Biomedical subjects
Publications and source records attributed to G W Hepner.
When prescribing mannitol to decrease intraocular pressure, the physician must be alert to potential complications. A 72-year-old woman suffered obtundation, intractable pulmonary edema, acidemia, and irreversible renal insufficiency despite vigorous hemodialysis. When renal function is compromised, careful monitoring of electrolyte levels, daily urine output, and renal function is necessary with mannitol therapy.
Aminopyrine metabolism was studied by the aminopyrine breath test in 21 control subjects, 24 patients with untreated chronic active hepatitis (CAH), 4 patients with treated CAH and 17 patients with chronic persistent hepatitis (CPH). Aminopyrine breath tests gave abnormal results in 20 of 24 patients with untreated CAH. Findings were normal in all patients with treated CAH or with CPH. This test may be helpful in discriminating between CAH and other forms of chronic hepatitis.
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In order to assess the effect of norethindrone on hepatic drug metabolism in man, hepatic N-demethylation of aminopyrine was studied by means of the aminopyrine breath test (ABT) in 7 healthy women during two menstrual cycles. Aminopyrine metabolic clearance rates were also studied in 3 women. The women were examined at the ends of the first, second, and third weeks before starting progestogen therapy and at the same times during a second menstrual cycle during which they took norethindrone, 350 microgram/day. The ABT was 5.1 +/- 1.9% (mean +/- SD) during the three control weeks and lower (p less than 0.001) during the three weeks on norethindrone, 3.9 +/- 0.9%. Aminopyrine metabolic clearance rate also fell during norethindrone therapy. The data suggest that progestogens inhibit hepatic microsomal function.
In order to assess the usefulness of nasogastric suction in acute alcoholic pancreatitis, 37 patients with alcoholic pancreatitis were prospectively investigated. The study failed to demonstrate efficacy of nasogastric suction in those patients with mild disease. Application of a system of prognostic signs proved useful in discriminating between mild and severe disease. Routine use of ultrasound examinations detected three pancreatic pseudocysts before they became clinically apparent. In instituting appropriate therapy in mild pancreatitis, factors such as patient comfort should be considered in the absence of proven significant value of nasogastric suction.
Nonthyroidal illness is frequently associated with subnormal serum thyroxine (T4) and free T4 index. To unravel the resultant diagnostic problems, we have studied several variables of thyroid function in the sera of 47 patients hospitalized with nonthyroidal illnesses and seven hypothyroid patients encountered during the same period. Of the 47 euthyroid sick patients, 18 had low T4. Among these 18, free T4 index was normal in only five, whereas free T4 concentration measured by equilibrium dialysis was normal or high in 15 and 3,3',5'-triiodothyronine (reverse T3) normal or high in all 18. Reverse T3, free T4 concentration, and free T4 index were subnormal in all seven hypothyroid patients. Thus, measurement of free T4 index may be misleading in evaluation of thyroid function in patients with nonthyroidal illnesses, whereas measurement of serum concentration of reverse T3 and free T4 is quite discriminating.
Rats pretreated with three agents known to stimulate cytochrome P-448-associated enzymes, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (3MC), and Aroclor 1254 were studied with a 14CO2 breath analysis technique after administration of [14C-dimethyl]aminoazobenzene (DMAB). The half-life of breath 14CO2 after [14C]DMAB administration was significantly decreased in the TCDD-, 3MC-, and Aroclor 1254-treated rats compared with controls. In vitro studies indicated that DMAB N-demethylase was increased by these three agents. Phenobarbital, an inducer of cytochrome P-450-associated enzymes, had no effect on 14CO2 half-life or on DMAB N-demethylase. Studies with [14C]aminopyrine, a cytochrome P-450 substrate, showed that TCDD and 3MC had no effect on 14CO2 half-life or aminopyrine N-demethylase; Aroclor 1254 and phenobarbital decreased 14CO2 half-life and stimulated aminopyrine N-demethylase. The data suggest that a [14C]DMAB breath analysis technique may be useful for in vivo studies of inducers of cytochrome P-448.
A patient with the cholestasis of Hodgkin's disease was investigated. Our studies failed to relate the cholestasis to endocrine abnormalities. The patient had severely abnormal aminopyrine metabolism, suggesting more profound hepatocellular dysfunction than had previously been appreciated.
Levels of serum triiodothyronine (T3), reverse triiodothyronine (rT3), and thyroxine (T4) were determined in 29 patients with alcoholic cirrhosis, seven patients with acute hepatitis, and 14 control patients hospitalized for chronic disease. Serum T3 levels were decreased significantly and serum rT3 levels increased significantly in the patients with alcoholic cirrhosis. Serum T3 and T4 levels were lower and rT3 levels higher in the cirrhotic patients who died within three months of the study compared with those who survived. A combination of prothrombin time, aminopyrine breath test results, and rT3 and T3 determinations gave significant predictive information about survival in patients with cirrhosis. The data suggest that assay of serum thyroid hormone levels together with prothrombin time and the aminopyrine breath test may be helpful in assessing the course and prognosis of patients with liver disease.
