Alternate-day Regimen Research Articles

A randomized study of two long-course prednisolone regimens for nephrotic syndrome in children

Background:Long-course prednisolone regimens have been shown to be more effective than short-course regimens in sustaining remission of nephrotic syndrome in children. However, the most beneficial approach among the long-course regimens remains unknown. Methods:Seventy-three children with new-onset nephrotic syndrome were allocated at random to the two long-course regimens and followed up for 2 years. Group A was administered prednisolone at a daily dose of 60 mg/m2 for 6 weeks, followed by an alternate-day dose of 40 mg/m2 for 6 weeks (the long daily regimen). Group B was administered the same daily dose for 4 weeks, followed by an alternate-day dose of 60 mg/m2 for 4 weeks, and doses were tapered by 10 mg/m2 every 4 weeks (the long alternate-day regimen). Results:Group B had a lower incidence of corticosteroid toxicities than group A during the initial treatment. Kaplan-Meier analysis of the sustained remission rate of the two treatment groups showed a marginally significant difference (P = 0.069) and showed a significant difference when patients were stratified for age of disease onset (P = 0.048). In a subgroup of younger children (<4 years at onset), group B had a greater rate of sustained remission (P < 0.01) and fewer children with frequent relapses (P < 0.05) than group A, whereas in older children (≥4 years at onset), both groups had similar good sustained remission rates. Conclusion:These findings collectively indicate that the long alternate-day regimen may be more beneficial, with less corticosteroid toxicities, than the long daily regimen, and children with younger age at disease onset may be susceptible to relapse and especially benefit from the long alternate-day regimen for sustaining remission of the disease.

Nutritional aspects of chronic liver disease and liver transplantation in children.

Nutritional aspects of chronic liver disease and liver transplantation in children.

Inflammatory Myopathy.

Patients with polymyositis or dermatomyositis should be treated with prednisone (approximately 1 mg/kg/d) for an initial period of 4 to 6 weeks. Once improvement occurs, the dose should be tapered and converted to an alternate-day regimen, which should be continued for at least 12 months. Methotrexate or azathioprine should be administered concomitantly to patients in whom there is inadequate control. The early introduction of one of these drugs allows more rapid reduction in the dose of prednisone and helps to avert serious side effects. Intravenous immunoglobulin therapy is indicated for patients who have immunodeficiency, who are unable to tolerate immu-nosuppressive drugs, whose conditions are deteriorating, or who have severe relapses. Cyclosporine or cyclophosphamide may be effective for resistant disease. Patients with inclusion body myositis should undergo a 3- to 6-month trial of prednisone, alone or in combination with methotrexate or azathioprine. Maintenance doses of these drugs should be continued if the patient's condition improves or stabilizes.

R-213. Alternate-day low-dose HMG regimen: a safer alternative for ovulation induction in anovulatory patients with PCOS

R-213. Alternate-day low-dose HMG regimen: a safer alternative for ovulation induction in anovulatory patients with PCOS

Immunosuppressive treatment of Berger's disease.

The aim of our study was to determine whether immunosuppressive treatment is effective in preventing and reversing the evolution of Berger's disease toward chronic renal failure. We studied 20 unselected, consecutive patients with biopsy-proven Berger's disease who met the criteria for disease progression. They had proteinuria, significant histologic changes, persistent hematuria, and red cell casts. The treatment consisted of prednisone in an alternate-day regimen and cyclophosphamide, either in a daily oral administration or in a monthly intravenous pulse injection, both given for a 6-month cycle. Five patients had chronic renal failure (as disclosed by plasma creatinine of 230 +/- 71 mumol/L), hypertension, and proteinuria (2.7 +/- 0.8 gm/day), whereas the remaining 15 patients had normal renal function (plasma creatinine, 97 +/- 18 mumol/L) and less severe proteinuria (1.9 +/- 1.1 gm/day). However, even these 15 patients had a significant number of risk factors heralding progression to chronic renal failure. Over an average follow-up of 8.7 +/- 3.7 years (range, 5 to 15 years), all patients but one had complete disease remission, including five patients with incipient chronic renal failure. Relapse occurred in two patients who were healed after a repeat treatment cycle. Over the entire follow-up period, no patient progressed to chronic renal failure and plasma creatinine concentration remained stable, even in subjects in whom it was high before treatment (257 +/- 79 versus 230 +/- 71 mumol/L; p > 0.05). The immunosuppressive treatment of patients with Berger's disease with high probability of progression appears to be effective in the prevention of end-stage renal disease.

