ReferencesThis is a list of references, mostly from the MedLine database.
Title: Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation.
Brun J - J Sleep Res - 1998 Jun; 7(2): 105-14
NLM Citation ID: 98347104
Full Source Title: Journal of Sleep Research
Publication Type: Clinical Trial; Journal Article; Randomized Controlled Trial
Author Affiliation: Service de Radiopharmacie et Radioanalyse, Centre de Medecine Nucleaire, Hopital NeuroCardiologique, Lyon, France.
Authors: Brun J; Chamba G; Khalfallah Y; Girard P; Boissy I; Bastuji H; Sassolas G;
Abstract: Modafinil is an alerting substance which has been used successfully to treat narcolepsy. Nothing is known about its effect on hormone secretions. For this purpose, eight healthy young men were enrolled in a double blind trial to test the effects of modafinil on daily plasma melatonin, cortisol and growth hormone (GH) rhythms. Blood was sampled for hormone assays, every hour during the daytime and every 30 min during the nighttime. In addition, rectal temperature and mental performances were determined during the study which comprised 3 sessions, two weeks apart: a 24 h control session including a night with sleep (S1) and two 48 h sessions S2 and S3 with a sleep-deprived night (N1) followed by a recovery night (N2). Modafinil (300 mg x 2) or placebo were randomly attributed during N1 at 22 h and 8 h. As expected, performance was improved after modafinil administration and body temperature was maintained or increased. Plasma melatonin and cortisol profiles were similar after modafinil and placebo administration. The levels observed during the recovery and the control nights (N2) displayed no difference. For GH, during both sleep deprived nights, secretion was dramatically reduced compared with the control one, although the number of secretory episodes was unchanged. These data show that the alerting property of modafinil is not related to an alteration of hormone profiles and suggest that the acute modafinil administration is devoid of short-term side-effects.
Chemical Compound Name:
(Benzhydryl Compounds); (Central Nervous System Stimulants); 12629-01-5
(Somatropin); 50-23-7 (Hydrocortisone); 68693-11-8 (modafinil); 73-31-4
Title: On the treatment of the alcoholic organic brain syndrome with an alpha-adrenergic agonist modafinil: Double-blind, placebo-controlled clinical, psychometric and neurophysiological studies. REFERENCE #13
Abstract: 1. In a double-blind study forty abstinent hospitalized male patients with an alcoholic organic brain syndrome (OBS) were treated for 6 weeks with either 200 mg modafinil or placebo. 2. Modafinil (CRL 40476) is a putative central alpha-1 adrenergic agonist. It's pharmacological profile is quite different from that of amphetamine, which can be seen by the lack of peripheral sympathomimetic effects. The vigilance promoting effect of modafinil has been shown previously in pharmaco-EEG and psychometric studies as well as in clinical studies involving treatment of daytime sleepiness in idiopathic hypersomniacs and narcoleptics. 3. The present clinical investigations demonstrated that the spontaneous restitution of the alcoholic OBS was significantly augmented and accelerated by modafinil. 4. Psychometric tests did not show significant intergroup differences. Modafinil- and placebo-treated patients improved continously over the 6-week period. 5. Psychophysiological and autonomous nervous system parameters were affected neither by placebo nor by modafinil. 6. Neurophysiological investigations by means of quantitative pharmaco-EEG showed partly inconsistent findings. However, superimposed dosages of modafinil (on the top of 6 weeks chronic administration) induced a decrease of slow activity and an increase of alpha activity suggesting an improvement of vigilance after the daily drug intake. 7. Considering the beneficial effects of modafinil in abstinent chronic alcoholic patients, it may be said that activation and improvement of adaptive behaviour by an alpha-adrenergic agonist could be regarded as a therapeutic principle in the treatment of the OBS, eventually due to noradrenergic deficits.
Author: Saletu B; Saletu M; Gr¨unberger J; Frey R; Zatschek I; Mader R
Address: Department of Psychiatry, University of Vienna, Austria.
