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SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy  [PDF]
Kathryn J. Swoboda,Charles B. Scott,Thomas O. Crawford,Louise R. Simard,Sandra P. Reyna,Kristin J. Krosschell,Gyula Acsadi,Bakri Elsheik,Mary K. Schroth,Guy D'Anjou,Bernard LaSalle,Thomas W. Prior,Susan L. Sorenson,Jo Anne Maczulski,Mark B. Bromberg,Gary M. Chan,John T. Kissel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012140
Abstract: Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.
Science review: Carnitine in the treatment of valproic acid-induced toxicity – what is the evidence?
Philippe ER Lheureux, Andrea Penaloza, Soheil Zahir, Mireille Gris
Critical Care , 2005, DOI: 10.1186/cc3742
Abstract: Valproic acid (VPA) is a broad-spectrum antiepileptic drug (AED) that has been used for more than 30 years and is effective in the treatment of many different types of partial and generalized epileptic seizure. It is also prescribed to treat bipolar and schizoaffective disorders, social phobias and neuropathic pain, as well as for prophylaxis or treatment of migraine headache. VPA is a branched chain carboxylic acid (2-propylpentanoic acid or di-n-propylacetic acid), with a chemical structure very similar to that of short chain fatty acids (Fig. 1) [1].It is usually well tolerated. Indeed, VPA has fewer common side effects than do other AEDs, especially on behaviour and cognitive functions. Moreover, its adverse effects can often be minimized by initiating the drug slowly. However, rare serious complications may occur in some patients receiving VPA chronically, including fatal haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity (VHT) and VPA-induced hyperammonaemic encephalopathy (VHE). Some data suggest that VHT and VHE may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se.Acute VPA intoxication also occurs as a consequence of intentional or accidental overdose. Its incidence is increasing [2-5], probably because of the use of VPA in psychiatric disorders. It usually results in mild and self-limited central nervous system (CNS) depression. However, serious toxicity and even deaths have been reported [2,6,7].This paper reviews clinical evidence concerning the use of carnitine supplementation in the management of VHT, VHE and acute VPA poisoning. The potential benefit of carnitine supplementation in the prevention of VHT of VHE in the setting of chronic VPA dosing is also briefly discussed.VPA potentiates γ-aminobutyric acid (GABA)ergic functions in some specific brain regions that are thought to be involved in the control of seizure generation and propagation by increasing both GABA synthesis
Randomized, Double Blind, Placebo Controlled Trial of Hydrosoluble Ubiquinol and Carnitine in Patients with Heart Failure: Longterm Follow up Results in the Tishcon Study
Viola Mechirova, Adarsh Kumar, Ram B. Singh, Rakesh Sharma, Pronobesh Chattopadhyay, Mohammad A. Niaz, Amar S. Thakur, Jan Fedacko, Daniel Pella and Lekh Juneja
The Open Nutraceuticals Journal , 2008, DOI: 10.2174/1876396000801010001]
Abstract: Background: Carnitine and coenzyme Q10 are important for myocardial- mitochondrial function, and are deficient in patients with congestive heart failure. It is possible that supplementation with ubiquinol + l- carnitine may be protective among these patients, which may improve the quality of life and morbidity in heart failure. Subjects and Methods: In this controlled trial, the effects of carni Q-gel (L-carnitine fumarate 2250mg/day+hydrosoluble reduced ubiquinol 270mg/day) were examined for 15 months, in 31 (intervention group A) and another 31(control group B) patients with heart failure. Hospitalization due to worsening of heart failure, heart transplantation, and deaths were the combined endpoints. Results: Echo cardiographic ejection fraction was lower at baseline (38.8±7.6 v/s 39.3±6.7%) among both the group of patients, indicating class II- IV heart failure. Baseline serum CoQ10 (0.21±0.11 v/s 0.19+0.10ug/ml) was low, however, after 12 weeks, serum CoQ showed a significant increase in the carniqgel group compared to the control group (2.7±1.2 v/s 0.76±0.14 ug/ml). After treatment for 12 months, the quality of life visual analogous scale revealed that dyspnea, palpitation and fatigue and NYHA class II-III-IV, which were present at rest, in all the patients, at baseline, showed beneficial effects in the intervention group compared to the placebo group. Six minutes walk test showed that there was a significant greater benefit in walking in the intervention group (215±17.6 v/s 281±20.6, P<0.02) compared to the placebo group (218.4±17.6 v/s 245.7±17.1, P<0.05). A change in the symptom scale showed that majority of the patients had improvement in the intervention group compared to the control group respectively (28 v/s 12 patients, P<0.02). The deaths (3 vs 8) and hospitalizations due to worsening of heart failure (2 vs 11) among intervention and control group respectively, were significantly lower in the carniqgel group compared to the control group (5 vs 19, P<0.02). Five patients had nausea and vomiting, which were controlled with symptomatic treatment. Treatment with carniqgel was stopped after 12 months. Follow up after another 3 months (total 15 months) revealed that there was a worsening of NYHA class heart failure, as well as in the quality of life symptom scale and physical performance, assessed by 6-min walk test. There was a nonsignificant increase in hospitalizations in the intervention group after cessation of carniqgel softsules, compared to hospitalizations during the last 3 months. Conclusions: The findings indicate that treatment with ubiquinol +L-carnitine fumarate can cause a significant improvement in the quality of life, exercise capacity, as well as NYHA heart failure, which became worst after cessation of CoQ. There was a significant greater benefit in combined endpoints (hospitalization and deaths) in the intervention group than in the control group.
