Clinical Studies

Treatment of Chronic Fatigue Syndrome and Fibromyalgia with D-Ribose– An Open-label, Multicenter Study (The Open Pain Journal, 2012)

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Jacob Teitelbaum*,1, Janelle Jandrain2 and Ryan McGrew3

The Open Pain Journal, 2012, 5, 32-37, 1Kona Research Center, 76-6326 Kaheiau St, Kailua Kona, Hawaii 96740, and Fibromyalgia and Fatigue Centers, Addison, Texas, USA; 2,3Schwabe North America, 3051 West Maple Loop Dr., Lehi, UT 84043, USA

Abstract: Objectives: Chronic Fatigue Syndrome and Fibromyalgia (CFS/FMS) are debilitating syndromes affecting ~2-4% of the population. Although they are heterogeneous conditions associated with many triggers, they appear to have the common pathology of being associated with impaired energy metabolism. As D-ribose has been shown to increase cellular energy synthesis, and was shown to significantly improve clinical outcomes in CFS/FMS in an earlier study, we hypothesized that giving D-ribose would improve function in CFS/FMS patients.

Design, Location, and Subjects: An open-label, unblinded study in which 53 US clinics enrolled 257 patients who had been given a diagnosis of CFS/FMS by a health practitioner. Interventions: All subjects were given D-ribose (Corvalen), a naturally occurring pentose carbohydrate, 5-g TID for 3 weeks. Outcome measures: All patients were assessed at baseline (1 week before treatment), and after 1,2, & 3 weeks using a Visual Analog Scale(1-7 points) rating energy, sleep, cognitive function, pain and overall well being.

Results: 203 patients completed the 3 week treatment trial. D-ribose treatment led to both statistically (p<.0001) and clinically highly important average improvements in all categories:

    • 61.3 % increase in energy
    • 37% increase in overall well being
    • 29.3% improvement in sleep
    • 30% improvement in mental clarity
    • 15.6% decrease in pain

Improvement began in the first week of treatment, and continued to increase at the end of the 3 weeks of treatment. The D-ribose was well tolerated. Conclusions: In this multicenter study, D-ribose resulted in markedly improved energy levels, sleep, mental clarity, pain relief, and wellbeing in patients suffering from fibromyalgia and chronic fatigue syndrome. clinicaltrials.gov NCT01108549.

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A targeted metabolic protocol with D-ribose for off-pump coronary artery bypass procedures: a retrospective analysis (Therapeutic Advances in Cardiovascular Disease, 2011)

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David J. Perkowski, Susan Wagner, Joseph R. Schneider and J. A. St. Cyr

Therapeutic Advances in Cardiovascular Disease, 21 June 2011

Objectives: 
Coronary revascularization using cardiopulmonary bypass is an effective surgical procedure for ischemic coronary artery disease. Complications associated with cardiopulmonary bypass have included cerebral vascular accidents, neurocognitive disorders, renal dysfunction, and acute systemic inflammatory responses. Within the last two decades off-pump coronary artery bypass has emerged as an approach to reduce the incidence of these complications, as well as shorten hospital stays and recovery times. Many patients with coronary artery disease have insulin resistance and altered energy metabolism, which can exacerbate around the time of coronary revascularization. D-ribose has been shown to enhance the recovery of high-energy phosphates following myocardial ischemia. We hypothesized that patient outcomes could improve using a perioperative metabolic protocol with D-ribose.

Methods:
A perioperative metabolic protocol was used in 366 patients undergoing off-pump coronary artery bypass during 2004_2008. D-ribose was added in 308 of these 366 patients. Data were collected prospectively as part of the Society of Thoracic Surgeons database and retrospectively analyzed.

Results:
D-ribose patients were generally similar to those who did not receive D-ribose. There was one death, two patients suffered strokes and renal failure requiring dialysis occurred in two patients postoperatively among the entire group of patients. D-ribose patients enjoyed a greater improvement in cardiac index postrevascularization compared with non-D-ribose patients (37% vs. 17%, respectively, p<0.001).

