We treated 93 children with nephropathic cystinosis with oral cysteamine (mean dose, 51.3 mg per kilogram of body weight per day) for up to 73 months. This agent is known to be effective in depleting cells of cystine. In our study, the mean cystine depletion from leukocytes was 82 percent. A historical control group of 55 children received either ascorbic acid (27 children) or placebo (28). At age six, 2 of 17 controls had a serum creatinine level less than 1.0 mg per deciliter, as compared with 17 of 27 patients treated with cysteamine for at least one year (odds ratio, 12.8; 95 percent confidence interval, 2.1 to 33.9). At the end of the study, creatinine clearance was higher in the cysteamine group than in the control group (38.5 vs. 29.7 ml per minute per 1.73 m2; 95 percent confidence limits on the difference, 1.8 and 15.8), even though the cysteamine group was on average 1.4 years older than the control group. Cysteamine also improved growth; those in the cysteamine group between two and three years of age grew at 93 percent of the normal velocity, as compared with 54 percent in the control group. Fourteen percent of the patients could not tolerate the taste and smell of cysteamine. Concurrent controls treated in a blinded fashion with a placebo were not included in this study. With this limitation in mind, we conclude that oral cysteamine, by depleting cells of cystine, helps maintain renal glomerular function, improves growth, and constitutes the current treatment of choice for nephropathic cystinosis.

We conducted a multicenter, randomized, prospective study comparing medical therapy alone with coronary-artery bypass surgery plus medical therapy in 468 men with unstable angina pectoris. Patients were entered in the study from June 1, 1976, to June 30, 1982. Among those assigned to surgery who received bypass grafts, operative mortality was 4.1 percent. Arteriography performed after one year of follow-up revealed that 74.8 percent of the grafts studied were patent. The cumulative rate of crossover from medical to surgical therapy after two years was 34 percent; the operative mortality among patients crossed over was 10.3 percent. Nonfatal myocardial infarction occurred in 11.7 percent of the patients treated surgically and 12.2 percent of those treated medically (no significant difference). Most of the nonfatal myocardial infarctions in the surgical group occurred in the perioperative period. Overall, the two-year survival rate computed by life-table analysis did not differ between the two groups. However, the curves reflecting mortality as a function of left ventricular ejection fraction were significantly different (P = 0.03); surgery was associated with a significantly reduced mortality among patients with lower ejection fractions. We conclude that patients with unstable angina pectoris have a similar outcome after two years whether they receive medical therapy alone or coronary bypass surgery plus medical therapy. However, patients with reduced left ventricular ejection fractions may have a better two-year survival rate after coronary bypass surgery.

We conducted a prospective, randomized study to clarify the role of radiotherapy of the primary tumor in limited small-cell cancer of the lung. After stratification for sex and for performance score based on the ability to ambulate, patients were randomly assigned to receive initial radiotherapy plus chemotherapy, delayed radiotherapy plus chemotherapy, or chemotherapy alone. The chemotherapy consisted of cyclophosphamide, etoposide (VP-16-213), and vincristine, with doxorubicin subsequently replacing etoposide in alternate cycles 7 through 18. Chemotherapy was given every three weeks for 18 months. The radiotherapy comprised 4000 rad in four weeks, followed by a 1000-rad "boost" directed against residual disease. All patients received prophylactic whole-brain radiation. The patients enrolled totaled 426, and 399 were evaluable. There was a statistically significant difference in the frequency of complete responses in favor of the two radiotherapy regimens (P = 0.0013). Failure-free survival was also longer with these two regimens (P less than 0.001), as was the interval before treatment failure in the chest (P less than 0.001) and overall survival (P = 0.0099). As expected, toxic effects--chiefly neutropenia--were also increased. The addition of radiotherapy of the primary tumor to combination chemotherapy improved both complete-response rates and survival, with increased but acceptable toxicity.

