Ritalin Side Effects: Placebo Controlled Evaluation

Background:Dental anxiety is a relatively frequent problem that can lead to more serious problems such as a child entering a vicious cycle as he/she becomes reluctant to accept the required dental treatments. The aim of this randomized double-blind clinical trial study was to evaluate the anxiolytic and sedative effect of pregabalin in children.Materials and Methods:Twenty-five children were randomized to a double-blind placebo-controlled crossover clinical trial. Two visits were scheduled for each patient. At the first visit, 75 mg pregabalin or placebo was given randomly, and the alternative was administered at the next visit. Anxiolytic and sedative effects were measured using the visual analogue scale. The child's behavior was rated with the Frankl behavioral rating scale and the sedation level during the dental procedure was scored using the Ramsay sedation scale. The unpaired, two-tailed Student's t-test was used to compare the mean changes of visual analog scale (VAS) for anxiety in the pregabalin group with that of the placebo group. A repeated measures MANOVA model was used to detect differences in sedation level in the pregabalin and placebo groups regarding the interaction of 3-time measurements; sub-group analysis was performed using Student's t-test. The Mann–Whitney U-test was used to analyze the nonparametric data of the Frankl and Ramsay scales. A P < 0.05 was considered significant.Results:The reduction of the VAS-anxiety score from 2 h post-dose was statistically significant in the pregabalin group. From 2 h to 4 h post-dose, the VAS-sedation score increased significantly in the pregabalin group. The child's behavior rating was not significantly different between the groups. The number of “successful” treatment visits was higher in the pregabalin group compared to the placebo group.Conclusion:Significant anxiolytic and sedative effects can be anticipated 2 h after oral administration of pregabalin without serious side effects.

Nifedipine in chronic stable angina: A double-blind placebo-controlled crossover trial

We investigated the influence of 2 weeks of treatment with deprenyl on the acute effect of a single dose of 200 mg of L-dopa in a double-blind cross-over placebo-controlled trial in 16 parkinsonian patients with wearing-off phenomena. Deprenyl induced no significant benefit in the duration or the maximal improvement of L-dopa's effect. Moreover, deprenyl treatment did not improve the patient's motor status.

BackgroundThe objectives of this study are to determine the effects of regularly scheduled administration of paracetamol (acetaminophen) on quality of life (QoL), discomfort, pain and neuropsychiatric symptoms of persons with dementia living in long-term care facilities (LTCFs).MethodsA multicentre randomised double-blind placebo-controlled crossover trial for 13 weeks (January 2018 to June 2019) in 17 LTCFs across the west of the Netherlands. Inclusion criteria were age ≥ 65 years, (advanced) dementia and a moderate to low QoL, independent of the presence of pain (QUALIDEM ≤ 70). Exclusion criteria were the use of regular pain treatment, allergies to the study medication, severe liver disease, use of > 4 units of alcohol/day, weight < 50 kg and/or concomitant use of flucloxacillin. Participants received study medication (paracetamol/placebo) in two periods of 6 weeks each (1 week in between as a wash-out period). Randomisation decided in which order participants received paracetamol and placebo. Primary outcomes included QoL (QUALIDEM) and discomfort (DS-DAT), secondary outcomes included pain (MOBID-2) and neuropsychiatric symptoms (NPI-NH).ResultsNinety-five LTCF residents (mean age 83.9 years [SD 7.6], 57.9% females) were included. Repeated linear mixed models showed no difference in mean differences of QUALIDEM (paracetamol +1.3 [95% CI -1.0–3.5], placebo +1.5 [95% CI -0.7–3.8]), DS-DAT (paracetamol -0.1 [95% CI -1.4–1.2], placebo 0.6 [95 CI -0.7–1.8]), MOBID-2 (paracetamol 0.0 [95% CI -0.5–0.5], placebo -0.2 [95% CI -0.7–0.3]) and NPI-NH (paracetamol +1.5 [95% CI -2.3–5.4], placebo -2.1 [95% CI -6.0–1.7]) in favour of either paracetamol or placebo.ConclusionsCompared to placebo, paracetamol showed no positive effect on QoL, discomfort, pain and neuropsychiatric symptoms in persons with advanced dementia with low QoL. It is important to find out more specifically which individual persons with advanced dementia could benefit from pain treatment with paracetamol, and for clinicians to acknowledge that a good assessment, monitoring and multidomain approach is vital for improving QoL in this vulnerable group.Trial registrationNetherlands Trial Register NTR6766. Trial registration date: 20 October 2017

