Cytological and cytogenetical analysis of thoracic duct lymph in patients with pulmonary carcinomas.

Seven patients with squamous cell carcinomas of the lung and nodular metastases underwent Daniels' biopsy and cannulation of the thoracic duct. Lymph specimens obtained by aspiration the day after catheter insertion were examined by cytologic and cytogenetical techniques, including chromosome banding methods. In five of the seven cases maligant cells could be detected by karyotype analysis, whereas standard cytologic examinations yielded no positive diagnoses. This indicates that chromosome analysis is applicable as a diagnostic tool in lymph fluid.

Modeling of plasma disappearance of unlabeled insulin in man.

Fifty-two portal and 68 peripheral, brief infusions of unlabeled insulin were given to ambulant, nondiabetic patients. After intraportal insulin infusion (5--50 mU/kg), plasma clearance rate (PCR, dose/area of the incremental plasma insulin concentrations) decreased with increasing dose, varying from 32 to 14 ml-min-1-kg-1 at normoglycemia. After peripheral insulin infusion (5--30 mU/kg), PCR (mean value 15 ml-min-1-kg-1) showed no certain dose-dependence, but transfer rate constants and distribution volumes did. Despite a detectable reentry of insulin from one or more extravascular pools to the plasma pool, transfer rate constants or distribution volumes could not be accurately determined. The shortcomings of conventional noncompartmental and compartmental models did not appear to be due to the dose-dependence demonstrated. Instead, the limitations of these models were caused mainly by the difficulty of defining a proper base-line concentration and, in particular, by the imprecision of the experimental data, indicating that it will be difficult to find more appropriate models from data obtained with unlabeled insulin.

Small bowel transit time and roentgenological changes of the intestinal mucosa after jejunoileostomy in obese patients.

In ten patients, operated jejunoileostomy and ileocolostmy because of longstanding obesity resistant to conventional therapy, roentgenological examinations of the small bowel were performed before and after the operation. Seven patients were examined preoperatively, and all were investigated at least twice during a period from 1 to 38 months postoperatively. Preoperatively, the passage time pylorus-cecum was 80-270 min, and postoperatively, it varied between 1 and 30 min. There was no tendency to slowing of the gastrointestinal passage with time. Immediately postoperatively, the patients had 6 to 12 loose stools daily. At investigations performed 6-38 months after the operation, the stool frequency had diminished to 1-4 a day, and the patients had lost 21 to 98 kg in weight. Roentgenologically, an increased thickness of the mucosal folds of the small bowel could be demonstrated in 9 of the 10 patients. The results suggest that in patients with jejunoileostomy, the gastrointestinal passage time is decreased. The bowel function tends to normalize with time, but the passage time remains shorter than normal. Compensatory changes in the intestinal mucosa occur.

Proscillaridin activity in portal and peripheral venous blood after oral administration to man.

The absorption of proscillaridin A was studied in four patients undergoing catheterization of the portal vein for diagnostic purposes. Proscillaridin 1.5 mg was given as a single oral dose and plasma glycoside activity was analyzed by the 86Rb-uptake inhibition technique. Proscillaridin appeared rapidly in the portal blood, peak activity being found after 15 min in three and after 30 min in one patient. In peripheral blood the peak activity occurred after approximately 35 min. Despite rapid passage across the gut wall, porto-peripheral differences in glycoside activity were small; they were zero after 4h. The mean amount absorbed as active porscillaridin during the first 4h after the dose was calculated to be only 7.1% of the given amount. Late porto-peripheral differences, probably due to enterohepatic recycling, appeared after 6h in three patients; The results suggest that proscillaridin undergoes first pass inactivation in the gut wall. Enterohepatic recirculation may contribute to the amounts of active glycoside that reach the systemic circulation.

Activities of proscillaridin A in thoracic duct lymph after single oral doses in man.

