Cyclic GMP-dependent and cyclic AMP-dependent protein kinases, protein kinase modulators and phosphodiesterases in arteries and veins of dogs. Distribution and effects of arteriovenous fistula and arterial occlusion.

Possible involvement of cyclic GMP-dependent and cyclic AMP-dependent protein kinases, protein kinase modulators and cyclic nucleotide phosphodiesterases in functions of vascular tissues were investigated in the dog. All of the above activities, localized in the smooth muscle-rich inner layer of the blood vessels, were found to be higher in the arteries than in the veins. The peripheral arteries were disproportionately richer in cyclic GMP-dependent protein kinase (as indicated by high ratios of cyclic GMP-dependent to cyclic AMP-dependent protein kinase) than were the veins, with the exception of the pulmonary artery, an atypical arterial tissue exposed to low blood pressure. Interestingly, the protein kinase ratio for the aorta, an artery with no significant role in blood pressure regulation, was not higher than that for the vena cava. Creation of femoral arteriovenous fistulae in the dogs led to preferential reductions in the cyclic GMP-dependent enzyme activity both in the proximal and distal arteries, whereas it was elevated in the stressed vein distal to the anastomotic site. The cyclic GMP-dependent enzyme was preferentially reduced in the saphenous artery distal to occlusion. Changes in the cyclic GMP-dependent enzyme activity appeared to precede gross atrophy or hypertrophy of the vessels. It is suggested that the vascular cyclic GMP-dependent protein kinase may be closely related to peripheral resistance and its regulation.

Furosemide binding to human albumin and plasma of nephrotic children.

The extent and nature of furosemide (F) binding to human albumin (HA) and to the plasma of 6 children with nephrotic syndrome were studied by equilibrium dialysis at 37 degrees C and pH 7.4 with 14C-F. At a total concentration of 3.4 mug/ml (therapeutic range), the unbound fraction of F to 4 gm per 100 ml HA was 2.79 plus or minus 0.35. The degree of binding was relatively constant from 1.8 to 36 mug/ml of F concentration. The percentage of unbound F doubled when total concentration of the drug was increased more than 130 times (1.8 to 245 mug/ml). F has two classes of binding sites (n1 = 1.42, k1 = 5.07 times 10-4 M-minus 1; n2 = 3.4, k2 = 1.58 times 10-4 M-minus 1); interaction with HA involves hydrophobic, ionic, and hydrogen forces. Acetylsalicylic acid (ASA), acetazolamide, diazoxide, phenylbutazone, sulfisoxazole (S), and tolbutamide (T) decreased F binding. Combinations of ASA, S, and T exerted a strong additive displacing effect. The binding of the F metabolite (4-chloro-5-sulfamoylanthranilic acid, CSA) was studied at 1.3 and 2.6 mug/ml. The unbound fraction was 5 times that of F. CSA did not influence F binding. Studies with plasma of 7 healthy adults showed that albumin is the only plasma protein responsible for F binding. The plasma albumin concentration range of the children with nephrotic syndrome was 0.6 to 2.1 gm per 100 ml. There was some correlation between albumin concentration and binding of F (2.8 to 9.6% unbound); this corresponded with findings with HA. Albumin concentrations lower than 2 gm per 100 ml seemed to influence the extent of the unbound fraction of F considerably.

Variations in the fate of triameterene.

Triamterene is a pteridine used therapeutically as a diuretic. In order to better understand variations in effect and toxicity of triamterence in individuals, the fate of the drug in man was investigated. Both nonradioactive and 14C-labeled forms of the drug were administered, and specific methods of analysis were used to separate the parent compound from its metabolite. Individual variation in absorption, binding, and elimination was noted. The drug was excreted in bile as well as urine. Rapid and extensive metabolism of the agent occurred after oral and intravenous doses in healthy adult men. The peak plasma levels of the drug after an oral dose (200 mg) were under 0.3 microng/ml, but the concentration of the primary metabolite. (2,4,7-triamino-6-p-hydroxyphenylpteridine) was higher. The urinary excretion of the metabolite was at least three times that of the parent drug.

Depression of renal clearance of furosemide in man by azotemia.

The renal clearance of furosemide and tetraethylammonium (TEA) were compared in 10 patients with hypertensive nephropathy. BUN and creatinine ranges were 10 to 88 mg/dl and 0.9 to 3.8 mg/dl, respectively. Diuretics were discontinued 48 hr prior to the study, and 2 consecutive clearances (ml/min/1.73 m2BSA) of creatinine were performed. The patient then received a bolus followed by a constant infusion of furosemide-14C and tetraethylammonium-14C (analyzed by specific methodology for plasma and urine), both in subpharmacologic doses. After 40-min equilibration sequential 20-min clearance periods were obtained. Both the clearance of furosemide (range 17 to 133) and TEA (range 99 to 443) correlated negatively with BUN and serum creatinine and positively with creatinine and urea clearances. Thus, by using a constant-infusion technique we demonstrated that the renal clearance of furosemide is depressed by azotemia in man and that there was greater depression with furosemide than with TEA.

A complex pattern of disposition of phenytoin in severe intoxication.

A 5-year-old child developed phenytoin (diphenylhydantoin, DPH) toxicity after receiving 500 mg of the drug daily for 3 weeks. Plasma, urine, and duodenal fluid were collected for assay of DPH and its metabolites. The peak plasma concentration of DPH was 108 mug/ml, and the decline in plasma level did not fit first-order kinetics. The para-hydroxy, meta-hydroxy, and dihydrodiol metabolites of DPH were measured in urine; duodenal aspirate contained both DPH and the para-hydroxy metabolite. Plasma pH may affect distribution of DPH since in vitro binding of DPH to human albumin increased as pH increased.