Conclusions:
This metabolic protocol was associated with very low mortality and morbidity with a significant early postoperative improvement in cardiac index using D-ribose supplementation. These preliminary results support a prospective randomized trial using this protocol and D-ribose.

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D-RIBOSE AIDS ADVANCED ISCHEMIC HEART FAILURE PATIENTS (International Journal of Cardiology, 2008)

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Dean MacCarter, PhD; Nampalli Vijay, MD; Melinda Washam, MS; Linda Shecterle, PhD; Helen Sierminski, BA; J.A. St. Cyr, MD, PhD; Aurora Denver Cardiology Associates, P.C.; Denver, CO

International Journal of Cardiology, July 2008

Abstract

Patients with advanced heart failure are exercise intolerant. Low cellular energy levels in the failing heart have been proposed. Energy enhancing substrates have revealed mixed results. Ribose, a pentose monosaccharide, has shown to replenish low myocardial energy levels, improving cardiac dysfunction following ischemia, and improving ventilation efficiency in patients with heart failure. As current pharmaceuticals do not address cellular energy levels, this study was designed to investigate the role of ribose on ventilation at anaerobic threshold in congestive heart failure patients. D-ribose (5gms/dose, tid) was assessed in 16 NYHA class III-IV, heart failure patients with VO2, tidal volume/VCO2, heart rate/tidal volume evaluated at 8 weeks. All patients had a significant improvement in ventilator parameters at anaerobic threshold, along with a 44% Weber class improvement. Ribose improved the ventilator exercise status in advanced heart failure patients.

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Energizing Diastole (Heart Failure Clin 4, 2008)

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Ragavendra R. Baliga, MD, MBA
James B. Young, MD

Heart Failure Clin 4 (2008) ix–xiii

 

Epidemiologic studies suggest that diastolic dysfunction is present in more than half of the patients admitted to the hospital with congestive heart failure [1], and the mortality rate in these patients appears comparable to that of patients with depressed left ventricular ejection fraction.  As there are few randomized clinical trials that include patients who have diastolic heart failure, current therapies have focused on the management of factors that exacerbate the clinical manifestations, such as lowering systolic and diastolic blood pressure, controlling ventricular rate in atrial fibrillation, and decreasing volume overload [2]. Unfortunately, the impact of available therapies on diastolic heart failure has been, at best, moderate, making the search for a more effective treatment urgent [3,4]. Recent work suggests that modulating myocardial energetics merit attention in this quest [5–7].

Intuitively, it is well recognized that sarcomeric relaxation is an active process because skeletal muscle goes into contracture (rigor mortis) rather than relaxation when metabolism stops.Abundant evidence exists that ventricular diastole is also an active process [8,9], because adenosine triphosphate (ATP) is required for the dissociation of actin and myosin in the cardiac myocyte [10–12]. Agents such as D-ribose that enhance recovery of depressed myocardial ATP levels improve diastolic compliance [13,14]. ‘‘Runningout-of-gas,’’ or energy depletion, in the cardiac myocyte [10] was described in heart failure more than three decades ago [15,16], and several studies have characterized the impaired myocardial metabolism in diastolic dysfunction [17–22] and left ventricular hypertrophy (LVH), which often precedes diastolic dysfunction [23–28].

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The Use of D-Ribose in Chronic Fatigue Syndrome and Fibromyalgia: A Pilot Study (THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 12, Number 9 , 2006)

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JACOB E. TEITELBAUM, M.D.,1 CLARENCE JOHNSON, M.S.,2 and JOHN ST. CYR, M.D., Ph.D.2

The Journal of Alternative and Complementary Medicine Volume 12, Number 9, 2006, pp. 867-862

ABSTRACT
Objectives: Fibromyalgia (FMS) and chronic fatigue syndrome (CFS) are debilitating syndromes that are often associated with impaired cellular energy metabolism. As D-ribose has been shown to increase cellular energy synthesis in heart and skeletal muscle, this open-label uncontrolled pilot study was done to evaluate if D-ribose could improve symptoms in fibromyalgia and/or chronic fatigue syndrome patients.

