Suppressive effects of 24,25-dihydroxycholecalciferol on bone resorption induced by acute bilateral nephrectomy in rats.

The possible suppressive effects of 24,25-dihydroxycholecalciferol on secondary hyperparathyroidism and increased bone resorption were investigated in adult rats raised on a diet normal in calcium, phosphorus, and vitamin D, and subjected to acute bilateral nephrectomy. The animals had received subcutaneous radiocalcium 4 wk before the experiment. 5 h after nephrectomy an increase in serum total calcium, (45)Ca-specific activity, citrate, phosphorus, and magnesium concentrations were observed. Serum immunoreactive parathyroid hormone increased, while serum calcitonin decreased. The osteoclast count in the tibial metaphyses was augmented. The biochemical and histological changes observed were partly parathyroid hormone and calcitonin independent, as they also occurred in parathyroidectomized hypocalcemic rats. Pretreatment with 650 pmol of 24,25-dihydroxycholecalciferol 16 h before nephrectomy prevented bone calcium mobilization and diminished the rise in serum total calcium and citrate both in parathyroid-intact and in parathyroidectomized animals. In parathyroid-intact rats, serum immunoreactive parathyroid hormone and calcitonin remained normal in spite of the fall in serum-ionized calcium, and the number of osteoclasts did not increase. In parathyroidectomized rats, 24,25-dihydroxycholecalciferol did not prevent the postnephrectomy rise in the osteoclast count. This latter observation suggests that this metabolite exerts its effect on bone either by acting on cells other than osteoclasts, i.e., the osteocytes, or by inhibiting cell activity. At equimolar dosage 1,25-dihydroxycholecalciferol had a potent stimulatory effect on bone resorption. This effect of 1,25-dihydroxycholecalciferol was partly blocked by the simultaneous administration of 24,25-dihydroxycholecalciferol. The potential clinical significance of these observations remains to be determined.

Vitamin A and hyperparathyroid bone disease in uremia.

The possible contribution of hypervitaminosis A to bone disease in uremia was examined in 50 dialysis-treated patients with end-stage chronic renal failure. None of the patients received dietary supplements of vitamin A. In common with previous investigations, plasma concentrations of total vitamin A and the retinol-binding protein (RBP) were increased in patients, but the molar ratio of vitamin A to RBP was significantly lower than control values. A significant correlation was noted between concentrations in plasma of vitamin A and RBP. No significant relationship was found between vitamin A or the vitamin A/RBP ratio, and the measured biochemical, radiographic, or histological indices of hyperparathyroidism and bone resorption. We conclude that the elevated plasma values of vitamin A in uremia are largely attributable to the high concentrations of RBP and do not contribute significantly to the pathogenesis of renal osteodystrophy.

Altered insulin sensitivity, hyperinsulinemia, and dyslipidemia in individuals with a hypertensive parent.

PURPOSE: Essential hypertension is, in some patients, complicated by impairment of insulin-mediated glucose disposal and hyperinsulinemia. Whether this metabolic disturbance is a consequence of the hypertensive process or whether it may precede, and thus possibly promote, the development of hypertension has been unknown. SUBJECTS AND METHODS: Searching for hereditary or familial defects in hypertension-prone humans, we prospectively investigated insulin sensitivity, plasma insulin and glucose, and serum lipoproteins in normotensive offspring of essential hypertensive as compared with age- and body habitus-matched offspring of normotensive families. RESULTS: Compared with 78 control subjects, 70 offspring of essential hypertensive parents had similar age (mean +/- SEM: 24 +/- 1 versus 24 +/- 1 years, respectively) and body mass index (22.3 +/- 0.2 versus 22.4 +/- 0.2 kg/m2), a blood pressure of 127/77 +/- 1/1 versus 123/76 +/- 1/1 mm Hg (p less than 0.05 for systolic), and significantly elevated (p less than 0.01 to 0.001) fasting plasma insulin levels (9.9 +/- 0.3 versus 8.6 +/- 0.3 microU/mL), serum total triglycerides (1.03 +/- 0.06 versus 0.83 +/- 0.03 mmol/L), total cholesterol (4.37 +/- 0.08 versus 3.93 +/- 0.07 mmol/L), low-density lipoprotein cholesterol (2.45 +/- 0.08 versus 2.14 +/- 0.07 mmol/L), and total/high-density lipoprotein cholesterol ratio (4.3 +/- 0.1 versus 3.7 +/- 0.1). Insulin sensitivity was lower (9.4 +/- 0.7 versus 13.2 +/- 1.1 x 10(-4) x minute-1/microU/mL, p less than 0.001), while post-glucose-load plasma insulin levels were higher (p less than 0.05) in the 41 offspring of essential hypertensive parents than in the 38 offspring of normotensive parents so investigated. CONCLUSION: These findings demonstrate that young normotensive humans in apparently excellent health but with one essential hypertensive parent tend to have an impairment of insulin-mediated glucose disposal, hyperinsulinemia, and dyslipidemia. It follows that a familial trait for essential hypertension seems to coexist commonly with defects in carbohydrate and lipoprotein metabolism that can be detected before or at least at a very early stage of the development of high blood pressure as judged by resting blood pressure measurements.

