The outcome of clinical parameters in adults with severe Type I Gaucher disease using very low dose enzyme replacement therapy

Enzyme replacement therapy is now well established as the treatment of choice in Type I Gaucher disease. Historically higher dosage regimens have been used in preference to lower doses despite the little clinical evidence in the way of large controlled clinical trials to support this. Moreover, the extraordinary cost of therapy means that not all eligible patients are able to be treated at the higher dose. Twelve type I adult patients with relatively severe disease were commenced on a very low dose of 7.5U of alglucerase/imiglucerase per kg every two weeks (initially given thrice weekly and later weekly). Follow-up 5 year data reveal a good visceral and haematological response with outcomes consistent with recently published treatment guidelines. Satisfactory clinical and radiological skeletal improvement was also demonstrated in most patients. Three patients had an inadequate overall skeletal response to therapy. Biomarkers also steadily improved although perhaps not quite at the same rate as that seen in higher doses. Very low dose enzyme replacement therapy may be appropriate for adult type I Gaucher patients with mild-moderate skeletal disease.     

Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease

BACKGROUND AND METHODS. Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease. RESULTS. The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed. CONCLUSIONS. Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.     

Chloroquine treatment of severe malaria in children. Pharmacokinetics, toxicity, and new dosage recommendations

Although empirical regimens of parenteral chloroquine have been used extensively to treat severe malaria for 40 years, recent recommendations state that parenteral chloroquine should no longer be used because of potential toxicity. We studied prospectively the pharmacokinetics and toxicity of seven chloroquine regimens in 58 Gambian children with severe chloroquine-sensitive falciparum malaria. In all regimens the total cumulative dose was 25 mg of chloroquine base per kilogram of body weight. Chloroquine was rapidly absorbed after either intramuscular or subcutaneous administration (5 mg of base per kilogram every 12 hours), producing high peak blood concentrations but transient hypotension in 5 of 18 patients (28 percent). Intermittent intravenous infusion (5 mg of base per kilogram over 4 hours, repeated every 12 hours) also produced wide fluctuations in chloroquine levels, suggesting incomplete distribution from a small central compartment. Continuous infusion (0.83 mg of base per kilogram per hour for 30 hours) and smaller, more frequent intramuscular or subcutaneous injections of chloroquine (3.5 mg of base per kilogram every 6 hours) produced smoother blood-concentration profiles with lower early peak levels and no adverse cardiovascular or neurologic effects. Chloroquine given by nasogastric tube (initial dose, 10 mg of base per kilogram) was absorbed well, even in comatose children. We conclude that simple alterations in dosage and frequency of administration can give parenteral chloroquine an acceptable therapeutic ratio and reinstate it as the treatment of choice for severe malaria in areas where chloroquine resistance is not a major problem.     

Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial

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.     

Absorption of chloramphenicol sodium succinate after intramuscular administration in children

Because it is thought that chloramphenicol is poorly absorbed after intramuscular administration, we compared blood levels of chloramphenicol after intramuscular administration with those after intravenous administration in children with a variety of diagnoses. Fifty-seven children were studied on 62 occasions while they were receiving chloramphenicol sodium succinate (25 mg of chloramphenicol per kilogram of body weight) intramuscularly every six hours. The peak level of chloramphenicol was 19.5 +/- 5.99 micrograms per milliliter (mean +/- S.D.) in 11 children after the first dose and 31.4 +/- 12.99 micrograms per milliliter in 51 children after two or more doses. The lowest peak level after intramuscular administration was 13 micrograms per milliliter, which is in the therapeutic range of 10 to 30 micrograms per milliliter. Thirteen children were studied on 17 occasions while they were receiving chloramphenicol sodium succinate (25 mg of chloramphenicol per kilogram) intravenously every six hours. The peak level of chloramphenicol was 19.4 +/- 6.37 micrograms per milliliter in eight children after the first dose and 28.2 +/- 11.09 micrograms per milliliter in nine children after two or more doses. The area under the serum level curve was not significantly different after intramuscular and intravenous administration. We conclude that chloramphenicol sodium succinate is well absorbed after intramuscular administration. This route is cheaper, it demands less staff time, and it does not carry the risks of sepsis and overhydration associated with intravenous therapy.     

Interferon treatment of NZB mice: accelerated progression of autoimmune disease.

The effect of long-term administration of interferon in New Zealand Black and New Zealand Black/New Zealand White F1 hybrid mice was studied. Treatment with moderate doses of interferon (10(4) units, five times weekly for 8 weeks) did not depress murine leukemia virus gp69/71 levels in serum and spleen, nor p30 levels in the spleen. Interferon given at 10(5.1) units (three times weekly for 37 weeks) caused an increased incidence of anti-erythrocyte antibodies in New Zealand Black mice. Finally, the hybrid mice given interferon at 10(6.0) units (three times weekly for 33 weeks) had increased renal immune complex deposits and increased incidences of proteinuria and anemia.     