Design: Forty-one (41) patients with a diagnosis of FMS and/or CFS were given D-ribose, a naturally occurring pentose carbohydrate, at a dose of 5 g t.i.d. for a total of 280 g. All patients completed questionnaires containing discrete visual analog scales and a global assessment pre– and post–D-ribose administration. Results: D-ribose, which was well-tolerated, resulted in a significant improvement in all five visual analog scale (VAS) categories: energy; sleep; mental clarity; pain intensity; and well-being, as well as an improvement in patients’ global assessment. Approximately 66% of patients experienced significant improvement while on D-ribose, with an average increase in energy on the VAS of 45% and an average improvement in overall well-being of 30% (p _ 0.0001).

Conclusions:
D-ribose significantly reduced clinical symptoms in patients suffering from fibromyalgia and chronic fatigue syndrome.

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On the Hypothesis that the Failing Heart Is Energy Starved: Lessons Learned from the Metabolism of ATP and Creatine

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Corresponding author Joanne S. lngwall, PhD 

NMR Laboratory for Physiological Chemistry, Brigham and Women's Hospital, 221 Longwood Avenue, Room 247, Boston, MA 02115, USA.

Current Hypertension Reports
2006, 8:457-464

Current Science Inc. ISSN 1522-6417
Copyright© 2006 by Current Science Inc.

Adenosine triphosphate (ATP) and phosphocreatine fall in the failing heart. New insights into the control of ATP synthesis, supply, and utilization, and how this changes in the failing heart, have emerged. In this article, we address four questions: What are the mechanisms explaining loss of ATP and creatine from the failing heart? What are the consequences of these changes? Can metabolism be manipulated to restore a normal ATP supply? Does increasing energy supply have physiologic consequences (ie, does it lead to improved contractile [systolic and/or diastolic] performance)? In part 1 we focus on ATP, in part 2 on creatine, and in part 3 on the relationship between creatine and purine metabolism and purine nucleotide signaling.

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Effect of D-Ribose on Insulin and Blood Glucose: A Chronological Examination (2003)

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Summary

The effect of D-ribose (ribose) on insulin secretion and plasma glucose has been investigated since 1957, when the effect of insulin on the transport of various sugars, including ribose, across cell membranes was first studied. Over the decades, research has consistently shown that oral or intravenous ribose administration produces a transient, asymptomatic, and dose dependant decrease in plasma blood glucose to a nadir that is reached 30- to 75-minutes post-administration, before returning to baseline levels in approximately 60- to 120-minutes once administration is discontinued. The mechanism of this blood glucose lowering effect has not been fully elucidated, but several have been studied and more than one appear to contribute to the effect. Suggested mechanisms include direct stimulation of insulin secretion by the pancreas, indirect stimulation of insulin secretion by the liver and other tissues, a saturation of carbohydrate receptors in the liver and various tissues affecting insulin release, increased glucose utilization or decreased glucose production resulting from rising levels of blood ribose, and the competition in the liver for the enzyme phosphoglucomutase responsible for glycogen recruitment. Increased glucose utilization does not appear to materially contribute to the mechanism. Instead, the blood glucose lowering effect of ribose appears to result from a combination of factors including indirect stimulation of pancreatic insulin secretion, stimulation of humoral effectors causing secretion of minor, but important, amounts of insulin from tissues in the hepatic-portal pathway, and delayed glucose recruitment in the liver, likely due to competition for phosphoglucomutase activity.

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Purine Salvage to Adenine Nucleotides in Different Skeletal Muscle Fiber Types (J. Appl. Physiol.91: 231-238, 2001)

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Jeffrey J. Brault and Ronald L. Terjung.

