AU2554792A - Method of neutralizing il-1 using dsrnas - Google Patents

Description

METHOD OF NEUTRALIZING IL-1 USING dsRNAs

Described are methods of neutralizing the adverse effects of the cytokine IL-1 and like proteins and related pathogenic materials. IL-1 neutralization is evidenced by the improvement or return to normal of the patient's immune system and/or improvement in the patient's clinical

condition in terms of symptomology characteristic of elevated levels of IL-1.

BACKGROUND OF THE INVENTION

Interleukin-1 (IL-1) is the term for two polypeptides (IL-1α and IL-1β) that possess a wide spectrum of inflammatory, metabolic, physiologic, hematopoietic and immunologic properties. Although both forms of Il-1 are distinct gene products, they recognize the same cell surface receptors and share the various biologic activities. In general, significant amounts of IL-1 are not observed in health in most individuals. However, there is a dramatic increase in IL-1 production, and hence blood level, by a variety of cells in response to stimuli including infection, microbial toxins notably retroviruses and human herpes virus, inflammatory agents, products of activated lymphocytes, complement, and clotting components. Elevated IL-1 production has been reported in the following various human disease states:

Rheumatoid arthritis

Rheumatoid arthritis(synovial lining cells)

HIV infection and AIDS

Bacterial infection

Respiratory distress syndrome (alveolar

macrophages)

Smokers (alveolar macrophages)

Coal miner pneumoconiosis (alveolar macrophages) Alcoholic cirrhosis

Cuprophane hemodialysis

Cardiopulmonary bypass

Chronic hepatitis B

Thermal injury (burn) Reticulohistiocytosis

Sarcoidosis; tuberculosis

Obstructive jaundice

Pagets's disease and osteomalacia

Insulin dependent diabetes mellitus (newly

diagnosed)

Kawasaki's disease

Inflammatory bowel disease (mucosal mononuclear cells)

Luteal phase; strenuous exercise (1,2) The production and biologic activities of IL-1 contribute to the pathogenesis of certain diseases. IL-1 contributes to pathogenesis of a variety of diseases by virtue of a range of

biological functions. The reported biological effects of IL-1 include • T cell activation

• IL-2 release

• NK activation

• Neutiophilia

• Neuro peptide release

• Eosinophil degranulation

• Hypotension, shock, death

• Beta islet cell toxicity

• Hyperlipidemia

• Synthesis of collagenase and collagen and

osteoblast activation

• Synovial cell activation

Systemic symptoms include fever, myalgia, headache, lassitude and even sleepiness. Other biological effects include fever, chills, rigors, headache, increased muscle proteolysis, nausea, vomiting, increased heart rate, histamine release, depressed myocardial function, pulmonary congestion, meningeal irritation and brain parenchymal lesions. IL-1 is but one of several lymphokines (see below) which when upset starts a cascade effect of the immune system in which the immune system eventually attacks the host itself.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph of Karnofsky Performance scores in patients with elevated IL-1 during the 24 week study with the solid line

representing the placebo group and the broken line representing the treated group; and

Figure 2 is a chart showing the relative improvement of patients having elevated IL-1 treated with dsRNA in Activities of Daily Living modules from baseline ( ) to week 24 [ ] for activities the patient was unable to do through stages to no help needed.

DESCRIPTION OF THE INVENTION

I have discovered and hereby disclose a means to neutralize pathogenic material of the IL-1 type having a broad role in several diseases, a procedure not previously reported or anticipated. My studies have determined that although the elevated levels of IL-1 were not reduced, the patient's clinical symptomology is drastically improved as assessed by a number of performance and cognitive functions as well as the patient's own sense of well being, improved attitude and continued will to live and progress. These results are achieved by the administration of double stranded RNA (dsRNA), as more fully described below.

Unexpected and dramatic results of this therapy have produced an increase in the amount of physical work a patient is able to accomplish, an increase in the rate of oxygen consumption and an increase in the patient's exercise duration, meaning the patient is able to exercise longer.

Provided is a novel means of neutralizing IL-1 which, when present, is associated with a variety of symptoms related to various diseases. These symptoms cause morbidity among the range of characteristic symptoms such as lack of activity or loss of the ability to think clearly. While

different patients react in different ways as assessed by memory and physical performance, the procedures described herein neutralize the adverse effects of IL-1 over the entire range of IL-1

symptoms even though the assessable level of IL-1 remains the same or substantially the same.

