Inappropriate phosphate excretion in idiopathic hypercalciuria: the key to a common cause and future treatment?

AIMS: To present experimental evidence in support of a proposed common cause for absorptive hypercalciuria, renal hypercalciuria, renal phosphate leak and enhancement of 1,25-(OH)2-vitamin D concentrations in patients presenting with renal stone disease; and to suggest further investigation with a view to new management. METHODS: An oral calcium loading test was administered to 15 patients with renal stones and 10 normal controls in the fasting state: urine and blood were collected hourly. After the second urine sample, 400 mg calcium dissolved in water was administered orally. Serum calcium, albumin, parathyroid hormone (PTH), and phosphate were measured together with urine calcium clearance and urinary phosphate from which the TmPO4/glomerular filtration rate (GFR) ratio was calculated. Serum 1,25-(OH)2-vitamin D was measured in the first serum sample. In addition, 24 hour urine calcium results were collected retrospectively from the patients' case notes over the previous 18 months. RESULTS: In the basal state, renal stone patients had an overall greater phosphaturia (lower TmPO4/GFR: median 1.72 compared with 2.10 in controls) and increased calcium clearance. Serum corrected calcium and PTH concentrations did not differ between the groups. After calcium loading, serum calcium and urine calcium clearance rose in both groups, with patients with renal stones experiencing a greater percentage fall in phosphaturia. In both groups TmPO4/GFR fell (greater phosphaturia) with increased serum corrected calcium, with the patients showing notably greater phosphaturia for any given calcium concentration. Patients also had notably greater phosphaturia compared with the serum calcium concentration for any given PTH value. Serum 1,25-(OH)2-vitamin D was higher in patients than controls and for any 1,25-(OH)2-vitamin D concentration phosphaturia measured against serum calcium was greater in patients than controls. 1,25-(OH)2-vitamin D did not correlate with phosphaturia relative to serum calcium concentrations within the patient and control groups. CONCLUSIONS: It is proposed that patients with idiopathic hypercalciuria have an "inappropriately' high phosphate excretion for any given serum calcium concentration. Loss of phosphate may induce increased activation of 1,25-(OH)2-vitamin D. Some of the commonly described causes of stone formation may be manifestations of a single mechanism.     

Elevated plasma 1,25-dihydroxyvitamin D concentrations in infants with hypercalcemia and an elfin facies

We measured plasma concentrations of 1,25-dihydroxyvitamin D (1,25-(OH)2D) in the course of a 6-to-37-month survey of four children with hypercalcemia and an elfin facies (Williams syndrome). Levels of 1,25-(OH)2D were elevated (160 to 470 pg per milliliter) during the hypercalcemic phase of the disease, when the children were five to nine months old, and they decreased thereafter. Plasma 1,25 (OH)2D levels were higher than those found in three children (16 to 60 months old) with the elfin facies syndrome and no hypercalcemia (42 to 71 pg per milliliter) and eight children (1 to 36 months old) with hypercalcemia and no dysmorphy (12 to 140 pg per milliliter), including two children with vitamin D intoxication. Hypercalcemia in the three children with elfin facies was controlled by a low-calcium diet. Serum calcium levels fell to the normal range, and plasma 1,25-(OH)2D levels were normal for age (18 to 105 pg per milliliter) at 14 to 47 months of age, even after appropriate therapy had been discontinued. These observations suggest that hypercalcemia may be the consequence of abnormal synthesis or degradation of 1,25-(OH)2D in children with the elfin facies syndrome.     

Response of 1alpha,25-dihydroxyvitamin D3 to hypocalcemia in human subjects.

We determined the response of 1alpha,25-dihydroxyvitamin D3 after mithramycin-induced hypocalcemia in eight subjects with polyostotic Paget's disease of bone. Thirty-six hours after infusion of mithramycin (25 microgram per kilogram), the average calcium declined from 9.9 +/- 0.14 (S.E.M.) to 8.0 +/- 0.19 mg per deciliter (P less than 0.005). Serum parathyroid hormone increased from 122 +/- 6 to 226 +/- 36 microliter eq per milliliter (P less than 0.05), serum phosphate decreased from 3.8 +/- 0.11 to 2.9 +/- 0.14 mg per deciliter (P less than 0.005), and urinary cyclic 3,5'-adenosine monophosphate increased from 4.6 +/- 0.35 to 7.5 +/- 0.80 mumol per gram of creatinine (P less than 0.005). Serum 1alpha25-dihydroxyvitamin D3 rose from 98 +/- 12 to 332 +/- 61 pM (P less than 0.05), the increase following the changes in parathyroid hormone and phosphate by 12 to 24 hours. When this lag period was taken into account, there was a significant relation (P less than 0.01) between the increase in 1alpha,25-dihydroxyvitamin D3 and changes in parathyroid hormone (correlation coefficient, r = +0.91) and phosphate (r = -0.96). The relatively rapid response of 1alpha,25-dihydroxyvitamin D3 to hypocalcemia occurs with a time course consistent with regulation by parathyroid hormone and phosphate.     