Physiology. College of Medicine Biomedical Sciences, College of Veterinary Medicine, and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211

The rates of purine salvage of adenine and hypoxanthine into the adenine nucleotide (AdN) pool of the different skeletal muscle phenotype sections of the rat were measured using an isolated perfused hindlimb preparation. Tissue adenine and hypoxanthine concentrations and specific activities were controlled over a broad range of purine concentrations, ranging from 3-100 fold normal, by employing an isolated rat hindlimb preparation perfused at a high flow rate. Incorporation of H-adenine or 3H-hypoxanthine into the AdN pool was not meaningfully influenced by tissue purine concentration over the range evaluated (-0.10 to 1.6 µmol/g). Purine salvage rates were greater (p<0.05) for adenine (35-55 nmol/h/g), compared to hypoxanthine (20-30 nmol/h/g), and moderately different (p<0.05) among fiber types. The low oxidative fasttwitch white muscle section exhibited relatively low rates of purine salvage that were -65% of the rates in the high-oxidative fast twitch red section of the gastrocnemius.  The soleus muscle, characterized by slowtwitch red fibers, exhibited a high rate of adenine salvage, but a low rate of hypoxanthine salvage. Addition of ribose to the perfusion medium increased salvage of adenine (up to 3-6 fold; p<0.00 1) and hypoxanthine (up to 6-8 fold; p<0.001), depending upon the fiber type, over a range of concentrations up to 10 mM. This is consistent with tissue 5-phosphoribosyl-1-pyrophosphate being rate limiting for purine salvage. Purine salvage is favored over de novo synthesis, as delivery of adenine to the muscle decreased (p<O.OOS) de novo synthesis of AdN. Providing ribose did not alter this preference of purine salvage pathway over de novo synthesis of adenine nucleotides. In the absence of ribose supplementation purine salvage rates are relatively low, especially compared the AdN pool size in skeletal muscle.

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AMP deamination and purine exchange in human skeletal muscle during and after intense exercise (The Journal of Physiology, 1999)

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Y. Hellsten, E.A. Richter, B. Kiens and J. Bangsbo

The Journal of Physiology. 1999;520;909-920

  1. The present study examined the regulation of human skeletal muscle AMP deamination during intense exercise and quantified muscle accumulation and release of purines during and after intense exercise.
  2. Seven healthy males performed knee extensor exercise at 64·3 W (range: 50-70 W) to exhaustion (234 s; 191-259 s). In addition, on two separate days the subjects performed exercise at the same intensity for 30 s and SO% of exhaustion time (mean, 186 s; range, 153-207 s), respectively. Muscle biopsies were obtained from m.v. lateralis before and after each of the exercise bouts. For the exhaustive bout femoral arterio-venous concentration differences and blood flow were also determined.
  3. During the first 30 s of exercise there was no change in muscle adenosine triphosphate (ATP), inosine monophosphate (IMP) and ammonia (NH3), although estimated free ADP and AMP increased 5- and 45-fold, respectively, during this period. After 186 sand at exhaustion muscle ATP had decreased (P < 0·05) by 15 and 19%, respectively, muscle IMP was elevated (P < 0·05) from 0·20 to 3·65 and 5·67 mmol (kg dry weightf\ respectively, and muscle NH3 had increased (P < 0·05) from 0·47 to 2·55 and 2·33 mmol (kg d.w.f1 , respectively. The concentration of H+ did not change during the first 30 s of exercise, but increased (P < 0·05) to 245·9 nmoll-1 (pH 6·61) after 186 sand to 374·5 nmoll-1 (pH 6·43) at exhaustion.
  4. Muscle inosine and hypoxanthine did not change during exercise. In the first 10 min after exercise the muscle IMP concentration decreased (P < 0·05) by 2·96 mmol (kg d.w.f1 of which inosine and hypoxanthine formation could account for 30%. The total release of inosine and hypoxanthine during exercise and 90 min of recovery amounted to 1·07 mmol corresponding to 46% of the net ATP decrease during exercise or 9% of ATP at rest.
  5. The present data suggest that AMP deamination is inhibited during the initial phase of intense exercise, probably due to accumulation of orthophosphate, and that lowered pH is an important positive modulator of AMP deaminase in contracting human skeletal muscle in vivo. Furthermore, formation and release of purines occurs mainly after intense exercise and leads to a considerable loss of nucleotides.