Dose-response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1

PurposeTo determine whether enzyme therapy with imiglucerase/alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients.MethodsAnalyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to <29 U/kg/2 weeks), Group B (29 U to <48 U/kg/2 weeks), Group C (48 U to <75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (E_max) and half-time to E_max (T₅₀) of enzyme therapy for each parameter were compared across dosing groups.ResultsPropensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to E_max and T₅₀ over 96 months for each disease parameter.ConclusionsEnzyme therapy with imiglucerase/alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries.     

Activity of rifampicin administered daily and intermittently on experimental tuberculosis in mice

Intermittent regimens with rifampicin (RMP) for chemotherapy of pulmonary tuberculosis are cheaper and can be usually supervised more easily than daily regimens. They are recommended, specially, in developing countries. The present study is designed to evaluate the reduction of RMP activity as the interval between doses is increased in experimental mouse tuberculosis. The mice are given 10 mg/kg oral doses of RMP once, twice, three times or six times a week. The RMP activity is measured as the decrease of viable counts (cfu) in the spleen of mice. RMP given once a week has no activity neither in combination with isoniazid and streptomycin on a large population of organisms nor alone on a small population. RMP given alone twice a week has an activity slightly better than RMP given once a week. RMP given alone three times a week has a weak but not worthy activity: the mean number of cfu after a three times weekly treatment is significantly lower than the mean number of cfu in control (p less than 0.001) but significantly higher than the mean number of cfu after a six times weekly treatment (p less than 0.001). These experimental results are consistent with the experimental data on the effects of RMP on the RNA polymerase. They are not favourable to the intermittent administration of RMP in the chemotherapy of tuberculosis.     

Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia.

BACKGROUND. The pathophysiologic aspects of pruritus in patients with chronic renal insufficiency are poorly understood, and there is no universally effective treatment. The improvement of pruritus in several patients receiving erythropoietin therapy raised the possibility that erythropoietin affects uremic pruritus directly. METHODS. We undertook a 10-week placebo-controlled, double-blind, crossover study in a group of patients receiving hemodialysis who had severe pruritus, to investigate the effects of recombinant human erythropoietin on their pruritus and plasma histamine levels. Twenty patients with uremia, of whom 10 had severe pruritus and 10 did not, received erythropoietin (36 units per kilogram of body weight three times weekly) and placebo in random order, each for five weeks. The severity of pruritus was scored weekly, and plasma histamine levels were measured at the beginning and end of each five-week period. RESULTS. Eight of the 10 patients with pruritus had marked reductions in their pruritus scores during erythropoietin therapy. The mean (+/- SE) pruritus score decreased from 25 +/- 3 to 6 +/- 1 in these patients. The pruritus returned within one week after the discontinuation of therapy. The improvement was not related to the change in hemoglobin level. These eight patients were successfully treated again with low doses of erythropoietin (18 units per kilogram three times weekly), and the effect has persisted for six months. The patients with pruritus had elevated plasma histamine concentrations (20.7 +/- 2.7 nmol per liter), as compared with the patients without pruritus (4.2 +/- 0.6 nmol per liter; P less than 0.001) and normal subjects (2.1 +/- 0.2 nmol per liter; P less than 0.001). Therapy with erythropoietin induced a decrease in plasma histamine concentrations in both groups of patients with uremia, and recurrences of pruritus after the discontinuation of erythropoietin were accompanied by increases in plasma histamine concentrations. CONCLUSIONS. Erythropoietin therapy lowers plasma histamine concentrations in patients with uremia and can result in marked improvement of pruritus.     