Substrate-product relation of 1-hydroxylase activity in primary hyperparathyroidism

The synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH)2D), is thought to be relatively insensitive to the serum concentration of its precursor, 25-hydroxyvitamin D (25-OH-D). We compared the effect of oral administration of 25-OH-D3 (50 micrograms per day for one month) on serum concentrations of calcium, phosphate, parathyroid hormone, 25-OH-D, and 1,25-(OH)2D in five healthy adults and in six patients with primary hyperparathyroidism. In normal adults the mean (+/- S.D.) serum level of 25-OH-D rose from 18 +/- 9 to 136 +/- 47 ng per milliliter; no significant changes were observed in the other serum levels. In contrast, comparable increases in the levels of circulating 25-OH-D in patients with primary hyperparathyroidism caused a consistent slight rise in serum calcium and phosphate levels, a partial suppression of parathyroid hormone, and a sharp increase in the level of 1,25-(OH)2D. During this period a significant positive correlation was found between serum concentrations of 25-OH-D and 1,25-(OH)2D (P less than 0.001). These results provide evidence that in patients with primary hyperparathyroidism, levels of circulating 1,25-(OH)2D may be more dependent on the prevailing serum concentrations of 25-OH-D than they are in normal adults.     

Prevention of cardiac disease by subcutaneous deferoxamine in patients with thalassemia major

We examined the efficacy of long-term subcutaneous deferoxamine therapy in the prevention of iron-related cardiac disease in patients with thalassemia major who began treatment after the age of 10 years. Of 36 such patients without preexisting cardiac disease, 19 did not comply with the program of chelation therapy. Over the course of treatment (1977 to 1983) serum ferritin and aspartate aminotransferase levels fell in the compliant group, from mean values (+/- S.D.) of 4765 +/- 2610 to 2950 +/- 1850 ng per milliliter and 58.1 +/- 22 IU to 30 +/- 20 IU per liter, respectively (P less than 0.05), but rose in the noncompliant group, from 5000 +/- 2316 to 6040 +/- 2550 ng per milliliter and 56.6 +/- 20 to 90 +/- 35 IU per liter, respectively. Only one patient in the compliant group acquired cardiac disease and died of fulminant congestive heart failure. In contrast, 12 noncompliant patients acquired cardiac disease, and 7 died. In addition, the mean age of the compliant population (18.9 +/- 4.5 years) now approaches the mean age of acquisition of cardiac disease in the noncompliant group (19 +/- 4.3). These data demonstrate that compliance with treatment with deferoxamine may protect patients from cardiac disease induced by iron overload.     

Treatment of chronic congestive heart failure with captopril, an oral inhibitor of angiotensin-converting enzyme.

The renin-angiotensin system is thought to maintain elevated systemic vascular resistance in heart failure. The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with stable congestive heart failure poorly controlled by digitalis and diuretics. At single daily doses of 25 to 150 mg, the cardiac index rose from 1.75 +/- 0.18 to 2.27 +/- 0.39 (mean +/- S.D.) liters per minute per square meter (P less than 0.001), and pulmonary-wedge pressure fell from 26.5 +/- 7.5 to 17.3 +/- 6.1 mm Hg (P less than 0.01). Systemic vascular resistance decreased from 2006 +/- 300 to 1393 +/- 238 dyne seconds per centimeter (P less than 0.001), and mean arterial pressure fell from 83.7 +/- 7.0 to 70.3 +/- 9.9 mm Hg (P less than 0.001) (mean +/- S.D.). Heart rate did not change appreciably. Hemodynamic alterations peaked at 90 minutes and persisted for three to four hours. Control plasma renin activity ranged from 1.1 to 7.3 ng per milliliter per hour and did not correlate with changes in hemodynamic values. Three patients on long-term treatment maintained clinical improvement. Although its mechanism of action has not been completely elucidated, captopril may prove useful in the treatment of chronic congestive heart failure.     

Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanism and clinical implications.

Administration of quinidine with digoxin increased serum digoxin concentrations in 79 patients and five volunteers. In 38 patients on a constant glycoside maintenance dose, the addition of quinidine to digoxin therapy resulted in a mean 2.5-fold increase (from 0.98 +/- 0.37 to 2.47 +/- 0.71 ng per milliliter, mean +/- 1 S.D.) (P less than 0.001). The addition of quinidine decreased renal glycoside clearance (from 91.6 +/- 27.8 to 40.6 +/- 15.8 ml per minute) (P less than 0.001). Unlike other investigations, our studies provided no evidence that quinidine displaced digoxin at specific cardiac binding sites. The elevated digoxin levels found during quinidine administration suggest a 30 to 50 per cent reduction of the digoxin dose. Adverse reactions to combined quinidine-digoxin therapy may be partly due to digitalis intoxication.     

Aluminum intoxication from aluminum-containing phosphate binders in children with azotemia not undergoing dialysis

Aluminum intoxication developed in three infants with azotemia who were not undergoing dialysis and who had been treated with aluminum hydroxide from the first month of life. Biopsies of the iliac crest demonstrated the presence of severe osteomalacia and massive deposition of aluminum in the bone. Serum aluminum levels were significantly (P less than 0.001) higher in these 3 infants and in 1 other, all of whom received more than 100 mg of elemental aluminum per kilogram of body weight per day (mean +/- S.D., 371.0 +/- 178.9 ng per milliliter [13.75 +/- 6.6 mumol per liter] ) than they were in 8 older children with azotemia who were not undergoing dialysis and who received less than 100 mg of elemental aluminum per kilogram per day (27.0 +/- 18.6 ng per milliliter [1.0 +/- 0.68 mumol per liter] ), 7 such children who did not receive aluminum hydroxide (20.28 +/- 9.2 ng per milliliter [0.75 +/- 0.34 mumol per liter] ), and 16 children with normal renal function (21.04 +/- 4.9 ng per milliliter [0.78 +/- 0.18 mumol per liter] ). In all the children with azotemia who were treated with aluminum hydroxide, there was a positive correlation (r = 0.90; P less than 0.01) between the serum aluminum level and the daily dose of elemental aluminum. These studies indicate that gastrointestinal absorption of aluminum can lead to aluminum intoxication in children with azotemia, and that infants may be particularly susceptible to this complication of therapy.     

Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease.

The serum concentration of 1,25-dihydroxylvitamin D (1,25-[OH]2D) in normal children and in children with inherited diseases of bone was compared by use of a competitive binding assay. Observed values were: in 12 normal children and adolescents, 37.1 +/- 1.9 pg per milliliter (mean +/- S.D.); in 14 patients with X-linked hypophosphatemic rickets treated with vitamin D2 and phosphate supplements, 15.6 +/- 7.8 (P less than 0.01 versus control); in six patients with autosomal recessive vitamin D dependency treated with vitamin D2, 9.5 +/- 2.9 (P less than 0.01 versus control); and in four untreated patients with autosomal dominant hypophosphatemic (non-rachitic) bone disease, 30.2 +/- 6.3 (not significantly different from the controls). The difference in bone disease between X-linked hypophosphatemia (severe) and hypophosphatemic bone disease (mild) at comparable low serum levels of phosphate implies that 1,25-(OH)2D and phosphate may have independent roles in the pathogenesis of defective bone mineralization.     

Sustained effectiveness of converting-enzyme inhibition in patients with severe congestive heart failure

Eight patients with severe congestive heart failure refractory to conventional therapy, including vasodilators, were given captopril (seven patients) or teprotide (one patient). All had dyspnea, edema, elevated pulmonary wedge pressure (28.0 +/- 2.6 mm Hg), low cardiac index (1.6 +/- 0.1 liters per minute per square meter), and elevated levels of serum creatinine (2.3 +/- 0.2 mg per deciliter [203.3 +/- 17.7 mumol per liter]), blood urea nitrogen (48 +/- 5 mg per deciliter [17.1 +/- 1.8 mmol of urea per liter]), plasma renin activity (21 +/- 7 ng of angiotensin I per milliliter per hour), plasma angiotensin II (271 +/- 51 pg per milliliter), and plasma aldosterone (65 +/- 14 ng per deciliter). After one week of therapy, all indexes improved. Creatinine and p-aminohippurate clearances were also increased (P less than 0.01). Improvement was sustained (more than six months) and was associated with a statistically significant increase in the cardiac ejection fraction (12 +/- 3 to 26 +/- 7 per cent). With a mean follow-up of seven months, the New York Heart Association Functional Class has been reduced from IV to II, and the number of days of hospitalization to less than 10 per cent of that before captopril therapy. We conclude that captopril reduces afterload in advanced congestive heart failure and induces sustained improvements in clinical status and renal function.     

