PRACTICAL ASPECTS OF THE LOW SODIUM DIET

The advantages of the oral administration of cortisone, when compared with cortisone given intramuscularly, include the more rapid appearance of therapeutic effects, which is of importance in the therapy of acute disease, and the faster dissipation of effects when the hormone is discontinued, which is of value when dangerous reactions occur. Oral dose schedules depend upon the degree of urgency or chronicity of the treated disease. In acute diseases the therapeutic results, in general, were disappointing. Cortisone may be of greater value in the long-term maintenance treatment of certain chronic diseases. By long-term therapy the authors mean practically continuous treatment until either the disease goes into spontaneous remission or undesirable effects of the drug require cessation of treatment. Critical selection of patients and constant supervision of therapy are vital to the successful administration of cortisone. Even with these precautions, however, the therapeutic use of cortisone must be regarded as experimental until the passage of time permits better appraisal of harmful effects.     

THE EFFECTS OF CORTISONE AND ADRENOCORTICOTROPIC HORMONE (ACTH) ON CERTAIN RHEUMATIC DISEASES

The adrenal cortical hormone, cortisone, and the pituitary adrenocorticotropic hormone (ACTH) possess potent antirheumatic properties. Their administration produces strikingly beneficial effects on a number of rheumatic diseases including rheumatoid arthritis, rheumatoid (ankylosing) spondylitis, acute rheumatic fever, disseminated lupus erythematosus, periarteritis nodosa, psoriatic arthritis, dermatomyositis, and gout. In general the effects of these substances are temporary and they cause suppression rather than cure of the disease processes. Improvement is maintained usually only by continuing administration, and on hormonal withdrawal prompt or fairly prompt relapse of the disease manifestations ensues. In addition to their antirheumatic effects cortisone and ACTH influence a wide variety of physiologic functions. Administration of them therefore may produce a number of metabolic and clinical changes, some of which are not advantageous from a therapeutic standpoint. Adverse side-reactions are more liable to occur when large doses of the hormones are given for prolonged periods; such reactions appear to be reversible and disappear when administration of the hormones is stopped. With cortisone, comparatively few untoward signs develop when smaller amounts are administered continuously even for periods of months.Greater clinical experience is needed before optimal doses and schedules of administration are finally determined. It appears that some severe cases, many moderately severe cases, and most moderate and mild cases of rheumatoid arthritis may be adequately controlled with smaller “maintenance” doses of cortisone ranging from 32 to 65 mg. a day, providing larger doses to suppress the disease manifestations are employed initially.Neither cortisone nor ACTH should be considered as a therapeutic agent for general use until more information regarding their physiologic activities and the consequences of prolonged or repeated administration of them are available. Until the potential dangers of these hormones can be determined precisely, the use of them should be considered as an investigative procedure.     

RESULTS OF LONG-CONTINUED CORTISONE ADMINISTRATION IN RHEUMATOID ARTHRITIS

The administration of cortisone acetate to patients with rheumatoid arthritis usually produces prompt and often dramatic suppression of the disease manifestations. The effects of the hormone are not lasting, however, and after withdrawal relapse ensues. For sustained improvement in a chronic disease such as rheumatoid arthritis, it appears that cortisone must be given more or less continuously. This raises the question whether administration may be continued effectively and safely for long periods.Seventy-six patients with rheumatoid arthritis were given cortisone in the hope that treatment could be continued uninterruptedly for extended periods. For various clinical reasons it was necessary to discontinue treatment in 16 of these before six months, but the remaining 60 patients received the hormone uninterruptedly for six to 15 months. By using initial large suppressive amounts, then gradually reducing the dosage, and finally employing smaller maintenance doses, adequate degrees of rheumatic control were maintained in approximately two-thirds of the original 76 patients. The ability to sustain satisfactory improvement varied indirectly, in general, with the severity of the rheumatoid arthritis. The chief detriment to better results in the more severe cases was the intervention of adverse hormonal side effects which developed frequently when large or relatively large maintenance doses were required to support satisfactory improvement.Unwanted signs of hormonal excess developed in 40 per cent of cases at some time during the course of treatment. Most of them were mild or transient and disappeared or lessened when the dose of cortisone was reduced, but when the dose was reduced the degree of improvement often declined also.During prolonged cortisone therapy evidence of functional suppression of the adrenal cortices, as indicated by a decreased response of circulating eosinophils to exogenous ACTH, was present. The depression of cortical function was temporary, however. Whether irreversible damage may result when the drug is employed for longer periods cannot yet be answered.     