BackgroundIn an observational study in Geneva (Switzerland), we found that administering a standardized THC/CBD oil was feasible, safe, and beneficial in an elderly polymedicated population with severe dementia, behavioral troubles, and pain. Those findings need to be confirmed in a randomized clinical trial.ObjectivesThe MedCanDem trial is a randomized, double-blind cross-over placebo-controlled trial to study the efficacy of cannabinoids in improving painful symptoms during severe dementia disorders in patients living in long-term care facilities in Geneva. This manuscript describes the MedCanDem trial protocol.Materials and methodsParticipants will be patients suffering from severe dementia associated with pain and behavioral troubles and living in long-term care facilities. We selected five facilities specialized in caring for severely demented patients in Geneva (Switzerland). A total of 24 subjects will be randomized 1:1 to the sequence study intervention/placebo or the sequence placebo/study intervention. Patients will receive study intervention treatment or placebo for eight weeks, and then after a one-week wash-out, treatments will be inversed for another eight weeks. The intervention will be a standardized THC/CBD 1:2 oil extract, and the placebo will be a hemp seed oil. The primary outcome is the reduction from the baseline of the Cohen-Mansfield score; secondary outcomes include the reduction in the Doloplus scale, the reduction of rigidity, the monitoring of concomitant drugs prescription and de-prescription, the safety assessment, and a pharmacokinetic evaluation. The primary and secondary outcomes will be assessed at the baseline, after 28 days, and at the end of both study periods. In addition, safety laboratory analysis, pharmacokinetic evaluation, and therapeutic drug monitoring for the cannabinoids will be evaluated through a blood sample analysis conducted at the beginning and the end of both study periods.Discussion and conclusionThis study will allow us to confirm the clinical results observed during the observational study. It represents one of the few studies aiming to prove natural medical cannabis efficacy in a population of non-communicating patients with severe dementia, experimenting with behavioral troubles, pain, and rigidity.Trial registrationThe trial has Swissethics authorization (BASEC 2022-00999), and it is registered on clinicaltrials.gov (NCT05432206) and the SNCTP (000005168).

Anecdotal reports in Tourette's syndrome (TS) have suggested that marijuana (cannabis sativa) and delta-9-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive ingredient of marijuana, reduce tics and associated behavioral disorders. We performed a randomized double-blind placebo-controlled crossover single-dose trial of Delta(9)-THC (5.0, 7.5 or 10.0 mg) in 12 adult TS patients. Tic severity was assessed using a self-rating scale (Tourette's syndrome Symptom List, TSSL) and examiner ratings (Shapiro Tourette's syndrome Severity Scale, Yale Global Tic Severity Scale, Tourette's syndrome Global Scale). Using the TSSL, patients also rated the severity of associated behavioral disorders. Clinical changes were correlated to maximum plasma levels of THC and its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). Using the TSSL, there was a significant improvement of tics (p=0.015) and obsessive-compulsive behavior (OCB) (p = 0.041) after treatment with Delta(9)-THC compared to placebo. Examiner ratings demonstrated a significant difference for the subscore "complex motor tics" (p = 0.015) and a trend towards a significant improvement for the subscores "motor tics" (p = 0.065), "simple motor tics" (p = 0.093), and "vocal tics" (p = 0.093). No serious adverse reactions occurred. Five patients experienced mild, transient side effects. There was a significant correlation between tic improvement and maximum 11-OH-THC plasma concentration. Results obtained from this pilot study suggest that a single-dose treatment with Delta(9)-THC is effective and safe in treating tics and OCB in TS. It can be speculated that clinical effects may be caused by 11-OH-THC. A more long-term study is required to confirm these results.