Elevated levels of IL-1 in a patient are commonly caused by viral or bacterial pathogens or can be elevated by an external pathogenic event. The acute effects of increased IL-1 levels, as for instance by injection of IL-1, are different from the chronic effects. For purposes of clarity, acute means within hours or up to a day after IL-1 administration, subacute refers to a period of from 1 to 6 months after IL-1 administration and, if the symptoms persist for six months or longer, the elevated IL-1 levels are deemed to be chronic and the appropriate almost predictable symptoms result.

As reported, elevated IL-1 levels cause divergent derangement of multiple aspects and components of the immune system. In the patient's studied, all of them had increased IL-1 levels. In addition, an increase in the level of one or more of the following lymphokines was also reported: IL-1α, IL-4, IL-6, TNFα, TNFβ, GM-CSF, sIL2R, sCD8, and Neopterin. Not all patients had increased levels of all of these lymphokines but all patients were observed to have increased IL-1 levels. The successfully treated patient is able to restore his or her ability to generate antibodies against viruses, such as retroviral and herpes family viruses. The invention also provides a means to neutralize and achieve an improvement or return to normalcy of the ability of a patient to generate antibodies against retroviral and human herpes virus infections.

Importantly, IL-1 in elevated quantities stimulates the production of tumor necrosis factor (TNF), a lethal cytokine which can cause brain damage and loss of other quality of life and/or basic functions. Elevated TNF levels, in turn, are implicated in kakexia (weight loss) which is often secondary to the presence of many types of solid tumors. The ability to ameliorate such weight loss leads to an improvement of quality of life for patients having tumors associated with elevated IL-1 and TNF levels. As examples, elevated TNF levels are present during disease levels including HIV and malaria. Several patients reported in this study have been observed to have reduced or impaired cerebral blood flow as determined by SPEC scanning.

The dsRNA used in the procedures described herein may be a complex of a polyinosinate and a

polycytidylate containing a proportion of uracil bases or guanidine bases, e.g., from 1 in 5 to 1 in 30 such bases (poly I · poly(C_4-2gx>U or G)).

The dsRNA may be of the general formula rl_n·r(C _11-14,U)_n or rl_n·r(C₁₂ ,U)_n. Other suitable examples of dsRNA are discussed below.

By "mismatched dsRNA" are meant those in which hydrogen bonding (base stacking) between the counterpart strands is relatively intact, i.e., is interrupted on average less than one base pair in every 29 consecutive base pair residues. The term "mismatched dsRNA" should be understood

accordingly.

The mismatched dsRNAs preferred for use in the present invention are based on copolynucleotides selected from poly (C_n,U) and poly (C_n,G) in which n is an integer having a value of from 4 to 29 and are mismatched analogs of complexes of polyriboinosinic and polyribocytidilic acids, formed by modifying rI_n·rC_n to incorporate unpaired bases (uracil or guanidine) along the polyriboσytidylate (rC_n) strand. Alternatively, the dsRNA may be derived from poly(I)·poly(C) dsRNA by modifying the ribosyl backbone of polyriboinosinic acid (rl_n), e.g., by including 2'-O-methyl ribosyl residues. The mismatched complexes may be complexed with an

RNA-stabilizing polymer such as lysine and

cellulose. These mismatched analogs of rI_n·rC_n, preferred ones of which are of the general formula rI_n·(C_11-14'U)_n or rI_n·r(C₂₉,G)_n, are described bY Carter and Ts'o in U.S. Patents 4,130,641 and

4,024,222. The dsRNAs described therein generally are suitable for use according to the present invention. The preferred mismatched dsRNA is rl_n·(C_11-14,U)_n or AMPLIGEN^® of HEM Pharmaceuticals

Corporation of Rockville, MD, USA, available as a lyophilized powder.

