Category: Treatment

Bupropion augmentation in the treatment of chronic fatigue syndrome with coexistent major depression episode

Abstract:

While psychoeducational strategies and general support are always indicated for the treatment of chronic fatigue syndrome (CFS), pharmacological strategies are yet not well established. Antidepressants such as selective serotonin re-uptake inhibitors have been shown to influence positively symptoms and immunological parameters. However, a considerable part of CFS patients do not satisfactorily respond to them. Bupropion, a centrally acting catecholamine-transporter blocker without classic psycho-analeptic properties, shows theoretical potential to improve fatigue symptoms. In the reported case paroxetine was augmented with bupropion at high dosage, a strategy which consecutively led to a rapid relief of CFS-symptoms.

 

Source: Schönfeldt-Lecuona C, Connemann BJ, Wolf RC, Braun M, Freudenmann RW. Bupropion augmentation in the treatment of chronic fatigue syndrome with coexistent major depression episode. Pharmacopsychiatry. 2006 Jul;39(4):152-4. https://www.ncbi.nlm.nih.gov/pubmed/16871471

 

How relevant are exercise capacity measures for evaluating treatment effects in chronic fatigue syndrome? Results from a prospective, multidisciplinary outcome study

Abstract:

OBJECTIVE: To evaluate the outcome of a multidisciplinary treatment programme for patients with chronic fatigue syndrome, including health-related quality of life (HRQoL) and psychosocial variables, and exercise capacity measures.

DESIGN: A six-month prospective outcome study.

SETTING: University outpatient rehabilitation clinic; group setting.

SUBJECTS: One hundred and sixteen women fulfilling chronic fatigue syndrome criteria.

INTERVENTIONS: Cognitive behaviourally and graded exercise-based strategies; emphasis on adaptive lifestyle changes.

MEASURES: Short Form General Health Survey (SF-36); Symptom Checklist (SCL-90); Causal Attribution List (CAL); Self-Efficacy Scale (SE); maximum progressive bicycle ergometer test with respiratory gas analysis; and isokinetic leg strength test, before and after treatment.

RESULTS: The total group significantly improved on nearly all reported HRQoL/psychosocial variables. Changes in exercise capacity measures were rather modest and did not correlate or only weakly correlated with HRQoL/psychosocial variables. Subgroup analyses indicated that less fit patients improved significantly more on exercise capacity measures than their more fit counterparts. Patients who were fitter at baseline scored better on pretreatment HRQoL/psychosocial variables, but both subgroups improved similarly on these variables.

CONCLUSIONS: Health-related quality of life and psychosocial functioning in patients with chronic fatigue syndrome improves after a six-month cognitive behaviourally and graded exercise-based multidisciplinary treatment programme. Increase in exercise capacity measures is not a necessary condition for reported improvements, except for less fit patients.

 

Source: Pardaens K, Haagdorens L, Van Wambeke P, Van den Broeck A, Van Houdenhove B. How relevant are exercise capacity measures for evaluating treatment effects in chronic fatigue syndrome? Results from a prospective, multidisciplinary outcome study. Clin Rehabil. 2006 Jan;20(1):56-66. https://www.ncbi.nlm.nih.gov/pubmed/16502751

 

Does methylphenidate reduce the symptoms of chronic fatigue syndrome?

Abstract:

PURPOSE: Chronic fatigue syndrome is a clinical entity consisting of prolonged and debilitating fatigue in which concentration disturbances are very frequent. Until now, no medical treatment has shown any efficacy. The objectives of this study were to investigate the short-term effects of methylphenidate, an amphetamine derivative, on fatigue, concentration disturbances, and quality of life.

SUBJECTS AND METHODS: A double-blind randomized placebo-controlled crossover study was conducted in 60 patients who fulfilled the 1994 Centers for Disease Control criteria for chronic fatigue syndrome and had concentration difficulties. Patients were enrolled between March 2003 and March 2004 at the outpatient department of a university hospital referral center for chronic fatigue syndrome patients. Random assignment to 4 weeks treatment with methylphenidate 2 x 10 mg/day, followed by 4 weeks of placebo treatment, or 4 weeks of placebo treatment, followed by methylphenidate treatment. Fatigue and concentration were measured with a Checklist Individual Strength (CIS) and a Visual Analogue Scale (VAS).

