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  • 1
    Language: English
    In: PLoS Neglected Tropical Diseases, 2010, Vol.4(12), p.e923
    Description: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DND i ) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of fexinidazole have been assessed. ; Standard and anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active against African trypanosomes (IC against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 µg/mL) and oral administration of fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a C of 500, 14171 and 13651 ng/mL respectively, and an AUC of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells or as assessed in an micronucleus test on human lymphocytes, an mouse bone marrow micronucleus test, and an unscheduled DNA synthesis test in rats. ; The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years. ; This article describes the preclinical profile of fexinidazole, a new drug candidate with the potential to become a novel, oral, safe and effective short-course treatment for curing both stage 1 and 2 human African trypanosomiasis and replace the old and highly problematic treatment modalities available today. Fexinidazole is orally available and rapidly metabolized in two metabolites having equivalent biological activity to the parent and contributing significantly to the efficacy in animal models of both stage 1 and 2 HAT. Animal toxicology studies indicate that fexinidazole has an excellent safety profile, with no particular issues identified. Fexinidazole is a 5-nitroimidazole and, whilst it is Ames-positive, it is devoid of any genetic toxicity in mammalian cells and therefore does not pose a genotoxic risk for use in man. Fexinidazole, which was rediscovered through a process of compound mining, is the first new drug candidate for stage 2 HAT having entered clinical trials in thirty years, and has the potential to revolutionize therapy of this fatal disease at a cost that is acceptable in the endemic regions.
    Keywords: Research Article ; Infectious Diseases -- Neglected Tropical Diseases ; Pharmacology -- Drug Development
    ISSN: 19352727
    E-ISSN: 1935-2735
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  • 2
    Language: English
    In: Physiotherapy Theory and Practice, 01 January 2010, Vol.26(3), pp.167-172
    Description: Many trigger point therapies, such as deep pressure massage and injection, are painful. Thermal ultrasound might be a comfortable procedure used to soften trigger points. Our objective was to compare thermal ultrasound with sham ultrasound in...
    Keywords: Physical Therapy
    ISSN: 0959-3985
    E-ISSN: 1532-5040
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  • 3
    Language: English
    In: Clinical EEG and Neuroscience, July 2009, Vol.40(3), pp.173-179
    Description: About one third of patients with epilepsy do not benefit from medical treatment. For these patients electroencephalographic (EEG) biofeedback is a viable alternative. EEG biofeedback, or neurofeedback, normalizes or enhances EEG activity by means of operant conditioning. While dozens of scientific reports have been published on neurofeedback for seizure disorder, most have been case series with too few subjects to establish efficacy. The purpose of this paper is to meta-analyze existing research on neurofeedback and epilepsy. We analyzed every EEG biofeedback study indexed in MedLine, PsychInfo, and PsychLit databases between 1970 and 2005 on epilepsy that provided seizure frequency change in response to feedback. Sixty-three studies have been published, 10 of which provided enough outcome information to be included in a meta-analysis. All studies consisted of patients whose seizures were not controlled by medical therapies, which is a very important factor to keep in mind when interpreting the results. Nine of 10 studies reinforced sensorimotor rhythms (SMR) while 1 study trained slow cortical potentials (SCP). All studies reported an overall mean decreased seizure incidence following treatment and 64 out of 87 patients (74%) reported fewer weekly seizures in response to EEG biofeedback. Treatment effect was mean log (post/pre) where pre and post represent number of seizures per week prior to treatment and at final evaluation, respectively. Due to prevalence of small groups, Hedges's g was computed for effect size. As sample heterogeneity was possible (Q test, p=.18), random effects were assumed and the effect of intervention was −0.233, SE= 0.057, z −4.11, p〈.001. Based on this meta-analysis, EEG operant conditioning was found to produce a significant reduction on seizure frequency. This finding is especially noteworthy given the patient group, individuals who had been unable to control their seizures with medical treatment.