Sarcoidosis

Sarcoidosis is a systemic granulomatous process of unknown cause. Pathologically, it is characterized by noncaseous granuloma, and in more than 90% of patients, the lung or intrathoracic lymph nodes are affected. A roentgenographic staging system (stages I, II, and III), based on the appearance of the plain chest roentgenogram, conveys important information about prognosis, degree of symptoms, and pulmonary function abnormalities. The diagnosis should be confirmed by histopathologic examination and exclusion of known causes for the noncaseous granulomatous reaction. When indicated, treatment with alternate-day regimens of prednisone is highly effective. Serial chest roentgenography, pulmonary function studies, and the serum angiotensin-converting enzyme level are useful for monitoring the course of the disease.

Omeprazole Versus Cimetidine in the Treatment of Gastric Ulcers

The objectives of this study were to determine the optimal duration of acid suppression required for the initial treatment of gastric ulcer, and to compare the acid-suppressive effects of omeprazole with the H2-blocker cimetidine in patients with gastric ulcer as determined by 24-hour measurement of intragastric pH. Cimetidine was administered daily to 31 patients, while omeprazole was administered daily to 16 patients and every second day to an additional 16 patients. Ulcers healed within 2 months of treatment in 16 of the 31 patients administered cimetidine. The pH 4 holding time (the proportion of the total 24-hour period of measurement during which intragastric pH was 4 or higher) was 51.9 ± 4.6% of the 24-hour period of measurement for these 16 patients. Patients with unhealed ulcers had significantly shorter durations of ‘pH 4 holding time’ (15.8 ± 2.9% of the 24-hour period). There was no difference in the ‘pH 4 holding time’ of the 24-hour period between those receiving cimetidine who had a curable ulcer within 2 months and those administered omeprazole on alternate days (57.5 ± 7.9%). These findings suggest that obtaining the optimal duration of acid suppression is necessary for the treatment of gastric ulcers. Omeprazole administered as an alternate-day regimen is useful not only for the prevention of recurrence, but also for the initial treatment of gastric ulcer.

Immunosuppressive Treatment of Membranoproliferative Glomerulonephritis

The treatment of membranoproliferative glomerulonephritis (MPGN) is considered by most authors as unrewarding, and the disease progresses to end-stage renal disease (ESRD). We studied the effectiveness of a new immunosuppressive (IS) regimen by analyzing the rates of remission, relapse and progression to ESRD in 19 patients with MPGN. The treatment consisted of 4 phases: (1) induction with intravenous boluses of methylprednisolone plus cyclophosphamide (CPM) orally; (2) maintenance with oral prednisone (PDN) in an alternate-day regimen and CPM in a daily oral dose; (3) tapering during which PDN alone was slowly decreased; (4) discontinuation when CPM was omitted and PDN slowly withdrawn according to the steroid withdrawal schedule. At the end of the treatment that lasted on average 10 +/- 1 months, 15 patients remitted, 3 improved and 1 progressed. There were 8 relapses in 6 patients: 4 in 3 patients were treated with repeat cycles and remitted completely. Four patients who had relapsed after 4, 8, 11 and 13 years of remission refused retreatment and progressed rapidly to ESRD. All patients treated and retreated after relapsing had remissions, while renal failure and disease progression occurred in 1 patient only. Plasma creatinine averaged, in the whole group, 165 +/- 26 before, 156 +/- 30 after treatment and 224 +/- 57 microM/l at the end of 7.4 +/- 0.8 years of follow-up. An intensive IS regimen combining steroids and alkylating agents in high doses and for a prolonged time is effective in inducing remission and halting progression to ESRD in patients with MPGN.

Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates.

Glucocorticoids are pleiotropic hormones that at pharmacologic doses prevent or suppress inflammation and other immunologically mediated processes. At the molecular level, glucocorticoids form complexes with specific receptors that migrate to the nucleus where they interact with selective regulatory sites within DNA; this results in positive and negative modulation of several genes involved in inflammatory and immune responses. At the cellular level, glucocorticoids inhibit the access of leukocytes to inflammatory sites; interfere with the functions of leukocytes, endothelial cells, and fibroblasts; and suppress the production and the effects of humoral factors involved in the inflammatory response. Clinically, several modes of glucocorticoid administration are used, depending on the disease process, the organ involved, and the extent of involvement. High doses of daily glucocorticoids are usually required in patients with severe diseases involving major organs, whereas alternate-day regimens may be used in patients with less aggressive diseases. Intravenous glucocorticoids (pulse therapy) are frequently used to initiate therapy in patients with rapidly progressive, immunologically mediated diseases. The benefits of glucocorticoid therapy can easily be offset by severe side effects; even with the greatest care, side effects may occur. Moreover, for certain complications (for example, infection diathesis, peptic ulcer, osteoporosis, avascular necrosis, and atherosclerosis), other drug toxicities and pathogenic factors overlap with glucocorticoid effects. Minimizing the incidence and severity of glucocorticoid-related side effects requires carefully decreasing the dose; using adjunctive disease-modifying immunosuppressive and anti-inflammatory agents; and taking general preventive measures.

Growth rate in children receiving alternate-day corticosteroid treatment after kidney transplantation

A controlled study of growth in children receiving alternate-day versus daily corticosteroid regimens was performed with 60 children and adolescents with kidney grafts. The study started 14 to 27 months after transplantation in patients with normal graft function, after a graft biopsy. Thirty-five patients were available for the growth study; 17 were randomly allocated to receive alternate-day therapy and 18 remained on a daily regimen. The cumulative dose was similar in the two groups, as were bone age and renal function. After 1 year of follow-up, the mean statural growth, expressed as change in SD score, was significantly better in those on the alternate-day regimen (+0.49 +/- 0.42 SD/yr) than in those on the daily regimen (-0.12 +/- 0.53 SD/yr; p less than 0.005). The difference was also significant when prepubertal and pubertal children were analyzed separately. During the second year of the study most children who were receiving daily treatment were given alternate-day therapy; their mean growth velocity increased to +0.29 +/- 0.35 SD/yr (p less than 0.05 vs the first year); children who had been on the alternate-day regimen since the outset of the study continued to have similar positive SD scores (0.52 +/- 0.37 SD/yr). Renal function remained stable throughout the study regardless of corticosteroid regimen, except in the case of one patient undergoing daily therapy who had a rejection crisis. We conclude that in children with a kidney graft a given cumulative dose of corticosteroid has a significantly lesser inhibitory effect on growth velocity when given on alternate days.

Growth rate in children receiving alternate-day corticosteroid treatment after kidney transplantation