In patients with nephropathic cystinosis, corneal crystals develop by one year of age; they progressively accumulate and eventually cause recurrent corneal erosions and photophobia. After an in vitro study of cystinotic corneal stromal cells showed cystine depletion by cysteamine and after topical cysteamine was determined to be nontoxic in rabbits, we performed a controlled double-blind clinical trial of 10 mM cysteamine eyedrops in young patients with cystinosis, using one eye for treatment and the other as the control. Two children begun on the protocol before two years of age had a striking decrease in the number of corneal crystals in the cysteamine-treated eye within four to five months of entering the study. Cysteamine eyedrops appear to be safe and efficacious in the short-term treatment of patients with cystinosis who are under two years of age. The long-term value of such treatment and its effectiveness in older patients remain to be determined.

We randomly assigned 20 patients with progressively worsening generalized myasthenia gravis of recent onset whose illness was not controlled by anticholinesterase therapy to treatment with either cyclosporine (6 mg per kilogram of body weight per day) or placebo. Patients who had been treated with thymectomy, steroids, or other immunosuppressive agents were excluded. The duration of treatment was 12 months. Disease activity was assessed by quantified strength testing and by measurements of antihuman acetylcholine-receptor antibody. Patients were assessed at 6 months and 12 months, or at the following early end points: drug failure (doubling of creatinine), treatment failure (respiratory or swallowing difficulty), or protocol violation (stopping medication for more than five days). At six months, patients in the cyclosporine group had had significantly more objective improvement in strength; one early end point had been reached (drug failure; no treatment failures). In the placebo group, three early end points had been reached (all treatment failures). The decline in titers of acetylcholine-receptor antibody was larger in the treated group, although the difference was not statistically significant. At the end of the study (after 12 months of treatment or arrival at an earlier end point), improvement in strength and reduction in titers of anti-receptor antibody continued to be greater in the cyclosporine group. Nephrotoxicity occurred in three patients receiving cyclosporine but was nonprogressive with a reduction in dosage and reversible with discontinuation of the drug. These results are preliminary and need confirmation, but we conclude that cyclosporine is probably an effective therapy in some patients with myasthenia gravis.

In a randomized, double-blind, placebo-controlled trial involving 518 infants and children who had otitis media with effusion ("secretory" otitis media), we evaluated the efficacy of a two-week course of amoxicillin (40 mg per kilogram of body weight per day) with and without a four-week course of an oral decongestant-antihistamine combination. Among the 474 subjects who were evaluated at the four-week end point, the rate of resolution of middle-ear effusion was twice as high in those treated with amoxicillin, either with or without the decongestant-antihistamine, as in those who received placebo (P less than 0.001), but 69.8 percent of the amoxicillin-treated subjects still had effusion. Among both the amoxicillin-treated subjects and the placebo-treated subjects, resolution was more likely in those with initially unilateral effusion, in those who had had effusion for eight weeks or less, and in those without an upper respiratory tract infection at the four-week end point. Side effects were reported more often in subjects who received decongestant-antihistamine than in those who did not. Among the subjects without effusion at the four-week end point, recurrent effusion developed in approximately half those in both the amoxicillin and placebo groups during the subsequent three months. We conclude that in infants and children with otitis media with effusion, amoxicillin treatment increases to some extent the likelihood of resolution.

Systemically disseminated cutaneous T-cell lymphoma is generally resistant to chemotherapy and radiotherapy. We tested a treatment involving the extracorporeal photoactivation of biologically inert methoxsalen (8-methoxypsoralen) by ultraviolet A energy to a form that covalently cross-links DNA. After oral administration of methoxsalen, a lymphocyte-enriched blood fraction was exposed to ultraviolet A (1 to 2 J per square centimeter) and then returned to the patient. The combination of ultraviolet A and methoxsalen caused an 88 +/- 5 percent loss of viability of target lymphocytes, whereas the drug alone was inactive. Twenty-seven of 37 patients with otherwise resistant cutaneous T-cell lymphoma responded to the treatment, with an average 64 percent decrease in cutaneous involvement after 22 +/- 10 weeks (mean +/- SD). The responding group included 8 of 10 patients with lymph-node involvement, 24 of 29 with exfoliative erythroderma, and 20 of 28 whose disease was resistant to standard chemotherapy. Side effects that often occur with standard chemotherapy, such as bone marrow suppression, gastrointestinal erosions, and hair loss, did not occur. Although the mechanism of the beneficial effect is uncertain, an immune reaction to the infused damaged cells may have restricted the activity of the abnormal T cells. This preliminary study suggests that extracorporeal photochemotherapy is a promising treatment for widespread cutaneous T-cell lymphoma.

