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.

Analysis of ambulatory blood pressure monitoring: the problem of 'white-coat' hypertension, responders and non-responders.

OBJECTIVE: To analyse a randomized study undertaken to compare the antihypertensive efficacy of dihydropyridine calcium antagonists in patients with essential hypertension. METHOD: Blood pressure was measured both conventionally by a doctor and by non-invasive ambulatory monitoring. RESULTS: During amlodipine therapy (5 mg once a day for 4 weeks, n = 121), the mean daytime diastolic blood pressure was lowered by 8.2+/-7.1 and 0.9+/-7.4 mmHg (means +/- SD) in patients with a pretreatment daytime diastolic blood pressure >/= 90 (n = 89) and < 90 mmHg (n = 32), respectively. In 60 (67%) among the 89 patients who had an initial daytime diastolic blood pressure >/= 90 mmHg the daytime diastolic blood pressure was lowered by >/= 5 mmHg, with a mean fall of 12.0+/- 5.2 mmHg. The decrease in daytime diastolic blood pressure averaged 0.6+/- 3.5 mmHg in the remaining non-responder patients (n = 29). CONCLUSION:It seems important to evaluate the efficacy of a given antihypertensive drug by analysing patients with white-coat hypertension separately from responders to the medication. This allows one to gain maximum information concerning the effect of therapy in the individual hypertensive patients.

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.

[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.

Clinical utility of ambulatory blood pressure monitoring in the evaluation of patients with borderline hypertension.

Blood pressure measured in the physician's office often differ considerably from those recorded during everyday activities away from the medical environment. This fact is particularly important in patients whose office blood pressures are only mildly elevated because, in a large proportion of these people, the elevation is observed only when blood pressures are measured in the physician's office and not when they are measured during normal activities. There is little evidence that this 'white-coat' hypertension is associated with increased cardiovascular risk, but patients with the condition are prone to develop sustained hypertension over time. It is therefore advisable to monitor these individual regularly so that antihypertensive therapy can be initiated when appropriate.

[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.

Lack of effect of long-term amlodipine on insulin sensitivity and plasma insulin in obese patients with essential hypertension.

To evaluate the effects of long-term treatment antihypertensive with the dihydropyridine calcium antagonist amlodipine on insulin sensitivity, plasma insulin, and lipoprotein metabolism in obese hypertensive patients. We measured the insulin sensitivity index (SI), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure in 20 obese, non-diabetic patients with essential hypertension before and after 6 weeks of placebo and again after 6 months of amlodipine. Ten patients [mean body mass index (BMI) 30.2 kg.m-2] had been on prior treatment with a thiazide diuretic in low dosage and/or a beta-adrenoceptor blocker (group A), and 10 matched patients [BMI 31.8 kg.m-2] had been previously untreated (group B). Amlodipine was started in a dose of 5 mg and was increased to 10 mg once daily in 14 patients who were hypertensive after 8 weeks on the lower dosage. At entry (before placebo), SI was slightly but not significantly lower in group A than B [2.7 vs. 3.6 x 10(-4) ml.microU-4.min-1]; fasting plasma insulin was 13.6 vs. 12.9 microU.ml-1. After 6 weeks on placebo, S1 averaged 3.7 in group A and 4.4 x 10(-4) microU.ml-1.min-1 in group B; fasting plasma insulin was 14.6 vs. 15.1 microU.ml-1, and glucose 5.5 vs. 5.5 mmol.l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.

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.

Unaltered insulin sensitivity during calcium channel blockade with amlodipine.