A controlled study of growth in children receiving alternate-day versus daily corticosteroid regimens was performed with 60 children and adolescents with kidney grafts. The study started 14 to 27 months after transplantation in patients with normal graft function, after a graft biopsy. Thirty-five patients were available for the growth study; 17 were randomly allocated to receive alternate-day therapy and 18 remained on a daily regimen. The cumulative dose was similar in the two groups, as were bone age and renal function. After 1 year of follow-up, the mean statural growth, expressed as change in SD score, was significantly better in those on the alternate-day regimen (+0.49 +/- 0.42 SD/yr) than in those on the daily regimen (-0.12 +/- 0.53 SD/yr; p less than 0.005). The difference was also significant when prepubertal and pubertal children were analyzed separately. During the second year of the study most children who were receiving daily treatment were given alternate-day therapy; their mean growth velocity increased to +0.29 +/- 0.35 SD/yr (p less than 0.05 vs the first year); children who had been on the alternate-day regimen since the outset of the study continued to have similar positive SD scores (0.52 +/- 0.37 SD/yr). Renal function remained stable throughout the study regardless of corticosteroid regimen, except in the case of one patient undergoing daily therapy who had a rejection crisis. We conclude that in children with a kidney graft a given cumulative dose of corticosteroid has a significantly lesser inhibitory effect on growth velocity when given on alternate days.

High or low dose steroid therapy for acute renal transplant rejection after prophylactic OKT3 treatment: a prospective randomized study

In this prospective randomized study, acute renal transplant rejections occurring in patients who received prophylactic OKT3 therapy were treated with either 3 pulses of 8 mg/kg methylprednisolone (MPS) in an alternate-day regimen (total dose 25 mg/kg in 1 week, H group, n = 24) or 5 daily pulses of 3 mg/kg MPS (total dose 17 mg/kg, L group, n = 22). Acute rejection was proven by biopsy in more than 85% of cases in both groups. No difference was observed in rejection reversal (H 88%, L 91%), graft losses in the following 3 months (H 11%, L 4%) or the time evolution of the serum creatinine levels. The number (H 14, L 21) as well as the nature and severity of infections were similar in both groups. Only one death occurred in a patient who received OKT3 rescue therapy for corticoresistant rejections and developed Epstein-Barr virus (EBV)-related lymphoma. In conclusion, low dose MPS pulses appear as effective and safe as a higher dose to reverse acute rejection occurring after OKT3 prophylaxis. Thus, we favour the use of the low dose regimen in these patients.

Glucose tolerance in children with renal allografts and effect of growth hormone treatment

We performed oral glucose tolerance tests (oGTTs) on 15 children who had functioning renal allografts received greater than or equal to 18 months previously, had adequate renal function, and had heights greater than 2.5 SD below the mean height for age. Three of the children had impaired glucose tolerance; their mean glucose levels during the last 2 hours of the oGTT were higher (p less than 0.05) than published control values. Integrated glucose concentrations correlated inversely with the prednisone dose on the first day of an alternate-day dosage schedule (R2 = 0.383) and directly with adiposity (partial R2 = 0.322). The integrated insulin concentration correlated directly with the prednisone dose on day 1 of an alternate-day regimen (R2 = 0.355) and with age (partial R2 = 0.163). In 10 children with renal transplants who had been treated with growth hormone for greater than or equal to 6 months, the mean fasting glucose concentration, integrated glucose concentration, and integrated insulin concentration during the oGTTs obtained after 6 months or 12 months of growth hormone treatment were not significantly different (p greater than 0.05) from values measured before the treatment. We conclude that increased integrated concentrations of both glucose and insulin during oGTTs in children with renal allografts correlate with the dose of prednisone administered on the first day of an alternate-day schedule, with age, and with adiposity index. Growth hormone treatment of children with renal allografts who are growing poorly does not significantly affect glucose metabolism as assessed by oGTT.