Other examples of mismatched dsRNA for use in the invention include: - poly (I) • poly (C₄,U)

poly (I) • poly (C₇,U)

poly (I) • poly (C₁₃,U)

poly (I) • poly (C₂₂,U)

poly (I) • poly (C₂₀,G)

poly (I) • poly (C₂₉,G) and

poly (I) • poly C_p23 G>p

Another class of dsRNAs suited to the practice of this invention are short dsRNAs of defined structure, for example oligonucleotides of the formula:

5'lock-(I)_n-lock 3'

3'lock-(C)_m-lock 5' where m and n are each more than 5 and less than 100, I is inosine monophosphate, C is cytidine monophosphate, and where the locks in one strand are complementary to locks in the opposite strand, or an oligonucleotide of the structure:

5'lock-[(I)_χA]_j-lock 3'

3'lock-[(C)_yU]_k-lock 3' where x and y are each more than 5 and less than 25, j and k each at least 1 and less than 10, I and C are as identified above, A is a nucleotide which is not I, and U is a nucleotide which base pairs with A.

Alternatively, the short oligonucleotide may have the structure: 5' (I)_n-hinge-(C)_m3' where n, m, I and C are as defined above. These oligonucleotides may have

substitutions in one strand not complementary to nucleotides in the opposite strand. Preferably these oligonucleotides are stabilized by internal registers of complementary heteropolymer and

desirably the lock or hinge or both contain regions of complementary heteropolymer. These

oligonucleotides desirably have single-stranded tails. These oligonucleotides are described in more detail in PCT/US89/02172.

The dsRNA may be administered concurrently with agents used to treat the underlying disease condition, for example an antiviral agent or agents when the underlying cause is a retrovirus of human herpes virus.

Elevated IL-1 levels in various disease conditions, of which malaria is an example, provide the patient a number of unwanted and painful

symptoms including high levels of pain, debilitation and brain effects. These distressing and unpleasant effects sometimes lead to a relatively high suicide rate or attempted suicide. In the study that follows those patients receiving the test drug

(dsRNA) were not hospitalized for attempted suicides nor did they exhibit extreme depression.

EXAMPLES

Thirty-eight patients participated in a six-month randomized, placebo-controlled,

double-blind study and all were diagnosed as having elevated levels of IL-1 in addition to one or several clinical symptoms such as fever chills, rigors, headache, etc. as specified in Table 1, below.

Clinical symptoms of the patients

beginning the study included:

Fever

Painful cervical or axillary lymph nodes

Generalized muscle weakness

Prolonged fatigue

Myalgia or muscle discomfort

Migratory Arthralgia

Generalized headaches

Sleep disturbances

Neuropsychologic complaints

Patients were assessed for their general level of debilitation and only those considered severely debilitated, according to the assessments employed and as discussed below, were selected.

Because of the diversity in clinical symptoms exhibited, in addition to debilitation, the 38 patients in this study were matched to the extent possible. This allowed investigators to study the natural history of high levels of IL-1 and potential ability of dsRNA to neutralize symptoms. This also allowed for the creation of a "standard" of

comparison for the two sets of individuals, one to receive the placebo and the other to receive the dsRNA matched patients were assigned one to the placebo and the other to the dsRNA group.

Two highly regarded, reliable tests were used to determine the patient's condition and performance. Karnofsky Performance Scores and

Activities of Daily Living were used to assess patient status and quality of life. Tests were used and evaluated weekly during the course of therapy. Each week each patient was evaluated and assigned a patient Karnofsky Performance Score (KPS) based upon an investigator's clinical observations and

questioning of the patient or his or her spouse, companion, or custodian who was needed to care for the patient's daily need in light of the patient's severe chronic debilitation.

The KPS is a global evaluation of the patient's ability to conduct activities of daily living and is sensitive to effective therapeutic intervention in chronic disease states, especially where the patient's functional status declines, such as those associated with severe debilitation, e.g., AIDS, various neoplastic diseases, etc. (3, 4, 5). On a scale of 100 to 0 with 100 being a normal healthy individual with no evidence of disease and no complaints and 0 being death, those patients having a score of 50 or lower on the Karnofsky

Performance Scale, that is those patients requiring considerable assistance for daily care, were

selected for this study.

Second, to compliment the investigators global evaluation, the patient or caretakers

determination of the patient's ability to perform a broad range of specific activities routinely

encountered in daily living were recorded using a modified Barthel's Activities of Daily Living (ADL) index. The original ADL test was designed to evaluate the abilities and progress of patients with neuromuscular or muscular skeletal disorders to care independently for themselves evaluated over a series of ten categories or modules of basic self-care activities such as eating, dressing, grooming, personal toilet and functional mobility (6, 7, 8). The score assigned is based upon the patient's actual, not potential, ability to perform specific activities.

