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Biomedical subjects

A J Moolenaar

Publications and source records attributed to A J Moolenaar.

At least 37 records · Page 2Linked to original sources
PubMed1989

Distribution of drugs over whole blood: III. The transport function of whole blood for hydrocortisone.

Hydrocortisone (HC) distribution over the three main components of blood, i.e., plasma water, plasma proteins, and erythrocytes, was studied in vitro at various HC concentrations in plasma, in a suspension of washed erythrocytes in plasma water, and in whole blood. The distribution ratio of HC in the system of erythrocytes in plasma water was 2.1 when HC, 0.18-10.8 micrograms/ml, was added. In whole blood, however, this ratio was 2.4 for the same concentration range. In the HC range of 0.18-0.68 micrograms/ml of whole blood, the uptake percentage of HC by erythrocytes increased from about 16 to 28% of the amount of HC added. By adding blank ultrafiltrate to HC-enriched blood, it appeared that the erythrocyte fraction released HC in overproportional quantities compared with the release by plasma proteins. Similar findings have previously been reported regarding the drugs valproic acid and phenytoin. Migration of HC from HC-spiked plasma to blank erythrocytes reached an equilibrium within 5 min.

Blood Proteins↗
PubMed1987

Paget's disease of bone: early and late responses to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD).

Early and late responses to treatment with either oral (600 mg/day) or intravenous (20 mg/day) (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (aminohydroxypropylidene bisphosphonate; APD) were studied in 142 patients with Paget's disease of bone who had not previously been treated with bisphosphonate. The efficacy of three therapeutic regimens was compared: (a) oral aminohydroxypropylidene bisphosphonate given continuously until six months after the serum alkaline phosphatase activity had returned to normal (long term); (b) oral aminohydroxypropylidene bisphosphonate given until urinary hydroxyproline excretion had returned to normal (short term); (c) intravenous aminohydroxypropylidene bisphosphonate for 10 days. With either oral or intravenous treatment the decrease in urinary hydroxyproline excretion was rapid and always preceded the fall in serum alkaline phosphatase activity. Normal urinary hydroxyproline excretion is essential for return of the serum alkaline phosphatase activity to normal. Complete biochemical remission, defined as return of the serum alkaline phosphatase activity to normal, was obtained in 129 patients (91%). The median duration of remission as assessed by actuarial analysis was 2.7 years. This study found no difference in the long term among the three modes of treatment, suggesting that for most patients with Paget's disease a short course of intravenous aminohydroxypropylidene bisphosphonate will produce longlasting, complete remission without need for maintenance treatment.

Administration, Oral↗
PubMed1987

DNA ploidy and survival in breast cancer patients.

Flow cytometric DNA ploidy measurements using frozen or deparaffinized tumor specimens were performed on 565 primary breast cancers from patients treated in the period 1975-1984. Twenty-nine percent of the cases were diploid, 61% had a single aneuploid stemline, and 10% were multiploid. Aneuploid tumors more often had negative estrogen receptor values than diploid tumors, but no significant correlation was found between ploidy class and TNM stage. Patients with more than ten positive axillary lymph nodes had predominantly aneuploid tumors. Overall and distant relapse-free survival were higher for patients with diploid tumors and low-aneuploid tumors. Stratification of the patients according to degree of lymph node involvement, TNM stage, and menopausal stage showed that the prognostic effect of aneuploidy was apparent predominantly in patients with locally advanced disease. Postmenopausal node-positive patients with diploid tumors had a significantly better prognosis than those with aneuploid tumors, but this difference was not found for the comparable premenopausal group. Multivariate analysis with the Cox proportional hazards model indicated that ploidy is an additional, independent prognostic factor in postmenopausal patients.

Aneuploidy↗
PubMed1987

Interference by cyclosporine with the endocrine function of the canine pancreas.

