Corticosteroid-induced osteopenia and vitamin D metabolism. Effect of vitamin D2, calcium phosphate and sodium fluoride administration.

Thirty-one patients scheduled for long-term (24 weeks) treatment with prednisone in comparatively high doses were randomly allocated to two further treatment groups. Group A received prednisone plus 'triple-treatment' (vitamin D2 45000 iu twice weekly, sodium fluoride 50 mg and calcium phosphate 4.5 g daily), group B received only prednisone. The study was undertaken in order to evaluate the effect of prednisone- and triple-treatment upon bone mineral content (BMC) and vitamin D metabolism. The groups were comparable with regard to age, sex and prednisone dose. BMC fell rapidly and similarly in both groups, demonstrating that the triple-treatment has no preventive effect on corticosteroid induced osteopenia. Serum concentrations of 25OHD2, 25OHD3 and 1,25(OH)2D were unchanged in group B (without triple-treatment), whereas in group A 25OHD2 increased enormously, 25OHD3 was suppressed possibly by substrate competition for hydroxylation in the liver and 1,25(OH)2D was halved. The suppression of 1,25(OH)2D may be an effect of raised 25OHD2 alone, or in combination with corticosteroid excess.

Estimation of acute myocardial infarct size in man by serum CK-MB measurements.

This study was performed to determine the relationship between myocardial infarct size estimated by serum CK-MB methods and the extent of irreversible injury in acute myocardial infarction. In 321 consecutive patients, infarct size was estimated by different mathematical models, and in 22 patients who died in hospital, the extent of myocardial necrosis was determined by autopsy. We also investigated the depletion of CK-MB in infarcted tissue, the recovery of CK-MB in the plasma volume, and the estimation of CK-MB from plasma. Myocardial CK-MB depletion was relatively greater in the larger infarcts, whereas the recovery of enzyme in plasma was independent of the infarct size. Correction of serum CK-MB for changes in plasma volume improved the estimate significantly (p less than 0.05). The correlation between the measured infarct size (g) and the estimated infarct size (units per liter and gram-equivalents) was highly significant (r = 0.85--0.89, SEE = 23--27%, p less than 0.001). Thus, a semiquantitative expression of the extent of myocardial necrosis can be determined in vivo.

A possible direct effect of 24,25-dihydroxycholecalciferol on the parathyroid gland in patients with chronic renal failure.

Seventeen undialysed adult patients with chronic renal failure took part in a controlled study of the effects of 1,25(OH)2D3 and D3. After a 6-month observation period the patients were allocated at random to two groups for 6 months of treatment with either 1,25(OH)2D3 (mean dose 0.5 microgram daily) or D3 (dose 100 microgram daily). The treatment was then discontinued and the patients were studied for a further 3 months. In the 1,25(OH)2D3 group the mean serum concentration of 1,25(OH)2D rose significantly during treatment, whereas serum concentratins of 25OHD and 24,25(OH)2D remained unchanged. In the D3 group there was a highly significant increase in serum concentrations of 25OHD and 24,25(OH)2D, whereas serum 1,25(OH)2D remained unchanged. There was a significant fall in serum iPTH in both treatment groups. This fall was unrelated to serum calcium in the D3 group unlike the findings in the 1,25(OH)2D3 group. The data support previous experimental evidence that serum iPTH can be suppressed by 24,25(OH)2D3 and suggest that this analogue may be of clinical importance in the treatment of chronic renal failure without inducing hypercalcaemia.

Acute myocardial infarct size estimated by serum CK-MB determinations: clinical accuracy and prognostic relevance utilizing a practical modification of the isoenzyme approach.