BackgroundSome probiotics have shown efficacy for patients with irritable bowel syndrome (IBS). Lactobacillus (L.) plantarum MF1298 was found to have the best in vitro probiotic properties of 22 strains of lactobacilli. The aim of this study was to investigate the symptomatic effect of L. plantarum MF1298 in subjects with IBS. Primary outcome was treatment preference and secondary outcomes were number of weeks with satisfactory relief of symptoms and IBS sum score.MethodsThe design was a randomised double blind placebo-controlled crossover trial. 16 subjects with IBS underwent two three-week periods of daily intake of one capsule of 1010 CFU L. plantarum MF 1298 or placebo separated by a four-week washout period.ResultsThirteen participants (81%; 95% CI 57% to 93%; P = 0.012) preferred placebo to L. plantarum MF1298 treatment. The mean (SD) number of weeks with satisfactory relief of symptoms in the periods with L. plantarum MF1298 and placebo were 0.50 (0.89) and 1.44 (1.26), respectively (P = 0.006). IBS sum score was 6.44 (1.81) in the period with L. plantarum MF1298 treatment compared with 5.35 (1.77) in the period with placebo (P = 0.010). With a clinically significant difference in the IBS sum score of 2 in disfavour of active treatment, the number needed to harm was 3.7, 95% CI 2.3 to 10.9.ConclusionsThis trial shows for the first time an unfavourable effect on symptoms in subjects with IBS after intake of a potential probiotic.The trial registration numberClinical trials NCT00355810.

Sympathetic blockade is used in the management of complex regional pain syndromes in children, but there are no data on the efficacy or mechanism(s) by which it produces pain relief. The purpose of this study is to compare the efficacy of lidocaine administered by lumbar sympathetic to IV route. Under general anesthesia, children with unilateral lower limb complex regional pain syndromes received catheters along the lumbar sympathetic chain. In a double-blind placebo-controlled crossover design, patients received IV lidocaine and lumbar sympathetic saline or lumbar sympathetic lidocaine and IV saline. Spontaneous and evoked pain ratings and sensory thresholds were assessed before and after these two lidocaine/saline doses and between routes of lumbar sympathetic blockade and IV. Twenty-three patients, ages 10-18 yr, were enrolled. There was evidence for reduction of mean pain intensity of allodynia to brush (mean -1.4, 95% confidence interval [CI] -2.5 to -0.3) and to pinprick temporal summation (mean -1.3, 95% CI -2.5 to -0.2) with lidocaine treatment via the lumbar sympathetic blockade compared to IV route. Lumbar sympathetic blockade also produced significant reduction in pain intensity compared to pretreatment values of allodynia to brush, pinprick and pinprick temporal summation and verbal pain scores. IV lidocaine did not produce significant changes in spontaneous and evoked pain intensity measurements compared to pretreatment values. There were no carryover effects as assessed by route-by-period interaction. Under the conditions of this study, the results provide some direct evidence that a component of pain may be mediated by abnormal sympathetic efferent activity.