Rheumatoid arthritis; an evaluation of long-term treatment with cortisone

Fifty-six patients with rheumatoid arthritis were treated continuously with cortisone for periods ranging between 4 and 38 months, in daily doses of 15 to 100 mg. Concomitant therapy included periods of rest, physical therapy, and salicylates. The incidence of subjective improvement exceeded that of objective improvement. The incidence of objective improvement was higher in females; also, in those patients whose disease was in an early stage and of short duration at the time therapy was begun, and who required relatively smaller maintenance doses of cortisone. Therapeutic results were not affected by the age of the patient or by the presence of spondylitis. Despite precautions, the long-term administration of cortisone was, in some patients, productive of serious undesirable side-effects. Although cortisone usually suppressed the symptoms and signs of rheumatoid arthritis, progression of the disease was frequently noted during its long-term administration.     

CORTISONE IN COCCIDIOIDOMYCOSIS

Cortisone administered orally, in low dosages for brief periods, promptly suppressed the allergic manifestations accompanying primary pulmonary coccidioidomycosis in 19 cases. There was no interference with the coccidioidin skin test reaction or with the usual serologic pattern.Dissemination of the disease as a sequel to the administration of cortisone and/or corticotropin has not been reported. A survey of physicians and of the known instances of disseminated coccidioidomycosis in Kern County failed to reveal any such episode.In none of the cases in which the authors gave cortisone in the presence of coccidioidomycosis was there any complication or undesirable sequel—specifically, no subsequent dissemination of the disease.The data presented are not to be interpreted as a therapeutic recommendation, but as a contribution to the information available concerning the effects of these drugs in infectious diseases.     

Focus: The Aging Brain: Side effects of a dopamine agonist therapy for Parkinson’s disease: a mini-review of clinical pharmacology

Dopamine agonists (DA) are therapeutic agents that are commonly used in the treatment of Parkinson’s disease (PD). They can reduce undesired motor fluctuations and delay the administration of levodopa therapy. However, this drug family is associated with specific side effects that can significantly diminish the quality of life among PD patients. Some of them impose significant risks for individuals who have a history of cardiovascular diseases, psychosis, and depression, or those older patients who suffer from renal or hepatic insufficiency. Various pharmacokinetic and pharmacodynamic considerations need to be taken into account when administering DA therapy. The goal of this review is to provide a comprehensive, up-to-date overview of DA therapeutic modalities for PD.     

THE TOPICAL AND SYSTEMIC USE OF CORTISONE IN DERMATOLOGY

Part I of this report deals with the topical use of cortisone in a variety of skin diseases. Fifteen patients with chronic discoid lupus erythematosus, four patients with necrobiosis lipoidica diabeticorum, four with psoriasis, one with lichen planus and one with granuloma annulare were treated with cortisone ointment. All the patients with chronic discoid lupus erythematosus had some degree of improvement. In two patients with chronic lupus erythematosus, complete clearing of the eruption occurred. In four patients with necrobiosis lipoidica diabeticorum remarkable involution resulted. Patients with psoriasis, lichen planus and granuloma annulare were not benefited.Part II deals with the systemic use of cortisone. Eight patients with severe serum sickness-like penicillin reaction responded dramatically to parenterally administered cortisone. In two cases of pemphigus vulgaris and one case of Sulzberger-Garbe disease, the disease was kept in remission with cortisone administered intramuscularly as well as orally. Partial improvement resulted in a case of localized myxedema associated with malignant exophthalmus. Two patients with exfoliative dermatitis due to therapy with heavy metals responded dramatically to cortisone. No beneficial effects were noted in patients with chronic urticaria and atopic dermatitis.The systemic use of ACTH and cortisone in dermatology at present should be confined to patients with known fatal or hopelessly incapacitating diseases and to patients with extreme hypersensitivity reactions which may be protracted or life-endangering, and which can be controlled or cured with a relatively small total dosage of the agents in a short time.     