A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus

BACKGROUND: Indomethacin is the conventional treatment for hemodynamically important patent ductus arteriosus in preterm infants. However, its use is associated with various side effects. In a prospective study, we compared ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of patent ductus arteriosus in preterm infants. METHODS: We studied 148 infants (gestational age, 24 to 32 weeks) who had the respiratory distress syndrome and an echocardiographically confirmed, hemodynamically important patent ductus arteriosus. The infants were randomly assigned at five neonatal intensive care centers to receive three intravenous doses of either indomethacin (0.2 mg per kilogram of body weight, given at 12-hour intervals) or ibuprofen (a first dose of 10 mg per kilogram, followed at 24-hour intervals by two doses of 5 mq per kilogram each), starting on the third day of life. The rate of ductal closure, the need for additional treatment, side effects, complications, and the infants' clinical course were recorded. RESULTS: The rate of ductal closure was similar with the two treatments: ductal closure occurred in 49 of 74 infants given indomethacin (66 percent), and in 52 of 74 given ibuprofen (70 percent) (relative risk, 0.94; 95 percent confidence interval, 0.76 to 1.17; P=0.41). The numbers of infants who needed a second pharmacologic treatment or surgical ductal ligation did not differ significantly between the two groups. Oliguria occurred in 5 infants treated with ibuprofen and in 14 treated with indomethacin (P=0.03). There were no significant differences with respect to other side effects or complications. CONCLUSIONS: Ibuprofen therapy on the third day of life is as efficacious as indomethacin for the treatment of patent ductus arteriosus in preterm infants with the respiratory distress syndrome and is significantly less likely to induce oliguria.     

Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.

BACKGROUND: Vitamin A supplementation may reduce the risk of chronic lung disease and sepsis in extremely-low-birth-weight infants. The results of our pilot study suggested that a dose of 5000 IU administered intramuscularly three times per week for four weeks was more effective than the lower doses given in past trials. METHODS: We performed a multicenter, blinded, randomized trial to assess the effectiveness and safety of this regimen as compared with sham treatment in 807 infants in need of respiratory support 24 hours after birth. The mean birth weight was 770 g in the vitamin A group and 769 g in the control group, and the respective gestational ages were 26.8 and 26.7 weeks. RESULTS: By 36 weeks' postmenstrual age, 59 of the 405 infants (15 percent) in the vitamin A group and 55 of the 402 infants (14 percent) in the control group had died. The primary outcome - death or chronic lung disease at 36 weeks' postmenstrual age - occurred in significantly fewer infants in the vitamin A group than in the control group (55 percent vs. 62 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.99). Overall, 1 additional infant survived without chronic lung disease for every 14 to 15 infants who received vitamin A supplements. The proportions of infants in the vitamin A group and the control group who had signs of potential vitamin A toxicity were similar. The proportion of infants with serum retinol values below 20 microg per deciliter (0.70 micromol per liter) was lower in the vitamin A group than in the control group (25 percent vs. 54 percent, P<0.001). CONCLUSIONS: Intramuscular administration of 5000 IU of vitamin A three times per week for four weeks reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in extremely-low-birth-weight infants.     

Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial

BACKGROUND. Severe plaque-type psoriasis has been successfully treated with orally administered cyclosporine, but there has been no comparative, controlled evaluation of various dosages and their efficacy and side effects. METHODS. In a 16-week, double-blind trial, we randomly assigned 85 patients with severe psoriasis to receive 3, 5, or 7.5 mg of cyclosporine per kilogram of body weight per day or a placebo consisting of the vehicle for the drug. After eight weeks the dose could be adjusted to improve safety or efficacy while maintaining blinding. RESULTS. The psoriasis improved in a dose-dependent fashion. After eight weeks of fixed-dose therapy, 36, 65, and 80 percent of the patients receiving 3, 5, and 7.5 mg of cyclosporine per kilogram per day, respectively, were rated as being clear or almost clear of psoriasis; each group had significant improvement (P less than 0.0001) as compared with the group receiving vehicle, in which none of the patients were rated as clear or almost clear. The patients who received 5 mg per kilogram were the least likely to require dosage adjustments because of side effects or a lack of efficacy. The glomerular filtration rate, measured in a subgroup of 34 patients receiving cyclosporine, decreased by a median of 16 percent. Higher doses of cyclosporine had greater adverse effects on systolic blood pressure, glomerular filtration rate, and serum levels of creatinine, uric acid, bilirubin, and cholesterol. Delayed-type hypersensitivity reactions to skin-test antigens were reduced by cyclosporine administration. Cyclosporine appears to become concentrated in skin. CONCLUSIONS. Cyclosporine therapy leads to a rapid and thorough clearing of psoriasis; an initial dose of 5 mg per kilogram per day seems to be appropriate. However, the safety of cyclosporine for the long-term treatment of psoriasis remains to be determined.     