This study addresses itself to the eventual interference of cyclosporine (CsA) with the function of pancreatic beta cells in vivo. We have used dogs that had at least six weeks previously been subjected to segmental pancreatic autotransplantation. This model has been well established to be associated with stable normoglycemia but with incomplete endocrine reserve capacity, which renders it suitable for detecting eventual toxic drug effects. CsA was administered for 6 weeks in an oral dose of either 30 mg/kg/day (first series of 4 dogs) or 40 mg/kg/day (second series of 7 dogs). CsA trough levels in blood were determined at least weekly, and the mean of the levels in each dog ranged from 218 to 1274 ng/ml, with one exception (2191 ng/ml). The endocrine function was tested not only before and after 6 weeks of CsA administration, but also at 4 weeks after cessation of CsA administration. The postprandial insulin output was reversibly reduced in the first series (P less than 0.05) and the i.v. glucose-stimulated insulin output was reversibly reduced in the second series (P less than 0.001). Other parameters, like postprandial peak and mean blood glucose levels and K-values, showed reversible changes that, although not always statistically significant, were compatible with a reversible suppressive effect by CsA in all instances. Finally, we found that the severity of suppression as expressed in individual reduction of i.v. glucose-stimulated insulin output correlated with the individual mean CsA trough level (r = 0.71, P less than 0.015). It is concluded that CsA exerts a detrimental effect on the function of canine beta cells in vivo, which effect is reversible and dependent upon the CsA blood level.

Animals↗
PubMed1987

Systemic availability of o,p'-DDD in normal dogs, fasted and fed, and in dogs with hyperadrenocorticism.

The systemic availability of o,p'-DDD was studied in 12 normal dogs and seven dogs with pituitary-dependent hyperadrenocorticism (PDH). The drug was given by mouth at 50 mg kg-1 and plasma o,p'-DDD concentrations were determined by gas-liquid chromatography. First, six normal dogs were given the drug three times at intervals of one week in a Latin square pattern. Systemic drug availability was found to be very poor from intact tablets in fasted dogs, better with pure drug dissolved in maize oil given by stomach tube, and best with ground tablets mixed in oil poured on dog food. Then six normal dogs and five with PDH were given one dose of o,p'-DDD as intact tablets in dog food. Systemic drug availability was good in the normal animals and, for unknown reasons, better in dogs with PDH. The half-time of elimination was shorter in dogs with PDH than in normal ones. There was evidence of a gradual rise in plasma o,p'-DDD concentrations in seven dogs with PDH treated with 25 mg kg-1 every 12 hours for 14 or 20 days. The interaction between food and o,p'-DDD probably contributes to the variation in clinical response of dogs treated with the drug. The efficiency of therapy with o,p'-DDD should be improved considerably by administering the drug with food.

Administration, Oral↗
PubMed1986

Computed tomography in untreated adults with virilizing congenital adrenal cortical hyperplasia.

Thirteen adult patients with biochemically proven congenital adrenal hyperplasia (CAH) were examined by computed tomography (CT). Six patients had never received glucocorticoid therapy. In three of those six patients, CT revealed a tumorous transformation in one of the hyperplastic adrenal glands. In the seven patients with CAH who were treated since childhood, no mass could be demonstrated on CT. The development of an adrenocortical tumour due to chronic adrenal cortical stimulation by excessive adreno-cortico-trophic hormone (ACTH) production in adult patients with untreated CAH may not be a rare occurrence, as is demonstrated in this series. It is important not to confuse this entity with a primary virilizing adrenal tumour which requires a different form of treatment. In case of tumorous transformation in untreated adults with CAH, suppressive therapy with CT control should be favoured over surgery, as long as the tumour is ACTH-dependent. Moreover, these observations illustrate the desirability of lifelong glucocorticoid therapy in patients with CAH, including adult males who biochemically may not require suppression of steroid androgen excess.

Adrenal Hyperplasia, Congenital↗
PubMed1985

Morphologic characteristics of benign and malignant adrenocortical tumors.

Differentiation between benign and malignant tumors of the adrenal cortex was studied by means of seven histologic parameters. Each separate criterion was significantly different in two groups, one consisting of patients without metastases within 10 years after operation and one of patients with metastatic tumors. Discrimination on the basis of single parameters in individual patients, however, was of little value. When a histologic index was calculated using the same parameters but after "weighing," a much better discrimination was obtained. The histologic index and, to a lesser degree, the mitotic activity seems to be related to the survival time of the patients with adrenal cortical carcinoma. The authors conclude that the calculation of a histologic index based on a summation of different parameters makes it possible to differentiate between malignant and benign adrenal cortical tumors. As single parameters, tumor weight and mitotic activity have the highest discriminating value.