Evaluation of the efficacy, safety and toleration of azithromycin vs. penicillin V in the treatment of acute streptococcal pharyngitis in children: results of a multicenter, open comparative study. The Swiss Tonsillopharyngitis Study Group.

BACKGROUND: For many years alternatives to penicillin have been studied for the management of pediatric group A beta-hemolytic Streptococcus (GABHS) pharyngitis. As a result of its pharmacokinetic profile azithromycin is unique among these alternative antimicrobials in allowing once daily dosing and shorter duration of treatment. However, the optimum dose (e.g. 10 or 12 mg/kg/day) and duration (e.g. 3 or 5 days) of azithromycin therapy have not been defined yet. METHODS: An open, comparative multicenter study was conducted in 343 children with clinical symptoms of GABHS pharyngitis and a positive culture to evaluate the efficacy and safety of azithromycin (10 mg/kg) once daily for 3 days compared with penicillin V three times daily for 10 days. RESULTS: Among the evaluable patients bacteriologic eradication documented at follow-up visits was inferior with azithromycin when compared with penicillin V therapy: at Days 9 to 20 (mean, 12 days), negative cultures in 65% (99 of 152 patients) vs. 82% (128 of 126 patients) (P < 0.001); and at Days 17 to 57 (mean, 25 days), in 55% vs. 80% (P < 0.001). Overall clinical success (cure or improvement) was achieved in 93% (149 of 160 patients) of azithromycin-treated and in 89% (143 of 160 patients) of penicillin-treated patients (P > 0.50). There was no correlation between bacteriologic response and clinical outcome, as assessed shortly after completion of therapy or during 6-month follow-up. Both treatments were well-tolerated. CONCLUSIONS: In the present study on GABHS pharyngitis in children, a once daily (10-mg/kg), 3-day oral regimen of azithromycin was as clinically effective and as safe as traditional penicillin but appeared inferior in eliminating GABHS from the throat.

Proteoglycan metabolism in isolated chondrocytes from human cartilage and in short-term tissue-cultured human articular cartilage.

The effect of piroxicam on proteoglycan metabolism of human cartilage cells was investigated in two in vitro models. Cells or tissue samples were obtained from six different donors. Piroxicam levels used in the test systems ranged from 2 to 6 micrograms r/ml and were comparable with serum concentrations in humans after oral intake. Piroxicam increased the synthesis rates of proteoglycan in some batches of isolated and monolayer-cultured chondrocytes and in tissue-cultured articular cartilage. The fact that this increase in the synthesis of proteoglycan was restricted to some of the donors whereas isolated cells or tissue samples from other individuals remained unaffected illustrates the heterogeneity of different human donors. Depression of proteoglycan synthesis in the presence of the drug was not observed.

Lymphocyte sub-population counts after a single 40 mg administration of piroxicam in 20 patients with rheumatoid arthritis. A placebo-controlled study.

Patients with active rheumatoid arthritis are characterized by a decrease in the number of circulating T-suppressor lymphocytes (identified by OKT8), resulting in an imbalance between helper (identified by OKT4) and suppressor cells. Piroxicam is a non-steroidal anti-inflammatory agent which modulates lymphocytic functions, especially by reducing the concentration of the rheumatoid factor in vitro and in vivo. A double-blind placebo-controlled study was performed in 20 patients suffering from active RA to investigate the acute effect of a single administration of piroxicam 40 mg on the number of circulating OKT3, T4, T8 and IA1 positive cells. Blood samples were obtained 16 hours before and 0, 2, 6, 8, 24, 48, and 72 h after administration of piroxicam or placebo. There was a significant decrease (P less than 0.05) in T4/T8 cell ratio 48 and 72 h after piroxicam, whereas placebo had no effect. There were no significant changes in absolute numbers of total T-lymphocyte (OKT3 positive cells), T-helper-inducer (OKT4 positive cells) and T-suppressor cytotoxic lymphocytes (OKT8 positive cells). The number of IA1 positive cells (B-cells and activated T-lymphocytes) was significantly higher in the afternoon samples (at 14.00 and 16.00 hours) than in the morning samples (at 08.00 and 10.00 hours) after both placebo and piroxicam administration (P less than 0.05). These data show that piroxicam decreases the T4/T8 cell ratio in active RA, but only 48 h after the first administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiological and pharmacological aspects of 24,25-dihydroxycholecalciferol in man.