Altered Mental Status and Hyperammonemia after Overdose of Valproic Acid with Therapeutic Valproic Acid Concentrations  [PDF]
Evan S. Schwarz, Mark Thoelke
International Journal of Clinical Medicine (IJCM) , 2014, DOI: 10.4236/ijcm.2014.510075

Valproic acid is used in the treatment of multiple disorders. Adverse effects from valproic acid include hepatotoxicity, hypotension, metabolic acidosis, and decreased mental status. Valproic acid also causes hyperammonemia. Many physicians assume that this is due to a supratherapeutic valproic acid concentration; when in fact, it can occur with therapeutic valproic acid concentrations. This is because the hyperammonemia may be related to carnitine deficiency and disruption of the urea cycle, which can both occur with therapeutic valproic acid concentrations. We report a patient presented to the emergency department with alteration of mental status after ingesting valproic acid for recreational purposes, who developed hyperammonemia with a therapeutic valproic acid concentration.

L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN) - a randomized multicentre trial
Kraft Matthias,Kraft Kathleen,G?rtner Simone,Mayerle Julia
Nutrition Journal , 2012, DOI: 10.1186/1475-2891-11-52
Abstract: Background Cachexia, a >10% loss of body-weight, is one factor determining the poor prognosis of pancreatic cancer. Deficiency of L-Carnitine has been proposed to cause cancer cachexia. Findings We screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-centre, placebo-controlled, randomized and double-blinded trial to receive oral L-Carnitine (4 g) or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 ± 2,5 (SEM) kg. During treatment body-mass-index increased by 3,4 ± 1,4% under L-Carnitine and decreased ( 1,5 ± 1,4%) in controls (p < 0,05). Moreover, nutritional status (body cell mass, body fat) and quality-of-life parameters improved under L-Carnitine. There was a trend towards an increased overall survival in the L-Carnitine group (median 519 ± 50 d versus 399 ± 43 d, not significant) and towards a reduced hospital-stay (36 ± 4d versus 41 ± 9d,n.s.). Conclusion While these data are preliminary and need confirmation they indicate that patients with pancreatic cancer may have a clinically relevant benefit from the inexpensive and well tolerated oral supplementation of L-Carnitine.
Effects of Oral L-Carnitine Administration in Narcolepsy Patients: A Randomized, Double-Blind, Cross-Over and Placebo-Controlled Trial  [PDF]
Taku Miyagawa, Hiromi Kawamura, Mariko Obuchi, Asuka Ikesaki, Akiko Ozaki, Katsushi Tokunaga, Yuichi Inoue, Makoto Honda
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053707
Abstract: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in β-oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral l-carnitine for the treatment of narcolepsy, we performed a clinical trial administering l-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). l-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. l-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality and mental health subscales did not reach statistical significance between l-carnitine and placebo. This study suggests that oral l-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients. Trial Registration University hospital Medical Information Network (UMIN) UMIN000003760
Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy  [PDF]
Kathryn J. Swoboda, Charles B. Scott, Sandra P. Reyna, Thomas W. Prior, Bernard LaSalle, Susan L. Sorenson, Janine Wood, Gyula Acsadi, Thomas O. Crawford, John T. Kissel, Kristin J. Krosschell, Guy D'Anjou, Mark B. Bromberg, Mary K. Schroth, Gary M. Chan, Bakri Elsheikh, Louise R. Simard
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005268
Abstract: Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2–3 years, 29 SMA type II ages 2–14 years and 11 type III ages 2–31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p≤0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Δ7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p≤0.0036) and maximum ulnar CMAP scores (p≤0.0001) increased significantly. Conclusions While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects. Trial Registration ClinicalTrials.gov
Results of a single blind, randomized, placebo-controlled clinical trial to study the effect of intravenous L-carnitine supplementation on health-related quality of life in Indian patients on maintenance hemodialysis  [cached]
Rathod Rahul,Baig Mirza,Khandelwal P,Kulkarni S
Indian Journal of Medical Sciences , 2006,