The clinical reliability and relevance of a practical enzymatic method to estimate infarct size (IS) were evaluated in patients with acute myocardial infarction (AMI). The technique utilized was that of relatively few sequential determinations of serum heart specific isoenzyme CK-MB, as corroborated by studies of numerous CK-MB measurements. Isoenzyme IS was determined in 321 consecutively admitted patients with AMI. Autopsies were performed in 22 of the 43 decedents for quantification of myocardial necrosis by histochemical and histologic techniques. A highly significant correlation (r = 0.83 p less than 0.001, SEE = 28%) was observed between IS values calculated from serum CK-MB and IS defined by necropsy examination. The CK-MB median IS was significantly increased in decedents compared to survivors (p less than 0.005), with IS ranges having substantial overlap between the two groups. The present study demonstrates that a practical and reliable estimation of IS in vivo is obtainable by serum CK-MB. While such estimated IS is of relatively moderate value for predicting in-hospital prognosis in single patients, the isoenzyme method appears particularly well suited for clinical evaluation of potentially beneficial interventions anticipated to limit myocardial necrosis in groups of AMI patients.

Normalization of bone mineral content to height, weight, and lean body mass: implications for clinical use.

The main object of the present study was to reduce the large biological variation in forearm bone mineral content (BMC) by correction for individual variation in gross morphology. In 315 normal females aged 45--54 years, determinations of height, weight, and 24-h urinary creatinine excretion rates were performed, and lean body mass was calculated, BMC was measured by photon absorptiometry on both forearms. BMC was correlated to height (r = 0.19, P less than 0.01), to weight (r = 0.09, P greater than 0.05), to lean body mass (r = 0.15, P less than 0.05), and to creatinine excretion rate (r = 0.29, P less than 0.001). The biological variation in BMC of the 315 females was for raw BMC 15.8%; after correction of BMC for height 15.5%, for weight 15.8%, for lean body mass 15.6%, and for creatinine excretion rate 15.2%. Regression analysis with two independent variables (creatinine excretion and height or weight) increased in both cases the correlation coefficient to 0.32 and decreased the interindividual coefficient of variation of BMC to 15.0%. For diagnostic purposes BMC must be corrected for age and sex, but further corrections seem of minimal benefit.

Zinc metabolism in patients with chronic renal failure during treatment with 1.25-dihydroxycholecalciferol: a controlled therapeutic trial.

Serum concentrations and urinary excretion rates of zinc, calcium and magnesium were measured in 17 patients with chronic renal failure before and after treatment with 1.25(OH)2D3 or vitamin D3. Initially the patients showed hypozincemia (P less than 0.001), hypocalcemia (P less than 0.01) and hypermagnesemia (P less than 0.01). The distribution of zinc between albumin and alpha 2-macroglobulin was calculated. The reduction in serum zinc was due to a fall in the albumin bound fraction, which could not be explained by a reduction in the serum albumin concentration. During treatment with 1.25(OH)2D3 no significant changes in serum and urinary levels of zinc and magnesium were observed, while the serum concentrations and urinary excretion rates of calcium increased. It is concluded that 1.25(OH)2D3 and vitamin D3 are of minor importance in the intestinal absorption of zinc and magnesium.

Decreased renal function in association with administration of 1,25-dihydroxyvitamin D3 to patients with stable, advanced renal failure.

A controlled study of the effects of 1,25-dihydroxycholecalciferol (1,25[OH]2D3) and vitamin D3 (D3) was performed in 18 non-dialyzed patients with chronic renal failure (CRF) (creatinine clearance below 35 ml/min) and mild renal osteodystrophy. After 6 months observation of the spontaneous course, the patients were randomly allocated to 6 months oral treatment with either 1,25(OH)2D3 or D3 in initial daily doses of 1 and 100 microgram, respectively, combined with 0.5 g calcium (Calcium Sandoz). 1,25(OH)2D3 had a fast normalizing effect on the biochemical changes of calcium metabolism. D3 had similar, but less pronounced effects. The percent fall in creatinine clearance was greater during than before treatment in all patients on 1,25(OH)2D3 (p less than 0.01) and in 7 of 9 patients on D3 treatment (n.s.). Deterioration of renal function is a major limitation to clinical use of 1,25(OH)2D3 (and D3) in non-dialyzed patients with CRF. In fact, the decreased formation of 1,25(OH)2D3 seen in CRF might protect renal function through the abnormalities in mineral metabolism.