A controlled trial of ivermectin and diethylcarbamazine in lymphatic filariasis

Ivermectin is a new antifilarial drug that can be given in a single oral dose. To compare the efficacy and side effects of ivermectin with those of diethylcarbamazine, the standard antifilarial treatment, we conducted a randomized, double-blind trial in 40 South Indian men with lymphatic filariasis caused by Wuchereria bancrofti. Patients were randomly assigned to one of three treatments: a single low dose of ivermectin (mean [+/- SE], 21.3 +/- 0.7 micrograms per kilogram of body weight; n = 13) followed by placebo for 12 days; a single high dose of ivermectin (mean, 126.2 +/- 3.7 micrograms per kilogram; n = 13) followed by placebo for 12 days; or diethylcarbamazine for 13 days (6 mg per kilogram per day for 12 days preceded by 3 mg per kilogram for 1 day; n = 14). Eleven patients were initially assigned to receive placebo and after five days were reassigned to one of the three treatment groups. At day 12 there was complete clearance of microfilariae from the blood in all 26 men who took ivermectin and in 11 of the 14 men who took diethylcarbamazine. At six months the numbers of detectable microfilariae (as a percentage of the pretreatment values) were 18.3 percent after low-dose ivermectin and 19.5 percent after high-dose ivermectin, as compared with 6.0 percent after diethylcarbamazine (P less than 0.05). The side effects were confined to the first five days and were similar in the three treatment groups. We conclude that in lymphatic filariasis, the clinical response to a single dose of ivermectin compares favorably with that after the standard 12-day course of diethylcarbamazine. Given the practical advantages of single-dose administration, ivermectin should become a useful medication for the control of bancroftian filariasis.     

Restoration of impaired immune functions of aged animals by chronic bestatin treatment.

An attempt to correct the state of immunodeficiency in old age was made by repeatedly injecting a chemically defined immunostimulating agent, bestatin, to 16 month old (C57Bl/6 x BALB/c) F1 mice. Aged mice were found to have depressed T-cell and B-cell responses but increased ADCC activity. Weekly injections of bestatin over a period of 6 months resulted in varying effects depending on the dose administered. Small doses (10 microgram per injection) were more effective in restoring humoral responses to SRBC rather than delayed-type hypersensitivity reactions, whereas large doses (100 microgram per injection) acted in the opposite way. Macrophage activation was only obtained after the administration of the high doses of bestatin. Continuous treatment with bestatin did not prevent the appearance of suppressor cells induced by ageing. It led to a significant reduction of ADCC activity in aged animals near to the base line value of young animals. Animals were examined for the presence of spontaneous tumours from the end of the treatment until the age of 28 months. A significant reduction of spontaneous tumour incidence was observed in mice given repeated injections of 100 microgram bestatin when compared to untreated aged mice and to mice given the low doses of bestatin.     

Improved neurologic function after long-term correction of vitamin E deficiency in children with chronic cholestasis

We studied the effect of long-term correction of vitamin E deficiency on neurologic function in 14 children with chronic cholestasis. Vitamin E repletion was achieved in all, either by large oral doses (up to 120 IU per kilogram of body weight per day) or by intramuscular administration of dl-alpha-tocopherol (0.8 to 2.0 IU per kilogram per day). With early institution of therapy, neurologic function remained normal in two asymptomatic children below the age of three years after 15 and 18 months of therapy. Neurologic function became normal in three symptomatic children below age three after 18 to 32 months of therapy. Restitution of neurologic function was more limited in nine symptomatic children 5 to 17 1/2 years old after 18 to 48 months of therapy. We conclude that vitamin E repletion therapy should be initiated at an early age in children with chronic cholestasis complicated by vitamin E deficiency, to prevent irreversible neurologic injury.     

Low-dose ciprofloxacin for selective decontamination of the digestive tract in human volunteers

The effect on the faecal aerobic and anaerobic flora of ciprofloxacin given in low doses for selective decontamination of the digestive tract was investigated in ten human volunteers. The volunteers received 50, 100 and 200 mg of ciprofloxacin every 12 h for five days at intervals of three and five weeks respectively. No significant differences in the numbers of aerobes or anaerobes were seen after the 2 × 50 mg regime. The colony counts of most anaerobes and the total aerobe count were significantly decreased after the 2 × 200 mg regime. Whereas the aerobe count was also significantly decreased after administration of 2 × 200 mg, the anaerobe count remained stable.Clostridium difficile was not detected during or after treatment. From these results it can be concluded that ciprofloxacin in a dose of 2 × 100 mg can be recommended for selective decontamination of the digestive tract.     

Immunomodulation of autoimmune diseases by high-dose intravenous immunoglobulins

Conclusion  IVIG represents a promising immunoregulatory agent which has the ability to control autoimmune disorders without subsequent predisposition to infectious complications. However, it is extremely expensive: the approximate average wholesale price is U.S. $1,800 per dose for a 70-kg patient. Further studies and controlled clinical trials will be necessary to prove the efficacy of this therapy for specific autoimmune disorders.     