In order to study the possibility that orally administered proscillaridin after absorption is transported by the lymph to the systemic circulation, the concentrations of the glycoside in thoracic duct lymph were analyzed in two patients with thoracic duct drainage. They received the drug as a single oral dose; plasma and lymph concentrations were measured by 86Rb-technique. Lymph was collected at various intervals for 24 hrs. The proscillaridin activity in thoracic duct lymph was low and followed closely that the plasma. During the sampling period, a total of 300 ng and 240 ng, respectively, was recovered in the lymph, corresponding to less than 0.03% of the administered dose. The results indicate that proscillaridin is not transported by the thoracic duct lymph.

Scanning electron microscopy of cells in the lymph of the human thoracic duct in advanced malignancies.

At scanning electron microscopy of cells from the lymph of the thoracic duct, collected by cannulation of patients with malignant tumours of different types, lymphocytes and red blood cells were found, but few malignant cells. The latter came from patients with pulmonary carcinoma and mammary carcinoma with lung metastases. Various abnormal shapes of the red blood cells were observed, possibly due to extrinsic factors such as administered drugs of abnormal metabolites from the malignant disease. The lymphocytes had no consistent pathologic shape, but appeared to act as immunologic, active cells against the malignant cells in the thoracic lymph.

The absorption metabolism, and excretion of Estracyt (NSC 89199) in patients with prostatic cancer.

Estraumustine phosphate (estradiol, 3-N-[bis(2-chloroethyl)-] carbamate-17beta-dihydrogenphosphate (Estracyt) labeled with 3H in the estradiol moiety and 14C in the carbamate moiety was synthesized, and its absorption, metabolism, and excretion were studied after oral administration to three patients with prostatic carcinoma. One of the patients was also given the same dose by intravenous injection. In addition to monitoring isotope levels in peripheral blood, urine, and feces, samples of portal vein blood were obtained through a catheter in the umbilical vein. Analyses of portal blood samples revealed that most of the estramustine phosphate was dephosphorylated to estramustine during absorption. Estramustine was found to be the major metabolite in peripheral blood after oral as well as after intravenous administration. The urinary excretion data appeared to warrent the conclusion that most of the carbamate ester of estraumustine is hydrolyzed before it is excreted. In the patient given estramustine phosphate by both routes the absorption of the compound when given by mouth was found to be approximately 75 per cent.

Intestinal metabolism of estrogens.

Estrogen metabolism in the human intestine was studied in two ways. Firstly, by measuring the excretion of 12 estrogens in pooled human late pregnancy feces before and during the administration of ampicillin (2 g/day). Secondly, by administering 5.4 and 20 mg of 16alpha-hydroxyestrone orally to two postmenopausal women and analyzing the estrogens in simultaneously drawn portal and peripheral venous blood samples at time intervals from 0 to 150 min after steroid administration. The majority of the estrogens in normal pregnancy feces were unconjugated. The amounts of estradiol, estreon and 16-epiestriol excreted, relative to the principal estrogen estriol, were greater than in pregnancy bile or urine and 16alpha-hydroxyestrone, an important biliary estrogen, was only present in trace amounts. Considerable quantities of 15alpha-hydroxyestradiol-17beta were also found. Ampicillin administration, which decreases intestinal bacterial steroid metabolism, caused a huge increase in the fecal excretion of conjugated estrogens. In particular it caused very striking increases in the excretion of both unconjugated and conjugated, estriol, 15alpha-hydroxyestrone, 15alpha-hydroxyestradiol and 2-methoxyestrone. These findings emphasize the active role played by the intestinal microflora in estrogen metabolism under normal conditions. Administration of 16alpha-hydroxyestrone resulted in increases in portal venous unconjugated and conjugated 16alpha-hydroxyestrone, 16-oxoestradiol-17beta, 15alpha-hydroxyestrone, 16-epiestriol and conjugated estriol levels. The most significant finding in both subjects was the large increase in portal venous unconjugated 15alpha-hydroxyestrone. This would suggest that the human intestine (or intestinal contents) has the ability to carry out the transformation, 16alpha-hydroxyestrone leads to 15alpha-hydroxyestrone. Increases in the same estrogens were found in peripheral plasma, with the increase in conjugated estriol occurring in peripheral blood before it was seen in portal blood. The largest elevations in peripheral plasma values were seen in unconjugated estriol and conjugated 16alpha-hydroxyestrone in the subject who received the 20 mg dose and in unconjugated 16alpha-hydroxyestrone and 16-oxoestradiol-17beta in the subject who had the 5.4 mg dose. The intestinal and enterohepatic metabolism of estrogens is discussed in relation to these findings.

