scholarly journals Efficacy of Probucol on cognitive function in Alzheimers disease: Study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA Study)

2021 ◽  
Author(s):  
Virginie Lam ◽  
Roger Clarnette ◽  
Roslyn Francis ◽  
Michael Bynevelt ◽  
Gerald Watts ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Plasma Concentrations ◽  
Peripheral Circulation ◽  
Epidemiological Studies ◽  
Primary Objective ◽  
Alzheimers Disease ◽  
Double Blind ◽  
Lowering Drug ◽  
Disease Study ◽  
Brain Microvasculature

Preclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid-beta (Aβ) in the peripheral circulation is causally related to the development of Alzheimers disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-Aβ compromises the brain microvasculature, resulting in extravasation and retention of the lipoprotein-Aβ moiety. The latter results in an inflammatory response and neurodegeneration ensues. Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-Aβ secretion, concomitant with maintaining blood-brain-barrier function and suppressing neurovascular inflammation. Probucol has also been shown to protect cognitive function in dietary-induced amyloidogenic mice. This protocol details the Probucol in Alzheimers Study (PIA-study), a double-blind, randomised, placebo-controlled drug intervention trial investigating if Probucol attenuates cognitive decline in patients with mild-to-moderate AD. Objectives: The primary objective of the 104-week study is to assess whether Probucol supports cognitive function and delays brain atrophy in AD patients. A secondary objective is to determine whether Probucol treatment will reduce cerebral amyloid burden.

Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Ex Vivo ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Vaginal Ring ◽  
Vaginal Fluid ◽  
Cervical Tissue ◽  
Double Blind ◽  
Group A ◽  
Group B ◽  
Anti Hiv

Objectives: Self-administered vaginal rings are a promising method for delivery of topical anti-HIV microbicidesand might offer an adherence advantage over daily or coitally-dependent dosage forms such as gels. This trialassessed the safety and pharmacokinetic aspects of the Dapivirine Vaginal Ring-004 when worn as multiple rings oversequential periods of ring use by healthy, sexually-active, HIV-negative women.Methods: This double-blind trial was conducted among 48 women (18-40 years). Participants were randomlyassigned to two groups (A or B) and received (3:1) either the dapivirine or a placebo vaginal ring. Group A used tworings over a 56-day period and Group B used three rings over a 57-day period. Safety evaluations were conductedthroughout the trial. Dapivirine concentrations were measured in plasma, vaginal fluid and cervical tissue samplescollected during and after the 56 days (Group A) or 57 days (Group B) of vaginal ring use.Results: Ring-004 was safe and well tolerated in all participants. The pharmacokinetic profile demonstrated arapid increase in plasma and vaginal fluid concentrations and achieved concentrations in vaginal fluids and cervicaltissue well above the in vitro IC99 in cervical tissue (3.3 ng/mL) that were sustained for a 28 to 35-day ring use period(approximately 3000 times higher in vaginal fluids and 14 -1000 times higher in cervical tissue). Drug levels wereassociated with significant inhibitory activity of genital secretions against HIV ex vivo, a biomarker of pharmacodynamics.Individual plasma dapivirine concentrations did not exceed 553 pg/mL and were well below plasma concentrations atthe maximum tolerated dose for oral treatment (mean Cmax 2286 ng/mL).Conclusions: The consecutive use of several rings over a period of up to 57 days was safe and well tolerated, andPK data indicate that a single Ring-004 is likely to be protective for at least 35 days.

scholarly journals Incidence of Kawasaki disease before and during the COVID-19 pandemic: a retrospective cohort study in Japan

2021 ◽  
Vol 5 (1) ◽  
pp. e001034
Author(s):  
Kyohei Iio ◽  
Kousaku Matsubara ◽  
Chisato Miyakoshi ◽  
Kunitaka Ota ◽  
Rika Yamaoka ◽  
...  
Keyword(s):  
Cohort Study ◽  
Kawasaki Disease ◽  
Infectious Diseases ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Bacterial Infections ◽  
Epidemiological Studies ◽  
Primary Objective ◽  
Temporal Association ◽  
Difference In Difference