A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study

Studies in animals indicate that methylprednisolone and naloxone are both potentially beneficial in acute spinal-cord injury, but whether any treatment is clinically effective remains uncertain. We evaluated the efficacy and safety of methylprednisolone and naloxone in a multicenter randomized, double-blind, placebo-controlled trial in patients with acute spinal-cord injury, 95 percent of whom were treated within 14 hours of injury. Methylprednisolone was given to 162 patients as a bolus of 30 mg per kilogram of body weight, followed by infusion at 5.4 mg per kilogram per hour for 23 hours. Naloxone was given to 154 patients as a bolus of 5.4 mg per kilogram, followed by infusion at 4.0 mg per kilogram per hour for 23 hours. Placebos were given to 171 patients by bolus and infusion. Motor and sensory functions were assessed by systematic neurological examination on admission and six weeks and six months after injury. After six months the patients who were treated with methylprednisolone within eight hours of their injury had significant improvement as compared with those given placebo in motor function (neurologic change scores of 16.0 and 11.2, respectively; P = 0.03) and sensation to pinprick (change scores of 11.4 and 6.6; P = 0.02) and touch (change scores, 8.9 and 4.3; P = 0.03). Benefit from methylprednisolone was seen in patients whose injuries were initially evaluated as neurologically complete, as well as in those believed to have incomplete lesions. The patients treated with naloxone, or with methylprednisolone more than eight hours after their injury, did not differ in their neurologic outcomes from those given placebo. Mortality and major morbidity were similar in all three groups. We conclude that in patients with acute spinal-cord injury, treatment with methylprednisolone in the dose used in this study improves neurologic recovery when the medication is given in the first eight hours. We also conclude that treatment with naloxone in the dose used in this study does not improve neurologic recovery after acute spinal-cord injury.     

Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) has been reported to increase the leukocyte count in subhuman primates subjected to total-body irradiation and in patients with the acquired immunodeficiency syndrome. We administered this substance to 19 patients with breast cancer or melanoma treated with high-dose combination chemotherapy and autologous bone marrow support. Groups of three or four patients were treated with 2.0, 4.0, 8.0, 16.0, or 32.0 micrograms per kilogram of body weight per day of glycosylated rHuGM-CSF by continuous intravenous infusion for 14 days, beginning three hours after bone marrow infusion. Total leukocyte and granulocyte recovery was accelerated in these patients as compared with 24 historical controls matched for age, diagnosis, and treatment. Leukocyte counts (mean +/- SD) obtained 14 days after transplantation were 1511 +/- 1003 per microliter in patients given 2 to 8 micrograms per kilogram per day, 2575 +/- 2304 in those given 16 micrograms, and 3120 +/- 1744 in those given 32 micrograms, as compared with 863 +/- 645 per microliter in the controls. No consistent effect on platelet counts was noted. Toxic effects were generally mild and not clearly dose-related in patients given 2 to 16 micrograms per kilogram per day. Edema, weight gain, or myalgias occurred in all patients given 32 micrograms per kilogram; marked weight gain, generalized edema, pleural effusions, and hypotension developed in two patients, one of whom also had acute renal failure. Our results indicate that rHuGM-CSF can accelerate myeloid recovery after high-dose chemotherapy and autologous bone marrow transplantation, over a range of doses that can be tolerated. In this setting the ability to increase the dose is limited by the development of myalgias and fluid retention.     

The cost effectiveness of stopping preterm labor with beta-adrenergic treatment

We retrospectively compared the costs of maternal and neonatal medical care after beta-adrenergic drug treatment, given to arrest preterm labor, with expected costs associated with no gestational delay. The treatment arrested labor for at least three days in 61 per cent of patients; gestation was extended by 14.1 +/- 1.1 weeks (mean +/- S.E.M.) in infants with the earliest gestational age at treatment (20 to 25 weeks) and by 2.3 +/- 0.7 weeks in those with the latest gestational age (36 to 37 weeks). Costs were based on hospital charges and physicians' fees, including high-risk obstetric outpatient charges, obstetric prenatal and delivery inpatient charges, and pediatric inpatient charges. Treatment provided between 26 and 33 weeks of gestation was clearly cost effective, resulting in expected savings of $11,240 (1981 dollars) per birth. After 33 weeks there was no substantial difference in expected costs with or without treatment. Between 20 and 25 weeks of gestation, the expected costs per surviving infant were $39,000 lower with treatment; however, the number of mothers who were not treated at this early stage of gestation (three patients) was too small to permit statistical significance. When the improved survival of infants after prenatal treatment was taken into account, treatment before 25 weeks was also cost effective. Thus, the increased costs of prenatal medical care were offset by decreased costs of neonatal medical care when treatment was given before 34 weeks of gestation.