As the largest physician-owned private multispecialty healthcare practice in central and northern Wisconsin and one of the largest in the nation, Marshfield Clinic has a long-standing track record in scientific research to support its healthcare mission. The Clinic’s staff of 790 physicians serves over 40 regional centers in a largely rural setting in 80 clinical specialties and undertakes research in a broad range of disciplines. In addition, the Clinic’s Research Foundation employs a staff of scientists who collaborate with clinician investigators. A rich research environment pervades the Marshfield system, supported by a state-of-the-art informatics environment, access to an epidemiologically-defined study population for which detailed medical and demographic data are available, with its status as the largest population-based genetics repository in the USA. Not surprisingly, this rich research environment attracts researchers with a broad range of expertise and experience. An additional layer of complexity is added with multidisciplinary or multi-institutional research. Preparing competitive scientific grant proposals responsive to emerging public health priorities is especially daunting for individuals collaborating on interdisciplinary and translational projects who lack experience and traditional training in grantsmanship. New page limits and a revision of the peer review process at the National Institutes of Health have created new challenges, even for seasoned investigators. To assist researchers in navigating the process of preparing successful grant proposals in an increasingly competitive research environment, a full-service research infrastructure was established over time at the Clinic’s Research Foundation, including a Clinical Research Center, Epidemiological Study Center, Bioinformatics Research Center, Offices of Scientific Writing and Publication, Research Integrity and Protection, Sponsored Programs, and a Core Laboratory. However, coordinating assistance to busy clinicians proved challenging, and supplemental, conveniently-accessible resources were required by researchers for navigating the rich, but complex research environment. To this end, Marshfield Clinic Research Foundation personnel teamed up to create a comprehensive informatics-based resource, Research Mentor, designed to support both new and established investigators in successful grant writing and manuscript preparation. The overarching purpose envisioned for Research Mentor was to serve as an educational resource on scientific writing related to research and as a bridge to internal resources, policies, and documents. The concept was to have scientific writing specialists centralize access to these resources to save investigators valuable time scouring the web in search of support tools. In addition, for internal personnel and investigators at institutions collaboratively working on research projects with Marshfield investigators, access to forms, policies, and support service personnel is also provided. Thus, Research Mentor was created as a web-based interactive resource that would provide direct links to other web-based educational resources which promote grantsmanship and scientific publication on the internet. Institutional resources that support investigators and sponsored programs offices are not unique. As example, Duke University,1 Stanford University,2 and Virginia Polytechnic Institute and State University (Virginia Tech),3 all have websites for their Sponsored Programs/Research office that provide some online tutorials regarding grant writing, and Purdue’s ‘The Owl’4 offers assistance with various aspects of manuscript development. However, we found none as comprehensive in their scope as Research Mentor, in providing support from research conceptualization, grant development, and submission to manuscript preparation within the context of the institutional research environment. To facilitate access across its network of regional centers, Research Mentor was originally launched on Marshfield Clinic’s intranet in 2008. Partially in response to requests for access from external collaborators who appreciated its value, and following exhibition of its contents and capabilities at several national conferences, Research Mentor was transferred to its current internet website at http://www.marshfieldclinic.org/mcrf/researchmentor in 2010, where it is a publically available resource. Access to research-related services and personnel, however, must remain limited to Marshfield Clinic investigators and their collaborators in the context of specific collaborative efforts, due to workload constraints on service personnel.

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for paediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a 'responder', defined as ≥2 of: >50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (P < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (P < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (P < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention-deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.

Although, as yet, there is no specific treatment of epidermolysis bullosa (EB) simplex, anecdotal reports suggest the possible efficacy of one of the newer topical nonsteroidal anti-inflammatory agents, bufexamac. To determine whether bufexamac has any role in the management of this disease, a double-blind placebo-controlled crossover clinical trial was undertaken with ten patients (nine, Weber-Cockayne variant; one, generalized EB simplex). Each of the two preparations was applied four times daily during the 2 four-week treatment periods. Weekly assessments included counts of blisters, crusts, and erosions, and assessments of alterations in cutaneous pain, healing times, and activity times before further blister formation. Although considerable variability in individual responses was noted, no significant difference was detectable between the active drug and its matched placebo. On the basis of these findings, it was concluded that 5% topical bufexamac is ineffective in the treatment of EB simplex.

