score was 46.8+/-14.2, multiple system organ failure score was 1.8+/-1.6, Murray score was 3.4+/-0.4, PaO2 was 75.3+/-31.3 (fraction of inspired oxygen [FIO2]=1) for a positive end-expiratory pressure level of 12.3+/-3.4 cm H2O. Nineteen of 36 patients improved their gas exchange within 2 days and their mortality was 21%. The seventeen remaining patients did not improve PaO2/FIO2; PaCO2 and airway pressures remained high and their mortality was 88%. This different response to therapeutic optimization appeared using stepwise logistic regression as the most predictive factor for mortality (p<0.05). CONCLUSIONS: In patients with severe ARDS, the response to an early performed therapeutic optimization used to improve hypoxemia appeared to be a highly discriminant factor distinguishing deceased from surviving patients.

Impact of sleep in COPD.

Sleep has well-recognized effects on breathing, including changes in central respiratory control, airways resistance, and muscular contractility, which do not have an adverse effect in healthy individuals but may cause problems in patients with COPD. Sleep-related hypoxemia and hypercapnia are well recognized in COPD and are most pronounced in rapid eye movement sleep. However, sleep studies are usually only indicated in patients with COPD when there is a possibility of sleep apnea or when cor pulmonale and/or polycythemia are not explained by the awake PaO(2) level. Management options for patients with sleep-related respiratory failure include general measures such as optimizing therapy of the underlying condition; physiotherapy and prompt treatment of infective exacerbations; supplemental oxygen; pharmacologic treatments such as bronchodilators, particularly ipratropium bromide, theophylline, and almitrine; and noninvasive positive pressure ventilation.

Assessment of the therapeutic activity of a combination of almitrine and raubasine on functional rehabilitation following ischaemic stroke.

BACKGROUND AND OBJECTIVES: Stroke is a major cause of disability. Certain experimental studies have suggested that a combination of almitrine + raubasine (Duxil) increases the supply of oxygen to cerebral tissues and may be beneficial in post-stroke rehabilitation. This multicentre clinical study was carried out in order to assess the efficacy of this combination on poststroke rehabilitation. METHODS: The trial was a randomised, double-blind, placebo-controlled study. Patients that had experienced an ischaemic cerebrovascular accident (confirmed by CT scan) were included 4-6 weeks after the acute onset and received randomised treatment of either almitrine + raubasine or placebo 2 tablets daily for 3 months. Before treatment, there was a 2-week washout period for stopping all other drugs, except for antihypertensive and antidiabetic drugs. We assessed the patients by Barthel Index (BI), Neurological Functional Deficit Scores (NFDS), and Hasagawa Dementia Scales (HDS) each month after treatment. RESULTS: A total of 83 patients were entered into the study and data were available for 74. Of these, 38 patients received almitrine + raubasine and 36 received placebo. The baseline characteristics were comparable between both groups. Almitrine + raubasine was significantly more effective than placebo at increasing BI at 1, 2 or 3 months (14.6 +/- 13.8 versus 3.3 +/- 13.2, p = 0.01; 19.3 +/- 13.6 versus 8.8 +/- 14.0, p = 0.02; 22.6 +/- 14.7 versus 10.7 +/- 17.0, p = 0.02 respectively) and reducing NFDS at 1 month (3.6 +/- 3.2 versus 1.9 +/- 3.5, p = 0.034) after treatment. More almitrine + raubasine-treated patients' NFDS had improved compared with placebo-treated patients at 2 and 3 months (97 versus 78%, p = 0.013; 100 versus 86%, p = 0.023 respectively). Compared with pretreatment, there was a strong tendency towards an improvement of HDS with almitrine + raubasine. The number of adverse events reported was low for the almitrine + raubasine-treated group and the placebo group and all events were mild, of short duration and resolved without treatment. Almitrine + raubasine had no clinically significant effect on blood pressure, heart rate or other laboratory tests. CONCLUSION: The results indicate that almitrine + raubasine can accelerate neurological function recovery after stroke to some degree and is well tolerated.

Cor pulmonale in chronic obstructive pulmonary disease. Circulatory pathophysiology and management.

The development of pulmonary hypertension and right ventricular failure in COPD patients signals a poor prognosis. In hypoxic patients, long-term oxygen therapy prolongs life and appears to prevent or lessen the progression of pulmonary hypertension. However, oxygen therapy does not benefit and is not indicated for all COPD patients, and even in those patients who improve with oxygen, there remains a need to further improve survival. Therefore, there continues to be active investigations into pharmacologic agents that might reduce pulmonary hypertension or improve right ventricular function. Although many agents appear to have salutary acute effects, it has been more difficult to establish evidence for sustained hemodynamic benefits from chronic drug therapy. Furthermore, some effective agents may not provide additive benefit when combined with standard supplemental oxygen use, although the available data are limited. Clearly, further research is necessary to identify which COPD patients, if any, may benefit from either beta-agonists or vasodilators for the treatment or prevention of cor pulmonale at some time during the natural history of their disease.