RESULTS: Fatigue scores fell significantly during methylphenidate intake in comparison with baseline (mean difference: -0.7, P = .010 for VAS; mean difference: -11.8, P <.0001 for CIS) and in comparison with placebo (mean difference: -1.0, P = .001 for VAS; mean difference: -9.7, P <.0001 for CIS). Concentration disturbances, measured with a VAS improved significantly under methylphenidate treatment compared with baseline (mean difference: -1.3, P <.0001) and compared with placebo (mean difference: -1.1, P <.0001). A clinical significant effect (> or =33% improvement or CIS < or =76) on fatigue was achieved in 17% of patients, who were considered responders; on concentration in 22% of patients.

CONCLUSIONS: Methylphenidate at a dose of 2 x 10 mg/day is significantly better than placebo in relieving fatigue and concentration disturbances in a minority of chronic fatigue syndrome patients. Further studies are needed to investigate the long-term effects of this treatment.

 

Source: Blockmans D, Persoons P, Van Houdenhove B, Bobbaers H. Does methylphenidate reduce the symptoms of chronic fatigue syndrome? Am J Med. 2006 Feb;119(2):167.e23-30. https://www.ncbi.nlm.nih.gov/pubmed/16443425

 

Treatment of chronic fatigue syndrome with antibiotics: pilot study assessing the involvement of Coxiella burnetii infection

Abstract:

OBJECTIVE: To examine whether Coxiella burnetii (C. burnetii) is involved in chronic fatigue syndrome (CFS), we administered tetracycline antibiotics to subjects with CFS, and followed changes in clinical symptoms, PCR findings, and C. burnetii antibody titers.

PATIENTS AND METHODS: The subjects were 8 patients with CFS and 213 with nonspecific complaints such as chronic fatigue and low-grade fever for several months or longer but not meeting the diagnostic criteria for CFS. All were examined for C. burnetii infection by nested PCR and the indirect immunofluorescence test (IF).

RESULTS: Four CFS patients (the CFS group) and 54 controls [the post-Q fever fatigue syndrome (QFS) group] positive for C. burnetii were treated mainly with minocycline or doxycycline (100 mg/day) for 3 months. After treatment, all 58 patients tested negative for C. burnetii infection. In the CFS group, no significant difference was noted between the mean pre- and post-treatment temperatures or headache scores. Similarly, there was no significant improvement in performance status (PS) scores. In the QFS group, however, mean temperatures and headache scores were significantly decreased after treatment (p<0.001). PS scores were also improved.

CONCLUSION: These results suggest the possibility of direct involvement of C. burnetii in the pathological state of CFS to be low, despite the C. burnetii infection rate being high in CFS patients. This is a pilot study and further larger investigations are necessary to confirm our preliminary results.

 

Source: Iwakami E1, Arashima Y, Kato K, Komiya T, Matsukawa Y, Ikeda T, Arakawa Y, Oshida S. Treatment of chronic fatigue syndrome with antibiotics: pilot study assessing the involvement of Coxiella burnetii infection. Intern Med. 2005 Dec;44(12):1258-63. https://www.ncbi.nlm.nih.gov/pubmed/16415546

 

Drug targets in stress-related disorders

Abstract:

Nervous and immune systems mutually cooperate via release of mediators of both neurological and immunological derivation. Adrenocorticotropin hormone (ACTH) is a product of the hypothalamus-pituitary adrenal axis (HPAA) which stimulates secretion of corticosteroids from adrenals. In turn, corticosteroids modulate the immune response in virtue of their anti-inflammatory activity.

On the other hand, catecholamines, products of the sympathetic nervous system (SNS), regulate immune function by acting on specific beta-adrenergic receptors. Conversely, cytokines released by monocytes/macrophages and lymphocytes, upon antigenic stimulation, are able to cross the blood-brain-barrier, thus modulating nervous functions (e.g., thermoregulation, sleep, and appetite). However, cytokines are locally produced in the brain, especially in the hypothalamus, thus contributing to the development of anorexic, pyrogenic, somnogenic and behavioural effects.