    Keywords: EEG Biofeedback ; Epilepsy ; Meta-Analysis ; Neurofeedback ; Neurotherapy ; Seizure ; Medicine
    ISSN: 1550-0594
    E-ISSN: 2169-5202
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  • 4
    Language: English
    In: The Journal of Thoracic and Cardiovascular Surgery, 2010, Vol.140(3), pp.564-572
    Description: Under the Freedom of Information Act, we obtained the follow-up data of the National Emphysema Treatment Trial (NETT) to determine the long-term outcome for “a heterogeneous distribution of emphysema with upper lobe predominance,” postulated by the NETT hypothesis to be optimal candidates for lung volume reduction surgery. Using the NETT database, we identified patients with heterogeneous distribution of emphysema with upper lobe predominance and analyzed for the first time follow-up data for those receiving lung volume reduction surgery and those receiving medical management. Furthermore, we compared the results of the NETT reduction surgery group with a previously reported consecutive case series of 250 patients undergoing bilateral lung volume reduction surgery using similar selection criteria. Of the 1218 patients enrolled, 511 (42%) conformed to the NETT hypothesis selection criteria and received the randomly assigned surgical or medical treatment (surgical = 261; medical = 250). Lung volume reduction surgery resulted in a 5-year survival benefit (70% vs 60%; = .02). Results at 3 years compared with baseline data favored surgical reduction in terms of residual volume reduction (25% vs 2%;  〈 .001), University of California San Diego dyspnea score (16 vs 0 points;  〈 .001), and improved St George Respiratory Questionnaire quality of life score (12 points vs 0 points;  〈 .001). For the 513 patients with a homogeneous pattern of emphysema randomized to surgical or medical treatment, lung volume reduction surgery produced no survival advantage and very limited functional benefit. Patients most likely to benefit from lung volume reduction surgery have heterogeneously distributed emphysema involving the upper lung zones predominantly. Such patients in the NETT trial had results nearly identical to those previously reported in a nonrandomized series of similar patients undergoing lung volume reduction surgery.
    Keywords: 11.5 ; Fev 1 ; Lvrs ; Nett ; Rv;
    ISSN: 0022-5223
    E-ISSN: 1097-685X
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  • 5
    Language: English
    In: International Journal of Cardiology, 20 October 2014, Vol.176(3), pp.589-594
    Description: Current data on characteristics and outcomes of patients with high blood pressure (BP) managed under clinical practice conditions are limited. The 3A registry is an open, prospective observational cohort study in German primary care offices, with a 4:1:1 inclusion ratio to either aliskiren (ALIS), an ACE inhibitor/angiotensin receptor blocker (ACEI/ARB), or to an antihypertensive agent not affecting the renin angiotensin system (non-RAS). A nonlinear mixed regression model was used to assess BP changes during follow-up regarding different BP values at inclusion in the various groups. ClinicalTrial.gov identifier is . In the total cohort of 13,433 patients with 1-year follow-up results, the mean age of patients was 64.7 years, 54% were men. Mean number of antihypertensive drugs was higher in the ALIS group compared to the other groups (3.0 drugs versus 2.5 in ACEI/ARB versus 1.6 in non-RAS; p 〈 0.0001). Statistical regression analysis revealed baseline BP as the dominant covariate. After adjustment for baseline BP and 12 other confounders, no significant differences in BP reduction between the three groups were observed. The rate of major cardiac events (death, myocardial infarction, and stroke) was 1.3% in the total cohort, and did not differ across groups. ALIS at beginning of the observation was mostly used by the physicians in patients with higher BP at entry and in higher risk populations. By study end, in all groups, stringent BP lowering measures, usually with combination therapy, led to significant improvements; more than half of these at-risk patients reached the BP targets.
    Keywords: Essential Hypertension ; Renin Angiotensin System ; Clinical Practice ; Management ; Control Rates ; Outcomes ; Effectiveness ; Long-Term ; Medicine
    ISSN: 0167-5273
    E-ISSN: 1874-1754
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  • 6
    Language: English
    In: American Heart Journal, October 2015, Vol.170(4), pp.787-795.e1
    Description: Drug-eluting stents (DES) improve outcomes in elderly patients with small coronary artery disease compared with bare-metal stents (BMS), but randomized data in elderly patients in need of large coronary stents are not available. Planned secondary analysis of patients ≥75 years recruited to the “BASKET-PROVE” trial, in which 2,314 patients undergoing percutaneous coronary intervention for large (≥3.0 mm) native vessel disease were randomized 2:1 to DES (everolimus- vs sirolimus-eluting stents 1:1) versus BMS. All patients received 12 months of dual antiplatelet therapy. The primary end point was a composite of cardiac death or nonfatal myocardial infarction at 2 years. Comparison of DES versus BMS among 405 patients ≥75 years showed significantly lower rates of the primary end point for DES (5.0% vs 11.6%; hazard ration (HR) 0.64 [0.44-0.91]; = .014). Rates of nonfatal myocardial infarction (1.2% vs 5.5%, hazard ration (HR) 0.44 [0.21-0.83]; = .009), all-cause death (7.4% vs 14.4%; HR 0.7 [0.51-0.95]; = .02), and target vessel revascularization (TVR) (2.3% vs 6.2%; HR 0.59 [0.34-0.99]; = .046) were also lower, whereas stent thrombosis and bleeding rates were similar. In contrast, among patients 〈75 years (n = 1,909), the only significant benefit of DES was a reduced rate of TVR (4.0% vs 8.7%, HR 0.66 [0.55-0.80]; 〈 .0001). In patients ≥75 years requiring large (≥3.0 mm) coronary stents, use of DES was beneficial compared with BMS and reduced the rate of ischemic events, mortality, and TVR. These data suggest that DES should be preferred over BMS in elderly patients.