The KPS and the ADL data classify performance status and quality of life numerically. Each method independently allows evaluation of individual patient progress over time as well as interpatient comparisons. For convenience and analysis, the weekly KPS were averaged for each patient over a four week treatment interval. An increase in ten units on the KPS scale reflects a performance increase of one full level. As an illustration, a KPS change of from 50 to 60

represents a significant improvement in patient performance status as reflected by the reduced need for assistance for daily care.

The ADL is comprised of 13 individual modules and factor analysis was performed to analyze the relative effect of the 13 individual ADL modules and the total ADL score. The ADL score was measured weekly and averaged over each four week study interval. The ADL score is the average for scores in 13 modules multiplied by 20. Since there are 15 levels of performance within the component modules, the maximum score is 100 which reflects an

asymptomatic individual who can fully perform all 83 discrete activities of daily living. A 10 unit ADL score increase reflects an average increase of 0.5 unit of ability in each 13 activity modules. It also represents significant improvement in patient's ability to perform independently the routine

activities of daily living. Similarly, a 15 unit ADL score increase represents a further 50%

improvement in patient's ability to function

independently.

The data that follow may be interpreted following the above general guidelines or the more precise references that follow, the disclosures of which are incorporated by reference.

Poly I:Poly C₁₂U patients received 200 mg for their first four doses to minimize the

possibility of mild, flu-like symptom side effects and inadvertent unblinding of the study.

Statistical analysis of adverse events demonstrated no significant differences (p > 0.10, student's t test) between treatment groups in reports of these

symptoms. After the two weeks at 200 mg twice weekly, the Poly I:Poly C₁₂U patients were increased to 400 mg twice weekly for the duration of the six months study.

Upon qualification for entry and matching, patients were randomly assigned to receive either Poly I:Poly C₁₂U or placebo. To assure balance of patient performance status between the two study arms, randomization was stratified according to the patient's average baseline Karnofsky Performance Score (20 to 40 and 41 to 60). Patients received their assigned study treatment as twice weekly intravenous infusions given over 35 minutes ± 5 minutes.

Patients received 4,189 of 4,240 scheduled doses, a 98.9% rate of compliance. Concomitant medication (prescribed and over-the-counter

products) used by patients was captured through principal investigator interviews with the patients.

Laboratory Testing--Plasma Interleukin 1α(IL-1α) concentrations were measured under blinded conditions at the laboratory of Diagnostic

Immunology, University of Miami School of Medicine, Miami, FL, using a commercially available Elisa assay (Endogen Inc. Boston, MA). Briefly, patient plasma samples (50 ul) were incubated in sequence with mouse antibodies specific for human IL-1α, rabbit antibody to human IL-lα and enzyme-labeled goat anti-rabbit immunoglobulin-g (conjugated with alkaline phosphorylase). Between each incubation, unbound material was washed away and discarded. The bound specific anti-IL-1α antibody was quantitated by an enzymatic reaction resulting in a detectable color change using an Elisa reader. The measured absorbance was proportional to the concentration of IL-1α in the test sample. A standard curve was obtained by plotting IL-1α concentrations of diluted standards versus absorbance. Patient samples and controls were processed concurrently with the standards, and sample concentrations were determined by comparison with the standard curve. The lower limit of quantitation for this assay is 10pg/ml although lower IL-1α levels are detectable. Since IL-1α has not been reported in individuals in the absence of immunological stimulation, the presence of IL-1α in concentrations of 10pg/ml or greater in the population under study was defined as elevated.

The 38 patients studied prior to therapy all exhibited elevated IL-1α protein level in blood sera. Global performance of these patients was relatively low (median KPS 50; mean KPS 48.7) evidencing significant debilitation.

Patients were arranged into two groups prior to instituting therapy. The groups were closely matched in terms of the patients' ADL and KPS scores.

¹ PLPCU - Poly t Poly C₁₂U

² Comparisons by Mann-Whitney

³ Comparisons by student t test.

