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1.
Efficacy and safety of inhaled nitrite in addition to sildenafil in thalassemia patients with pulmonary hypertension: A 12-week randomized, double-blind placebo-controlled clinical trial.
Sasiprapha, T, Pussadhamma, B, Sibmooh, N, Sriwantana, T, Pienvichit, P, Chuncharunee, S, Yingchoncharoen, T
Nitric oxide : biology and chemistry. 2022;:38-43
Abstract
Pulmonary hypertension is a significant complication in thalassemia patients. Recent studies showed that inhaled nebulized nitrite could rapidly decrease pulmonary artery pressure. We conducted a multicenter, randomized, double-blind, placebo-controlled trial in thalassemia patients with symptomatic pulmonary hypertension diagnosed by right heart catheterization. Eleven patients were recruited; five were assigned to the nitrite group and six to the placebo group. Patients were treated with the optimal doses of sildenafil for pulmonary hypertension and randomly assigned into the placebo or nitrite groups. Patients in the nitrite group were given inhaled nebulized 30 mg sodium nitrite twice a day for 12 weeks. The clinical outcomes measured at week 12 were the changes in 6-min walk distance (6MWD), mean pulmonary artery pressure (MPAP), and N-terminal pro B-type natriuretic peptide. The MPAP estimated by echocardiography was significantly reduced from 33.6 ± 7.5 mmHg to 25.8 ± 6.0 mmHg (mean difference = 7.76 ± 3.69 mmHg, p = 0.009 by paired t-test). Furthermore, 6MWD was slightly increased from 382.0 ± 54.0 m to 432 ± 53.9 m (mean difference = 50.0 ± 42.8 m, p = 0.059 by paired t-test) in the nitrite group. At week 12, the nitrite group had lower MPAP than the placebo group (25.8 ± 6.0 vs. 45.7 ± 18.5 mmHg, p = 0.048 by unpaired t-test). No significant difference in 6MWD and N-terminal pro B-type natriuretic peptide between the two groups was observed at week 12. There was no hypotension or other significant adverse effects in the nitrite group.
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2.
A randomized double-blinded placebo-controlled clinical trial on protective effects of pentoxifylline on gentamicin nephrotoxicity in infectious patients.
Mousavinasab, SR, Akhoundi-Meybodi, Z, Mahmoudi, L, Karimzadeh, I
Clinical and experimental nephrology. 2021;(8):844-853
Abstract
BACKGROUND AND OBJECTIVE Renal toxicity has limited gentamicin use in clinical practice. The aim of the present clinical trial was to assess the possible nephroprotective effects of pentoxifylline (PTX) against gentamicin nephrotoxicity. MATERIALS AND METHODS A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted on patients who had the indication for systemic gentamicin for at least 7 days. Sixty people were selected and randomly assigned. For patients in the intervention and control groups, 400 mg PTX sustained release tablet and placebo were given orally three times daily, respectively. Demographic, clinical, laboratory, and therapeutic information of patients were recorded. malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) levels in serum were measured on days 0 and 7. RESULTS The incidence of nephrotoxicity in the placebo group was 19.6 times higher than that in the PTX group (OR = 19.6, 95%CI = 3.08-114.32; P value = 0.001). The mean ± SD time onset of ATN was 4.00 ± 2.32 and 5.58 ± 1.59 days in PTX and placebo recipients, respectively (P value < 0.001). No significant differences were observed for hypokalemia, hypomagnesemia, potassium and magnesium wasting between the two groups. The mean ± SD levels of serum MDA and TNF-α at day 7 were significantly lower in the PTX compared to those in the placebo group (P value < 0.001 for both indexes). CONCLUSION The co-administration of 400 mg PTX orally three times daily along with gentamicin was both well-tolerated and effective in preventing the nephrotoxicity of gentamicin in patients with different infectious diseases.
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3.
Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease.