Source: Prog Neuropsychopharmacol Biol Psychiatry, 14(2):195-214 1990
Unique Identifie 90175919
MESH Headings: Adrenergic alpha-Agonists *TU ; Adult ; Alcoholism *DT/PP/PX ; Attention DE ; Benzhydryl Compounds AE/*TU ; Blood Pressure DE ; Central Nervous System Stimulants *TU ; Clinical Trials ; Comparative Study ; Double-Blind Method ; Heart Rate DE ; Human ; Male ; Memory DE ; Middle Age ; Motor Activity DE ; Psychological Tests ; Random Allocation ; Reaction Time DE ; Substance-Related Disorders *DT/PP/PX
Publication Type: CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; JOURNAL ARTICLE
Country of Publication: ENGLAND
CAS Registry Number 0 (Adrenergic alpha-Agonists); 0 (Benzhydryl Compounds); 0 (Central Nervous System Stimulants); 68693-11-8 (modafinil)
Title: Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil.
Abstract: 1. Modafinil, a putative central alpha 1 adrenergic agonist, was tested in idiopathic hypersomnia and narcolepsy. 2. Sleep attacks and drowsiness were significantly decreased in 83% of 18 hypersomniac subjects and 71% of 24 narcoleptics. 3. When cataplectic episodes were not totally suppressed the association of a low dose of Clomipramine was successful in improving them. 4. Modafinil, used for at least 3 years in some patients, produces, in most cases, no peripheric sides effects, does not disturb night sleep and is never responsible of tolerance of drug dependence.
Author: Bastuji H; Jouvet M
Address: Lab. Neurophysiologie Clinique, H^opital Neurologique, Lyon, France.
Source: Prog Neuropsychopharmacol Biol Psychiatry, 12(5):695-700 1988
Unique Identifier: 89129435
MESH Headings: Adrenergic alpha-Agonists *TU ; Adult ; Benzhydryl Compounds *TU ; Female ; Human; Hypersomnia *DT ; Male ; Middle Age ; Narcolepsy *DT ; Sleep DE ; Sleep Disorders *DT
Publication Type: JOURNAL ARTICLE
Country of Publication: ENGLAND
CAS Registry Number: 0 (Adrenergic alpha-Agonists); 0 (Benzhydryl Compounds); 68693-11-8 (modafinil)
CLINICAL OVERVIEW OF THE TREATMENT OF CFS/ME WITH AMPLIGEN
Our objective was to review physical and quality oflife improvements derived from four separate clinical studies of Ampligen in Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME). Chronic Fatigue Syndrome is a symptom complex characterised by both chronic physical debilitation as well as impairments in concentration and short-term memory. Although the etiology of CFS remains elusive, abnormalities in immune function and viral reactivation have been reported. We have investigated the role of a double-stranded RNA, Ampligen, which acts as a biological response modifier with both antiviral and immunomodulatory activity. We have examined the utility of measuring components of the Rnase L pathway and have also initiated studies of physical activity in CFS using activity monitors(AM). The aggregate of the four clinical trials reviewed, three open-label and one placebo controlled, includes 171 individuals meeting the CDC case definition for CFS. The results of these four clinical studies, which utilized similar Ampligen dosage levels, duration of therapy and data endpoints and collection intervals, were analyzed.