Effects of oral base therapy on serum ionized calcium, phosphorus and parathyroid hormone in chronic hemodialysis patients

The purpose of this study was to evaluate the effects of oral base therapy on selected chemical parameters in chronic hemodialysis patients. Oral base supplements were administered to 20 acidotic chronic hemodialysis patients for one month. Serum bicarbonate levels rose from 18.6 +/- 2.9 to 22.5 +/- 4.0 mEq/L (p less than 0.0005) and pH rose from 7.35 +/- 0.03 to 7.39 +/- 0.04 (p less than 0.0005). Serum ionized calcium levels fell from 5.03 +/- 0.37 to 4.83 +/- 0.34 mg/dL (1.25 +/- 0.09 to 1.21 +/- 0.08 mmol/L) (p less than 0.01), while intact parathyroid hormone (PTH) levels rose from 547 +/- 697 to 619 +/- 776 pg/mL (p less than 0.05). Base therapy did not result in significant changes in serum levels of total calcium, phosphorus, alkaline phosphatase, urea nitrogen, creatinine, total protein, albumin or potassium. If empiric therapy with exogenous base is given to dialysis patients, ionized calcium levels should be closely monitored since changes in calcium supplement or vitamin D therapy may be required to maintain ionized calcium and parathyroid hormone values at the pre-treatment levels.     

"Idiopathic" hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect

Among 59 closely related members of one Bedouin tribe, we identified 9 who had the characteristic features of hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We found "idiopathic" hypercalciuria in 21 of the 50 asymptomatic members. The biochemical abnormalities observed in these 21 subjects were qualitatively similar to those in the 9 with HHRH, but were quantitatively milder. The urinary calcium concentration was 0.43 +/- 0.14 mg per milligram of creatinine (mean +/- SD) in the patients with HHRH, 0.34 +/- 0.07 in the subjects with idiopathic hypercalciuria, and 0.14 +/- 0.05 in normal subjects from the same tribe. Tubular reabsorption of phosphorus and serum phosphorus concentrations were 3.0 and 4.3 SD units below the age-related mean, respectively, in HHRH, and 1.1 SD units below the normal mean for both variables in idiopathic hypercalciuria. Mean serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D) were 303 pg per milliliter in HHRH and 145 pg per milliliter in idiopathic hypercalciuria (upper normal limit, 110). We conclude that the subjects with hypercalciuria and the patients with HHRH shared a hereditary renal phosphate leak that led to hypophosphatemia, elevated serum concentrations of 1,25-(OH)2D, increased intestinal calcium absorption, and hypercalciuria. The magnitude of the hypophosphatemia, which regulates 1,25-(OH)2D levels, appears to determine which subjects will have hypercalciuria alone and which will also have bone disease.     

Selective deficiency of 1,25-dihydroxycholecalciferol. A cause of isolated skeletal resistance to parathyroid hormone.

To investigate the role of vitamin D metabolites in the pathogenesis of pseudohypoparathyroidism, we studied an elderly man with a unique variant of the disease, which was characterized by hypocalcemia, elevated serum parathyroid hormone (513 +/- 13 pg per milliliter, mean +/- S.E.M., normal, less than 450) but normal renal responses (phosphate and cyclic AMP) to exogenous parathyroid extract. Treatment with parathyroid extract did not produce a calcemic effect, suggesting an isolated skeletal hyporesponsiveness to parathyroid hormone. Although 25-hydroxyvitamin D levels were not reduced, levels of 1,25-dihydroxycholecalciferol were extremely low (0.52 ng per deciliter; normal 3.3 +/- 0.06, S.D.). Treatment with 1,25-dihydroxycholecalciferol (1 microgram by mouth per day for four days) increased circulating levels to normal (4.60 ng per deciliter) and restored to normal the calcemic response to parathyroid (change in calcium 3.0 mg per deciliter). These data suggest that 1,25-dihydroxycholecalciferol deficiency may explain the skeletal resistance, but not the renal resistance, often present in classic pseudohypoparathyroidism.     