Long-term effects and safety of almitrine-raubasine in age-associated cognitive decline.

Twenty elderly patients (8 men, 12 women, mean age 67.5 years, range 59-74 years) with age-associated cognitive decline (memory impairment, slowing of thought and inability to concentrate, mean Mini Mental State score 22.0, range 18-24) were included by their general practitioners in an open study of the efficacy and safety of long-term combination therapy with almitrine and raubasine. After a 2-week washout period, patients received almitrine-raubasine for 13 months. Efficacy was evaluated at 2-month intervals using two well-being scales (visual analog and psychoaffective profile) and two behavioral scales (Widlocher's scale, and a scale derived from the Sandoz Clinical Assessment Geriatric scale). Memory was assessed every 6 months. Safety was evaluated by full medical examination and routine laboratory parameters at 2- and 6-month intervals, respectively. On treatment, scores on all scales improved significantly (two-way analysis of variance) throughout the study, as did scores in the two objective memory tests (Friedman test). Safety was demonstrated by the lack of any changes in clinical or laboratory parameters outside the normal range.

Progress in understanding the pathophysiology of cerebral ischemia: the almitrine-raubasine approach.

Cerebral ischemia occurs frequently and is disabling. In addition to preventing and correcting risks factors, drugs prevent cell death induced by ischemia-hypoxia. Precise knowledge of the pathophysiology of cerebral ischemia is the prerequisite for drug development, and the main proofs of efficiency are histopathological and clinical (i.e., the results of controlled studies). Different animal models are considered valid for global, focal, or multifocal ischemia. These models have enabled the identification of deleterious phenomena that could be corrected or neutralized by drugs: hypoxia, lactic acidosis, release of neurotransmitters, influx of calcium, activation of phospholipase A2, release of excitatory amino acids, excess of free radicals, and neuronal cell metabolic paralysis (decrease of oxygen and glucose consumption). The chronology of these events clearly described herein will prompt the choice of the best drug, based on the delay between the ischemic event and the decision to treat. The main pharmacological effects required are the following: antagonism of hypoperfusion, oxygenation improvement, blockade of calcium influx and neurotransmitters action, reduction of acidosis and potassium efflux, blockade of arachidonic cascade and free radicals production, and antiedematous effect. The analysis of almitrine-raubasine (Duxil) pharmacological properties will be used as an example of these potentially anti-ischemic drugs. Almitrine-raubasine pharmacological studies indicate that this drug has several beneficial effects on cerebral ischemic processes. These studies have dealt with effects of hypobaric hypoxia on deoxyglucose uptake in the rat, protective effects on permanent or temporary cerebral ischemia-induced neurobehavioral problems in the gerbil, and preservation of the glycogen content and of the swelling in astrocytes after bilateral occlusion of the carotid arteries in the rabbit.

Efficacy of almitrine-raubasine in cognitive disorders of aging: a double-blind, placebo-controlled, clinical and psychometric study.

Early treatment of age-related cognitive impairment can be decisive in enabling elderly patients to remain at home. A double-blind, placebo-controlled trial of almitrine-raubasine was conducted in 40 elderly outpatients (25 women, 15 men; mean age: 73.5 years) with moderate cognitive impairment randomized into two groups, one receiving almitrine and raubasine, the other placebo, two tablets daily for 90 days. They were assessed at T0, T45 and T90 days, using the Toulouse-Pieron test, 8 subtests from the Wechsler Adult Intelligence Scale (WAIS) and the Sandoz Clinical Assessment for Geriatrics (SCAG). End-of-study results were significantly better in the almitrine-raubasine group in all tests: Toulouse-Pieron test (p less than 0.001), WAIS (p less than 0.001), and SCAG (p less than 0.001).

Association of oral almitrine and medroxyprogesterone acetate: effect on arterial blood gases in chronic obstructive pulmonary disease.

Almitrine (A) and medroxyprogesterone acetate (MA) given separately improve arterial blood gases in some patients with chronic obstructive pulmonary disease (COPD); the aim of this study was to assess the effect of the two drugs given together. Forty-eight patients with irreversible COPD and hypoxaemia were prospectively enrolled into a 14-day run-in period and received single-blind oral treatment with double placebo. Patients whose PaO2 remained stable (less than 10% change; n = 29, 25 males, mean age 65.6 years) were included in a 14-day active treatment period and randomly assigned to three groups. They received double-blind oral treatment with: A (50 mg bid, group A, n = 10); MA (20 mg tid, group MA, n = 9); A (50 mg bid) and MA (20 mg tid, group A+MA, n = 10). Anthropometric and spirometric measurements were similar in the three groups and so were the arterial blood gas values at the beginning and the end of the run-in period. At the end of the active treatment period, blood gas changes (mean+/-SE) were significantly different between groups (P<0.05, Kruskal-Wallis test), with improvement in both hypoxaemia and hypercapnia in group A+MA only: delta PaO2 = 7.4+/-1.9 mmHg, delta PaCO2 = -5.1+/-1.7 m mHg (P<0.05, Wilcoxon test). In short-term treatment, the association of A and MA is more efficient than either drug alone at improving arterial blood gases in COPD patients.

