Category: Treatment

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)

 

The effect of granisetron, a 5-HT3 receptor antagonist, in the treatment of chronic fatigue syndrome patients–a pilot study

Abstract:

OBJECTIVE: To explore the effect of granisetron, a 5-HT3 antagonist, on fatigue and functional impairment in patients with chronic fatigue syndrome (CFS).

METHODS: Five female patients were eligible to receive oral granisetron for one month (1 mg a day for the first two weeks and 2 mg a day for the second two weeks). The patients had to be between 18 and 65 years of age and suffering from CFS according to the CDC criteria. The effect was assessed by pre- and post-testing, using validated instruments designed to assess the different dimensions of CFS. Treatment response was also evaluated by visual analogue scales (VAS) for fatigue. Analysis was based on intention to treat.

RESULTS: Treatment with granisetron resulted in significant improvement in fatigue severity and functional impairment. Activity level showed no significant increase.

CONCLUSION: The promising results of this study have encouraged us to perform a placebo-controlled, double-blind study to evaluate the efficacy of 5-HT3 receptor antagonists in the treatment of CFS.

Comment in: Pilot studies: one swallow does not make a summer… [Neth J Med. 2003]

 

Source: The GK, Prins J, Bleijenberg G, van der Meer JW. The effect of granisetron, a 5-HT3 receptor antagonist, in the treatment of chronic fatigue syndrome patients–a pilot study.  Neth J Med. 2003 Sep;61(9):285-9. http://www.njmonline.nl/getpdf.php?id=16 (Full article)

 

Pilot studies: one swallow does not make a summer…

Abstract:

What should we expect from pilot studies, done in small series of patients? In the literature there are many examples of small studies with very promising results, that in subsequent larger or better controlled studies proved to be much less promising, or even disastrous. In some instances the initial favourable outcome was due to selection bias. In others the use of nonvalidated methods of measuring outcome made the reproducibility of promising observations problematic. However, we have to start somewhere. In ths issue The et al. report favourable results of granisetron treatment in four out of five patients with chronic fatigue syndrome. A prospective, randomised, placebo-controlled, double-blind clinical trial with granisetron in patients with chronic fatigue syndrome is now ongoing.

Comment on: The effect of granisetron, a 5-HT3 receptor antagonist, in the treatment of chronic fatigue syndrome patients–a pilot study. [Neth J Med. 2003]

 

Source: van Gelder T, Smits P. Pilot studies: one swallow does not make a summer… Neth J Med. 2003 Sep;61(9):270-2. http://www.njmonline.nl/getpdf.php?id=13 (Full article)

 

Medication use by persons with chronic fatigue syndrome: results of a randomized telephone survey in Wichita, Kansas

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is characterized by profound fatigue, which substantially interferes with daily activities, and a characteristic symptom complex. Patients use a variety of prescribed and self-administered medications, vitamins, and supplements for relief of their symptoms. The objective of this study was to describe utilization of medications and supplements by persons with CFS and non-fatigued individuals representative of the general population of Wichita, Kansas.

METHODS: We used a random-digit dialing telephone survey to identify persons with CFS in the general population of Wichita, Kansas. Subjects who on the basis of telephone interview met the CFS case definition, and randomly selected non-fatigued controls, were invited for a clinic evaluation that included self-reported use of medications and supplements. Sex-adjusted odds ratios and 95% confidence interval were estimated to measure the association between CFS and use of various drug categories.

RESULTS: We clinically evaluated and classified 90 subjects as CFS during the study and also collected clinical data on 63 who never described fatigue. Subjects with CFS reported using 316 different drugs compared to 157 reported by non-fatigued controls. CFS subjects were more likely to use any drug category than controls (p = 0.0009). Pain relievers and vitamins/supplements were the two most common agents listed by both groups. In addition CFS persons were more likely to use pain relievers, hormones, antidepressants, benzodiazepines, gastro-intestinal, and central nervous system medications (Sex-adjusted odds ratios range = 2.97 – 12.78).

CONCLUSION: Although the reasons for increased use of these agents were not elucidated, the data indicated the CFS patients’ need for symptom relief.

 

Source: Jones JF, Nisenbaum R, Reeves WC. Medication use by persons with chronic fatigue syndrome: results of a randomized telephone survey in Wichita, Kansas. Health Qual Life Outcomes. 2003 Dec 2;1:74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC293479/ (Full article)

 

Chronic fatigue syndrome. The patient centred clinical method–a guide for the perplexed

Abstract:

BACKGROUND: Chronic fatigue states are common in general practice and over the past 20 years there has been considerable worldwide consensus developed on the criteria for chronic fatigue syndrome (CFS) also commonly known as myalgic encephalomyelitis (ME). Chronic fatigue syndrome is an illness characterised by the new onset of disabling fatigue, accompanied by cognitive, musculoskeletal and sleep symptoms. There are no specific diagnostic tests or biological markers and the diagnosis is made by ruling out other causes of fatigue. The pathophysiology of CFS is still unclear.

OBJECTIVE: This article discusses the application of the patient centred clinical method to the diagnosis and treatment of CFS.

DISCUSSION: There is no new breakthrough in the diagnosis or management of CFS in spite of much research and controversy. There is considerable evidence that the best place to manage CFS is in primary care under the care of the patient’s own general practitioner, but it has been suggested that doctors feel unable to deal with the problem. The patient centred clinical method offers a constructive guide to management. The author considers that the best hope for sufferers is self management guided by a supportive and helpful health professional, preferably the patient’s own GP.

 

Source: Murdoch JC. Chronic fatigue syndrome. The patient centred clinical method–a guide for the perplexed. Aust Fam Physician. 2003 Nov;32(11):883-7. http://www.ncbi.nlm.nih.gov/pubmed/14650782

 

The head-up tilt test in the diagnosis and management of chronic fatigue syndrome

Fatigue, as a symptom, refers to a sense of lethargy or loss of energy. Fatigue is common in infections, endocrine disorders, heart failure, chronic diseases of the lungs, liver or kidneys, malignancies, anemia, nutritional deficits, inflammatory arthritis, Parkinson’s disease, depression, anxiety states, effect of certain medications, or drug withdrawal [1]. Population-based studies show that fatigue is one of the most common somatic symptoms, with as much as 20± 30% of the population complaining of chronic fatigue [2]. Only a small fraction of these satisfy the clinical definition criteria for chronic fatigue syndrome [1].

You can read the rest of this article here: https://www.ima.org.il/FilesUpload/IMAJ/0/54/27402.pdf

 

Source: Naschitz JE, Sabo E, Dreyfuss D, Yeshurun D, Rosner I. The head-up tilt test in the diagnosis and management of chronic fatigue syndrome. Isr Med Assoc J. 2003 Nov;5(11):807-11. https://www.ima.org.il/FilesUpload/IMAJ/0/54/27402.pdf (Full article)

 

Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome

Abstract:

Three cases of chronic fatigue syndrome (CFS) that followed acute parvovirus B19 infection were treated with a 5-day course of intravenous immunoglobulin (IVIG; 400 mg/kg per day), the only specific treatment for parvovirus B19 infection. We examined the influence of IVIG treatment on the production of cytokines and chemokines in individuals with CFS due to parvovirus B19. IVIG therapy led to clearance of parvovirus B19 viremia, resolution of symptoms, and improvement in physical and functional ability in all patients, as well as resolution of cytokine dysregulation.

 

Source: Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN.  Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin Infect Dis. 2003 May 1;36(9):e100-6. Epub 2003 Apr 22. http://cid.oxfordjournals.org/content/36/9/e100.long (Full article)