Abnormalities in parathyroid hormone secretion and 1,25-dihydroxyvitamin D3 formation in women with osteoporosis

We investigated the parathyroid hormone-1,25-dihydroxyvitamin D3 (1,25(OH)2D) axis in osteoporosis by administering phosphate to 8 postmenopausal women with osteoporosis (49 to 78 years old) and to 10 normal women matched for age (50 to 74 years). All subjects responded with a similar increase in the serum phosphorus concentration (women with osteoporosis, 1.15 +/- 0.06 to 1.79 +/- 0.09 mmol per liter; controls, 1.14 +/- 0.05 to 1.73 +/- 0.08 mmol per liter) and a fall in the ionized calcium concentration (women with osteoporosis, 1.12 +/- 0.03 to 1.06 +/- 0.03 mmol per liter; controls, 1.17 +/- 0.01 to 1.11 +/- 0.02 mmol per liter). Parathyroid hormone levels rose 2.5-fold in the control group (15.4 +/- 2.2 to 37.9 +/- 6.1 pg per milliliter) but increased by only 43 percent in the group with osteoporosis (14.8 +/- 2.8 to 21.2 +/- 4.1 pg per milliliter), an increase similar to that previously reported in young normal subjects (53 percent). In healthy older and younger subjects, the levels of 1,25(OH)2D did not change; in the subjects with osteoporosis, however, they decreased significantly (50 percent). We conclude that older women require a greater parathyroid hormone stimulus than younger women to maintain vitamin D homeostasis, because of an age-related decline in the formation of 1,25(OH)2D in response to parathyroid hormone, and that in osteoporosis the age-appropriate parathyroid hormone response to the same hypocalcemic signal is diminished. Our results are consistent with the presence of an abnormality in parathyroid hormone secretory function in osteoporosis in addition to the universal decline in 1,25(OH)2D responsiveness associated with aging.     

Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria

In previous studies, we observed increases in the circulating concentration and production rate of 1,25-dihydroxyvitamin D (1,25-(OH)2D) in a large majority of patients with the syndrome of absorptive hypercalciuria. In the present study, the hypothesis that 1,25-(OD)2D production might be relatively autonomous in this syndrome was tested by fashioning a suppression test in which patients were challenged with a short-term increase in dietary calcium intake. We found that contrary to our hypothesis, the circulating concentration of 1,25-(OH)2D was remarkably sensitive to calcium intake in 15 patients with absorptive hypercalciuria (mean decrease, from 74 to 49 pg per milliliter, P less than 0.001). When this challenge was prolonged for two weeks, however, patients with absorptive hypercalciuria had evidence of an apparent "escape" phenomenon, in which the circulating concentration of 1,25-(OH)2D rebounded toward its initial level and the renal tubular phosphate threshold fell markedly. These findings provide evidence for disordered control of renal phosphate handling and 1,25-(OH)2D production in absorptive hypercalciuria and suggest a linked rather than a cause-and-effect relation between these two abnormalities.     

Bone marrow changes in patients with hairy cell leukemia treated by recombinant alpha2-interferon

Bone marrow specimens from 21 patients with hairy cell leukemia (HCL) who were entered into a program to study the efficacy of treatment with recombinant alpha 2-interferon were evaluated. Patients were treated with the interferon, 2 X 10(6) U/m2 subcutaneously three times weekly, and were scheduled to undergo bone marrow aspiration and biopsy at study entry and after three (21 patients) and six (16 patients) months of treatment. Bone marrow samples after three months of treatment showed an overall decline in cellularity, from an average of 77 +/- 20 to 57 +/- 22 per cent, with a marked decrease in the percentage of neoplastic mass (from 87 +/- 9 to 59 +/- 24 per cent). The bone marrow changes were associated with significant improvement in hematologic values, including hemoglobin levels and granulocyte and platelet counts. The bone marrow changes and improved hematologic values remained stable with continuation of interferon therapy. However complete bone marrow remission did not occur in any of the patients after three or six months of interferon therapy. The HCL cell mass in more than 60 per cent of the patients remained at or above 50 per cent of the marrow cellularity and dropped to less than 25 per cent in 14 per cent of the patients. In all of the patients increased amounts of reticulin fibers were identified in the bone marrow prior to therapy, and 89 per cent of bone marrow aspirations failed (dry tap). The amounts of reticulin fibers remained increased in most of the patients (91 per cent), with a high incidence of dry taps (73 per cent), after therapy. Interferon therapy also changed the tartrate-resistant acid phosphatase(TRAP)-positive HCL cells to TRAP-negative, suggesting inhibition of activity and/or production of TRAP in HCL cells.     