The Pharmacokinetics of Plasma Total and Free Prednisolone during an Alternate-day Regimen

To determine the pharmacokinetic changes of prednisolone associated with an alternate-day regimen, 12 patients with various diseases were studied longitudinally. There were 9 patients (6 with systemic lupus erythematosus, 2 with sarcoidosis and one with polymyositis), who were treated with prednisolone (daily period) and subsequently put on an alternate-day regimen (alternate-day period). In 2 of the other patients (one with systemic lupus erythematosus and one with multiple sclerosis), the alternate-day regimen was preceded by the daily regimen, and subsequently an intermittent regimen consisting of 4 consecutive days on therapy and 3 days off therapy was followed. In the remaining patient with systemic lupus erythematosus, the treatment with the alternate-day regimen was initiated and followed throughout the treatment period. The mean duration and the mean total administered dose during the study were 1.1 months and 1.9 g in the daily period, and 7.8 months and 7.7 g in the alternate-day period. The test was done and blood was drawn for 6 hours after an intravenous administration of 20 mg prednisolone (0.36 mg/kg on the average) at the end of the respective regimen periods. In the daily period and the on-day of the alternate-day regimen, the pharmacokinetic study of iv prednisolone injection was done before the ingestion of oral prednisolone. The off-day test was done the next morning of the on-day. Plasma total and free prednisolone concentrations were measured by RIA. On-day and off-day tests in the alternate-day period were performed during the same week. The mean half life of both total and free prednisolone was prolonged significantly in the daily period and during the on-day and off-day of the alternate-day regimen compared with the pretreatment values. The mean metabolic clearance rates (MCR) of both total and free prednisolone decreased significantly in the daily period and during the on-day and off-day of the alternate-day period in comparison with the pretreatment values. No significant difference was found between either mean half life or MCR during the on-day and off-day of the alternate-day period. These findings were in contrast with our previously observed prednisolone pharmacokinetics during the intermittent regimen (4 days on therapy and 3 days off therapy within one week), in which pharmacokinetic parameters during the on-day (after 3 days of prednisolone ingestion) and off-day (after 3 off-days of prednisolone ingestion) periodically changed and were similar to those in the pre-treatment period and during the daily therapy period, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Danazol Therapy for Chronic Immune-Mediated Thrombocytopenic Purpura in a Patient with Common Variable Immunodeficiency

We describe a patient with common variable immunodeficiency (CVI) and chronic immune-mediated thrombocytopenic purpura (ITP), refractory to treatment with corticosteroids, splenectomy, and intravenous immunoglobulin. He had a prompt response to danazol, and the platelet counts have been maintained in the normal range with low-dose, alternate-day, danazol therapy. This case provides evidence that danazol is effective in the treatment of chronic ITP in patients with immunodeficiency and indicates that some patients can be maintained on an alternate-day regimen.

Current Treatment Recommendations for Lupus Nephritis

Renal disease is common in patients with systemic lupus erythematosus and may run an extremely variable course. Specific therapy is not necessary in patients with mild kidney involvement but a careful surveillance is needed to recognise possible transformations to more severe disease classifications or flare-ups. Vigorous treatment must be started early in patients with nephritic syndrome and/or active lesions at renal biopsy, i.e. glomerular cell proliferation, necrosis and inflammation. Corticosteroids remain the cornerstone for treating lupus nephritis. However, every attempt should be made to minimise their possible toxic effects. A short course of intravenous high-dose methylprednisolone followed by moderate doses of prednisone is a relatively nontoxic regimen which is generally effective in reversing the flare-ups of the disease. Once the activity is quenched the maintenance dosage of steroids should be reduced to the lowest possible dose, trying to switch the patient to an alternate-day regimen whenever possible. In patients with persisting activity the administration of a cytotoxic agent may obviate the need for protracted high-dose corticotherapy. Intermittent intravenous cyclophosphamide pulses may be considered in nonresponding patients. Other approaches, with cyclosporin, lymphoid irradiation, etc. although promising, are still preliminary. Although we are still far from an optimal treatment of lupus nephritis, the refined use of corticosteroid and cytotoxic agents and a careful monitoring of patients may allow excellent patient and kidney survival rates for 10 or more years.

Myasthenia Gravis: A Review

Myasthenia Gravis: A Review

Corticosteroids in the treatment of asthma.