During intense exercise the rate of ATP utilisation in skeletal muscle is higher than the rate of ATP regeneration, which leads to an accumulation of ADP and AMP. To avoid a large accumulation of AMP within the cell, AMP is deaminated to IMP and ammonia/ammonium (in this paper we will represent both as 'NH3 ') via the enzyme AMP deaminase (Lowenstein, t990). The maximal activity of AMP deaminase is high in skeletal muscle and the accumulation of IMP and NH3 in human muscle after intense exercise may amount to t 0 mmol (kg d.w.f1 (Sahlin et al. 1978; Graham et al. 1990; Bangsbo et al. 1992a; Tullson et al. 1995). The mechanism underlying the regulation of AMP deamination in human skeletal muscle is, however, unclear.

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Decreased resting levels of adenine nucleotides in human skeletal muscle after high-intensity training (J. Appl. Physiol. 74(5): 2523-2528, 1993)

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Ylva Hellsten-Westing, Barbarba Norman, Paul D. Balsom, and Bertil Sjodin

Department of Physiology 111, Karolinska Institute, S-11486 Stockholm; and Department of Clinical Physiology, Huddinge Hospital, S14186 Huddinge, Sweden

J. Appl. Physiol. 74(5): 2523-2528, 1993

The effect of high-intensity intermittent training on the adenine nucleotide content of skeletal muscle was studied. Eleven male subjects (group A) performed high-intensity intermittent training on a cycle ergometer three times per week for 6 wk, followed by 1 wk of the same kind of training with two sessions per day. Nine males (group B) exclusively performed 1 wk of training with two sessions per day. In group A, skeletal muscle total adenine nucleotide (TAN) levels decreased from 25.1 ± 0.7 (SE) to 22.0 ± 0.6 mmollkg dry wt over the 6-wk period (P < 0.01). The subsequent intensive week did not further alter TAN levels. In group B, the intensive week of training reduced TAN levels from 25.1 ± 0.5 to 19.4 ± 0.6 mmol/kg dry wt (P < 0.001). The decrease was sustained 72 h after training (P < 0.001). During the intensive week, there was no change in plasma creatine kinase activity in either group A or group B. The plasma activity was, however, higher in group B than in group A on days 4 and 7 of the intensive week (P < 0.05). The results from this study indicate that high-intensity intermittent exercise causes a decrease in resting levels of skeletal muscle adenine nucleotides without a concomitant indication of muscle damage. A training-induced adaptation appears to occur with training by which a further loss of adenine nucleotides is prevented despite an increased training dose.

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Effects of Oral Ribose on Muscle Metabolism during Bicycle Ergometer in AMPD-Deficient Patients (Ann Nutr Metab, 1991)

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D.R. Wagner, U.Gresser, N. Zollner

Medizinishe Poliklinik der Universitat Munchen, FRG

Ann Nutr Metab 1991:35:297-302

Abstract. Three patients with AMP deaminase deficiency (AMPD deficiency) performed exercise on a bicycle ergometer with increasing work load \~hout and with administration of ribose (3 g p.o. every l 0 min. beginning l h before exercise until the end). The patients performed exercise until heart rate was 200 minus age. Maximum capacity was not increased by administration of ribose. but postexertional muscle stiffness and cramps disappeared almost completely in 2 of 3 AMPD-deficient patients. Plasma concentrations of lactate and inosine were increased in AMPD-deficient patients after oral administration of ribose. Our data suggest that ribose may both serve as an energy source and enhance the de novo synthesis of purine nucleotides.