EXPERIENCES WITH ACTH AND CORTISONE IN SELECTED DERMATOSES

Fifty patients with various kinds of skin diseases who were not adequately relieved by conventional therapy were treated with ACTH or cortisone given systemically.Almost all patients with disseminated neurodermatitis had dramatic initial response, but in only about half the cases was improvement maintained when use of the drugs was discontinued.It appeared that in other skin diseases, such as lupus erythematosus, scleroderma, psoriasis, dermatomyositis and pemphigus, while improvement may be noted for a time, relapse to the original state occurs after the treatment is stopped.In four cases of chronic discoid lupus erythematosus, although some improvement was observed when steroid therapy was given, the histologic pattern of biopsy material taken from the lesions after treatment still was characteristic of the disease.     

CORTISONE IN TREATMENT OF BRONCHIAL ASTHMA

Twenty patients with intractable asthma were treated with cortisone on various dosage schedules. Results indicated that a rapid improvement in the asthmatic state may be expected in four to five days with high level dosage of the hormone—usually a total dose exceeding 200 mg. per day at the beginning. If treatment is discontinued after a week, relapse usually will occur within a period of eight days. If small doses are given two or three times weekly, following initial response, relapse may not occur for 20 or 30 days. The interspersed administration of ACTH during an attempt to discontinue cortisone apparently was of no value. It therefore appears that cortisone control of intractable asthma is dependent on large dosage until clinical improvement is obtained, then approximately 100 mg. two or three times a week for maintenance of a reasonable state of health.     

Characterization of a surrogate murine antibody to model anti-human CD3 therapies

Fc-modified anti-human CD3ε monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3ε mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind FcγR in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration.     

NEWER THERAPY FOR LEUKEMIA,POLYCYTHEMIA, AND LYMPHOMA

X-radiation remains the treatment of choice in most cases of leukemia and lymphoma, but new agents are playing an increasing role in therapy. Radioactive phosphorus does not produce radiation sickness and results with it are comparable to those of x-ray therapy in chronic leukemia. Urethane and nitrogen mustard may produce remissions in patients with chronic leukemia who have become resistant to radiation. Triethylene melamine may be administered orally with nitrogen mustard-like effects and is undergoing further trial. Aminopterin, ACTH and cortisone often cause short remissions in acute leukemia. Urethane is the best treatment available for multiple myeloma. Polycythemia vera is well controlled by radioactive phosphorus combined with venesection. Nitrogen mustard is often effective and triethylene melamine shows promise in Hodgkin''s disease. Antianemic substances such as iron and liver extract are of no value in the treatment of anemia caused by leukemia, lymphoma and myeloma.     

The 1952 outbreak of encephalitis in California; vector control aspects

X-radiation remains the treatment of choice in most cases of leukemia and lymphoma, but new agents are playing an increasing role in therapy. Radioactive phosphorus does not produce radiation sickness and results with it are comparable to those of x-ray therapy in chronic leukemia. Urethane and nitrogen mustard may produce remissions in patients with chronic leukemia who have become resistant to radiation. Triethylene melamine may be administered orally with nitrogen mustard-like effects and is undergoing further trial. Aminopterin, ACTH and cortisone often cause short remissions in acute leukemia. Urethane is the best treatment available for multiple myeloma. Polycythemia vera is well controlled by radioactive phosphorus combined with venesection. Nitrogen mustard is often effective and triethylene melamine shows promise in Hodgkin's disease. Antianemic substances such as iron and liver extract are of no value in the treatment of anemia caused by leukemia, lymphoma and myeloma.     