Poly I:Poly C₁₂U produced statistically significant increases in KPS as illustrated in

Figure 1. Poly I:Poly C₁₂U also produced a median increase in KPS (7.5) in Il-1α non elevated patients (n=25) as compared to placebo (n=28). Sustained and progressive increases in median performance scores began approximately eight weeks after initiating Poly I:Poly C₁₂U treatment. These differences became statistically significant relative to placebo through week 24. In contrast, the placebo patients experienced no change in performance status.

The ADL increases in the Poly I:Poly C₁₂U patients with elevated IL-1α demonstrated a greater global ability to perform activities of basic self care independently as well as more complex

activities of daily living requiring sustained ability to perform work.

ANOVA analysis with baseline as covariate, the more appropriate test because of differences in baseline ADL between the two study arms, showed statistical differences in support of efficacy beginning at week twelve and continuing through study termination.

Poly I: Poly C₁₂U patients with elevated IL-1α experienced greater increases in ability in 13 of 13 activity modules than did the placebo treated patients (p < 0.001, Binomial Test).

Among the Poly I: Poly C₁₂U subjects, the patient/significant other reported increased patient abilities in all 13 activity modules. However, the largest increases, greater than 0.5 units per activity module, occurred within the eight modular activities requiring sustained physical and mental abilities. These 8 modules and these respective increases secondary to Poly I:Poly C₁₂U treatment are shown in Fig. 2.

Treadmill Exercise Testing --Patients underwent treadmill exercise testing according to a standard protocol. The VO₂ max (defined as oxygen uptake as a percentage of theoretical maximum) is a measure of the difference between the inspired and expired volumes of oxygen corrected for the

patient's theoretical maximum, based upon size (height and weight), age and sex. At rest, a person's oxygen utilization would remain constant. During work, increased cellular metabolism increases the difference between inspired and expired oxygen volumes. Thus, VO₂ max parallels the increases in workload.

Total exercise work performed during each treadmill test was calculated as the patient's total external work, the sum of the horizontal and the vertical workloads (9). The total external work during a specific treadmill test was calculated as the sum of each of its stages, completed and

partial. Vertical work (W_v in joules) for each stage was calculated from the increase in potential energy required to elevate the body mass (m, in kg) in time (T) to a height given by VTsine, where V and θ are the velocity and the angle of inclination of the treadmill belt, respectively, i.e. W_v = gmVTsine, where g is the acceleration of gravity. Horizontal work (W_H) for each stage, reflecting the motion of the body's center of gravity in the horizontal, vertical and lateral planes, was calculated by using the equation, W_H = 0.48mVTcose.

In addition to the increased ADL

activities and increased KPS, the Poly I:Poly C_I2U treatment significantly increased the patients' ability to perform exercise testing. There were significant differences in various parameters of exercise workload performed by elevated IL-1α patients treated with Poly I:Poly C₁₂U versus those receiving placebo. At the completion of 24 weeks of treatment, the increase in exercise work performed by the IL-1α elevated Poly I:Poly C₁₂U patients was statistically greater than that observed in the placebo group.

1 Four drop-out patients not carried forward to 24 weeks.

² Four drop-out patients are carried forward to 24 weeks.

³ PLPCU = Poly LPoty C₁₂U

Comparisons by student t test Thus, in the Poly I:Poly C₁₂U treated patients, the mean work level at 24 weeks was 26.32 Kjoules higher than at baseline (p = 0.003, paired t test). In contrast, the IL-1α elevated placebo patients ability to perform work actually declined 27% during the six month observational period.

Consistent with the increased work performed by the IL-1α positive subset treated with Poly I:Poly C_I2U the duration of exercise also increased in comparison with placebo treated patients.

1 Four drop-out patients not carried forward to 24 weeks.

2 Four drop-out patients carried forward to 24 weeks.

3 PLPCU = Poly tPolyC₁₂U

Comparisons by student t test The 17% increase in duration of exercise by the Poly I:Poly C₁₂U group was also significantly greater than the baseline performance level (p = 0.05, paired t test).

The rate of oxygen consumption as a percentage of theoretical maximum, VO₂ max, is also considered an indirect measurement of work. This defect is observed in the apparent absence of any detectable abnormality in cardiac output or any other evidence of pulmonary abnormality. In the subset of IL-1α elevated patients, Poly I:Poly C₁₂U increased the rate of oxygen consumption as a percentage of theoretical maximum significantly over the 24 week treatment period when compared to placebo.