Following 24 weeks of therapy, the most consistent finding was the degree of improvement evinced by the Karnofsky Performance Scores (KPS) and the Exercise Treadmill Testing (ETT). For the 124 Ampligen patients the average KPS improvement was 14.5 (jl% mean improvement over baseline) vs 3.7 (10%) for the 47 placebo subjects. ETT percentage changes were 41% and 17% (2 minutes and 1/3 minute gains) for Ampligen (p=0.0001, paired t-test) and placebo (p=0.063), respectively. A Pearson's correlation coefficient between the percent change in KPS vs. ETT was .69 (p=0.0001) for Ampligen and .04(p=0.78) for placebo groups. Wilcoxon ranskum tests showed that the probability that the medians for KPS percent change differ by chance for the Ampligen and placebo groups was 0.0001. Examination of the relationship between Rnase L and clinical benefit revealed that changes in Rnase L correlated with improve cognition perception (SCL-90-R) for the Ampligen group (R=0.52, p=0.0012), but not for the placebo group (R=0.13, p=0.44); Finally, activity monitors (AM's) were employed to provide an index of severity of CFS. Prior to treatment, se&mentation ofnormal controls and CFS patients was well delineated with no CFS patient achieving a daily score of over 250,000 activity units (based on a weekly average), while no normal control expressed a daily score of less than 250,000. Correlation between baseline KPS and AM scores was 0.83 (p-0.0001). Changes in AM with Ampligen therapy also correlated well (Pearson Correlation Coefïicient = 0.89) with KPS improvements (p<0.05). In these studies the twice weekly (200-400mg) Ampligen treatments produced no evidence of cumulative toxicities. No clinically significant abnormalities were revealed in blood chemistry, coagulation, or haematological parameters.
In summary, results of four separate studies using Ampligen in CFS firmly demonstrates the therapeutic advantages of the treatment asrevealed using the KPS, ETT and SCL-90-R. Both physical performance and cognition improved significantly during treatment in these four clinical trials and the treatment was generally well-tolerated.
FATIGUE 2000 AN INTERNATTONAL CONFERENCE
THE NATIONAL ME CENTRE in conjunction with ESSEX NEUROSCIENCES UNIT & SOUTH BANK UNIVERSITY
David R. Strayer, William A. Carter, Hemispherx, Biopharma Inc., USA and Kenny De Meirleir, Vrije Universiteit, Brussels, Belgium.
Biochemical Abnormalities in Chronic Fatigue Syndrome
1999 Sydney ME/CFS Conference Abstracts & Posters
Chronic fatigue syndrome is defined as a disorder in which the subject has unexplained prolonged fatigue, often worse after minimal exercise, frequently associated with impaired sleeping, painful muscles, intermittently swollen lymph glands and impaired cognitive function. The pathogenesis has eluded explanation. The bioanalytical research group of the University of Newcastle has developed methodology for examining excretion of amino acids and organic acids into the urine. In collaboration with the Department of Endocrinology at the Royal North Shore Hospital, the overnight urine excretion rate of a number of amino acids and organic acids was measured in 100 patients with chronic fatigue syndrome, and in 83 age- and sex-matched normal controls.
The excretion rate of the metabolites was measured in units/minute. The most striking differences between patients with chronic fatigue syndrome and controls was a reduction in urine asparagine (p<0.0001) and a reduction in urine succinic acid (p<0.0003) in patients with chronic fatigue syndrome.
The excretion of urinary asparagine and succinic acid was highly correlated (p<0.00001). Urinary tyrosine (p<0.04) and urinary 3-methyl histidine (p<0.03) were significantly increased in patients with chronic fatigue syndrome. The urinary excretion of tyrosine, a protein catabolism marker, was associated with symptoms of fatigue, muscle pain, lymph node pain and cognitive disturbance.
The overnight excretion of succinic acid was correlated with the fasting plasma glucose (p<0.002). It is not known at present whether urine excretion rates of succinic acid and asparagine are correlated with serum concentrations of these metabolites or whether renal tubular function independently influences the urine excretion rates, and if so, whether renal tubular function is itself altered in chronic fatigue syndrome.
It is possible that urine asparagine excretion rates are low because of reduced entry of asparagine into the circulation, and thence into the urine. If the rate of entry of asparagine into the circulation is reduced, this could come about because of more rapid metabolism of asparagine in cells or because total body stores of asparagine are depleted. Further work is necessary to define these issues.