BackgroundPrevious research has shown the oxidizing properties and microbiological efficacies of chlorine dioxide (ClO2), however, its clinical efficacies on oral malodor have been evaluated only with organoleptic measurements (OM) or sulphide monitors. No clinical studies have investigated the inhibitory effects of ClO2 on volatile sulfur compounds (VSCs) using gas chromatography (GC). The aim of this study was to assess the inhibitory effects of a mouthwash containing ClO2 on morning oral malodor using OM and GC.MethodsA randomized, double blind, crossover, placebo-controlled clinical trial was conducted among 15 healthy male volunteers, who were divided into 2 groups. In the first test phase, the group 1 subjects (N = 8) were instructed to rinse with the experimental mouthwash containing ClO2, and those in group 2 (N = 7) to rinse with the placebo mouthwash without ClO2. In the second test, phase after a one week washout period, each group used the opposite mouthwash.Oral malodor was evaluated before rinsing, right after rinsing and every 30 minutes up to 4 hours with OM, and concentrations of hydrogen sulfide (H2S), methyl mercaptan (CH3SH) and dimethyl sulfide ((CH3)2S), the main VSCs of human oral malodor, were evaluated with GC.ResultsThe baseline oral condition in the subjects in the 2 groups did not differ significantly. The mouthwash containing ClO2 improved morning bad breath according to OM and reduced concentrations of H2S, CH3SH and (CH3)2S according to GC up to 4 hours after rinsing. OM scores with ClO2 were significantly lower than those without ClO2 at all examination times. Significant reductions in the concentrations of the three kinds of VSCs measured by GC were also evident at all examination times. The concentrations of the three gases with ClO2 were significantly lower than those without ClO2 at most examination times.ConclusionIn this explorative study, ClO2 mouthwash was effective at reducing morning malodor for 4 hours when used by healthy subjects.Trial registrationClinicalTrials.gov NCT00655772

Background Proton pump inhibitors (PPIs) are commonly prescribed alongside Aspirin and Clopidogrel to reduce the risk of gastrointestinal bleeding. However, the latest European Society of Cardiology (ESC) diabetes guidelines recommend against the concomitant use of Omeprazole and Clopidogrel due to potential drug interactions that may reduce Clopidogrel’s antiplatelet effect. Despite this warning, resource-limited settings such as Thailand continue to widely use this combination, even among diabetic populations. The applicability of this recommendation in Thailand remains uncertain, warranting further investigation. Objective To assess platelet function, specifically platelet reactivity measured as P2Y12 reaction units (PRU), in diabetic patients on Aspirin and Clopidogrel with or without Omeprazole using the VerifyNow P2Y12 assay. Methods A double-blind, randomised, placebo-controlled cross-over trial was conducted in diabetic patients with coronary artery disease (CAD) on Aspirin 81 mg/day and Clopidogrel 75 mg/day without Omeprazole for over two weeks. Participants were randomised to receive either Omeprazole 20 mg daily or a placebo for two weeks, followed by a crossover for another two weeks. PRU was assessed at baseline, two weeks, and post-crossover. The primary outcome was the mean PRU change between Omeprazole and placebo. Secondary outcomes included changes in Clopidogrel responder status (non-responder: PRU &amp;gt;208) Results: Between August 2024 and January 2025, 50 patients were enrolled in this study. All of them had hypertension and dyslipidaemia. The time since events or revascularisation was 7 months (IQR 2–14), and age was 67 years (IQR 60–67). 58 % were male, with an HbA1c of 6.7% (IQR 6.4–8.1). No significant carryover effects were observed. Omeprazole co-administration significantly increased mean PRU by 18.4 (10.2%, p = 0.002) compared to baseline. The adjusted mean PRU still showed a rise of 20.7 (p = 0.002). The number of Clopidogrel non-responders increased from 22 (44%) to 28 (56%) after Omeprazole use, with 7 (25%) of responders transitioning to non-responders. Higher BMI was significantly associated with an increased likelihood of non-responder status (OR = 1.3, p = 0.02). Conclusions In diabetic patients, a high proportion were non-responders prior to Omeprazole administration, and one-quarter of the initial responders transitioned to non-responder status. Therefore, Clopidogrel and Omeprazole should be avoided in this setting. However, if use is necessary, screening for Clopidogrel response status is recommended before co-prescription, and close monitoring is advised.Difference means PRU change among group Responder status change

