Danazol for urinary incontinence in tropical spastic paraparesis.
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Adult↗
Biomedical subjects
W J Harrington
Publications and source records attributed to W J Harrington.
Human T lymphotropic virus type I-associated myelopathy. A report of 10 patients born in the United States.
Human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) (tropical spastic paraparesis/HAM) has rarely been reported in the United States. We present 10 well-documented cases with positive Western immunoblot test results and polymerase chain reactions for HTLV-I. The clinical and laboratory features of these American-born patients resemble those previously reported series of tropical spastic paraparesis and HAM from the Caribbean and Japan, but important differences were observed. In our study there were equal numbers of whites and blacks and of men and women. Age at onset was younger than that reported from the Caribbean and Japan. Rate of progression to paraparesis varied but was more rapid than previously reported. Half were transfusion recipients but six had multiple sexual partners, with one regularly interacting with prostitutes and reporting a history of drug abuse. Although more rapid progression was seen in the transfusion recipients, this did not explain the earlier age of onset in this group of patients. The HTLV-I, and the associated myelopathy, are endemic in Florida, suggesting that immigration from, and proximity, to the Caribbean basin are contributing risk factors.
Adult↗
The relapse of hairy cell leukemia after a 32-year remission.
The optimum therapy for hairy cell leukemia (HCL) is controversial. Dramatic responses to interferon-alpha and 2'-deoxycoformycin overshadow the established role of splenectomy in HCL, and patients currently can avoid surgery altogether. A case is presented of clinical remission lasting 32 years after splenectomy--a prolonged normal life, without medication or medical intervention. When relapse occurred, the patient's response to interferon-alpha was prompt and predictable. Prognostic variables are an important consideration at the time of diagnosis in predicting the response to splenectomy.
Aged↗
Danazol therapy for cyclic thrombocytopenia.
Cyclic thrombocytopenia is a rare disease characterized by cyclic oscillations of platelet counts from very low to normal or higher. Severe hemorrhage may occur during the thrombocytopenic phase. To date, treatments for this disorder have been disappointing. Its pathophysiology is unknown. We report a successful outcome using danazol therapy. Prior to danazol treatment, the patient had a 7 year history of cyclic thrombocytopenia, refractory to glucocorticoids, splenectomy, azathioprine, vinca alkaloids, plasma infusions, and hormonal manipulation with Premarin-Provera. Her platelet counts were found to be oscillating in a 21 day cycle between 1 x 10(9)/L and 500 x 10(9)/L. Platelet-associated antibodies were positive and chromium-labeled platelet survival time was shortened. Following 2 months of danazol therapy, her platelet counts at the nadirs were significantly higher than at previous nadirs, and at no time thereafter dropped to the critically low values seen before danazol. Also at 2 months of danazol treatment, the patient reported amelioration of petechiae, and at 9 months it was completely cleared. However, platelet-associated IgG remained positive and platelet counts continued to oscillate, typically between 100 x 10(9)/L and 300 x 10(9)/L in the second year, but stabilized at 3 years, when platelet-associated IgG also disappeared. Danazol was discontinued after 3.5 years. The patient remains in unmaintained remission today, approximately 5 years after discontinuance of danazol. It can be argued that the long-term outcome was due to spontaneous remission. However, significant improvement was noted from the outset of danazol therapy, and further improvement with long-term therapy, as seen in the response of chronic ITP to danazol therapy. Danazol may offer lasting benefit in cyclic thrombocytopenia.
Autoimmune Diseases↗
Tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM): treatment with an anabolic steroid danazol.
Tropical spastic paraparesis or HTLV-I-associated myelopathy is a progressive spastic disorder associated with the human T-lymphotropic virus type I. Some cases have responded to prednisone. Danazol is an attenuated androgen with minimal virilizing effects. It is used in the treatment of endometriosis and various autoimmune hematologic diseases shown to be responsive to prednisone. Because danazol is anabolic, useful in prednisone-responsive diseases, and less toxic than prednisone, we gave danazol to 6 patients with TSP and 1 with HIV, HTLV-I-associated myelopathy. Five patients had a favorable response. Two became ambulatory after having been confined to a wheelchair. Three were able to ambulate greater distances (in walkers) than prior to danazol. Three had noticeable decreases in spasticity. Urinary incontinence resolved in two. Physical therapy was variably employed in all except one patient. Two patients who had not responded to physical therapy responded to physical therapy and danazol. One patient did not tolerate danazol and one patient did not improve. Toxicities noted were mild elevations in liver enzymes in 4 patients; these responded to a decrease in dose of danazol; amenorrhea in one and mild fluid retention in one. We conclude that danazol is a useful agent in the management of TSP.