BackgroundEpidemiological studies in Kawasaki disease (KD) have suggested infectious aetiology. During the COVID-19 pandemic, measures for mitigating SARS-CoV-2 transmission also suppress the circulation of other contagious microorganisms. The primary objective is to compare the number and incidence of KD before and during the COVID-19 pandemic in Japan, and the secondary objective is to investigate temporal association between the KD epidemiology and activities of SARS-CoV-2 and other viral and bacterial infections.MethodsA retrospective cohort study was conducted between 2016 and 2020 in Kobe, Japan. We collected information of hospitalised KD children in Kobe. Child population was identified through the resident registry system. Activity of COVID-19 and 11 other infectious diseases was derived from a public health monitoring system. Monthly change of KD incidence was analysed using a difference-in-difference regression model.ResultsThroughout the study period, 1027 KD children were identified. KD had begun to decline in April 2020, coinciding with the beginning of the COVID-19 pandemic. The number of KD cases (n=66) between April and December 2020 was 40% of the average in the same period in 2016–2019 (165/year). Annual KD incidence was 315, 300, 353, 347 and 188/100 000 children aged 0–4 years in 2016–2020, respectively. The difference-in-difference value of KD incidence was significantly reduced in the fourth quarter in 2020 (−15.8, 95% CI −28.0 to −3.5), compared with that in 2016–2019. Sentinel surveillance showed a marked decrease of all infectious diseases except exanthema subitum after the beginning of the COVID-19 pandemic. There were 86 COVID-19 cases aged <10 years and no KD children associated with COVID-19.ConclusionThis study showed that the number and incidence of KD was dramatically reduced during the COVID-19 pandemic in Japan. This change was temporally associated with decreased activities of various infectious diseases other than COVID-19, supporting the hypothesis of infection-triggered pathogenesis in KD.

scholarly journals Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ekaterina Alexeeva ◽  
Gerd Horneff ◽  
Tatyana Dvoryakovskaya ◽  
Rina Denisova ◽  
Irina Nikishina ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Controlled Trial ◽  
Randomized Study ◽  
Primary Objective ◽  
Disease State ◽  
Inactive Disease ◽  
Open Label ◽  
Standard Regimen ◽  
Double Blind ◽  
Early Combination Therapy

Abstract Background Remission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease. Methods A multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit. Results By intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/−IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14–32) and 32 (24–40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients. Conclusions Early combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.

Effects of Folic Acid Combined with DHA Supplementation on Cognitive Function and Amyloid-β-Related Biomarkers in Older Adults with Mild Cognitive Impairment by a Randomized, Double Blind, Placebo-Controlled Trial

2021 ◽  
pp. 1-13
Author(s):  
Dong Bai ◽  
Junting Fan ◽  
Mengyue Li ◽  
Cuixia Dong ◽  
Yiming Gao ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Folic Acid ◽  
Mild Cognitive Impairment ◽  
Cognitive Function ◽  
Digit Span ◽  
Controlled Trial ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Double Blind ◽  
Full Scale Intelligence Quotient

Background: The neuroprotective benefits of combined folic acid and docosahexaenoic acid (DHA) on cognitive function in mild cognitive impairment (MCI) patients are suggested but unconfirmed. Objective: To explore the effects of 6-month folic acid + DHA on cognitive function in patients with MCI. Methods: Our randomized controlled trial (trial number ChiCTR-IOR-16008351) was conducted in Tianjin, China. We divided 160 MCI patients aged >  60 years into four regimen groups randomly: folic acid (0.8 mg/day) + DHA (800 mg/day), folic acid (0.8 mg/day), DHA (800 mg/day), and placebo, for 6 months. Cognitive function and blood amyloid-β peptide (Aβ) biomarker levels were measured at baseline and 6 months. Cognitive function was also measured at 12 months. Results: A total of 138 patients completed this trial. Folic acid improved the full-scale intelligence quotient (FSIQ), arithmetic, and picture complement scores; DHA improved the FSIQ, information, arithmetic, and digit span scores; folic acid + DHA improved the arithmetic (difference 1.67, 95% CI 1.02 to 2.31) and digital span (1.33, 0.24 to 2.43) scores compared to placebo. At 12 months, all scores declined in the intervention groups. Folic acid and folic acid + DHA increased blood folate (folic acid + DHA: 7.70, 3.81 to 11.59) and S-adenosylmethionine (23.93, 1.86 to 46.00) levels and reduced homocysteine levels (–6.51, –10.57 to –2.45) compared to placebo. DHA lower the Aβ40 levels (–40.57, –79.79 to –1.35) compared to placebo (p <  0.05), and folic acid + DHA reduced the Aβ42 (–95.59, –150.76 to –40.43) and Aβ40 levels (–45.75, –84.67 to –6.84) more than DHA (p <  0.05). Conclusion: Folic acid and DHA improve cognitive function and reduce blood Aβ production in MCI patients. Combination therapy may be more beneficial in reducing blood Aβ-related biomarkers.