Corticosteroid medications have been regularly used in the management of asthma for more than 30 years. Review of the published literature suggests that steroids may enhance sensitivity to beta-adrenergic agonists and reduce local inflammation. These effects may not be clinically evident for six to 12 hours after steroid administration. Optimum dose, dose forms, and the role of plasma levels remain to be determined. Iatrogenic side effects, notably cushingoid features and hypothalamic-pituitary-related adrenal suppression, are dose-related and may be minimized with alternate-day regimens or the use of inhaled beclomethasone dipropionate. Beclomethasone may facilitate weaning from systemic corticosteroid therapy but usually cannot replace systemic therapy unless the daily dose is less than 20 mg of prednisone or its equivalent. Weaning should be undertaken cautiously, using objective measurements of pulmonary function, to reach a goal of the lowest daily dose consonant with control of symptoms, rather than complete withdrawal.

Polyangiitis overlap syndrome: Classification and prospective clinical experience

Ten patients were prospectively studied who had features of systemic vasculitis that could not be classified into one of the well-defined vasculitic syndromes. Since many of these syndromes had overlapping features of several distinct vasculitides, they were classified as the polyangiitis overlap syndrome. Cutaneous disease was common (nine of 10 patients) and, some patients, had been mistakenly diagnosed as “hypersensitivity” or isolated cutaneous vasculitis. The polyangiitis overlap syndrome is a systemic vasculitis, and all of the patients required therapy with cyclophosphamide (2 mg/kg per day). Nine of 10 patients were also treated with corticosteroids, which were administered initially on a daily basis followed by an alternate-day regimen. A complete remission was induced in all of the patients, with a mean follow-up duration of 58.4 months. In eight of 10 patients, remission was maintained following discontinuation of cyclophosphamide. The mean duration of remission was 45.9 months, with a mean interval after discontinuation of all therapy of 22.3 months. Two patients had relapses after the immunosuppressive therapy was discontinued; however, complete remissions were reinduced following reinstitution of therapy.

The Effect of Prednisone in a High-Dose, Alternate-Day Regimen on the Natural History of Idiopathic Membranoproliferative Glomerulonephritis

Experience in 45 children with diffuse proliferative MPGN of all three types has provided evidence that a high-dose, alternate-day regimen of prednisone alters the natural history of the disease. The experience has been gained over a 17-year period and the patients have been followed on the regimen for an average of 6.5 years. Evidence that the regimen has a salutary effect was provided by several observations: Survival was better than that in four other series in which the patients were not treated or treated sporadically. The difference was particularly marked when survival was compared with that in series in which the patients had diffuse proliferative lesions exclusively. Mesangial proliferation was less in biopsies obtained after 2 or more years of the alternate-day regimen. This was quantitated as a significant increase in the estimated percentage of open glomerular capillary lumens and a significant diminution in the prominence of PAS-positive mesangial matrix. In the second biopsy, as compared to the pre-regimen biopsy, no patient had a diminution in the estimated percent of open capillary lumens and 65% had a meaningful increase. Likewise, only 3% had an increase in prominence of PAS positive matrix and 68% had a diminution in matrix prominence. Of 32 patients who were hypoalbuminemic when the regimen started, the level rose into the normal range in 62%. The level became subnormal in none of the 13 who had a normal level at the start of the regimen. While receiving the regimen, renal function, as measured by serum creatinine levels, continued to be normal or improved in 73% and deteriorated in 27%. Hematuria disappeared in 80% of the 41 in whom it was present when the regimen started. Urinalysis became completely normal in 27% and none of these have relapsed while under observation. Comparison of data from 20 patients who did not receive the regimen for an average of 42 months after clinical onset with data for 25 patients who likewise were, on the average, 42 months from clinical onset but who had received the regimen for an average of 38 of those months provided the most convincing evidence that the regimen altered the natural history. In those receiving the regimen, the frequency of hematuria, proteinuria, and hypoalbuminemia was significantly less.(ABSTRACT TRUNCATED AT 400 WORDS)