Besides pathogens and/or their products, the so-called stressors are able to activate both HPAA and SNS, thus influencing immune responses. In this respect, many studies conducted in medical students taking exams have evidenced an array of stress-induced immune alterations. Phobic disorders and migraine without aura (MWA) represent examples of stress-related disorders in which phagocytic immune deficits, endotoxemia and exaggerated levels of proinflammatory cytokines [Tumor Necrosis Factor-alpha (TNF- alpha), and interleukin- 1 beta] have been detected. Quite interestingly, administration of a thymic hormone could ameliorate clinical symptoms in phobic patients.

In MWA patients, a beta-blocker, propranolol, could mitigate migraine, whose cessation coincided with a drop of TNF-alpha serum concentration. In phobic disorders and in MWA, benzodiazepines are very often administered and, in this respect, some of them, such as diazepam, inhibit immune functions, while others, e.g., alprazolam, enhance immune responses. Alprazolam could improve clinical symptoms in MWA patients.

Chronic Fatigue Syndrome (CFS) is a disorder whose etiology and pathogenesis are still unknown. In this syndrome both abnormalities of nervous and immune systems have been reported. Despite many immune parameters evaluated in CFS no specific biomarkers of disease have been found. Our own data are in agreement with current literature in that we found decreased levels of serum (IFN)-gamma in these patients, thus indicating a predominance of T helper (h)1 response in CFS. Also leptin, a hormone which regulates food intake, fluctuates within normal ranges in CFS individuals. Quite interestingly, in depressed patients, used as controls, leptinaemia was more elevated than in CFS. Finally, in a series of recent therapeutic trials several immunomodulating agents have been used, such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin.

In conclusion, it seems that major drug targets in stress-related disorders are immune cells in terms of inhibition of proinflammatory cytokines and modulation of Th responses. In particular, according to recent evidences, antidepressants seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing IFN- beta release or augmenting NK activity in depressed patients.

 

Source: Covelli V, Passeri ME, Leogrande D, Jirillo E, Amati L. Drug targets in stress-related disorders. Curr Med Chem. 2005;12(15):1801-9. http://www.ncbi.nlm.nih.gov/pubmed/16029148

 

Treatments for chronic fatigue syndrome

Abstract:

AIMS: To review studies evaluating the treatment of chronic fatigue and chronic fatigue syndrome, to describe predictors of response to treatment and to discuss the role of the occupational health physician.

METHODS: A literature search was carried out using Medline and PsychInfo.

RESULTS: Studies evaluating cognitive behaviour therapy, graded exercise therapy, pharmacological interventions (e.g. antidepressants and corticosteroids), immunological interventions and nutritional supplements were reviewed. The most promising results have been found with cognitive behaviour therapy and graded exercise therapy, and some predictors of outcome have been identified. Most of the other interventions were evaluated in just one or two studies and therefore evidence is insufficient to draw firm conclusions.

CONCLUSIONS: By applying the models of fatigue that form the bases for cognitive behaviour therapy and graded exercise therapy, occupational health physicians may play an important role in helping the patients with chronic fatigue syndrome to reduce their symptoms, improve their functioning and return to work.

 

Source: Rimes KA, Chalder T. Treatments for chronic fatigue syndrome. Occup Med (Lond). 2005 Jan;55(1):32-9. http://occmed.oxfordjournals.org/content/55/1/32.long (Full article)

 

Mismatched double-stranded RNA: polyI:polyC12U

Abstract:

Ampligen [polyI:polyC12U] is a mismatched double-stranded RNA that acts by inducing interferon production (immunomodulator) and by activating an intracellular enzyme (RNase-L) against viral RNA transcripts (antiviral). Ampligen, currently under development by Hemispherx Biopharma in the US, acts on the immunological system through T-lymphocyte stimulation and is indicated for the treatment of chronic fatigue syndrome and acquired immunodeficiency deficiency syndrome (AIDS), as part of the combined therapy. Ampligen is available for licensing worldwide.