scholarly journals Rationale and Design of BeatNF2 Trial: A Clinical Trial to Assess the Efficacy and Safety of Bevacizumab in Patients with Neurofibromatosis Type 2 Related Vestibular Schwannoma

2021 ◽  
Vol 28 (1) ◽  
pp. 726-739
Author(s):  
Masazumi Fujii ◽  
Masao Kobayakawa ◽  
Kiyoshi Saito ◽  
Akihiro Inano ◽  
Akio Morita ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Neurofibromatosis Type ◽  
Primary Objective ◽  
Neurofibromatosis Type 2 ◽  
Efficacy And Safety ◽  
Multicenter Clinical Trial ◽  
Double Blind ◽  
Hearing Function ◽  
Initial Intervention

Neurofibromatosis type 2 (NF2) causes bilateral vestibular schwannomas (VSs), leading to deafness. VS is treated by surgery or radiation, but neither treatments prevent hearing loss. Bevacizumab was found to be effective in suppressing the tumor’s growth and may help to improve hearing. We are conducting a randomized, double-blind, multicenter clinical trial to verify the efficacy and safety of bevacizumab in NF2-related VS. The primary objective is to evaluate the efficacy of bevacizumab in improving hearing in the affected ear. One of the secondary objectives is to evaluate bevacizumab’s efficacy in rechallenge treatment in relapsed cases. Sixty patients will randomly receive either bevacizumab or a placebo and will be clinically observed for 48 weeks in the initial intervention phase. In the first half (24 weeks), they will receive either 5 mg/kg of bevacizumab or a placebo drug. In the second half, all patients will receive 5 mg/kg of bevacizumab. If hearing function deteriorated in a patient who had shown improvement during the first phase, a rechallenge dose with bevacizumab would be offered.

Tonabersat, a Gap-Junction Modulator: Efficacy and Safety in Two Randomized, Placebo-Controlled, Dose-Ranging Studies of Acute Migraineceph

Cephalalgia ◽  
2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 17-27 ◽  
Author(s):  
SD Silberstein ◽  
J Schoenen ◽  
H Göbel ◽  
HC Diener ◽  
AH Elkind ◽  
...  
Keyword(s):  
Adverse Events ◽  
North American ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Plasma Concentrations ◽  
International Study ◽  
Maximum Plasma ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Dose Ranging

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

Moderate to heavy infections ofTrichuris trichiuraaffect cognitive function in Jamaican school children

Parasitology ◽  
1992 ◽  
Vol 104 (3) ◽  
pp. 539-547 ◽  
Author(s):  
C. Nokes ◽  
S. M. Grantham-McGregor ◽  
A. W. Sawyer ◽  
E. S. Cooper ◽  
B. A. Robinson ◽  
...  
Keyword(s):  
Cognitive Function ◽  
School Children ◽  
Cognitive Functions ◽  
Short Term Memory ◽  
Control Group ◽  
Long Term Memory ◽  
Double Blind ◽  
Term Memory ◽  
Confounding Variables ◽  
Placebo Trial

A double-blind placebo trial was conducted to determine the effect of moderate to high loads ofTrichuris trichiura(whipworm) infection on the cognitive functions of 159 school children (age 9–12 years) in Jamaica. Infected children were randomly assigned to Treatment or Placebo groups. A third group of randomly selected uninfected children were assigned to a Control for comparative purposes. The improvement in cognitive function was evaluated using a stepwise multiple linear regression, designed to control for any confounding variables. The expulsion of worms led to a significant improvement in tests of auditory short-term memory (P< 0.02;P< 0.01), and a highly significant improvement in the scanning and retrieval of long-term memory (P< 0.001). After 9 weeks, treated children were no longer significantly different from an uninfected Control group in these three tests of cognitive function. The removal ofT. trichiurawas more important thanAscaris lumbricoidesin determining this improvement. The results suggest that whipworm infection has an adverse effect on certain cognitive functions which is reversible by therapy.

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