Adult↗
Estimating impacts on developing countries of the decrease in U.S. training opportunities for foreign medical graduates.
Between 1973 and 1983, the number of foreign nationals from developing nations who entered the United States for graduate medical education decreased by approximately 90%. Many of those who would have studied in the United States if this decrease had not occurred would have returned home to serve their countries. To estimate the impact of this loss, a survey was conducted in six major cities in Latin America between 1983 and 1989. Selected local medical students interviewed 554 physicians who had returned home after U.S. training and 60 of their classmates who had not trained there. The findings indicate that the returned physicians had given approximately twice as much time to teaching, research, and medical administration as did those who had not left home. The authors maintain that this and related findings show how the curtailment of opportunities for training foreign nationals in the United States is detrimental to both the aspirations of developing nations and the influence of the United States in world affairs.
Adult↗
HTLV-I-associated leukemia/lymphoma in south Florida.
We report here 10 cases of adult T-cell leukemia/lymphoma (ATL) seen in South Florida between February 1988 and July 1989. All were seropositive for human T-lymphotropic virus type I (HTLV-I) and seronegative for human immunodeficiency virus type 1 (HIV-1). DNA extracted from tumor biopsies/peripheral blood lymphocytes of nine patients was shown by the polymerase chain reaction (PCR) to contain HTLV-I proviral DNA. Blot hybridization of DNA extracted from seven patients with an HTLV-I cDNA probe revealed a monoclonal pattern of proviral integration consistent with a diagnosis of ATL. Eight of the 10 patients were women. Six patients were from Haiti, three from Jamaica, and one from the Bahamas. All patients had very aggressive non-Hodgkin's lymphoma. Two patients presented with sinus and retro-orbital involvement; another had gastric lymphoma that perforated. Nine patients developed hypercalcemia. Eight patients died within 1 year of diagnosis. Two were lost to follow-up. During the course of this study, 66 new cases of non-Hodgkin's lymphoma were diagnosed at this hospital. Ten of these cases were ATL. The prevalence of HTLV-I-related lymphoma in this sample was 15%. Since tissue from all patients was not available for HTLV-I screening, however, it is possible that other cases of ATL went undetected. We conclude from this initial survey that a retroviral etiology should be considered in patients from populations known to be at risk for HTLV-I infection who present with non-Hodgkin's lymphoma.
Adult↗
Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura. 1951.
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Adult↗
Is splenectomy an outmoded procedure?
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Anemia, Hemolytic↗
Long-term danazol therapy in autoimmune thrombocytopenia: unmaintained remission and age-dependent response in women.
STUDY OBJECTIVE: To assess the long-term benefit and side effects of danazol therapy, and to delineate factors influencing the responses in patients with autoimmune thrombocytopenia. DESIGN: Before and after trial. SETTING: Referral-based hematology clinics and the University of Miami teaching hospitals. PATIENTS: Data were collected on 96 patients (60 women and 36 men, 45 of whom had had splenectomies) receiving danazol therapy for autoimmune thrombocytopenia and analyzed. INTERVENTION: Danazol was added to the previous therapy or begun as an initial therapy. Glucocorticoids were tapered gradually. MEASUREMENTS AND MAIN RESULTS: The overall response rate to danazol was 61.4%. Among responders, the platelet counts (mean +/- SD) before and after danazol treatment were 36 +/- 24 x 10(9)/L and 145 +/- 77 x 10(9)/L, respectively, and the time to response was 2.7 +/- 3 months. Sex, age, and the status of the spleen (absent or present) influenced the responses to danazol. In women, but not in men, response rates improved with advancing age, especially in the nonsplenectomized women. This may be because estrogen levels are high in younger women and low in older women and men. Danazol, when given longer than a year, induced remissions lasting for years even after its discontinuation, but early relapses were frequent when danazol was administered for less than 6 months. Platelet-associated IgG returned to normal range during unmaintained remission. CONCLUSION: Danazol is best suited for long-term medical management of autoimmune thrombocytopenia. It is well tolerated, and lasting, unmaintained remissions often occur after prolonged danazol administration. Age, sex, and the status of the spleen influence the responses. When danazol therapy is used, glucocorticoids can be substantially reduced in dosage or withdrawn. Danazol is a good alternative to splenectomy in elderly persons, especially in women.