In February 2004, Fujisawa Deutschland GmbH, a subsidiary of Fujisawa Pharmaceutical Co., entered into an option agreement with Hemispherx Biopharma with the intent of becoming a distributor for Ampligen for the potential treatment of chronic fatigue syndrome in Germany, Switzerland and Austria. An option fee of 400,000 euros was paid pursuant to the terms of the option agreement and upon execution of the Distribution Agreement, Fujisawa will pay Hemispherx fees and milestone payments with a potential worth of several millions of dollars.

In September 2003, Hemispherx Biopharma Inc. entered into an agreement with Guangdong Medicine Group Corporation to organise clinical trials, marketing, sales and distribution for both of its lead compounds, Ampligen and Alferon N in the People’s Republic of China. The agreement stipulates that the Guangdong Medicine Group Corporation (GMC) will conduct clinical trials with Ampligen for the treatment of HIV. All costs related to the trials are to be covered by GMC. Additionally, GMC has to develop and implement marketing and promotional programmes.

In May 2003, Hemispherx Biopharma and the Center for Cell and Gene Therapy entered into a research project agreement that will see Ampligen implemented in a protocol used in patients with relapsed EBV-positive Hodgkin’s Lymphoma.

In March 2002, Esteve and Hemispherx Biopharma entered into a collaborative agreement under which Esteve will be the sole distributor of Ampligen in Spain, Portugal and Andorra for the treatment of chronic fatigue syndrome. Under this agreement, in addition to other terms, Esteve will also collaborate in the drug product development by conducting clinical studies in Spain in patients coinfected with HIV/HCV.

In July 2001 Hemispherx Biopharma announced that it had formed a strategic alliance with Empire Health Resources for clinical trials of Ampligen in the treatment of HIV and hepatitis C virus infections. Empire Health Resources, a healthcare management firm, will be responsible for accrual and retention of patients for HIV trials, and protocols for trials in patients with hepatitis C or both HIV and hepatitis C infections.

Hemispherx has entered into a collaboration with RED Laboratories, and RED Laboratories NV expects that this will facilitate the continued development of Ampligen. Hemispherx has also entered into an agreement with Schering Plough to use a Schering facility as its principal manufacturing platform in the US. This agreement may be expanded to include other territories. Hemispherx and AOP Orphan Pharmaceuticals have signed a marketing agreement for Ampligen for the treatment of chronic fatigue syndrome for Austria, the Czech Republic, Poland and Hungary. In an arrangement between Hemispherx and Bioclones, Bioclones has certain marketing rights for Ampligen in the Southern Hemisphere, UK and Ireland.

In the US, Ampligen has been granted orphan drug status for the treatment of AIDS, renal cell carcinoma (phase II, completed), chronic fatigue syndrome (phase III) and invasive/metastatic malignant melanoma (phase II).

In August 2004, Hemispherx announced that it intends to use the proceeds from the private placement of company stock to complete the clinical work for its immunotherapeutics/ antivirals Ampligen and Oragens. Previously, Hemispherx submitted an application to the EMEA for the approval of Ampligen for the treatment of chronic fatigue syndrome; the first stage of th;) for the treatment of chronic fatigue syndrome; the first stage of the regulatory review has been cleared.

In 2000, Hemispherx Europe (Hemispherx) obtained orphan drug status for Ampligen for the treatment of chronic fatigue syndrome in the EU, providing Hemispherx with 10 years of marketing exclusivity following the launch of the drug, as well as potential financial research benefits for the agent.

In February 2000, Crystaal Corporation (now Biovail Pharmaceuticals Canada) acquired exclusive marketing rights to Ampligen in Canada, where it submitted an NDA for the agent for the treatment of chronic fatigue syndrome. In the meantime, Ampligen has been available since May 1996 under the Canadian Emergency Drug Release Programme for the treatment of chronic fatigue syndrome and immune dysfunction syndrome by Rivex Pharma (Helix BioPharma).