PurposeDietary nitrate supplementation increases nitric oxide (NO) bioavailability and reduces blood pressure (BP). Inter-individual differences in these responses are suspected but have not been investigated using robust designs, e.g., replicate crossover, and appropriate statistical models. We examined the within-individual consistency of the effects of dietary nitrate supplementation on NO biomarkers and BP, and quantified inter-individual response differences.MethodsFifteen healthy males visited the laboratory four times. On two visits, participants consumed 140 ml nitrate-rich beetroot juice (~ 14.0mmol nitrate) and, on the other two visits, they consumed 140 ml nitrate-depleted beetroot juice (~ 0.03mmol nitrate). Plasma nitrate and nitrite concentrations were measured 2.5 h post-supplementation. BP was measured pre- and 2.5 h post-supplementation. Between-replicate correlations were quantified for the placebo-adjusted post-supplementation plasma nitrate and nitrite concentrations and pre-to-post changes in BP. Within-participant linear mixed models and a meta-analytic approach estimated participant-by-condition treatment response variability.ResultsNitrate-rich beetroot juice supplementation elevated plasma nitrate and nitrite concentrations and reduced systolic (mean:-7mmHg, 95%CI: -3 to -11mmHg) and diastolic (mean:-6mmHg, 95%CI: -2 to -9mmHg) BP versus placebo. The participant-by-condition interaction response variability from the mixed model was ± 7mmHg (95%CI: 3 to 9mmHg) for systolic BP and consistent with the treatment effect heterogeneity t = ± 7mmHg (95%CI: 5 to 12mmHg) derived from the meta-analytic approach. The between-replicate correlations were moderate-to-large for plasma nitrate, nitrite and systolic BP (r = 0.55 to 0.91).ConclusionsThe effects of dietary nitrate supplementation on NO biomarkers and systolic BP varied significantly from participant to participant. The causes of this inter-individual variation deserve further investigation. Trial registration: https://clinicaltrials.gov/study/NCT05514821.

We aimed to test the hypothesis, that octreotide has a suppressive effect on unstimulated and TRH-stimulated PRL levels in both normo- and hyperprolactinaemic acromegalic patients, and besides to evaluate the effect of octreotide on unstimulated TSH and thyroid hormones. The present study is a doubleblind placebo-controlled cross-over trial; the 12 acromegalic patients were treated with octreotide or placebo (300 micrograms/d) for 4 weeks separated by a 12 weeks washout period. Before and after each 4 weeks period a TRH-test (200 micrograms iv) was performed and serum GH and PRL levels were determined. Serum TSH and thyroid hormones were determined after 0, 2, 3, and 4 weeks. In the whole group unstimulated PRL levels were 18 micrograms/l +/- 5 before and 7 micrograms/l +/- 1 during octreotide treatment (p < 0.01). The PRL lowering effect of octreotide was significantly more pronounced in hyperprolactinemic patients compared to normoprolactinaemic patients (p < 0.05). Patients with the highest pretreatment PRL levels had the most pronounced percentage suppression of unstimulated PRL levels during octreotide treatment. Eight out of 12 patients had a TRH-stimulated PRL response > or = 100%, both during placebo and octreotide treatment, but in the group as a whole maximal TRH-stimulated PRL levels were suppressed during octreotide treatment, PRL levels were 50 micrograms/l +/- 20 before and 18 micrograms/l +/- 3 during octreotide treatment (p < 0.05). Unstimulated GH levels were 48 mU/l +/- 15 before and 13 mU/l +/- 2 during octreotide treatment (p < 0.01). Serum total T3 was significantly reduced during octreotide treatment (p < 0.05); serum TSH, total T4 or free T4 index were not significantly changed during treatment. We conclude that patients with acromegaly and hyperprolactinemia will normalize PRL levels during 4 weeks of octreotide treatment and octreotide will reduce total T3 levels in acromegalic patients.