Frölich, L, Wunderlich, G, Thamer, C, Roehrle, M, Garcia, M, Dubois, B
Alzheimer's research & therapy. 2019;(1):18
Abstract
BACKGROUND There are currently no approved treatments for the prodromal stage of Alzheimer's disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD. Efficacy and safety of BI 409306 was analysed in two phase II proof-of-concept clinical trials in cognitive impairment associated with prodromal AD (study 1) and mild AD (study 2). METHODS Two multicentre, double-blind, parallel-group, randomised controlled phase II studies were conducted (North America/Europe). Following study run-in, eligible subjects were randomised to one of four oral doses of BI 409306 (10-50 mg daily) or placebo (1:1:1:1:2 ratio) for 12 weeks. The primary efficacy endpoint was the change from baseline in Neuropsychological Test Battery (NTB) total z-score after 12 weeks' treatment. Secondary efficacy assessments included change from baseline in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog11) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; mild cognitive impairment [MCI] version for prodromal patients) after 12 weeks' treatment. Safety and tolerability assessments included adverse event reporting and vital sign monitoring. Change from baseline in NTB total z-score (primary endpoint) and CDR-SB were analysed using the restricted maximum likelihood-based mixed-effects model with repeated measurement. An analysis of covariance model was used to assess other secondary endpoints. RESULTS Four hundred fifty-seven patients were randomised (study 1 for prodromal AD, N = 128; study 2 for mild AD, N = 329); 427 (93.4%) completed. A prespecified pooled analysis of the primary endpoint revealed no significant changes in NTB total composite z-score at week 12 in the BI 409306 treatment groups compared with placebo, with similar findings observed in the individual studies. The analysis of all secondary endpoints, including pooled analysis of CDR-SB and ADAS-Cog11, ADCS-MCI-ADL (study 1), ADCS-ADL (study 2), also gave no indication of a treatment benefit for BI 409306, compared with placebo. BI 409306 was well tolerated. CONCLUSIONS Overall, the data do not demonstrate efficacy of BI 409306 in improving cognition in patients with prodromal and mild AD. BI 409306 is well tolerated. TRIAL REGISTRATION ClinicalTrials.gov, NCT02240693 and NCT02337907 . Registered 15 September 2014 and 09 January 2015, respectively.
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4.
Signal Transduction Pathways as Therapeutic Target for Chagas Disease.
Schoijet, AC, Sternlieb, T, Alonso, GD
Current medicinal chemistry. 2019;(36):6572-6589
Abstract
Trypanosomatids are a group of flagellated unicellular eukaryotes, causing serious human diseases including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.) and Leishmaniasis (Leishmania spp.). The second messenger cAMP is involved in numerous and fundamental processes in these parasites including differentiation between stages, proliferation, osmoregulation, oxidative stress and quorum sensing. Interestingly, its signaling pathway is quite different from that of mammals, including structurally different adenylyl cyclases, the shortage of orthologous effector proteins and the absence of G-protein-coupled-receptors, among others. These characteristics make the proteins involved in these transduction pathways good candidates for therapeutic targets. However, the identification of new unknown druggable targets involves extensive research time and is economically very expensive, making difficult the transition from basic research to the clinical phase. Trypanosomatid PDEs have characteristic binding pockets that allow for a differential inhibition from their human orthologs. Modification in the approved drugs for human to convert them into trypanocidal treatments could lead to more effective therapies, shorter lab time and lower costs. In view of the fact that kinetoplastid PDEs are highly conserved with their mammalian counterparts, and since there are already numerous drugs on the market against human PDEs, the drug repositioning approach is highly promising. The development of new technologies, higher government and industrial involvement and more scientists committed to basic investigation, are the key to ultimately find an effective treatment and cure for the neglected tropical diseases.
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5.
Medical expulsive therapy in urolithiasis: a mixed treatment comparison network meta-analysis of randomized controlled clinical trials.