Bioclones has initiated clinical studies with Ampligen for the treatment of chronic fatigue syndrome in Australia. The active substance for Ampligen is manufactured by F.H. Faulding Ltd.

Clinical treatment programmes for chronic fatigue syndrome in other Pacific Rim countries are planned. Ampligen is available for severe chronic fatigue syndrome on a named patient, cost-recovery basis in South Africa. Hemispherx has developed a ‘ready-to-use’ liquid formulation of the drug and has begun treating patients with chronic fatigue syndrome in ongoing clinical trials. Hemispherx has also developed an oral version of the drug (Oragen), which is undergoing preclinical evaluation.

In February 2001, Hemispherx Biopharma announced that it was initiating phase II/III trials of Ampligen in the treatment of late-stage, multidrug-resistant strains of HIV in the European Union. Patients treated in these studies will have exhausted all other treatment options.

In July 2001, Hemispherx stated that Ampligen was being evaluated in a phase IIb trial in patients with HIV in the US. The trial, comprising two studies, REARMI and REARMII (Research/Evaluation of Ampligen for Retroviral Mutations I and II), will evaluate the ability of Ampligen to prevent the emergence of mutated, drug-resistant strains of the virus. ‘Several hundred’ patients currently on antiretroviral therapy and at risk of viral relapse will be enrolled at centres in Connecticut, New York, Florida and California.

A second phase IIb study evaluating the effect of Ampligen on structured treatment interruptions (STI) is also underway. Final results from this study were reported in December 2002. NIH sponsored studies of potential therapies for SARS have identified Ampligen as having unusually high and consistent antiviral activity against human coronavirus, the pathogen implicated as the causative agent of the disease. Ampligen demonstrated very high potency at very low concentrations (0.4 microg/mL) and had a favourable safety profile.

In October 2003, Hemispherx announced that, based on these promising new results, the company will stockpile injectible and/or oral formats of Ampligen and Alferon N. Independent researchers have demonstrated the antiviral activity of Ampligen against flaviviruses (West Nile virus, Equine Encephalitis virus, Dengue fever virus and Japanese Encephalitis virus) as well as virus classes associated with bioterrorism. In an animal study, Ampligen was shown to prevent destruction of nerve cells, reduce virus concentrations in the brain and blood stream and increase survival rates. Researchers at the Rega Institute in Belgium have published results from an animal study demonstrating that Ampligen was superior at protecting mice against coxsackie B3 virus-induced myocarditis compared with pegylated interferon.

In May 2004 Hemispherx announced that it had filed an expanded US patent application covering the use of Ampligen for the potential treatment and prevention of severe acute respiratory syndrome (SARS) and dreaded emerging viruses.

Copyright 2004 Adis Data Information BV

Source: [No authors listed] Mismatched double-stranded RNA: polyI:polyC12U. Drugs R D. 2004;5(5):297-304. http://www.ncbi.nlm.nih.gov/pubmed/15357629

 

 

Cost-effectiveness of cognitive behaviour therapy for patients with chronic fatigue syndrome

Sir,

In their economic evaluations of treatments for chronic fatigue syndrome (CFS), Severens et al. compared the cost-effectiveness of cognitive behaviour therapy (CBT) with those of other interventions, and found that the percentage of CFS patients who improved with CBT performed for 8 months was 31% vs. 9% and 12% for other treatments. Considering that, in one study, 28% of CFS patients treated with low-dose hydrocortisone over just one month virtually recovered,  Severens et al. also should have compared the cost-effectiveness of CBT with that of low-dose hydrocortisone.

Treatment with low-dose hydrocortisone for CFS, besides being intuitively far less costly than CBT, is also better-founded clinically than any psychological therapy, because hydrocortisone corrects the hypocortisolism that characterizes at least some CFS patients. Given that ‘frank hypocortisolism’, rather surprisingly, was one of the exclusion criteria for enrolment in the trial of Cleare et al., the percentage of CFS patients who can be effectively treated with low-dose hydrocortisone in day-to-day health care is likely to be higher than the 28% found in that trial.