During a two-year study, we examined the effect of calcium supplementation on postmenopausal bone loss in 43 women in the early postmenopausal period who were assigned to one of three treatment groups: percutaneous 17 beta-estradiol (combined with progesterone during the second year), oral calcium (2000 mg daily), and placebo. All participants were examined every three months. Bone mineral content in the forearm (measured by single-photon absorptiometry) and in the entire body and spine (measured by dual-photon absorptiometry) remained constant in the estrogen-treated group but decreased significantly in the groups receiving calcium and placebo. In the calcium-treated group, we observed a tendency toward a slowed loss of compact bone (in the proximal forearm and total skeleton) as compared with the placebo group, while the rate of loss of trabecular bone (the distal forearm and spine) was the same as in the placebo group. Our preliminary data suggest that calcium supplementation in the dosage we used is not as effective as estrogen therapy for the prevention of early postmenopausal bone loss. Calcium supplementation may have had a minor effect on the loss of cortical bone, but it had no effect on the trabecular bone.

We administered recombinant human erythropoietin to 25 anemic patients with end-stage renal disease who were undergoing hemodialysis. The recombinant human erythropoietin was given intravenously three times weekly after dialysis, and transfusion requirements, hematocrit, ferrokinetics, and reticulocyte responses were monitored. Over a range of doses between 15 and 500 units per kilogram of body weight, dose-dependent increases in effective erythropoiesis were noted. At 500 units per kilogram, changes in the hematocrit of as much as 10 percentage points were seen within three weeks, and increases in ferrokinetics of three to four times basal values, as measured by erythron transferrin uptake, were observed. Of 18 patients receiving effective doses of recombinant human erythropoietin, 12 who had required transfusions no longer needed them, and in 11 the hematocrit increased to 35 percent or more. Along with the rise in hematocrit, four patients had an increase in blood pressure, and a majority had increases in serum creatinine and potassium levels. No organ dysfunction or other toxic effects were observed, and no antibodies to the recombinant hormone were formed. These results demonstrate that recombinant human erythropoietin is effective, can eliminate the need for transfusions with their risks of immunologic sensitization, infection, and iron overload, and can restore the hematocrit to normal in many patients with the anemia of end-stage renal disease.

In a continuation of a trial for which preliminary results were reported in the Journal two years ago, a total of 64 patients with Child Class C cirrhosis and variceal hemorrhage requiring six or more units of blood were randomly assigned to receive either a portacaval shunt (32 patients) or endoscopic sclerotherapy (32 patients). The duration of initial hospitalization and the total amount of blood transfused during hospitalization were significantly less in the patients receiving sclerotherapy (P less than 0.001). There was no difference in short-term survival (50 percent of the sclerotherapy group were discharged alive, as compared with 44 percent of the shunt-surgery group). Both groups were followed for a mean of 530 days after randomization. Rebleeding from varices, the duration of rehospitalization for hemorrhage, and transfusions received after discharge were all significantly greater in the sclerotherapy group (P less than 0.001). Forty percent of the sclerotherapy-treated patients discharged alive (7 of 16 patients) ultimately required surgical treatment for bleeding varices, despite a mean of 6.1 treatment sessions. Health care costs and long-term survival did not differ significantly between the groups (P greater than 0.05). We conclude that although endoscopic sclerotherapy is as good as surgical shunting for the acute management of variceal hemorrhage in poor-risk patients with massive bleeding, sclerotherapy-treated patients in whom varices are not obliterated and bleeding continues should be considered for elective shunt surgery.