Sridharan, K, Sivaramakrishnan, G
Expert opinion on pharmacotherapy. 2017;(14):1421-1431
Abstract
BACKGROUND Medical expulsive therapy (MET) using alpha blockers, calcium channel blockers (CCB), phosphodiesterase inhibitors (PDEI) and spasmolytics have been shown to be effective in clinical trials on urolithiasis. The present study is a network meta-analysis comparing the above mentioned drug classes. RESEARCH DESIGN AND METHODS Electronic databases were searched for randomized controlled trials comparing the above mentioned drug classes in patients with urolithiasis using appropriate search strategy. Inverse variance heterogeneity model was used for the mixed treatment comparisons. Stone expulsion rate (SER) was the primary and stone expulsion time (SET) was the main secondary outcome measure. RESULTS We included a total of 114 studies for systematic review and 108 studies for the network meta-analysis. Alpha blockers, PDEI, and combined alpha blockers and corticosteroids had significantly increased SER and shorter SET than placebo or standard of care. Alpha blockers have the highest probability of being the 'best' in the pool with regard to SER. This effect persisted in patients with stones ≥ 5 mm, children, after shockwave lithotripsy, proximal ureteric stones and distal ureteric stones. CONCLUSION To conclude, we observed a statistically significant increase in the expulsion rate and shorter expulsion time with alpha blockers, PDEI and combined alpha blockers with corticosteroids. Of these interventions, alpha blockers have the high probability of being the 'best'.
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6.
The potential of methylxanthine-based therapies in pediatric respiratory tract diseases.
Oñatibia-Astibia, A, Martínez-Pinilla, E, Franco, R
Respiratory medicine. 2016;:1-9
Abstract
Caffeine, theophylline and theobromine are the most known methylxanthines as they are present in coffee, tea and/or chocolate. In the last decades, a huge experimental effort has been devoted to get insight into the variety of actions that these compounds exert in humans. From such knowledge it is known that methylxanthines have a great potential in prevention, therapy and/or management of a variety of diseases. The benefits of methylxanthine-based therapies in the apnea of prematurity and their translational potential in pediatric affections of the respiratory tract are here presented.
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7.
Short-term effect of caffeine on olfactory function in hyposmic patients.
Meusel, T, Albinus, J, Welge-Luessen, A, Hähner, A, Hummel, T
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2016;(8):2091-5
Abstract
The purpose of this study was to investigate the potential effects of caffeine in patients with olfactory loss. The suggested mechanisms of action consist in the non-selective blocking of adenosine receptors as well as inhibition of the phospodiesterase. Olfactory function was tested twice in 76 hyposmic patients either because of URTI or because of sinunasal causes. For definition of hyposmia and for later assessment of phenyl ethyl alcohol odor threshold, and odor discrimination the Sniffin Sticks data test was used. Using a double-blinded design, the participants were divided into two groups: one received a cup of espresso with caffeine (65 mg/cup), the other a cup of espresso without caffeine (placebo). Before and approximately 45 min after espresso consumption olfactory function was assessed. Across all participants, in comparison to placebo there was no significant effect of caffeine on olfactory function, regardless whether it was caused by an acute infection of the upper respiratory tract or sinunasal disease. These results indicate that-under the current conditions-the phosphodiesterase-inhibitor/adenosine-receptor agonist caffeine has little or no short-term effect on olfactory function in patients with olfactory loss.
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8.
[Treatment of pulmonary arterial hypertension].
Roman, A, López-Meseguer, M, Domingo, E
Medicina clinica. 2015;(12):566-70
Abstract
Treatment of pulmonary arterial hypertension has achieved significant progress over the past 20 years. Currently, 3 groups of drugs have proven useful for the treatment of this disease: endothelin receptor antagonist, phosphodiesterase inhibitors and prostacyclin and its analogues. It is recommended to initiate treatment with one of these drugs, the choice depending on the initial severity of patient disease and the preferences of the treating physician. When the patient does not have a satisfactory response, new drugs acting at a different pathway are most commonly added. At this time, considering referral for lung transplantation could be an alternative. Most experts recommend grouping maximum experience in what is known as expert centers. Treatment has led to better survival in these patients, but there is still a long way to cure this life-threatening disease.
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9.
The perspective of caffeine and caffeine derived compounds in therapy.