Adolescent↗
Spontaneous remission of acute leukemia after the termination of pregnancy.
A 28-year-old woman in the third trimester of her pregnancy was found to have acute myelocytic leukemia. The baby was delivered by Cesarean section and her leukemia underwent spontaneous remission. However, 3 months later, she presented with massive painful leukemic infiltration of the breasts as initial manifestation of relapse, followed by systemic symptoms of leukemia. In vitro culture of the leukemic cells demonstrated characteristics of macrophage cell line. This case illustrates a unique sequence of events: spontaneous remission after the termination of pregnancy, which has profound hormonal alterations, and relapse in a very hormone-sensitive organ, the breast, a few months later when the hormonal milieu was resumed. This suggests hormonal dependence of her leukemic cells and potential for hormonal manipulation in a certain subset of human leukemia.
Adult↗
Sex difference in the CD4 + CD45R+ T lymphocytes in normal individuals and its selective decrease in women with idiopathic thrombocytopenic purpura.
Chronic idiopathic thrombocytopenic purpura (ITP) is a well-defined autoimmune hematologic disorder. It is more common in women than men. We have shown that patients with active disease have abnormal T cell subsets which are more perturbed in women than in men and functional abnormalities that are confined to the T lymphocytes. In the current study, the anti-2H4 (CD45R) monoclonal antibody was used to divide the CD4 subset into their CD4+ CD45R+ and CD4+ CD45R- T lymphocytes. The subpopulations were measured in the peripheral blood of 26 women and 15 men with active ITP, 16 women and 8 men with disease in remission, and 33 normal healthy women and men. Normal women had increased percentages (P less than 0.0001) and numbers (P less than 0.005) of the CD4+ CD45R+ lymphocytes compared to normal men. Women with active disease had reduced percentages and numbers of CD4+ CD45R+ lymphocytes compared to normal women (P less than 0.0001) and women with disease in remission (P less than 0.001). Those women with decreased CD4+ CD45R+ lymphocytes had a significantly depressed lymphocyte response to polyclonal T cell mitogens. In contrast, men with active disease had neither such phenotypic changes nor functional correlations. The percentages and numbers of CD4+ CD45R- lymphocytes were not changed in either sex with active disease. In conclusion, women, but not men, with active ITP appear to possess a reduced subpopulation of CD4+ CD45R+ T lymphocytes.
Antibodies, Monoclonal↗
Danazol therapy renders red cells resistant to osmotic lysis.
Danazol, an attenuated androgen, is useful in endometriosis, idiopathic thrombocytopenic purpura (ITP), and autoimmune hemolytic anemia (AIHA). However, its mechanism of action is unknown. We investigated the possibility that danazol affects cell membranes directly. Red cell osmotic fragility was studied in patients receiving danazol. A significant decrease in osmotic fragility was observed. Accompanying the change, peripheral blood smears showed many target cells and electron microscopy revealed extra folds in erythrocyte membranes. Twenty-two patients were studied prospectively before and after danazol. Osmotic fragility decreased significantly (P less than 0.001) in 1 month of therapy and progressed with further treatment. A rebound increase (P less than 0.01) was observed in 1 month after discontinuation of danazol among 16 patients. Incubation experiments showed that danazol-induced changes are not reversed with normal sera. Patient sera did not induce the changes in normal red cells. Danazol in vitro protected red cells from osmotic lysis at low concentrations but enhanced lysis at high concentrations. We suggest that danazol alters red cell membranes directly to increase their surface area, inducing target cell formation and increasing their resistance to osmotic lysis.
Danazol↗
Very low dose danazol in idiopathic thrombocytopenic purpura and its role as an immune modulator.