It is unclear whether hepatic drug metabolism which is decreased in patients with liver disease, can be stimulated by enzyme-inducing drugs. Hepatic microsomal reserve, defined as the difference between the basal and phenobarbital-stimulated ABT, was therefore studied in eight healthy control subjects and 12 patients with stable alcoholic cirrhosis. The ABT increased significantly (p less than 0.01) from a basal value of 6.1% +/- 0.8 (mean +/- S.D.) to 8.9% +/- 0.8 in the eight control subjects after phenobarbital ingestion. In the 12 patients with alcoholic cirrhosis the basal ABT was 2.9% +/- 1.5 and did not change significantly after phenobarbital ingestion, when the value was 3.0% +/- 1.6. A small increase in the ABT occurred after phenobarbital ingestion in five of the patients with alcoholic cirrhosis, but in no patient did this increase bring the ABT within normal limits. We conclude that in many patients with stable alcoholic cirrhosis aminopyrine metabolism is decreased and cannot be corrected by treatment with phenobarbital.
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The effect of immunotherapy and chemotherapy on hepatic N-demethylation of aminopyrine was studied by means of the aminopyrine breath test (ABT) in 32 patients with cancer. The aminopyrine breath test (ABT) was decreased in 3 of 11 patients (27.3%) receiving intradermal BCG (+/- DTIC) at a dose of 3 X 10(7) viable organisms. One of 4 (25%) patients receiving intradermal BCG (+/- DTIC) at 3 X 10(8) viable organisms per dose developed an altered ABT. Changes were not seen in patients receiving aerosol BCG (2 patients), and intravenous C. parvum (2 patients), subcutaneous C. parvum (3 patients), and intravenous Cyclophosphamide (2 patients). Six of 7 patients (85.7%) receiving both intravenous C. parvum and Cyclophosphamide had a decreased ABT. These data indicate that chemo-immunotherapy depressed hepatic aminopyrine N-demethylation and suggests that patients treated with chemoimmunotherapy should be carefully observed for possible alterations of hepatic drug metabolism.
In this 54 year old woman with celiac disease, osteomalacia developed while she was on a gluten-free diet which had caused regression of her steatorrhea. She was not responsive to large doses of parenterally administered dihydrotachysterol and calcium, but she was responsive to the oral administration of 25-hydroxyvitamin D3 (25-OHD3). The data suggest that 25-OHD3 is the treatment of choice for patients with vitamin D deficiency due to intestinal malabsorption.
Aminopyrine disposition was studied in 11 patients with congestive heart failure (CHF) and 15 control patients. The aminopyrine metabolic clearance rate was 29.7 +/- 7.1 ml/min (mean +/- SEM) in the patients with CHF and 125.1 +/- 5.7 ml/min (mean +/- SEM) in the control patients (p less than 0.01). The aminopyrine breath test was 2.6 +/- 0.4 per cent (mean +/- SEM) in the patients with CHF and 5.6 +/- 0.3 per cent (mean +/- SEM) in the control subjects (p less than 0.01). Probably due to fluid retention in CHF, the apparent volume of distribution of aminopyrine increased to 63.3 +/- 4.9 liters (mean +/- SEM) in patients with CHF from 43.1 +/- 1.9 liters (mean +/- SEM) in control patients, thereby further impairing aminopyrine elimination in patients with CHF (p less than 0.01). The aminopyrine breath test was measured in a group of eight patients before treatment for an acute episode of CHF and seven to 10 days after initiation of therapy: in each patient clinical improvement was associated with an increased aminopyrine breath test, mean values of aminopyrine breath test increasing from 2.8 per cent before treatment to 5.2 per cent after initiation of treatment (p less than 0.01). These results suggest that in patients with CHF hepatic drug-metabolizing activity is imparied, and the volume of distribution of drugs is increased, with consequent retardation in rates of drug elimination.
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Hepatocellular diseases, such as hepatitis, cirrhosis, or hepatic neoplasm, are associated with impaired metabolism of certain drugs, including aminopyrine, whereas cholestasis produced variable effects on aminopyrine metabolism. Reasons for the variable effects of cholestasis on hepatic aminopyrine metabolism were sought by performing in patients with hyperbilirubinemia the aminopyrine breath test (ABT), which consists of measurements of 14CO2 in breath 2 hr after oral administration of [14C]aminopyrine. Hyperbilirubinemia (total serum bilirubin less than 1.2 mg/100 ml) in these patients was due to hepatocellular disease or cholestasis. The ABT, defined as the percentage of the administered dose of 14C excreted in breath for 2 hr after [14C]aminopyrine administration, was 6.2 +/- 0.8% (mean +/- SD) in 107 control patients with normal total serum bilirubin. The ABT was severely abnormal (less than 3.1%) in 54 of 77 hyperbilirubinemic patients (70%) with hepatocellular disease and normal (greater than 4.5%) in only 5 of these patients (6%). In contrast, the ABT was severely abnormal in only 1 of 40 cases of cholestasis with hyperbilirubinemia and normal in 70% of these patients. Thus, aminopyrine metabolism is normal in most cases of hyperbilirubinemia due to cholestasis and is only rarely severely abnormal in these patients. On the other hand, severe abnormality in aminopyrine metabolism occurs in the majority of patients with hyperbilirubinemia due to hepatocellular disease. It therefore appears that the ABT may be useful in hyperbilirubinemia to distinguish patients with hyperbilirubinemia due to cholestasis form most patients with hyperbilirubinemia due to hepatocellular disease.