13-cis-Retinoic acid has been reported to be effective in treating oral leukoplakia. We randomly assigned 44 patients with this disease to receive 13-cis-retinoic acid (24 patients) or placebo (20), 1 to 2 mg per kilogram of body weight per day for three months, and followed them for six months. There were major decreases in the size of the lesions in 67 percent (16 patients) of those given the drug and in 10 percent (2 patients) of those given placebo (P = 0.0002); dysplasia was reversed in 54 percent (13 patients) of the drug group and in 10 percent (2 patients) of the placebo group (P = 0.01). The clinical response to the drug correlated with the histologic response in 56 percent (9 of 16) of the patients evaluated. Relapse occurred in 9 of 16 patients two to three months after treatment ended. The toxic effects of the drug were acceptable in all but two patients. Cheilitis, facial erythema, and dryness and peeling of the skin were common; conjunctivitis and hypertriglyceridemia also occurred. All adverse reactions could be reversed by reducing the dose or temporarily discontinuing the drug. We conclude that 13-cis-retinoic acid, even in short-term use, appears to be an effective treatment for oral leukoplakia and has an acceptable level of toxicity.

In a prospective, placebo-controlled study, 74 women with recurrent vulvovaginal candidiasis were treated with oral ketoconazole (400 mg daily for two weeks) and were then randomly assigned to receive placebo (Group A), prophylactic ketoconazole, 400 mg daily for five days beginning with the onset of menses for six menstrual cycles (Group B), or low-dose ketoconazole, 100 mg daily for six months (Group C). Within a six-month follow-up period, 15 of 21 women (71.4 percent) treated with placebo had symptomatic recurrence of candidal vaginitis. In contrast, candidal vaginitis recurred in 6 of 21 (28.6 percent) and in 1 of 21 (4.8 percent) women in Groups B and C (P less than 0.01; P less than 0.001). After the prophylaxis was discontinued, the recurrence rates of candidal vaginitis were high in women in Groups B and C. At the end of 12 months of follow-up, 23.8 percent of the women in Group A remained asymptomatic and attack-free, in contrast to 42.9 percent of the women in Group B (P greater than 0.05) and 52.4 percent in Group C (P less than 0.05). It appears that maintenance prophylactic therapy with oral ketoconazole is effective in preventing recurrent episodes of vulvovaginal candidiasis, but that relapse is common after withdrawal of the drug. Because of the risk of hepatotoxicity, caution is essential in selecting patients for long-term ketoconazole therapy and in following patients undergoing such treatment.

We entered 60 patients with primary biliary cirrhosis in a double-blind randomized controlled trial to determine whether colchicine is therapeutically effective. Thirty patients had early disease (Stages 1 and 2), and 30 had advanced disease (Stages 3 and 4). Fifteen patients with early disease and 15 with advanced disease received colchicine (0.6 mg twice daily), and the remainder received placebo. Patients were studied about every two months; those remaining in the blind phase at two years underwent repeat liver biopsy and were then placed on open-label colchicine (0.6 mg twice daily). With a few exceptions, the results in patients with early disease were similar to those in patients with advanced disease; hence, data on patients in all stages were combined in the main analysis. During the two-year study period the colchicine-treated patients, as compared with the placebo-treated patients, had improvement in levels of serum albumin, serum bilirubin, alkaline phosphatase, cholesterol, and aminotransferases. However, there was no such improvement in the severity of symptoms or physical findings; moreover, there was no significant difference in the histologic changes noted at liver biopsy in the two treatment groups. At four years after entry, the cumulative mortality from liver disease was 21 percent in patients given colchicine and 47 percent in those given placebo (P = 0.05). The only side effect of colchicine was diarrhea, noted in three patients. The consistent and significant improvement in a number of markers of liver disease and the apparent decreased mortality from liver disease suggest that colchicine may provide some long-term clinical benefit in patients with primary biliary cirrhosis. However, the failure of colchicine to reduce hepatic inflammation and fibrosis leaves uncertain the effect of the drug on the longterm outcome of this disease.