NONALLERGIC ASTHMA—Differential Diagnosis and Treatment

A classification of asthma into allergic and nonallergic has gained support from the more recent studies on the underlying causes of the disease.The majority of instances of nonallergic asthma occur after middle life and result from recurrent infections of the upper and lower respiratory tract. Status asthmaticus is a frequent complication of infectious asthma.Chronic and intractable asthma may be present also in a patient with allergic asthma complicated by a superimposed infection of the sinuses, bronchi and lungs.There are many secondary or precipitating causes that may bring on asthmatic paroxysms. The most important of these are acute respiratory infections, mechanical and chemical irritants, autonomic imbalance, hormonal deficiencies and psychogenic influences. These secondary causes play a more important role in nonallergic asthma because of the greater tendency to chronicity in this form of the disease.The effective treatment of chronic asthma depends largely on the successful control of the secondary or precipitating causes of the asthmatic attacks.The introduction of the antibiotics and corticosteroids in the treatment of infectious asthma has supplied potent weapons to combat the disease. The use of these therapeutic agents makes possible the control of two of the important pathologic lesions of asthma—bronchial infection and bronchial inflammation.At present combined antibiotic and cortisone or hydrocortisone therapy of asthma seems to be the most rational method of preventing the disease from becoming chronic and intractable. Their value in infectious asthma is due to their anti-infective and antiflammatory action.When prolonged treatment is essential, combined therapy also lessens the dangers arising from the presence of masked infections.     

NONSPECIFIC ANTI-INFLAMMATORY AGENTS—Some Notes on Their Practical Application,Especially in Rheumatic Disorders

A number of acute and chronic inflammatory disorders are amenable to varying degrees of therapeutic control with the administration of nonspecific anti-inflammatory drugs. An evaluation of these suppressive agents in the field of rheumatic diseases and practical suggestions regarding their administration are presented.Eight synthetically modified corticosteroid compounds are available commercially. Each of them exhibits qualitative differences in one or several physiologic actions, each has certain advantages and disadvantages in therapy, and each shares the major deterrent features of corticosteroids. Prednisone, prednisolone, methylprednisolone, fluprednisolone and paramethasone have similar therapeutic indices, and there is little choice between them for the usual rheumatoid patient requiring steroid therapy. Conversely, the therapeutic indices of dexamethasone, betamethasone and triamcinolone are lower than that of prednisolone; they are less desirable for routine use and should be reserved for specially selected cases.Salicylates are preferred to adrenocortical steroids in the treatment of the ordinary patient with acute rheumatic fever. Steroid therapy should be reserved for resistant cases and for those with significant carditis. Salicylates are mainstays for pain relief in rheumatoid arthritis, but with the analgesic doses usually employed their anti-inflammatory action is slight.Phenylbutazone is a highly useful anti-inflammatory agent, especially in management of acute gouty arthritis and ankylosing (rheumatoid) spondylitis; its metabolite, oxyphenylbutazone, does not exhibit clear-cut advantages.Colchicine specifically suppresses acute gouty arthritis. Its analogues, desacetylcolchicine and desacetylthiocolchicine, produce fewer unpleasant gastrointestinal symptoms, but may promote agranulocytosis and alopecia.A number of indole preparations with anti-inflammatory activity have been tested clinically. One of them, indomethacin, has received extensive therapeutic trial; with dosages that can be tolerated the drug is fairly effective in the symptomatic control of ankylosing (rheumatoid) spondylitis but it is of questionable value in peripheral rheumatoid arthritis.     

EXPERIENCE WITH CORTISONE AND ACTH IN A PRIVATE CLINIC

Cortisone and ACTH are valuable agents for treating a large variety of diseases. In appropriate situations they may save life. It may be possible to prevent loss of vision in eye disease or permanent damage to important viscera in generalized disease. With ready access to these agents through the pharmacist, it is important to know that cortisone and ACTH can be used in office practice provided patients are selected carefully and followed frequently and closely. Strict observation of criteria for selection of patients limited the size of the series of patients reported upon, but by the same token the incidence of complications from therapy was exceptionally small. Every physician who elects to employ these potent hormones must become familiar with their physiological effects and with the various methods of exhibiting them. Some of these effects are noted in this paper, but the experiences reviewed here provide an incomplete picture of the wide application of cortisone and ACTH.     