The present study describes the response to small oral doses (1--10 microgram/day) of 24,25-DHCC in man. Contrary to expectation, 24,25-DHCC was as potent as 1,25-DHCC in increasing intestinal absorption of calcium both in normal persons and in patients with a variety of disorders of calcium metabolism. Despite this increase in intestinal absorption, plasma and urine calcium did not increase after 24,25-DHCC as they did after 1,25-DHCC. Metabolic balance studies showed calcium balances to increase by 1.6 to 11.5 mmoles/day in 5 of the 6 patients studied. 24,25-DHCC increased intestinal absorption of calcium equally well in anephric patients, suggesting that conversion of 24,25-DHCC to 1,24,25-trihydroxycholecalciferol by the kidney cannot be the sole mechanism by which 24,25-DHCC expresses biological activity, even though in vitamin D deficient rats nephrectomy does abolish the ability of large doses of 24,25-DHCC to increase calcium absorption. It is concluded that 24,25-DHCC may be a calcium-regulating hormone in man. In view of the effects demonstrated here and its relatively high concentration in plasma and slow turnover rate, 24,25-DHCC has the properties that might be ideal for a long-acting stimulator of bone mineralisation. Further work is needed to explain why 24,25-DHCC has effects in man which are not readily seen in other species.

[Calcitonin, gastrin, parathyroid hormone and the autonomic nervous system]. / Calcitonima, gastrina, paratormone, sistema nervoso autonomo.

Stimulation of the beta-adrenergic terminations was employed to determine whether calcitonin-secreting thyroid C cells are derived from the neural crest. Calcitonin secretion was increased, whereas parathormone, insulin and gastrin values were not significantly changed. In addition, administration of a beta-blocking drug before ethanol led to a marked fall in calcitonin with respect to the baseline. Once again, other hormone levels were not affected.

[Thoughts about 20 cases of hyperparathyroidism (author's transl)]. / Réflexions à propos de 20 cas d'hyperparathyroïdie.

The analysis of 20 personal cases of parathyroid hyperplasia or adenoma suggest the following conclusions: 1. The importance of dosage of the parathormone is a decisive factor of the diagnosis and yields data: a) in relation with the volume of the adenoma; b) that return to normal 24 hours after resection; c) that constitute the proof of complete resection. 2. The little utility of the diagnosis of location bij means of elaborate paraclinical exams. The authors show false positive angiograms. Only the inspection of the four parathyroids and of the main heterotopic areas is a valid means of disclosing the lesions responsible of the hyperparathyroidism. It is essential to operate with a skilled pathologist who will read frozen sections.

[The effects of 1 alphahydroxycholecalciferol in patients with renal osteodystrophy, Paget's disease of bone and in normal subjects (author's transl)]. / Les effets de faibles doses de 1 alpha hydroxycholecalciferol chez le sujet normal.

The administration of 1 alpha hydroxycholecalciferol (1 alpha OHD3) (2 microgr. per day) increase the plasma immunoreactive calcitonin (i CT) concentration in normal subjects after six days. This effect is also observed in patients suffering from Paget's disease of bone, suggesting that the mechanism responsable for the secretion of CT following the administration of 1 alpha is not disturbed in that disease. By contrast, the absence of increase in plasma iCT in the patients suffering from chronic renal failure suggests an impaired secretion of CT in that disorder.

[Variations in parathormone serum levels during treatment of Paget's disease with calcitonin of human or salmon origin (author's transl)]. / Variations des taux sériques de parathormone au cours du traitement de la maladie de Paget par calcitonine humaine ou de saumon.

Biological effects of increasing doses of human and salmon calcitonin (CT) have been studied in 17 patients suffering from Paget's disease of bone. Results show a dose response relationship on indirect indices of bone turn-over. The plateau phenomenon occurs with both CT and more rapidly with the lower dosage. There is also a transient increase in parathyroid activity during the period of time when bone turn-over is decreasing. Calciuretic effect was more pronounced with salmon than with human CT.