Adrenal Cortex Neoplasms↗
PubMed1985

o,p'-DDD (mitotane) treatment for Cushing's syndrome: adrenal drug concentration and inhibition in vitro of steroid synthesis.

o,p'-DDD is an inhibitor of adrenal steroid synthesis currently used for therapy of Cushing's syndrome. Conflicting data have been published on the relationship between the plasma level of the drug and its clinical and biological effects. The levels of o,p'-DDD and o,p'-DDE in various tissues obtained from treated patients have been measured and are compared with data on in vitro steroidogenesis in adrenal tissues from the same patients. o,p'-DDD was found in all samples and o,p'-DDE in half of them, both levels being high when the tissue lipid concentration was high. There was considerable variability in lipid content from one tissue to another and within a tissue from one sample to another; only the drug to lipid ratio seems able to provide a reproducible index of drug entry into a tissue. No relationship was found between the tissue concentration of the drug and the total dose administered or inhibition of the steroid biosynthetic step studied.

17-alpha-Hydroxyprogesterone↗
PubMed1985

Interaction between digoxin and nifedipine at steady state in patients with atrial fibrillation.

The possible kinetic and hemodynamic interactions between digoxin and nifedipine were evaluated in nine patients with atrial fibrillation who were receiving chronic digoxin. After 2 control weeks, nifedipine (20 mg b.i.d.), in a new formulation with sustained release characteristics, was added to the therapeutic regimen for 2 weeks. Trough serum digoxin concentrations and peak nifedipine concentrations were determined repeatedly. On the same days, resting blood pressure and heart rate were measured. During nifedipine administration, serum digoxin levels increased by 15% from 0.87 +/- 0.38 to 1.04 +/- 0.37 ng/ml (mean +/- SD, p less than 0.05). This was accompanied by a reduction in systolic and diastolic blood pressure of 16 +/- 6 (p less than 0.01) and 12 +/- 5 mm Hg (p less than 0.001), respectively. In two patients, noncardiac side effects were reported. In two other patients, nifedipine was discontinued because of skin rash and severe headache, respectively. In conclusion, plasma digoxin levels were elevated slightly in the presence of nifedipine, but this probably has little clinical relevance.

Adult↗
PubMed1985

Pharmacokinetics and nephrotoxicity of cyclosporine in renal transplant recipients.

Pharmacokinetics of Cyclosporine (CsA) were studied in 14 renal transplant patients during a three-month period of treatment. At 3 and 15 days after transplantation 12-hr blood level studies of the drug were performed to calculate the elimination half-life, area under the curve (AUC), and total blood clearance; trough levels were measured twice weekly. In 9 patients terminal half-lives could be calculated after discontinuation of CsA treatment. In the course of CsA treatment, prolongation of half-life was found in most cases, with a significant decrease in clearance (46 +/- 17 L/hr on day 3 versus 28 +/- 10 L/hr on day 15). This resulted in a continuous increase in the CsA blood level. The terminal half-life varied considerably among the patients (24-93 hr) and did not correlate with other pharmacokinetic parameters. A good correlation (r = 0.9589) was observed between CsA trough levels before discontinuation of CsA and the increment in renal function two weeks after conversion to azathioprine. This indicates that short-term CsA treatment induces a dose-dependent reversible nephrotoxic effect in renal transplant recipients.

Adult↗
PubMed1984

Female pseudo-hermaphroditism due to an adrenal tumour in the mother.

This is a report of a case of almost complete external virilisation of a girl due to an adrenocortical adenoma of the mother. The tumour, though present for many years, caused only mild symptoms in the mother; therefore detection followed only after birth of the virilised girl.

Adenoma↗
PubMed1984

The treatment of adrenocortical carcinoma with o,p'-DDD: prognostic implications of serum level monitoring.

Thirty-four patients with adrenocortical carcinoma were treated with o,p'-DDD. Twenty-eight patients presented with metastases at entry, and spillage of tumour cells occurred at surgery in 6 other patients. Eight patients had objective tumour regression, of whom 7 had serum levels over 14 micrograms/ml. The 3 patients with a lasting remission had levels of greater than 15, greater than 25, greater than 25 micrograms/ml respectively during prolonged periods. Increased survival times were found in the group of 14 patients with o,p'-DDD serum levels higher than 14 micrograms/ml when compared with patients not treated after discovery of metastases. In the patients with levels less than or equal to 10 micrograms/ml no therapeutic effect was seen. Levels of over 20 micrograms/ml are associated with symptoms of reversible neuromuscular toxicity. Monitoring of serum levels during treatment is mandatory. It is suggested that serum levels of about 25 micrograms/ml during longer periods may be curative.