You can read the rest of this comment here: http://qjmed.oxfordjournals.org/content/97/6/378.long

Comment on: Cost-effectiveness of cognitive behaviour therapy for patients with chronic fatigue syndrome. [QJM. 2004]

 

Source: Baschetti R. Cost-effectiveness of cognitive behaviour therapy for patients with chronic fatigue syndrome. QJM. 2004 Jun;97(6):378-9. http://qjmed.oxfordjournals.org/content/97/6/378.long (Full article)

 

Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome

Abstract:

BACKGROUND: An association between chronic fatigue syndrome (CFS) and abnormalities of the hypothalamo-pituitary-adrenal axis has been described, and other adrenal steroid abnormalities have been suggested. Dehydroepiandrostenedione (DHEA) and its sulphate (DHEA-S), apart from being a precursor of sex steroids, have other functions associated with memory, depression and sleep. It has been suggested that CFS may be associated with a state of relative DHEA(-S) deficiency. Therefore we investigated basal levels of DHEA(-S), the cortisol/DHEA molar ratio and the responsiveness of DHEA to stimulation by corticotrophin-releasing hormone (CRH). Recent studies have also suggested that low dose hydrocortisone may be effective at reducing fatigue in CFS. We therefore also assessed these parameters prior to and following treatment with low dose oral hydrocortisone.

METHODS: Basal levels of serum DHEA, DHEAS and cortisol were measured in 16 patients with CFS without depression and in 16 controls matched for age, gender, weight, body mass index and menstrual history. CRH tests (1 g/kg i.v.) were carried out on all subjects and DHEA measured at 0, +30 and +90 min. In the patient group, CRH tests were repeated on two further occasions following treatment with hydrocortisone (5 or 10 mg, p.o.) or placebo for 1 month each in a double-blind cross over study protocol.

RESULTS: Basal levels of DHEA were higher in the patient, compared to the control, group (14.1+/-2.2 vs. 9.0+/-0.90 ng/ml, P=0.04), while levels of DHEAS in patients (288.7+/-35.4 microg/dl) were not different from controls (293.7+/-53.8, P=NS). Higher DHEA levels were correlated with higher disability scores. Basal cortisol levels were higher in patients, and consequently the cortisol/DHEA molar ratio did not differ between patients and controls. Levels of DHEA (8.9+/-0.97 ng/ml, P=0.015) and DHEAS (233.4+/-41.6 microg/dl, P=0.03) were lower in patients following treatment with hydrocortisone. There was a rise in DHEA responsiveness to CRH in the patients after treatment but this did not attain significance (AUCc: 2.5+/-1.7 ng/ml h pre-treatment vs. 6.4+/-1.2 ng/ml h post-hydrocortisone, P=0.053). However, those patients who responded fully to hydrocortisone in terms of reduced fatigue scores did show a significantly increased DHEA responsiveness to CRH (AUCc: -1.4+/-2.5 ng/ml h at baseline, 5.0+/-1.2 ng/ml h after active treatment, P=0.029).

CONCLUSIONS: DHEA levels are raised in CFS and correlate with the degree of self-reported disability. Hydrocortisone therapy leads to a reduction in these levels towards normal, and an increased DHEA response to CRH, most marked in those who show a clinical response to this therapy.

 

Source: Cleare AJ, O’Keane V, Miell JP. Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome. Psychoneuroendocrinology. 2004 Jul;29(6):724-32. http://www.ncbi.nlm.nih.gov/pubmed/15110921

 

Midodrine treatment for chronic fatigue syndrome

Abstract:

The long term results of midodrine treatment in a patient having debilitating chronic fatigue syndrome (CFS) are reported. Midodrine treatment, directed at the autonomic nervous system, resulted in correction of the dysautonomia followed by improvement of fatigue. This finding is consistent with the hypothesis that dysautonomia plays a major part in the pathophysiology of CFS and that therapies directed at the autonomic nervous system may be effective in the treatment of CFS.

 

Source: Naschitz J, Dreyfuss D, Yeshurun D, Rosner I. Midodrine treatment for chronic fatigue syndrome. Postgrad Med J. 2004 Apr;80(942):230-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1742969/pdf/v080p00230.pdf (Full article)