Abstract: Background: Carnitine insufficiency is responsible for various co-morbid conditions in maintenance hemodialysis (MHD) patients. L-carnitine supplementation is expected to improve the quality of life (QoL) of patients on MHD. Aims: To study the effect of L-carnitine supplementation on QoL of Indian patients on MHD. Setting and Design: This was a single (patient) blind, randomized, placebo-controlled clinical trial conducted on patients on MHD attending hemodialysis unit of the study center. MaterialS and Methods: Twenty patients on MHD suffering from hemodialysis-related symptoms were randomly assigned to receive intravenous L-carnitine 20 mg/kg or placebo after every dialysis session for 8 weeks. SF36 (Short Form with 36 questions) score for QoL, laboratory investigations and dialysis related symptoms were recorded at baseline and after 8 weeks. Improvement in QoL, laboratory parameters and dialysis related symptoms in the two groups after 8 weeks was compared. Statistical analysis used: Depending on normality of data, unpaired T test or Mann Whitney U test was used for comparison of change (8 weeks-baseline) in SF36 scores and laboratory parameters observed in the two groups. Results: L-carnitine supplementation increased total SF36 score by 18.29 ± 12.71 (95% CI: 10.41 to 26) while placebo resulted in reduction in total SF36 score by 6.4 ± 16.39 (95% CI: -16.59 to 3.73). L-carnitine also resulted in significant increase in hemoglobin and serum albumin and decrease in serum creatinine as compared to placebo. More patients were relieved of dialysis related symptoms in L-carnitine group. Conclusion: Intravenous L-carnitine supplementation improves QoL in patients on MHD.
Effects of Oral L-Carnitine Supplementation on Lipid Profile, Anemia, and Quality of Life in Chronic Renal Disease Patients under Hemodialysis: A Randomized, Double-Blinded, Placebo-Controlled Trial
Afsoon Emami Naini,Mahnaz Moradi,Mojgan Mortazavi,Asghar Amini Harandi,Mehdi Hadizadeh,Farhad Shirani,Hamed Basir Ghafoori,Pardis Emami Naini
Journal of Nutrition and Metabolism , 2012, DOI: 10.1155/2012/510483
Abstract: In patients on maintenance hemodialysis several factors reduce the body stored carnitine which could lead to dyslipidemia, anemia, and general health in these patients. We evaluated the effect of oral L-carnitine supplementation on lipid profiles, anemia, and quality of life (QOL) in hemodialysis patients. In a randomized, double-blinded, placebo-controlled trial, end-stage renal disease (ESRD) patients on hemodialysis received either L-carnitine 1 g/d (=24) or placebo (27 patients) for 16 weeks. At the end of the study, there was a significant decrease in triglyceride (?31.1±38.7 mg/dL, =0.001) and a significant increase in HDL (3.7±2.8 mg/dL, <0.001) levels in the carnitine group. Decrease in total cholesterol (−6.6±16.0 mg/dL, =0.075) and increase in hemoglobin (0.7±1.7 g/dL, =0.081) concentrations in the carnitine group were not significant. There was no statistically significant changes in LDL in any group (>0.05). Erythropoietin dose was significantly decreased in both the carnitine (?4750±5772 mg, =0.001) and the placebo group (?2000±4296 mg, <0.05). No improvement was observed in QOL scores of two groups. In ESRD patients under maintenance hemodialysis, oral L-carnitine supplementation may reduce triglyceride and cholesterol and increase HDL and hemoglobin and subsequently reduce needed erythropoietin dose without effect on QOL.
A Pilot Clinical Trial on L-Carnitine Supplementation in Combination with Motivation Training: Effects on Weight Management in Healthy Volunteers  [PDF]
Satoshi Odo, Koji Tanabe, Masamitsu Yamauchi
Food and Nutrition Sciences (FNS) , 2013, DOI: 10.4236/fns.2013.42030

A 4-week low dosage (500 mg/day) L-carnitine supplementation in combination with motivation training was carried out in 24 overweight (BMI 25.8 - 26.6 kg/m2) Japanese males in the course of a double-blind randomized placebo-controlled study. L-carnitine motivated group showed significant body weight loss and a decrement of serum triglyceride level vs. the non-motivated placebo group. Serum adiponectin levels increased in both L-carnitine supplemented groups. The beneficial effects of L-carnitine were amplified by motivation training. For clinical evaluation of supplements, whose efficacy is potentially affected by inter-individual life style variability, supportive motivation training might be advisable for future clinical trials.

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