Adrenal Cortex Neoplasms↗
PubMed1984

Apparent mineralocorticoid excess and deficient 11 beta-oxidation of cortisol in a young female.

A 19-year-old female, known to have had hypertension and hypokalemic alkalosis since the age of 9 months, was found to have suppressed renin, negligible plasma and urinary aldosterone and low plasma levels of other known sodium-retaining steroids. Despite the normal plasma cortisol the urinary excretion of 17-oxosteroids and 17-oxogenic steroids was low as was the cortisol secretion rate, suggesting a diminished metabolic clearance of cortisol. This was confirmed by the demonstration of a prolonged t 1/2 of 14C-cortisol. The abnormally high urinary excretion ratios of cortisol to cortisone, tetrahydracortisol to tetrahydrocortisone and 11-hydroxy-aetiocholanolone to 11-oxy-aetiocholanolone indicate that the diminished cortisol breakdown is the result of deficient 11 beta-oxidation. Moreover, the urinary excretion of free cortisol was elevated, probably due to diminished tubular reabsorption of cortisol. Hypokalemic alkalosis did not respond to spironolactone, but was partly corrected by amiloride. No response to dexamethasone was observed, but dexamethasone combined with aminogluthetimide normalized blood pressure and serum K. These findings support the involvement of a sodium-retaining, kaliuretic steroid in this rare syndrome.

Adrenocorticotropic Hormone↗
PubMed1984

The influence of bromocriptine and transsphenoidal surgery on urinary androgen metabolite excretion in acromegaly.

The urinary excretion of the androgen metabolites aetiocholanolone (E) and androsterone (A) as well as DHEA, 11-hydroxy-androsterone and the cortisol metabolites 11-oxo-aetiocholanolone and 11-hydroxyaetiocholanolone in normoprolactinaemic and hyperprolactinaemic male and female acromegalics was studied and compared with that of appropriate control groups. In addition several plasma hormones were also measured. The growth hormone level in the patient group varied from 10-550 mU/l. The excretion of both 11-hydroxy-androsterone and DHEA was normal. The excretion of androsterone had decreased, while aetiocholanolone and cortisol metabolite excretion had increased. The ratio between aetiocholanolone and androsterone (E/A) excretion was significantly increased in all patient groups, but no correlation was found between the growth hormone level and the E/A ratio. Treatment with bromocriptine caused a decrease in the E/A ratio in patients with decreased growth hormone levels, but not in patients in whom the growth hormone level remained unchanged. After selective transsphenoidal removal of the pituitary adenoma the E/A ratio decreased significantly. The increased E/A ratio in untreated patients could not be attributed to eventual changes in plasma levels of cortisol, thyroxine, prolactin, testosterone or oestrogens. We therefore suggest that growth hormone is involved in androgen metabolism in acromegaly.

Acromegaly↗
PubMed1984

Image and flow cytometric analysis of DNA content in breast cancer. Relation to estrogen receptor content and lymph node involvement.

A comparative flow-cytometric and image-cytometric study was performed on 166 human breast cancers. Parallel measurements of 67 cases showed a good correlation between the DNA indices measured with each of the techniques. However, minor ploidy abnormalities were detected with flow cytometry. Only with this technique about 70% of the tumors appeared to be aneuploid. DNA profiles obtained with image cytometry frequently contained DNA values above the modal G2 value of the tumor. At least part of these broadly scattered DNA profiles resulted from multiploid tumors, as was found with flow cytometry. The mean percentage of cells with DNA contents exceeding the modal G0G1 value in image-cytometric DNA profiles (non- G0G1 cells) appeared to be highest in aneuploid lymph-node-positive (N+) tumors and lowest in near-diploid lymph-node-negative (N-) tumors. Near-diploid tumors were more frequently (70%) estrogen receptor positive (ER+) than were aneuploid tumors (50%), whereas highly aneuploid tumors with low or negative ER contents tended to be N+. Tumors with a high percentage of non- G0G1 cells value were predominantly estrogen-receptor negative (ER-).

Breast Neoplasms↗