The sensitivity of peripheral tissues to insulin is of pathophysiological, therapeutic and possibly also of prognostic relevance. Calcium channel blockers are widely used in the treatment of cardiovascular disorders that are commonly associated with decreased insulin sensitivity (SI). To evaluate the effects of calcium channel blokkade on SI, glucose homoeostasis and lipid profiles, studies were made of SI (determined by the Minimal Model Method of Bergman), basal glucose and insulin levels, serum total triglyceride (Tg) and lipoprotein cholesterol (C) fractions and certain other variables in 38 healthy young men (24 y) during placebo and after 3 weeks of calcium channel blockade with amlodipine 5 mg once daily. Measurements were made after 3 days on a standard diet (2200 kcal.day-1, 45% carbohydrates, 40% fat and 15% proteins) and after an overnight fast. Compared to placebo, amlodipine decreased supine systolic blood pressure (P less than 0.01). Heart rate, body weight and 24 h urinary sodium excretion were unaltered, and so were fasting plasma glucose (placebo vs amlodipine: 4.86 vs 4.83 mmol.l-1, respectively) and insulin levels (7.7 vs 7.9 microU.ml-1), SI (10.5 vs 9.6.10(-4) x min-1 pro microU.ml-1), serum total Tg, C and lipoprotein C fractions. The findings demonstrate unchanged insulin sensitivity and secretion, as well as lipoprotein regulation, during maintenance administration of 5 mg amlodipine daily to healthy young men.

Proteoglycan metabolism in tissue cultured human articular cartilage. Influence of piroxicam.

Proteoglycan metabolism was investigated in longterm tissue cultured human cartilage. Visually intact cartilage from adult donors showed improving accumulation rates for 35sulfate labelled proteoglycans over a 6-week period. The loss of newly synthesized molecules in the nutrient culture media was low and constant. Fibrillated cartilage from a 17-year-old male showed higher basal 35S incorporation rates and the proportions of 35S proteoglycan aggregates were higher than in normal tissue. These observations may reflect the immature status of the tissue or an attempt at repair. However samples lost increasing amounts of 35S proteoglycans in the incubation media. This material appeared to be monomeric proteoglycan. The amount of 35S activity retained in the fibrillated tissue matrix fell during culture as did the proportion of proteoglycan aggregates. Thus catabolic events were postulated in these fibrillated cartilage samples. When piroxicam was added to the incubation media more newly synthesized proteoglycans were retained in the intercellular matrix of the fibrillated samples. Increased accumulation of 35S activity was seen in some of the batches of visually intact cartilage.

Revision total hip arthroplasty using uncemented components: preliminary report.

Revision of failed cemented total hip arthroplasties represents a major technical challenge to orthopaedic surgeons. One of the problems encountered is loss of femoral bone stock, making restoration of prosthetic stability difficult. Revision with uncemented components may allow healing of bone defects.

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.

Influence of the nature of calcium salts on serum calcium, phosphorus, calcitonin, growth hormone, and somatomedin C.

Twenty healthy males were randomly divided into three groups. Each subject received either 405 mg elemental calcium (Ca) as a salt linked to an amino acid precursor, 405 mg CaC12 or 1000 mg Ca as Ca gluconolactate and carbonate. In all three cases, Ca intake led to an increase of serum Ca and TCT production and a decrease of PTH liberation. However, when Ca is linked to the amino acid precursor, an elective stimulation of growth hormone (GH) and somatomedin C (SmC) occurs. Due to the nature of its amino acid precursor, this salt seems to stimulate GH and SmC liberation through hypophysis. This could be a major pathway in decoupling of the sequence resorption-formation and therapy of metabolic bone diseases.

Toleration and safety of piroxicam.

The purpose of this review is to define the toleration profile of piroxicam through the clinical experience gathered in 109,495 patients and to estimate how it compares with that of other commonly prescribed non-steroidal anti-inflammatory drugs (NSAIDs) in 37 comparative clinical trials involving 3,580 patients. The estimated total exposure to piroxicam in clinical trials reported here is approximately 2.6 million patient days. The toleration profile of piroxicam is typical of an inhibitor of prostaglandins, with a relatively low reported incidence of adverse events necessitating discontinuation of therapy. Pharmacokinetics are not age- or sex-dependent, and - with the exception of oedema - the incidence of adverse events does not increase with age. Piroxicam exhibits better toleration than indomethacin (75 to 150 mg daily), naproxen (1,000 mg daily), and enteric coated acetylsalicylic acid (3.5 to 5 g daily), and is as well tolerated as diclofenac (75 to 150 mg daily), naproxen (500 to 750 mg daily), and ibuprofen (2.4 g daily). Piroxicam has the advantage that once-daily dosage is sufficient to provide efficacy equal to or better than these comparative agents.