Zinc depletion in alcoholic liver diseases.

Liver and serum zinc concentrations were investigated in 24 patients with alcoholic liver diseases, 22 patients with non-alcoholic liver diseases, and in 36 control subjects. The liver samples were obtained by percutaneous liver biopsies, and the ratio of hepatocytes to fibrous connective tissue was estimated. The liver zinc concentration was expressed in relation to the amount of hepatocytes, and the serum zinc concentration was calculated in relation to total, albumin-, and alpha 2-macroglobulin-bound serum zinc. The results show that the liver zinc concentration was decreased in patients with alcoholic liver diseases (P < 0.01), in contrast to in patients with non-alcoholic liver diseases. Albumin-bound serum zinc was decreased in both groups (P < 0.001). The results indicate that alcoholic liver damage is associated with zinc deficiency.

An easy and reliable estimation of acute myocardial infarct size from serum CK-MB measurements.

The purpose of this study was to determine a simple and reliable procedure of estimating acute myocardial infarct (AMI) size by measuring serum creatine kinase MB (CK-MB) in few daily blood samples. In 13 patients with AMI blood samples were drawn every second hour for 60 h for determination of serum CK-MB activity. Infarct size was calculated using the CK-MB values of all samples and compared to the size calculated according to various models based on enzyme levels in few samples. Two models, using 3 daily samples, showed very high correlations and satisfactory standard errors of estimate when compared to the infarct size calculated from all samples. One of the 2 models was based on a computerized log-normal curve fit programme and one on accumulation of serum activities of CK-MB. The coefficient of variation of infarct size estimated from thrice-daily sampling was 7.4 and 9.4 for the 2 models. Considering the twenty-fold variation in infarct size a satisfactory quantitation is achieved from 3 daily samples.

Creatine kinase isoenzyme MB assay by electrophoresis.

A method for determination of the creatine kinase isoenzyme MB (CK-MB) is reported: separation of the isoenzymes was done by electrophoresis and the activity of the isoenzyme bands quantitated by scanning fluorometry. Total CK activity was used for calculation of CK-MB level. The precision of the method was satisfactory: coefficient of variation 5-10%. Its accuracy good: CK-MB was consistently found in high concentrations in tissue extracts of myocardium, but was virtually absent in skeletal muscle and could not be demonstrated in serum from patients with skeletal muscle damage. The sensitivity of the method fitted its clinical use: CK-MB was undetectable (less than 5 U/l) in normal sera, below 30 U/l in seventy-six out of seventy-seven patients in whom the diagnosis of acute myocardial infarction (AMI) was disproved, and above 30 U/l in all seventy-two patients with AMI according to WHO criteria. The CK-MB concentration in serum rises to a maximum about 20 h after onset of clinical symptoms of AMI and reaches baseline levels 20-30 h later. The electrophoretic CK-MB method is easy, fast and reliable and is considered as an important diagnostic test for AMI.

Hypozincaemia after jejuno-ileal bypass.

Serum zinc, albumin, alpha 2-macroglobulin, calcium, and magnesium were measured in 39 jejuno-ileal shunt-operated patients. The binding of serum zinc to albumin and alpha 2-macroglobulin were calculated. The results demonstrate that the patients as a group had a highly significant hypozincaemia (P less than 0.001), caused by a reduction of the albumin-bound serum zinc (P less than 0.001). Furthermore, the patients showed hypocalcaemia (P less than 0.001) and hypomagnesaemia (P less than 0.001). The findings indicate that patients with jejuno-ileal bypass for gross obesity develop deficiency of the divalent cations.

Plasma levels of perphenazine and its major metabolites during simultaneous treatment with anticholinergic drugs.