Nonallergic asthma; differential diagnosis and treatment

A classification of asthma into allergic and nonallergic has gained support from the more recent studies on the underlying causes of the disease. The majority of instances of nonallergic asthma occur after middle life and result from recurrent infections of the upper and lower respiratory tract. Status asthmaticus is a frequent complication of infectious asthma. Chronic and intractable asthma may be present also in a patient with allergic asthma complicated by a superimposed infection of the sinuses, bronchi and lungs. There are many secondary or precipitating causes that may bring on asthmatic paroxysms. The most important of these are acute respiratory infections, mechanical and chemical irritants, autonomic imbalance, hormonal deficiencies and psychogenic influences. These secondary causes play a more important role in nonallergic asthma because of the greater tendency to chronicity in this form of the disease. The effective treatment of chronic asthma depends largely on the successful control of the secondary or precipitating causes of the asthmatic attacks. The introduction of the antibiotics and corticosteroids in the treatment of infectious asthma has supplied potent weapons to combat the disease. The use of these therapeutic agents makes possible the control of two of the important pathologic lesions of asthma-bronchial infection and bronchial inflammation. At present combined antibiotic and cortisone or hydrocortisone therapy of asthma seems to be the most rational method of preventing the disease from becoming chronic and intractable. Their value in infectious asthma is due to their anti-infective and antiflammatory action. When prolonged treatment is essential, combined therapy also lessens the dangers arising from the presence of masked infections.     

Strategies for breast cancer therapy with antiestrogens

Current clinical research is focused upon the application of adjuvant therapy for the treatment of breast cancer. Combination chemotherapy is the most successful adjuvant therapy for premenopausal patients whereas the antiestrogen tamoxifen (1 or 2 yr) is successful in postmenopausal disease. We have developed a unifying strategy for the treatment of breast cancer. The thesis is based upon the application of continuous adjuvant therapy with tamoxifen in a low estrogen environment. Chemotherapy causes a chemical castration in premenopausal patients. In contrast, tamoxifen causes an increase in steroidogenesis. A combination of both approaches will work against each other until ovarian failure occurs. Patients should be checked for castration to provide a low estrogen environment in which tamoxifen, a competitive antagonist of estrogen action, can effectively work. Laboratory evidence using carcinogen-induced rat mammary tumor models demonstrates the efficacy of long-term therapy. Studies with the human breast cell line MCF-7 grown in athymic mice show that tamoxifen is a tumoristatic agent so that once the therapy is stopped, tumors can be regrown by estrogen administration. Patients should receive continuous tamoxifen therapy to prevent the growth-stimulating effects of adrenal steroids, environmental and phyto-estrogens.     

Le dosage des séromuco?des dans la cardite rhumatismale: (Etude de 120 cas)

Seromucoid values were determined in 120 patients with rheumatic carditis, aged 5 to 20 years, who were in the acute, subacute or chronic phase of the disease. The following results were obtained: (1) Seromucoid values were elevated in all 32 of the acute cases and remained above normal as long as rheumatic activity was present. (2) Seromucoid values were unaffected by cortisone therapy, unlike the sedimentation rate and the level of C-reactive protein. (3) Greater values for seromucoid were found in severe cases.This study suggests that seromucoid determination is a useful method for following rheumatic activity and may be of value in assessing the severity of the disease.     

Peritoneal Dialysis in Chronic Renal Failure

The long-term results of intermittent peritoneal dialysis in long-term treatment of renal disease have yet to equal those of intermittent hemodialysis. However, further exploration and refinement of this technique is justified.Performed in acute stages of disease, both peritoneal dialysis and hemodialysis relieve the symptoms of uremia and specifically “buy time” for the patient so that proper medical or surgical therapy may be instituted. In acute situations, peritoneal dialysis is the procedure of choice, and is an important adjunct to more conventional treatment for chronic renal disease. It may be useful sometimes even in chronically hemodialyzed patients—for example, when the hemodialysis cannula for one reason or another is inaccessible because of clots, replacement, or infection. It is especially valuable when the hemorrhagic complications of uremia contraindicate hemodialysis treatment.Its use in chronic uremia remains sharply limited in time, but for brief periods chronic peritoneal dialysis appears to be a reasonably satisfactory means of prolonging life while awaiting homotransplant or decision for maintenance hemodialysis therapy.