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)

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.

Calcium metabolism and hyperparathyroidism after renal transplantation.

Plasma calcium and albumin levels were measured serially in 100 patients for two years following successful renal transplantation. Mean plasma calcium increased during the first six months after grafting, in large part attributable to an increase in plasma albumin. The variance around the mean plasma calcium did not increase suggesting that mechanisms responsible for hypercalcaemia were common to the majority of patients. 36 per cent of patients developed hypercalcaemia within two years of grafting but the incidence fell to 11 per cent when more rigorous criteria for hypercalcaemia were used. The mechanisms maintaining plasma calcium were studied in 29 of the patients, nine of whom were hypercalcaemic and 20 of whom were normocalcaemic. Before transplantation, mean plasma calcium and phosphate levels were higher, the prevalence of subperiosteal erosions and extraskeletal calcification radiographically was greater, and the duration of haemodialysis treatment was longer in the hypercalcaemic patients than in the normocalcaemic recipients. At assessment after transplantation, hypercalcaemic patients had lower levels of plasma phosphate, higher plasma levels of alkaline phosphatase and parathyroid hormone, and higher hydroxyproline excretion. Renal function and 47Ca absorption were similar in the two groups. The major cause for apparent hypercalcaemia in transplanted patients appeared to be an increase in plasma albumin. In patients with true hypercalcaemia the major cause was pre-existing hyperparathyroidism where hypercalcaemia was mediated by increased renal tubular reabsorption of calcium.

Piroxicam suppositories for osteoarthritis and rheumatoid arthritis: an open multicentre study in 116 patients.

Efficacy and toleration of piroxicam suppositories 20 mg, given once daily for 4 weeks were assessed in 96 patients suffering from degenerative joint disease and 20 patients suffering from rheumatoid arthritis. The mean scores of objective parameters measured (tenderness, swelling, limitation of movement) decreased significantly 2 and 4 weeks after initiation of therapy. Patients' self-evaluation of pain and stiffness also significantly improved during the trial. Overall evaluation of efficacy and toleration were excellent or good in more than 80% of patients. Local toleration was excellent in all but two patients.

Familial benign hypercalcaemia. Study of a large family.

Twenty-seven hypercalcaemic subjects were identified in three generations of a family. There were no clinical complications of chronic hypercalcaemia, but five had had parathyroid surgery which was unsuccessful in four. Twenty of the twenty-seven subjects were compared with twenty-four normocalcaemic controls from the same family and the findings were also compared with those from forty patients with surgically proven primary hyperparathyroidism. The relation between the serum and urinary calcium levels was studied by means of an oral calcium loading test. The ratio of calcium clearance to creatinine clearance was normal in this family (but elevated in the patients with primary hyperparathyroidism) and the concentration of parathyroid hormone was normal, as was the total urinary excretion of cyclic AMP. Thus, there was no evidence of either suppressed or increased parathyroid activity in this familial condition. Basal urinary calcium excretion was normal under steady-state conditions indicating that the hypercalcaemia could not be attributed to either increased bone resorption or increased calcium absorption from the gut. In accordance with this, the serum levels of 1,25-dihydroxycholecalciferol were normal. The hypercalcaemia in this condition can be accounted for in full by an increase in renal tubular reabsorption of calcium, and thus differs from that of primary hyperparathyroidism in which there is increased production of calcium from gut and/or bone as well as an increase in renal tubular reabsorption of calcium. Although the serum phosphate and renal tubular reabsorption of phosphate were both low in patients with familial benign hypercalcaemia, they were not as low as in patients with the same degree of hypercalcaemia due to primary hyperparathyroidism. The changes in phosphate transport in familial benign hypercalcaemia could be explained as a secondary effect of the increased filtered load of calcium in the kidney. The tendency towards hypermagnesaemia in our patients, which contrasts with a tendency towards hypomagnesaemia in primary hyperparathyroidism, could also be explained as a secondary effect of the abnormality of renal tubular reabsorption of calcium. Increased renal tubular calcium reabsorption and persistent normal functioning of the parathyroid glands in the face of hypercalcaemia remain the sole definite abnormalities of the syndrome.