1 Four drop-out patients not carried forward to 24 weeks.

2 Four drop-out patients are carried forward to 24 weeks.

Comparisons by student t test

PLPCU = Pory tPoly C₁₂U The data collected suggest a deterioration in the placebo patients' ability to perform physical work over the twenty-four week course of

observation. This deterioration was corroborated by an increase in concomitant medication use, in the placebo group as a whole (n=47) relative to

baseline. The three indices of work capacity all declined during the six month observation interval. In the placebo group, mean exercise work, duration and oxygen consumption fell 19%, 13%, and 10.3%, respectively. The deterioration in oxygen

consumption relative to baseline was statistically significant (p = 0.049, paired test). These

physiological parameters of ability to perform work indicated that placebo patients were becoming progressively debilitated in their capacity to perform work as the study progressed.

Based on the evidence of physiological deterioration patients treated with placebo, the medication use over time was compared to their respective baseline values. Among the Poly I:Poly C₁₂U patients, the overall medication used,

including the three major categories of medications, did not significantly change over the 6 month observation interval. However, the placebo group's consumption increased as the six month study progressed. Towards the end of the study (weeks 21-24), the placebo group was taking significantly more medication of all types, including

significantly more medication specifically to relieve symptoms, to relieve CNS complaints, and to relieve pain, when compared to their consumption in weeks 1-4. These patterns of increased consumption were significantly increased for the four medication categories.

Effects of IL-1 on the central nervous system are widely reported in the literature. The ability to neutralize this pathogenic material having a broad role in several diseases has not been previously reported or anticipated. The procedures of neutralizing IL-1 as a harmful pathogen are thus suggested for additional indications and

conditions. For example, the inflammatory edema induced by interactions between IL-1 and the

neuropeptide calcitonin gene-related peptide [see Buckley et al. J. Immunol. 146(10), p. 3424-30, May 15, 1991] may be reduced. IL-1 has been reported [Quagliarello et al, J. Clin. Invest. 87(4), p.

1360-6, April 1991] as inducing meningitis and blood-brain barrier injury in the rat. Cytokine levels in the cerebro-spinal fluid and serum of patients with multiple sclerosis have been reported [Maimone et al. J. Neuroimmunol. 32 (1) p. 67-74, April 1991].

IL-1 has been reported to induce myocardial depression in the heart [Hosenpud et al, J. Heart Transplant. 8(6) p. 460-4, Nov.-Dec. 1989] which agrees with depressed myocardial function observed by the inventor in patients having elevated IL-1 levels.

IL-1 has also been reported as enhancing tumor necrosis factor (TNF) which in turn increases all necrosis and accelerates hepatitis [Lin et al, Gastroenterol. Jpn, 25(3), p. 339-42, June 1990]. TNF and IL-1 have been reported to inhibit Ia induction by interferon-gamma on endothelial cells from neurine central nervous system microvessels

[Tanaka et al, J. Neuroimmunol., 27(2-3) p. 209-15 May 1990] which agrees with the inventor's

observations of patients with elevated IL-1 levels showing disruption or damage to cerebral blood flow as determined by SPEC scanning.

There is evidence that IL-1 accentuates the deposition of abnormal materials, i.e. amyloid-like plagues, in animal brains. Such

plagues are specifically characteristic of

Alzheimer's disease [Blume et al, Neurobiol. Aging, 10(5) p. 406-8, Sept. -Oct. 1988]. Similarly, brain IL-1 has been reported to be elevated in Down

Syndrome and Alzheimer disease [Griffin et al. Proc. Natl. Acad. Sci. USA 86(19) p. 7611-5, October 1989].

The production of IL-1 by peripheral blood mononuclear cells in patients with chronic fatigue syndrome has been observed [Morte et al, J. Infect. Dis., 159(2), p. 362, Feb. 1989].

ABBREVIATED BIBLIOGRAPHY

1. Dinarello, C., Interleukin-1 and

Interleukin-1 Antagonism. Blood, 77:

1627-52, 1991.