Phillip Clifton Bligh2, Suzanne Niblett1, Leigh Hoskin2, R Hugh Dunstan1, Greg Fulcher2, Neil McGregor1,4, Julie Dunsmore3, Timothy K Roberts1, Henry L Butt1, Katrina King1, Iven Klineberg4
1 Collaborative Pain Research Unit, Bioanalytical Research Group, Dept of Biological Sciences, University of Newcastle, Callaghan, NSW 2308 Australia
2 Royal North Shore Hospital, CFS Research Unit, Dept of Endocrinology, Royal North Shore Hospital, St Leonards, NSW 2065
3 Royal North Shore Hospital, CFS Research Unit, Dept of Health Promotion and Education, Royal North Shore Hospital, St Leonards, NSW 2065
4 Neurobiology Research Unit, Centre for Oral Health Research, University of Sydney, Westmead Hospital Westmead, NSW 2084
Title: Candida osteomyelitis. Report of five cases and review of the literature.
Abstract: Candida species have emerged as important pathogens in human infection. Although a variety of deep-seated candidal infections have been reported, Candida osteomyelitis has rarely been described. Five patients with Candida osteomyelitis are presented, and the 32 adult cases previously reported are reviewed. Candida osteomyelitis is noted as a simultaneous occurrence or late manifestation of hematogenously disseminated candidiasis. Osteomyelitis may not be prevented by a course of amphotericin B adequate to control the acute episode of disseminated candidiasis, particularly in immunosuppressed patients. Less commonly, Candida osteomyelitis presents as a postoperative wound infection. Like bacterial osteomyelitis, the most common presenting symptom is local pain. The insidious progression of infection, the nonspecificity of laboratory data, and the failure to recognize Candida as a potential pathogen may lead to diagnostic delay. Diagnosis can be made by either open biopsy or closed needle aspiration. Successful therapeutic regimens have employed combinations of antifungal therapy (most often amphotericin B) with surgical debridement when indicated. It is anticipated that osteomyelitis will become a more commonly recognized manifestation of hematogenously disseminated candidiasis.
Unique Identifier: 87210292
Author: Gathe JC Jr; Harris RL; Garland B; Bradshaw MW; Williams TW Jr
Source: Am J Med, 82(5):927-37 1987 May
MESH Headings: Aged ; Antifungal Agents TU ; Candidiasis *DI/DT ; Case Report ; Human ; Male ; Middle Age ; Osteomyelitis *DI/DT
Publication Type: JOURNAL ARTICLE; REVIEW
Country of Publication: UNITED STATES
CAS Registry Number: 0 (Antifungal Agents)
Title:Bowel permeability and CD45RO expression on circulating CD20+ B cells in patients with ankylosing spondylitis and their relatives.
Abstract: OBJECTIVE: Ankylosing spondylitis (AS) is reportedly associated with subclinical endoscopic gut inflammation in up to 57% of patients. Studies of bowel permeability, however, have not consistently revealed abnormalities in these patients. CD20+CD45RO+ expression is associated with increased antigen exposure, and previous work has shown increased expression in this B cell isoform in patients with Crohn's disease and their relatives, correlating with intestinal permeability abnormalities. We sought to re-examine intestinal permeability in patients with AS and their relatives, and relate any observed alterations in permeability with evidence of increased antigen presentation as assessed by the number of circulating B cells that were CD45RO positive. METHODS: We studied small intestinal and gastric permeability by measurement of excretion of lactulose, mannitol, and sucrose in 60 patients with AS and 24 of their first-degree relatives. We also studied expression of CD20+CD45RO+ by flow cytometry in these patients. RESULTS: Both patients and first-degree relatives had significantly increased small intestinal, but not gastric, permeability compared to controls.
Among patients, current users of nonsteroidal anti-inflammatory drugs (NSAID) had significantly increased small intestinal permeability compared to nonusers, but relatives not using NSAID also had increased permeability. CD20+CD45RO+ expression was increased in one-third of patients but did not correlate with permeability abnormalities. CONCLUSION: Patients with AS have altered small intestinal, but not gastric, permeability. NSAID use cannot explain all the abnormality. Bowel permeability abnormalities, possibly genetically determined, may antedate development of bowel or joint symptoms. Increased CD20+CD45RO+ expression suggests increased antigen exposure, which may be related to previous or current intestinal permeability abnormalities.
Author: Vaile JH; Meddings JB; Yacyshyn BR; Russell AS; Maksymowych WP
Address: Department of Medicine, University of Alberta, Edmonton, Canada.