AMP deaminase deficiency (AMPD deficiency) is a relatively frequent enzyme defect of skeletal muscle ( 1.5% of muscle biopsies) [ 1]. Clinically, it is characterized by postexertional muscle stiffness and cramps. AMP deaminase (myoadenylate deaminase) is one component of the purine nucleotide cycle. The disruption of the purine nucleotide cycle induced by AMPD deficiency is probably the cause of the muscular disorder. So far, the only successful therapeutic approach has been the oral administration of ribose. The beneficial effect of ribose in AMPD deficiency has only been achieved by high oral doses (3-4 g) administered continuously (every I 0 min) during exercise, as first described by Zollner et al. [2]. Lower and not exercise-related doses of 500 mg ribose 4 times a day were not successful. Besides occasionally occurring diarrhea no side effects have been noted during ribose therapy. The beneficial effect of ribose has mainly been attributed to an additional energy source [2] and possibly also to enhanced de novo synthesis of purine nucleotides [3].

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Metabolism of D-Ribose Administered Continuously to Healthy Persons and to Patients with Myoadenylate Deaminase Deficiency (Klinische Wochenschrift, 1989)

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M. Gross, S. Reiter and N. Zollner

Medizinische Poliklinik der Universitat Munchen

Summary. D-ribose was administered orally or intravenously over at least 5 h to eight healthy volunteers and five patients with myoadenylate deaminC~ se deficiency. Intravenous administration rates were 83, 167, and 222 mg/kg/h, which were well tolerated but oral administration of more than 200 mg/kg/h caused diarrhea. The average steady state serum ribose level ranged between 4.8 mg/100 ml (83 mg/kg/h, oral administration) and 81.7 mg/100 ml (222 mg/kg/h, intravenous administration). Serum glucose level decreased during ribose administration. The intestinal absorption rate of orally administered ribose was 87.8%-99.8% or the intake at doses up to 200 mg/kg/h without first pass effect. Urinary losses were 23% of the intravenously administered dose at 222 mg/kg/h. Ribose appeared to be excreted by glomerular filtration without active reabsorption; a renal threshold could not be demonstrated. The amount of ribose transported back from the tubular lumen depended on the serum ribose level. There was no difference in ribose turnover in healthy subjects and patients with MAD deficiency.

D-ribose and xylitol are the only substances known to prevent the symptoms of patients with myoadenylate deaminase (MAD) deficiency. An oral administration of 15-20 g ribose per hour can prevent pain and stiffness of the muscles [33, 34].

In experiments with rats, Zimmer [31] showed that after temporary ischemia the myocardium loses its purine nucleotides; their pool has to be recompleted by purine synthesis de novo. The initial cellular purine concentration is regained after 72 h. If ribose is administered, the restoration of cardiac ATP pool takes only 12 h. These results may become important in the therapy of human coronary infarction or chronic coronary heart disease.

The first experiment with ribose in man were done in 1946 [30] but up to today, no investigations were done with long-lasting administration of ribose in man. These early experiments did not show whether a steady state concentration of serum ribose concentration after administering ribose for several hours is obtained.

A hypoglycemic effect of ribose has repeatedly been described [1, 2, 6-8, 21, 22, 24, 25] after short-term administrations. It is not known whether the hypoglycemia induced by ribose will persist during a continuous administration over several hours -an important question for the therapy of patients with MAD deficiency.

Experiments with human lymphocyte cultures revealed cytotoxic effects of ribose after an incubation in concentrations of 20-50 mmol/1 after 24 h [15, 23, 28, 35]. It is important to know whether such concentrations may be reached during therapy with this sugar.

The aim of the study was the investigation of basic pharmacological data of D-ribose for the treatment of patients with MAD deficiency. The main topics were intestinal resorption and urinary excretion after oral administration, serum ribose concentration after long-term administration, disappearance of ribose from blood, and side-effects including the known hypoglycemic effect.  

 

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