To study the ability of anticholinesterase drugs to reverse the potentially fatal paralytic effects of cobra venom, we conducted a placebo-controlled, double-blind crossover trial of intravenous edrophonium (Tensilon) in 10 adults with neurotoxic envenoming caused by bites of the Philippine cobra (Naja naja philippinensis). There was significantly more improvement in ptosis and endurance of upward gaze after edrophonium than after placebo. Five minutes after injection, the mean difference (+/- SD) in the percentage of the iris that was uncovered was 39 +/- 5.47 (70 vs. 31 percent; P less than 0.01), and the mean difference in the number of seconds of upward gaze was 33.1 +/- 9.29 (39.7 vs. 6.6 seconds; P less than 0.01). The expiratory and inspiratory pressures, forced vital capacity, and ability to cough, speak, and swallow also improved after edrophonium. In both the patients who were studied electromyographically, pretreatment and postplacebo responses were typical of myasthenia gravis and became normal after edrophonium. We conclude that anticholinesterases are beneficial in the management of neurotoxic envenoming by Asian cobras (Naja naja), and we recommended a test of edrophonium in any patient with signs of neurotoxic envenoming after snakebite.

In a double-blind study, we examined the efficacy of allopurinol in the prevention of recurrent calcium oxalate calculi of the kidney. Sixty patients with hyperuricosuria and normocalciuria who had a history of calculi were randomly assigned to receive either allopurinol (100 mg three times daily) or a placebo. After the study, the placebo group had 63.4 percent fewer calculi (P less than 0.001), whereas the allopurinol group had 81.2 percent fewer calculi (P less than 0.001). During the study period, the mean rate of calculous events was 0.26 per patient per year in the placebo group and 0.12 in the allopurinol group. When the treatment groups were compared by actuarial analysis, the allopurinol group was found to have a significantly longer time before recurrence of calculi (P less than 0.02). We conclude that allopurinol is effective in the prevention of calcium oxalate stones in patients with hyperuricosuria. The large reduction in the frequency of calculi in the placebo group underscores the positive treatment bias that regularly occurs in trials of prophylaxis against renal calculi when historical controls are used.

We conducted a randomized clinical trial comparing a single intramuscular dose of 125 mg of ceftriaxone with a single intramuscular dose of 75 mg of kanamycin followed by topical gentamicin for seven days, and with a single intramuscular dose of 75 mg of kanamycin followed by topical tetracycline for seven days, in the treatment of gonococcal ophthalmia neonatorum in Nairobi, Kenya. Of 122 newborns with culture-proved gonococcal ophthalmia neonatorum, 105 returned for follow-up. Sixty-one infants (54 percent) received ceftriaxone, 32 received kanamycin plus topical gentamicin, and 29 received kanamycin plus topical tetracycline. Sixty-six (54 percent) of the Neisseria gonorrhoeae isolates were penicillinase producing. All 55 newborns who received ceftriaxone and returned for follow-up were clinically and microbiologically cured. One of 26 returning newborns who received kanamycin plus tetracycline and 2 of 24 returning newborns who received kanamycin plus gentamicin had persistent or recurrent gonococcal conjunctivitis. Ceftriaxone also eradicated oropharyngeal gonococcal infection in 18 newborns, whereas oropharyngeal infection persisted in 2 of 8 newborns who had received kanamycin (P not significant). We conclude that 125 mg of ceftriaxone as a single intramuscular dose is very effective therapy for gonococcal ophthalmia neonatorum, with marked efficacy against extraocular infection and without the need for concomitant topical antimicrobial therapy.