[Renal osteodystrophy in two children : a comparison of the effects of 1 alpha-hydroxycholecalciferol (author's transl)]. / Comparaison de deux cas d'ostéodystrophie rénale sévère chez l'enfant, traités par la 1 alpha hydroxycholecalciferol (1 alpha OHD).

Two children suffering from renal osteodystrophy were treated by 1 alpha hydroxycholecalciferol (1 alpha OHD3) 1 microgr. each day, for 18 months. In both the level alkaline phosphatase decreased at the same time as endogenous immunoreactive CT increased, iPTH did not change steadily, whereas plasma creatinine rise. As plasma calcium concentration did not increase, it is suggested that the increase in endogenous CT concentration is a part of the favourable response to the treatment by 1 alpha OHD3.

[Amlodipine: pharmacokinetic and pharmacodynamic profile of a calcium antagonist with prolonged effect]. / Amlodipin: pharmakokinetisches und pharmakodynamisches Profil eines Kalziumantagonisten mit langanhaltender Wirkung.

Amlodipine is a new calcium antagonist of the 1.4-dihydropyridine group for treatment of hypertension and angina pectoris. Amlodipine is distinct from other calcium antagonists by its pharmacokinetic profile: slower onset of action with less acute vasodilatation associated side effects and a sustained antihypertensive and anti-anginal efficacy over 24 hours.

[Time of drug intake in hypertension and angina pectoris. A controlled monitoring study]. / Zeitpunkt der Medikamenten-einnahme bei Hypertonie und Angina pectoris. Eine kontrollierte Uberwachungsstudie.

A prospective cross-over study was performed in a general practice environment to assess and compare compliance data obtained by electronic monitoring on a BID or QD regimen in 113 patients with hypertension or angina pectoris. All patients were on a BID regimen (nifedipine SR) during the first month and switched to QD regimen (amlodipine) for another month. Taking compliance (i.e. the proportion of days with correct dosing) improved in 30% of patients (95% confidence interval 19 to 41%, p < 0.001), when switching from a BID to a QD regimen, but at the same time there was a 15% increase (95% confidence interval 5 to 25%, p < 0.02) in the number of patients with one or more no-dosing days. About 8% of patients had a low compliance rate, irrespective of the dosage regimen. Actual dosage intervals were used to estimate extent and timing of periods with unsatisfactory drug activity for various hypothetical drug durations of action, and it appears that the apparent advantage of QD regimen in terms of compliance is clinically meaningful only, when the duration of activity extents beyond the dosage interval in all patients.

[The importance of therapy compliance in the treatment of arterial hypertension]. / Importance de l'observance thérapeutique dans le traitement de l'hypertension artérielle.

The hypertensive patient remains mostly asymptomatic and requires medication over his entire life. A sufficient follow-up may sometimes be difficult. Poor control of blood pressure is frequently due to inadequate compliance with the prescribed medication. This compliance is therefore a factor to be considered in any instance of a follow-up consultation of a hypertensive patient.

Adverse reactions to the principal drugs used in rheumatoid arthritis--a review.

The five basic antirheumatic drugs: antimalarials, immunosuppressive agents, gold salts, penicillamine and levamisole induce side effects in a large number of patients. Some of these are specific to one group of drugs, while others are common to all of them.

Use of drugs with more than a twenty-four-hour duration of action.

AIM: To assess compliance with a drug regimen of two doses a day compared with one a day. PATIENTS AND METHODS: A prospective crossover study was set up in a general practice environment to compare compliance on a drug regimen of once a day versus twice a day. Data were collected by electronic monitoring in 113 patients with hypertension or angina pectoris. All patients were prescribed slow-release nifedipine twice a day during the first month and then crossed to a single daily dose of amlodipine for another month. RESULTS: Compliance, defined as the proportion of days on which the correct dose was taken, improved in 30% of patients (95% confidence interval 19-41%; P < 0.001) when the patients were switched from twice a day to once a day, but at the same time there was a 15% increase (95% confidence interval 5-25%; P < 0.02) in the number of patients with one or more no-dose days. Approximately 8% of patients displayed low compliance, irrespective of the dose regimen. Actual dose intervals were used to estimate the extent and timing of periods with unsatisfactory drug activity for various hypothetical drug durations of action. CONCLUSIONS: The apparent advantage of a single daily dose in terms of compliance appears to be clinically meaningful only when the duration of activity extends beyond the dose interval in all patients.