Pohanka, M
Bratislavske lekarske listy. 2015;(9):520-30
Abstract
Caffeine (1,3,7-trimethylxanthine) is a plant secondary metabolite with a significant impact on multiple processes and regulatory pathways in the body. Though major part of the population meets caffeine via coffee, tea or chocolate, it has also an important role in pharmacology and it is used as a supplementary substance in medicaments. Currently, the ability of caffeine to ameliorate some neurodegenerative disorders is proved in some studies. This review describes basic data about caffeine including toxicity, pharmacokinetics, biological mechanism of the action, and metabolism. Beside this, promising applications of caffeine, new medicaments and derivatives are discussed. Relevant papers and inventions are depicted in the manuscript. Caffeine is a pharmacologically promising substance that deserves big consideration in the current research and development. The compound has several reasons to be an object of scientific interest and to be used for pharmacology purposes. Despite an extensive research for a long time, no significantly negative effects on human health were proved hence caffeine can be considered as a completely safe compound. The recent data about amelioration of neurodegenerative and other disorders are promising and deserving more work on the issue. ARTICLE HIGHLIGHTS Caffeine is a purine alkaloid from plants and it has a broad use in current pharmacology. Caffeine is a competitive antagonist of neurotransmitter adenosine on adenosine receptors. The substance is added as a supplementary to drugs and food.Besides interfering on adenosine receptors, caffeine interacts with acetylcholinesterase, monoamine oxidase, phosphodiesterase, ryanodine receptors and others.Current research is devoted to the role of caffeine in neurodegenerative diseases and immunity alteration. New chemical compounds based on caffeine moiety are prepared (Tab. 4, Fig. 6, Ref. 149).
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10.
Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates.
Pammi, M, Haque, KN
The Cochrane database of systematic reviews. 2015;(3):CD004205
Abstract
BACKGROUND Mortality and morbidity due to neonatal sepsis and necrotizing enterocolitis (NEC) remain high despite the use of potent antimicrobial agents. Agents that modulate inflammation may improve outcomes. Pentoxifylline, a phosphodiesterase inhibitor, is one such agent. OBJECTIVES Our primary objectives were :1.To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis.2.To assess the effect of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in neonates with NEC. SEARCH METHODS We searched the Cochrane Neonatal Review Group Specialized Register, CENTRAL (The Cochrane Library Issue 2, 2014), EMBASE (January 1980 to May 2014), PubMed (January 1966 to May 2014), CINAHL (January 1982 to May 2014), Science Citation Index (January 1990 to May 2014), and BIOSIS (January 1992 May 2014) in May 2014. We checked references and cross-references from identified studies. We handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings (from January 1990 to May 2014). We placed no restrictions on language. SELECTION CRITERIA We included randomised or quasi-randomised trials assessing the efficacy of pentoxifylline as an adjunct to antibiotics for treatment of suspected or confirmed sepsis or NEC in neonates. DATA COLLECTION AND ANALYSIS We reported typical risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) using fixed-effect model for dichotomous outcomes and mean difference (MD) for continuous outcomes. We calculated the number needed to treat for an additional beneficial outcome (NNTB) if there was a statistically significant reduction in RD. MAIN RESULTS Pentoxifylline used as an adjunct to antibiotics in neonates with sepsis decreased all-cause mortality during hospital stay (typical RR 0.57, 95% CI 0.35 to 0.93; typical RD -0.08, 95% CI -0.14 to -0.01; NNTB 13, 95% CI 7 to 100; 6 studies, 416 participants, low-quality evidence). Subgroup analyses revealed decrease in mortality in preterm infants, infants with confirmed sepsis, and infants with gram-negative sepsis (low-quality evidence, four studies). Pentoxifylline decreased length of hospital stay (MD -7.59 days, 95% CI -11.65 to -3.52; 2 studies, 148 participants, low-quality evidence). Pentoxifylline did not change the risk of development of NEC, chronic lung disease, severe intraventricular haemorrhage, retinopathy of prematurity, or periventricular leukomalacia in neonates with sepsis (one to two studies, very low-quality evidence). Pentoxifylline therapy compared to pentoxifylline and immunoglobulin M-enriched intravenous immunoglobulin or immunoglobulin M-enriched intravenous immunoglobulin alone did not change mortality or development of NEC in neonates with sepsis (one study, very low-quality evidence). We noted no adverse effects due to pentoxifylline. We identified no trials evaluating pentoxifylline treatment for NEC. AUTHORS' CONCLUSIONS Low-quality evidence from six small studies suggests that pentoxifylline therapy as an adjunct to antibiotics in neonatal sepsis decreases mortality without any adverse effects. We encourage researchers to undertake large, well-designed multicentre trials to confirm or refute the effectiveness of pentoxifylline in reducing mortality and morbidity in neonates with sepsis or NEC.