2. Dinarello, C.A., et al, Interleukin-1 and its relevance in patients treated with hemodialysis. Kidney Int., 33 (suppl 24): S21-S26, 1988.

3. Capewell, S. and Sudlow, M.F., Performance and prognosis in patients with lung cancer. Thorax, 45:951-6, 1990.

4. McCIellan, W.M. et al, Functional status and quality of life: predictors of early mortality among patients entering treatment for end stage renal disease. J. Clin. Epidemiol., 44:83-9, 1991.

5. Wu, A.W., et al, Quality of life in a

placebo-controlled trial of Zidovudine in patients with AIDS and AIDS-related complex. J. Acguir. Immune Defic. Syndrome., 3:683-90, 1990. 6. Mahoney, F.I. and Barthel, D.W.,

Functional evaluation: the Barthel Index, Maryland State Med J., 14:61-5, 1965.

7. Gresham, G.E., et al, ADL status in

stroke: relative merits of three standard indexes. Arch. Phys. Med. Rehabil.

61:355-8, 1990.

8. Collin, C. et al, The Barthel ADL index: a reliability study. Int. Disabil. Studies, 10:61-3, 1988. 9. Pineda, H., et al, Treadmill exercise

training in chronic obstructive pulmonary disease. Arch. Med. Rehabil., 67:155-8, 1986.

Claims (13)

WHAT IS CLAIMED IS:

1. A method of neutralizing the effects of elevated IL-1, comprising administering to a patient having an elevated IL-1 level an effective amount of a dsRNA sufficient to alleviate the patient's clinical symptoms.

2. A method of ameliorating the untoward biological activity of elevated interleukin-l in a patient having diminished ability to perform the activities of daily living as assessed by the modified Barthel's Activities of Daily Living Index or exhibits chronic debilitation, comprising

administering to said patient an effective amount of a dsRNA.

3. A method of modulating the effect of interleukin-1 on divergent and multiple components of the immune system and restoring a patient's ability to raise antibodies against retroviral, herpes virus or other pathogens, said method

comprising administering an effective amount of a dsRNA to the patient.

4. The method according to claim 1, 2 or 3, wherein the patient, prior to treatment, requires assistance for daily care and the dsRNA is

administered with the patient's Karnofsky

Performance Score increases at least 10 units.

5. The method according to claim 1, 2 or 3, wherein the patient, prior to treatment, requires considerable assistance for daily care and the dsRNA is administered at least until the patient's

modified Barthel's Activities of Daily Living Index increases at least 10 units.

6. The method according to claim 5, wherein the patient is able to perform independently the routine activities of daily living.

7. The method according to claim 1, wherein the dsRNA is a mismatched dsRNA.

8. The method of claim 7 in which the mismatched dsRNA is a polyadenylic acid complexed with polyuridylic acid.

9. The method of claim 8, in which the mismatched dsRNA is a complex of polyisosinate and

polycytidylate containing from 1 in 5 to 1 in 30 uracil guanidine bases.

10. The method of claim 9 in which the mismatched dsRNA is rl_n·r(C_11-14, U)_n or the mismatched dsRNA contains regions of bond breakage and exhibits the favorable therapeutic ratio property of rI_n·r(C_11-14, U)_n.

11. The method of claim 7 in which the amount of mismatched dsRNA administered results in a level of from 2 to 1,000 micrograms of the

mismatched dsRNA per milliliter of the patient's systemic blood circulation.

12. The method of claim 7, in which the dsRNA is a short oligonucleotide of defined

structure of the formula:

5'lock-(I)_n-lock 3'

3'lock-(C)_m-lock 5' where m and n are each more than 5 and less than 100, I is inosine monophosphate, C is cytidine monophosphate, or

5'lock-[(I)_xA]_j-lock 3' 3'lock-[(C)_yU]_k-lock 3' where x and y are each more than 5 and less than 25, j and k each at least 1 and less than 10, I and C are as identified above, A is a nucleotide which is not I, and U is a nucleotide which base pairs with A, or

5'(I)_n-hinge-(C)_m3' where n, m, I and C are as defined above, provided that the locks in one strand are complementary to locks in the opposite strand.

13. The method according to claim 12 in which the oligonucleotide is stabilized by internal registers of complementary heteropolymer and the lock or hinge or both contain regions of

complementary heteropolymer.