1. A gas chromatographic method was applied to study plasma levels of perphenazine (PPZ) and its major metabolites in man before and during simultaneous antiparkinson treatment. Twenty-six psychotic patients received various forms of PPZ administration as well as antiparkinson drugs. 2. Biperidine (5 mg) was administered intravenously to each of five patients, who 5 days earlier had had a single dose of PPZ-enanthate i.m. No significant alterations in plasma concentrations of PPZ were observed. 3. In fourteen patients receiving oral PPZ treatment the plasma levels of PPZ and its metabolites did not deviate significantly from controls after addition of biperidine or orphenadine given for 3 weeks in fixed oral doses. 4. The ratio between PPZ plasma concentration measured 4 and 7 h after the morning dose was not affected by concomitant antiparkinson therapy. 5. It is concluded that no clinically relevant pharmacokinetic interaction takes place between PPZ and two generally used antiparkinson drugs during steady-state conditions in psychotic patients.

Mass fragmentographic quantitation of ethotoin and some of its metabolites in human urine.

A method for the determination of ethotoin and its p-hydroxylated and dealkylated metabolites in urine has been developed. Ethotoin and the metabolites were extracted from acidified urine with ethyl acetate and silylated before injection into a combined gas chromatograph--mass spectrometer. Four partly identified metabolites were recorded, but their exact quantitation was not possible as pure reference substances were not available. The limit of sensitivity was far below the amounts of ethotoin and of its metabolites found in urine from patients treated with therapeutic doses of ethotoin.

Clinical pharmacokinetic studies of perphenazine.

A gas-chromatographic method was used for the study in man of the kinetics of perphenazine (PPZ) and its sulphoxide metabolite (PPZ-SO). Various forms of PPZ administration were applied in eighteen schizophrenic patients and four healthy volunteers. Following an i.v. dose of 5 or 6 mg a considerable fluctuation in the plasma concentration was noted before the exponential elimination phase. The average terminal half-life of PPZ was approximately 9.5 hours. PPZ-SO showed up quickly but in low concentrations. After an oral dose of 6 mg no PPZ was detected in plasma and PPZ-SO only as traces. During continuous oral medication, 12 mg three times daily, a low systemic availability and a high PPZ-SO/PPZ ratio was found suggesting a marked first pass effect. PPZ-enanthate given i.m. fortnightly resulted in PPZ-levels comparable to those seen after continuous oral medication, but PPZ-SO concentration were much lower. No accumulation was observed. The systemic clearance rate (average approximately 100 1/h) was the same after PPZ-enanthate i.m. and PPZ i.v., but varied three-fold individually. Side effects were mostly, but not always, registered concomitant with high plasma levels of PPZ.

Saturable metabolic pathways for ethotoin in man.

1. The urinary excretion pattern of ethotoin and five metabolites were examined in three patients receiving continuous treatment with ethotoin at two dose levels, in order to investigate the mechanism behind the dose-dependent kinetics of this anticonvulsant drug. 2. The results suggest a partial saturation in the dealkylation process at high dose levels in three patients. 3. A rough approximation of the Michaelis-Menten constants for different enzymatic processes was attempted. On the basis of the results obtained, the p-hydroxylation may be a saturable process. 4. The dose-dependent kinetics of ethotoin in man seem to be explicable by the existence of partly saturable enzymatic pathways.

An easy procedure for in vivo estimation of protein binding and correction of elevated serum values induced by venous stasis.

Venous stasis augments the apparent concentrations of serum proteins. A theoretical mathematical model for the correction of serum protein-bound constituents is propounded and an easy procedure for such corrections described. It is suggested that the effect of venous stasis can also be utilized for in vivo estimation of the average protein binding. The hypotheses were tested in 19 epileptic patients. The results obtained by serum determinations of sodium, magnesium, calcium and phenytoin indicate the validity of the theories.