Effect of levamisole on E-rosette-forming cells in vivo and in vitro in Hodgkin's disease.

Incubation in vitro of lymphocytes from patients with Hodgkin's disease with 40 mug per milliliter of levamisole resulted in a rise in the number of E-rosette-forming cells from 33.6 +/- 12.5 per cent (mean +/- S.D.) to 56.7 +/- 14.6 per cent. The drug had no effect on normal lymphocytes. Ten patients with Hodgkin's disease treated six months previously with levamisole were restudied. The positive skin tests to PPD, candida and mumps persisted. However, the E-rosette-forming cells decreased to the pretreatment levels (34.7 +/- 6.4 per cent). Readministration of 150 mg of levamisole for three days raised the number of E-rosette-forming cells to 54.1 +/- 5.6 per cent. This effect was observed for at least two months. However, the drug had no effect in vitro as long as the in vivo effect persisted. These results demonstrate a clear immunologic effect of levamisole in Hodgkin's disease and indicate that the low number of E-rosette-forming cells is not due to a real T-cell depletion.     

Effect of parathyroidectomy on bone aluminum accumulation in chronic renal failure

In some patients with chronic renal failure, bone mineralization becomes defective after parathyroidectomy for secondary hyperparathyroidism. Because aluminum deposition in bone is associated with impaired bone formation and osteomalacia, we retrospectively studied bone-biopsy specimens from patients on hemodialysis who were not exposed to dialysate contaminated with aluminum, to determine whether aluminum accumulation on bone surfaces was enhanced by parathyroidectomy. Serial biopsy specimens taken before and after parathyroidectomy revealed an increase in the rate of aluminum deposition on the surface of mineralized bone after parathyroidectomy in each of the six patients studied. The accelerated rate of aluminum accumulation could not be explained by changes in the oral aluminum intake. The mean rate of bone formation (+/- S.E.M.) before parathyroidectomy was higher in the six patients than in six control patients who did not undergo parathyroid surgery (586 +/- 147 vs. 237 +/- 85 micron2 per square millimeter per day; P less than 0.05). After parathyroidectomy, the rate of bone formation fell to levels below normal (148 +/- 32 vs. 311 +/- 29 micron2 per square millimeter per day; P less than 0.05) but was not significantly different from the rate in the control group (319 +/- 126 micron2 per square millimeter per day). We conclude that parathyroidectomy in patients with chronic renal failure is associated with enhanced aluminum deposition on the bone surface, possibly as a result of low bone formation. Patients with secondary hyperparathyroidism who may be candidates for parathyroidectomy should be evaluated for aluminum excess before surgery, so that treatment with aluminum chelation may be considered.     

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.     

A crossover comparison of continuous insulin infusion and conventional injection treatment of type I diabetes

We evaluated the feasibility and effectiveness of continuous subcutaneous insulin infusion therapy (CSII) as compared to conventional injection treatment (CIT) in an ordinary diabetic clinic in a one-year randomized crossover study of 65 type I diabetic patients. Home blood glucose levels were lower during CSII (8.6 +/- 0.2 mmol/l, mean +/- SEM) than during CIT (9.1 +/- 0.3 mmol/l, p less than 0.05). During the first six months, HbA1 fell on CSII therapy (from 10.6 +/- 0.4 to 9.7 +/- 0.3%, p less than 0.001), whereas no change occurred during CIT. After the crossover, HbA1 decreased again on CSII (p less than 0.05), but rose in patients shifted from CSII to CIT (p less than 0.05). The fall in glycosylated haemoglobin during CSII correlated with the initial HbA1 level (r = 0.54, p less than 0.001). Ketoacidosis was more common during CSII (16 vs. 2 verified episodes). Hypoglycaemia occurred infrequently, without difference between CSII and CIT. Fifty-six per cent of the patients preferred CSII after the study. In conclusion, while CSII slightly improves the metabolic control, the improvement in the unselected study population is less than previously reported among highly selected patients.