    Keywords: Medicine
    ISSN: 0002-8703
    E-ISSN: 1097-6744
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  • 7
    In: Circulation, 2015, Vol.131(1), pp.74-81
    Description: BACKGROUND—: Biodegradable-polymer drug-eluting stents (BP-DES) were developed to be as effective as second-generation durable-polymer drug-eluting stents (DP-DES) and as safe 〉1 year as bare-metal stents (BMS). Thus, very late stent thrombosis (VLST) attributable to durable polymers should no longer appear. METHODS AND RESULTS—: To address these early and late aspects, 2291 patients presenting with acute or stable coronary disease needing stents ≥3.0 mm in diameter between April 2010 and May 2012 were randomly assigned to biolimus-A9–eluting BP-DES, second-generation everolimus-eluting DP-DES, or thin-strut silicon-carbide–coated BMS in 8 European centers. All patients were treated with aspirin and risk-adjusted doses of prasugrel. The primary end point was combined cardiac death, myocardial infarction, and clinically indicated target-vessel revascularization within 2 years. The combined secondary safety end point was a composite of VLST, myocardial infarction, and cardiac death. The cumulative incidence of the primary end point was 7.6% with BP-DES, 6.8% with DP-DES, and 12.7% with BMS. By intention-to-treat BP-DES were noninferior (predefined margin, 3.80%) compared with DP-DES (absolute risk difference, 0.78%; −1.93% to 3.50%; P for noninferiority 0.042; per protocol P=0.09) and superior to BMS (absolute risk difference, −5.16; −8.32 to −2.01; P=0.0011). The 3 stent groups did not differ in the combined safety end point, with no decrease in events 〉1 year, particularly VLST with BP-DES. CONCLUSIONS—: In large vessel stenting, BP-DES appeared barely noninferior compared with DP-DES and more effective than thin-strut BMS, but without evidence for better safety nor lower VLST rates 〉1 year. Findings challenge the concept that durable polymers are key in VLST formation. CLINICAL TRIAL REGISTRATION—: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01166685.
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 8
    Language: English
    In: The Lancet, 13 December 2014, Vol.384(9960), pp.2111-2122
    Description: Refinements in stent design affecting strut thickness, surface polymer, and drug release have improved clinical outcomes of drug-eluting stents. We aimed to compare the safety and efficacy of a novel, ultrathin strut cobalt-chromium stent releasing sirolimus from a biodegradable polymer with a thin strut durable polymer everolimus-eluting stent. We did a randomised, single-blind, non-inferiority trial with minimum exclusion criteria at nine hospitals in Switzerland. We randomly assigned (1:1) patients aged 18 years or older with chronic stable coronary artery disease or acute coronary syndromes undergoing percutaneous coronary intervention to treatment with biodegradable polymer sirolimus-eluting stents or durable polymer everolimus-eluting stents. Randomisation was via a central web-based system and stratified by centre and presence of ST segment elevation myocardial infarction. Patients and outcome assessors were masked to treatment allocation, but treating physicians were not. The primary endpoint, target lesion failure, was a composite of cardiac death, target vessel myocardial infarction, and clinically-indicated target lesion revascularisation at 12 months. A margin of 3·5% was defined for non-inferiority of the biodegradable polymer sirolimus-eluting stent compared with the durable polymer everolimus-eluting stent. Analysis was by intention to treat. The trial is registered with , number . Between Feb 24, 2012, and May 22, 2013, we randomly assigned 2119 patients with 3139 lesions to treatment with sirolimus-eluting stents (1063 patients, 1594 lesions) or everolimus-eluting stents (1056 patients, 1545 lesions). 407 (19%) patients presented with ST-segment elevation myocardial infarction. Target lesion failure with biodegradable polymer sirolimus-eluting stents (69 cases; 6·5%) was non-inferior to durable polymer everolimus-eluting stents (70 cases; 6·6%) at 12 months (absolute risk difference −0·14%, upper limit of one-sided 95% CI 1·97%, p for non-inferiority 〈0·0004). No significant differences were noted in rates of definite stent thrombosis (9 [0·9%] 4 [0·4%], rate ratio [RR] 2·26, 95% CI 0·70–7·33, p=0·16). In pre-specified stratified analyses of the primary endpoint, biodegradable polymer sirolimus-eluting stents were associated with improved outcome compared with durable polymer everolimus-eluting stents in the subgroup of patients with ST-segment elevation myocardial infarction (7 [3·3%] 17 [8·7%], RR 0·38, 95% CI 0·16–0·91, p=0·024, p for interaction=0·014). In a patient population with minimum exclusion criteria and high adherence to dual antiplatelet therapy, biodegradable polymer sirolimus-eluting stents were non-inferior to durable polymer everolimus-eluting stents for the combined safety and efficacy outcome target lesion failure at 12 months. The noted benefit in the subgroup of patients with ST-segment elevation myocardial infarction needs further study. Clinical Trials Unit, University of Bern, and Biotronik, Bülach, Switzerland.