Haemodynamics and gas exchange in liver cirrhosis: the effect of orally administered almitrine bismesylate.

The present study was conducted to analyse the effect on haemodynamics and to evaluate the role of hypoxic pulmonary vasoconstriction (HPV) in cirrhotic patients with hypoxaemia using almitrine bismesylate, an agent which increases the response of HPV. Six male patients, mean age of 51 years, with hepatic cirrhosis and associated hypoxaemia were studied. All patients had normal lung and cardiac function tests. When the patients were clinically stable, right heart and radial artery catheterization were performed. Data from the pulmonary artery catheter and blood gases were obtained before and after 4 days of oral almitrine bismesylate. The results indicated that these cirrhotics were in a mild hyperdynamic circulatory state. The cardiac output (CO), cardiac index (CI), oxygen delivery (DO2), and oxygen consumption (VO2) were elevated while the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) were low. Almitrine significantly increased PVR (P < 0.05) and mean pulmonary artery pressure (mPAP) (P < 0.01). In addition, almitrine improved alveolar arterial oxygen content difference [D(A-a)O2] (P < 0.01) and shunt fraction (Qva/QT) (P < 0.01). The PaCO2 and PaO2 increased slightly but this was not statistically significant. In conclusion, in our group of patients with hepatic cirrhosis, four days of treatment with almitrine improved their gas exchange. The data suggest a weak HPV response in this group of cirrhotics; that response may be enhanced by almitrine.

Almitrine-raubasine and cognitive impairment in the elderly: results of a 6-month controlled multicenter study.

Two-hundred four patients between 70 and 85 years of age were included in a double-blind randomized controlled multicenter study (almitrine-raubasine/placebo). Inclusion criteria were a complaint of cognitive disorders and an objective cognitive impairment evaluated by Folstein et al. "Mini-Mental State" (MMS) and by Sandoz Clinical Assessment for Geriatrics (SCAG). Patients were treated for 6 months and evaluations were performed at the beginning of the trial (T0), then 3 (T3) and 6 (T6) months later. Evaluations included a visual analogic self-rating scale and the following psychometric tests: Trail Making A (TMA), Shopping List Task, Word Fluency, Crossing Out Letters, Logical Memory, Digit Span, and Visual Retention. Anxiety and Depression Scales were also used to assess the effects of almitrine-raubasine on affective status. Statistical analysis involving the whole sample did not show any significant difference between the almitrine-raubasine and placebo groups concerning changes in assessment criteria from T0 to T6. However, these results may have been due to the wide heterogeneity of baseline performances in psychometric tests. To prevent this possible bias, further statistical analysis was performed for each psychometric test after patients had been divided into three classes according to baseline score levels. Considering scores on TMA and Digit Span for patients with scores in the intermediate class on TMA, almitrine-raubasine induced a significantly higher improvement in performance from T0 to T6 than that induced by placebo. On the other hand, no side effects were noted with almitrine-raubasine when compared with placebo. These data suggest that almitrine-raubasine enhances concentrated attention in patients with mild to moderate impairment of this function.

Metabolic and circulatory evaluation of cerebral ischemic accident in humans by positron emission tomography: a pilot study with almitrine-raubasine.

Positron emission tomography and oxygen-15 were used to evaluate the effect of almitrine-raubasine combination on cerebral blood flow and oxidative metabolism in patients with cerebral ischemia. In five patients aged between 58 and 74 years, with a cerebral ischemic accident in the territory of the middle cerebral artery, blood flow rate, oxygen metabolic rate, and cerebral oxygen extraction were measured before and after a 90-min intravenous perfusion of almitrine bismesilate 15 mg and raubasine 5 mg. Investigations were performed from day 2 to day 7 after stroke occurred. One patient showed evidence of initial relative luxury perfusion, the degree of which was reduced by such combined treatment. The other four patients had a focal reduction in cerebral blood flow and oxygen consumption prior to treatment. The statistical analysis of three cerebral areas (epicenter of lesion, anterior and posterior juxtalesional areas, and homologous heterolateral areas) showed a 3.6% increase in oxygen metabolic rate at the epicenter, when both hemispheres were taken together, and a significant increase in cerebral blood flow in all three areas (3% on the healthy hemisphere, 13% on the injured hemisphere). These changes were greater in some patients than in others. This suggests that heterogeneity of drug responses may correspond to the heterogeneity of the initial status.