Danazol, an attenuated androgen, has been used successfully at its conventional dose (400-800 mg/day) in the treatment of idiopathic thrombocytopenic purpura (ITP). To minimize side effects, the authors tried a very low dose (50 mg/day) regimen which has not been used in any other disease and observed its efficacy in ITP. Fifteen patients were given this dosage of danazol. Its effects on T-cell subsets, B cells, and blastogenic response to pokeweed mitogen (PWM) and staphylococcus aureus (Staph A) were studied before and during therapy. The percentage of CD3 and the percentage and numbers of CD4 were significantly increased during therapy. Responses to PWM, a T-cell dependent B cell mitogen, were also significantly elevated during therapy. However, no change in the percentage of B (CD19) lymphocytes and response to Staph A, a polyclonal B cell mitogen, were noted. There were seven excellent-good and eight fair-poor responses in platelet counts. The excellent-good responders were found to have a more stable CD4 subset between before and during therapy compared to the fair-poor responders (p less than 0.05, Fisher's exact test). Very low dose danazol regimen, therefore, produced a significant increase in the CD4 without affecting the B cells. However, the excellent-good responder patients showed no significant increase in the CD4 lymphocytes.
Adult↗
Differences in T cell subsets between men and women with idiopathic thrombocytopenic purpura.
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder, occurring predominantly in women. We studied by flow cytofluorimetry the T cell subsets in men and women with ITP and compared them with healthy sex-matched volunteers. In healthy controls, women were found to have higher proportions of T helper/inducer (Th/i) and lower T suppressor/cytotoxic (Ts/c) lymphocytes and consequently higher Th/i:Ts/c ratios than men. Accordingly, in clinical surveys, patients and controls should be matched for sex for proper comparisons. In patients with ITP in its active phase, an imbalance in T cell subsets was found in both sexes. The perturbation was more severe in women who had a marked decrease in number and proportion of Th/i lymphocytes and an increase in the proportion of Ts/c lymphocytes, whereas in men only, the proportion of Th/i lymphocytes was decreased. When patients with active disease were compared to those with ITP in remission, the decrease in Th/i subsets still persisted in both sexes but the Ts/c subset in women had returned to normal proportions. Therefore, the immune imbalance in ITP is more marked in women than men; imbalances in both Th/i and Ts/c are present in women while Ts/c appears not to be involved in men.
Danazol↗
The Ph.D. to M.D. program: the seven-year mark.
The Ph.D. to M.D. Program, a two-year, accelerated medical curriculum for Ph.D. scientists, has been in operation at the University of Miami for over seven years. Two hundred and nine students from a broad range of scientific disciplines have been admitted, and attrition has been remarkably low (less than 1 per cent). One hundred and thirty-five of the entering candidates (65 per cent) were nonbiologists, but their achievements in the curriculum were virtually equivalent to those of their biologically oriented peers. All graduates have commenced house-staff training, the vast majority at university or university-affiliated hospitals. Of the 46 graduates who have completed some aspect of postgraduate training, 22 are in private practice, 20 are in teaching and research positions and four are scientific administrators in industry. The record indicates that through intensive medical education, the program is able to bring a group of scientists with unusual talents to the theory and practice of medicine.
College Admission Test↗
Iatrogenic disorders from cancer treatment.
All cancer therapies have potential and often serious side effects. With judicious selection of therapies, the risks are acceptable as are the contributions to better care, including that of iatrogenic disorders from therapy. It should, again, be stressed that new drugs and new modalities in combinations of treatments increase iatrogenic disorders from cancer therapy; as this increase is more and more appreciated, adjustments in schedules are resulting in decreased incidences of such disorders. Truly long-term effects over decades or generations are, of course, not yet known for most of the modern cancer therapies.
Animals↗
The treatment of idiopathic thrombocytopenia with vinblastine-loaded platelets.
We devised a method to enhance delivery of vinblastine to macrophages, the cells believed to be responsible for platelet destruction in idiopathic thrombocytopenic purpura. Our strategy was based on the ability of platelets to bind vinca alkaloids such as vinblastine. Platelets were incubated with an excess of vinblastine, concentrated and then, after excess alkaloid had been removed, given to 11 patients with idiopathic thrombocytopenia refractory to other treatment (including intravenous injections of vinca alkaloids). Platelet antibodies in the patients' plasma led to ingestion of the vinca-laden platelets by macrophages. There were six complete remissions, three partial remissions and two failures. Side effects in a few patients, reversible but annoying, were minimized as technics were refined. We conclude that in patients with idiopathic thrombocytopenia refractory to all other measures, including the use of vinca alkaloids, platelet-vinca complex may be effective.
Adolescent↗