    Keywords: Medicine
    ISSN: 0140-6736
    E-ISSN: 1474-547X
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  • 9
    Language: English
    In: The American Journal of Cardiology, 15 February 2017, Vol.119(4), pp.501-507
    Description: Long-term clinical outcomes of new-generation drug-eluting stents in complex anatomic and clinical settings are not well defined. This study assessed the impact of patient and lesion complexity on 2-year outcomes after coronary revascularization with ultrathin strut biodegradable-polymer (BP) sirolimus-eluting stents (SES) versus durable-polymer (DP) everolimus-eluting stents (EES). In a prespecified analysis of the BIOSCIENCE randomized trial ( ), complex patients (911 of 2,119; 43%) were defined by the presence of acute ST-elevation myocardial infarction (MI); left ventricular ejection fraction ≤30%; renal dysfunction; insulin-treated diabetes; treatment of ostial lesion, bypass graft, unprotected left main lesion; or 3-vessel intervention. The primary end point was target lesion failure (TLF), a composite of cardiac death, target vessel MI, and clinically indicated target lesion revascularization. At 2 years, complex compared with simple patients had a greater risk of TLF (14.5% vs 7.4%, risk ratio 2.05, 95% confidence interval 1.56 to 2.69; p 〈0.001). The difference was sustained beyond 1 year on landmark analysis. Complex patients had higher rates of the patient-oriented composite end point of death, any MI, or any revascularization (23% vs 14.4%; p 〈0.001) as well as definite stent thrombosis (1.6% vs 0.4%, p = 0.006). There were no differences in TLF and patient-oriented composite end point between the BP-SES versus DP-EES, consistently among simple and complex patients. In conclusion, patient and lesion complexity had a durable adverse impact on clinical outcomes throughout 2 years of follow-up in this all-comers randomized trial. Safety and efficacy of new-generation BP-SES and DP-EES were comparable, irrespective of complexity status.
    Keywords: Medicine
    ISSN: 0002-9149
    E-ISSN: 1879-1913
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  • 10
    Language: English
    In: PLoS ONE, 01 January 2018, Vol.13(6), p.e0199313
    Description: This study evaluates the use of a mental health mobile clinic to overcome two major challenges to the provision of mental healthcare in resource-limited settings: the shortage of trained specialists; and the need to improve access to safe, effective, and culturally sound care in community settings. Employing task-shifting and supervision, mental healthcare was largely delivered by trained, non-specialist health workers instead of specialists. A retrospective chart review of 318 unduplicated patients assessed and treated during the mobile clinic's first two years (January 2012 to November 2013) was conducted to explore outcomes. These data were supplemented by a quality improvement questionnaire, illustrative case reports, and a qualitative interview with the mobile clinic's lead community health worker. The team evaluated an average of 42 patients per clinic session. The most common mental, neurological, or substance abuse (MNS) disorders were depression and epilepsy. Higher follow-up rates were seen among those with diagnoses of bipolar disorder and neurological conditions, while those with depression or anxiety had lower follow-up rates. Persons with mood disorders who were evaluated on at least two separate occasions using a locally developed depression screening tool experienced a significant reduction in depressive symptoms. The mental health mobile clinic successfully treated a wide range of MNS disorders in rural Haiti and provided care to individuals who previously had no consistent access to mental healthcare. Efforts to address these common barriers to the provision of mental healthcare in resource-limited settings should consider supplementing clinic-based with mobile services.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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