Hypertension, hyperreninemia and a solitary renal cyst in an adolescent.

Solitary renal cysts associated with hypertension and documented hyperreninemia are relatively uncommon. A 13 year old boy with these findings is described (pressure 160/120 mm Hg). Contrast studies of the urinary tract and arteriography with selective renal vein sampling demonstrated a solitary cyst in the right kidney. The ratio of plasma renin activity in the right renal vein to left renal vein (RRV:LRV) was 2.35:1. After drainage of the cyst, there was a marked reduction in both systolic and diastolic pressures (126/84 mm Hg). Hypertension has not recurred during 14 months' follow-up.

Plasma concentrations of isoniazid in children with tuberculous infections.

Six children with tuberculous infection were given their daily prescribed doses of isoniazid by the oral and the intramuscular route on different days. The plasma concentrations reached after both routes of administration were nearly equivalent. The plasma half-life of isoniazid ranged from 1.6 to 4.8 hours. The observed plasma concentrations in these children were higher than those reported in many adults. This difference is due to the larger doses of isoniazid prescribed for children.

The measurement of 3-o-methyldopamine in urine and plasma by a rapid and specific radioimmunoassay.

Antiserum against 3-O-methyldopamine (MD) was produced in rabbits immunized with MD hapten conjugated to hemocyanin. The antiserum was used to develop a radioimmunoassay (RIA) for MD. As little as 0.5 ng of MD in 0.1 ml can be detected. The major catecholamines and the phenolic aromatic amines (dopamine, norepinephrine, epinephrine, octopamine, and tyramine) and their metabolites (normetanephrine, metanephrine, homovanillic acid and 4-hydroxy-3-methxymandelic acid) did not bind significantly to the antibody. The RIA of MD was used to assay the endogenous level of MD in urine and plasma of hospitalized children. In children (7 mo to 13 yr), average concentration of MD in plasma was found to be 0.47 +/- 0.11 ng/ml, and in urine 0.15 +/- 0.05 microgram/mg of creatinine (45.0 +/- 16.3 microgram/24 hr). In children with neuroblastoma, there was a 3- to 10-fold increase in urinary excretion and plasma level of 3-O-methyldopamine. In adults, the average urine and plasma levels were found to be 87.4 +/- 3.4 microgram/24 hr and 0.6 +/- 0.2 ng/ml. The diagnostic applicability of the RIA of MD is discussed.

Congenital pulmonary lymphangiectasis. A case complicated by chylothorax.

A case is reported of an infant with features of Noonan Syndrome and congenital pulmonary lymphangiectasis. Soon after birth, persistent respiratory distress developed, and, at 4 months of ge, a chylothorax was noted. Medium chain triglyceride therapy by the enteral route was tried, but parenteral alimentation and chest-tube drainage were required. Diagnosis of pulmonary lymphangiectasis was confirmed by biopsy.

Profile of an inpatient population with a history of illicit drug use.

Using a data retrieval system, information was obtained from the records of all patients discharged over a three-year period with a primary or secondary diagnosis of illicit drug use. From 1987-1989, the number of patients and number of hospital days for patients with such diagnoses increased steadily. Seventy four percent of inpatients identified as users of illicit drugs were less than 35 years of age; this percentage was greatly influenced by the percentage (44-48%) of obstetrical patients in the population. Hospital charges for the major source of payment for the identified group exceeded $5 million in 1989. Medicaid was the major source of payment for the hospital care; the average length of hospital stay for that portion of the patients increased about 1.4 days over the three-year period. The number of hospitalized patients identified as users of illicit drugs increased over the period of study, and the population depended heavily on government sources for payment of inpatient services.

Pharmacokinetic, biliary excretion, and metabolic studies of 14C-furosemide in the rat.

1. Partition of furosemide into organic solvents at pH 3.8 was greatest for ethyl acetate (33:1) greater than 2-ethyl-1-hexanol (10:1) greater than ethyl ether (6:1). 2. Furosemide was highly bound to human, bovine, rabbit, and rat plasma or albumin (97.4-98.4%). 3. Furosemide was highly bound to rat tissues. One hour after i.p. injection of the drug, tissue to plasma concentration ratios were: adrenals (10:1), lung (4:1), kidney (4:1), spleen (3:1). 4. In rats with ligated renal pedicles, furosemide was excreted in bile, at least in part, by active transport. Hepatic clearance of a 1 mg/kg i.v. dose contributed 20% to total body clearance. Large doses (50 mg/kg and more) of furosemide exerted a choleretic effect. 5. Chromatography of bile showed that i.v. administration of 50 mg/kg and higher doses of furosemide to rats resulted in saturation of hepatic drug metabolism. 6. The bile of rats contained the parent drug, 4-chloro-5-sulphamoyl-anthranilic acid, and at least two unknown metabolites with the furan ring intact.

Management of clonidine ingestion in children.

Six cases of toxic ingestion of clonidine hydrochloride are reviewed. Apnea, respiratory depression, and rhythm disturbances were more frequent in our patients than in those previously reported; hypotension and bradycardia occurred at a similar frequency. Satisfactory management consisted of close attention to vital signs and judicious treatment of specific physiologic abnormalities. Atropine effectively corrected bradycardia. Tolazoline was found to be ineffective in reversing symptoms and signs of clonidine overdosage. Hypotension was managed by volume expansion, and if necessary, by a continuous infusion of dopamine. Naloxone, although not used in our patients, may be of both diagnostic and therapeutic value in treating clonidine overdosage.