Source: J Rheumatol, 26(1):128-35 1999 Jan
Unique Identifier: 99114785
Publication Type: JOURNAL ARTICLE
Country of Publication: CANADA
CAS Registry Number: 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Antigens, CD20); 0 (Antigens, CD45); 4618-18-2 (Lactulose); 57-50-1 (Sucrose)
Title: Effect of sulfite on the energy metabolism of mammalian tissues in correlation to sulfite oxidase activity :
Beck-Speier I - Biochim Biophys Acta - 1985 Jul 26; 841(1): 81-9 Beck-Speier I; Hinze H; Holzer H
Abstract: Mammalian tissues show significant differences in the activity of sulfite oxidase (EC 22.214.171.124) which detoxifies sulfite by oxidation to sulfate. Lung tissue and phagocytic cells such as alveolar macrophages, peritoneal macrophages, Kupffer cells and granulocytes show very low activities of sulfite oxidase. Liver tissue and hepatocytes, however, exhibit high activities of sulfite oxidase.REFERENCE #19
Lung tissue and macrophages show an almost 100% decrease of the intracellular ATP levels when incubated in 1 mM sulfite at pH 6 or 30 min. In addition, the O2 consumption of lung tissue is inhibited by 1 mM sulfite at pH 6 by more than 80%.
This sulfite-induced decrease of the ATP level and of the O2 consumption of lung tissue is enhanced between pH 6.0 and pH 7.4 with decreasing pH value of the incubation medium.
In contrast, the ATP levels in liver tissue and hepatocytes are not affected by 1 mM sulfite at pH 6. The O2 consumption of liver tissue and hepatocytes is significantly increased by sulfite due to the high activities of sulfite oxidase.
Therefore, the activity of the 'sulfite-detoxifying enzyme' sulfite oxidase and the sensitivity of the energy metabolism to sulfite show a reciprocal relationship in the tissues and cells studied."
Title: Increased expression of procoagulant activity on the surface of human platelets exposed to heavy-metal compounds.
Abstract: One of the essential roles for platelets in haemostasis is in the potentiation of blood clotting due to the contribution of anionic phospholipid from the surface of the cells, as an essential cofactor to the proteolytic reactions of coagulation (platelet procoagulant activity). Only a limited number of agonists are known to initiate platelet procoagulant activity. In this study the rate of thrombin formation on the platelet surface was observed to increase in a dose-dependent manner upon treatment of washed platelets with heavy-metal compounds. Unlike the immediate increase observed upon treatment of platelets with calcium ionophore, A23187, the change due to these agents was progressive, approaching a maximum after 10 min. The maximum-fold acceleration of the rate of thrombin formation compared with control platelets was calculated for HgCl2 (56-fold), AgNO3 (42-fold) phenylmercuriacetate (24-fold) and thimerosal (14-fold), compared with 70-fold observed for calcium ionophore. The increase in procoagulant activity due to HgCl2 coincided with a large increase in intracellular calcium and phosphorylation of 22 and 45 kDa proteins. It is considered that the mechanism responsible for the increase in procoagulant activity is exposure of anionic phospholipids. This was detected by a 2-fold increase in the binding of 125I-annexin V upon addition of HgCl2, compared with resting platelets (3-fold on treatment of platelets with calcium ionophore). In contrast to the generation of activity by A23187 and other known agonists of this reaction, heavy-metal compounds appeared to cause little or no release of microparticles from the platelet surface. Since HgCl2 did not cause aggregation of platelets or significant release of serotinin, these findings may give further support to the need for exposure and ligation of glycoprotein IIb:IIIa for vesiculization to occur. Treatment of platelets with heavy metals may constitute a new approach to investigating the early changes in the cell membrane which lead to increased expression of anionic phospholipid."
Author: Goodwin CA; Wheeler Jones CP; Namiranian S; Bokkala S; Kakkar VV; Authi KS; Scully MF
Address: Thrombosis Research Institute, London, U.K.
Source: Biochem J, 1995 May, 308 ( Pt 1):, 15-21