Hepatic angiography in ulcerative colitis and Crohn's disease.

Liver angiography was performed in 13 patients with Crohn's disease and three with ulcerative colitis. Of these patients, 13 underwent liver biopsy, and findings were correlated with results of angiography and biochemical tests. Twelve liver biopsies were abnormal, primarily showing fatty infiltration and reactive hepatitis. Thirteen angiographies were abnormal, with widened and tortuous liver arteries being the most common finding. Liver function tests were within normal limits for all but three of the 16 patients, thus correlating poorly with findings of the other tests. These data show that angiography is useful in detecting hepatic abnormality, but evaluation with liver biopsy is necessary to determine the nature of the lesion.

Intestinal absorption, demethylation, and enterohepatic circulation of imipramine.

The intestinal absorption and metabolism of single oral doses of imipramine (ip) have been studied in man by portal catheterization. The concentration of ip and the formed desipramine (dmi) was followed in blood-plasma obtained from the portal and cubital veins. The absorption of ip seemed to be completed 80 min after the administration of the drug. There was no sign of demethylation of ip during the passage across the intestinal wall. Evidence was found of an enterohepatic circulation of both ip and dmi.

Portal and peripheral plasma folates after ingestion of folic acid.

Folic acid in amounts of 2 mumol (0.88 mg) was given by mouth to four patients who had undergone portal vein catheterization. All had normal liver function. The increase in folates in plasma obtained from portal and peripheral veins was followed for three hours with the use of L. casei and S. faecalis as test organisms. The results lend support to the assumption that the liver is the main site of methylation of folic acid when given in physiological amounts.

Some aspects of the intestinal absorption of zinc in man.

Serum zinc concentrations in peripheral venous blood were determined in 8 healthy volunteers at various times after oral administration of 50 mg Zn++. The same dose was given to 6 patients surgically treated for obesity by jejuno-ileostomy. In the healthy volunteers the mean serum zinc concentration before dosing was 0.89 mug/ml and a mean peak concentration of 2.39 mug/ml was found after 3 h. In the patients the starting level was lower, 0.67 mug/ml, and a mean peak concentration of 1.31 mug/ml was found 90 min after treatment. In the patients the areas under the serum concentration-time curve was approximately 1/3 of that in the healthy subjects. Zn++ 50 mg was also given to 3 patients undergoing transumbilical catheterization of the portal vein for diagnostic purposes and serum zinc concentrations were measured in portal and peripheral venous blood sampled simultaneously. No significant differences were found between the concentration of zinc in portal and peripheral venous blood during absorption, which suggests slow passage of zinc across the intestinal wall.

Relationships between the concentrations of doxycycline in serum and in thoracic duct lymph after oral and intravenous administration in man.

The concentrations of doxycycline in serum and in thoracic duct lymph at various times after oral and intravenous administration of 200 mg of the drug were determined in 10 patients subjected to thoracic duct cannulation for diagnostic purposes. After oral administration, a mean peak serum concentration of 2.4 mug/ml (n=7) was obtained within 3 h; then the levels successively declined. The concentrations in thoracic lymph were lower, a mean peak concentration of 1.6 mug/ml being found 3 and 6 h after the intake. After intravenous administration (n=3), the concentrations of doxycycline in thoracic duct lymph were lower than but closely followed those in serum. The difference in concentrations between serum and lymph 1-6 h after the start of the infusion never exceeded 30%. The results suggest that doxycycline is rapidly distributed to the extracellular tissue fluids.

Pregnancy after jejuno-ileostomy because of obesity.

In four cases of pregnancy after jejuno-ileostomy because of massive obesity intestinal absorption was adequate for the nutrition of both the baby and the mother. It appears that such an operation because of obestiy does not contraindicate later pregnancy; In one case postoperative loss of body weight probably made pregnancy possible. In extremely adipose women who are for some unknown reason infertile and wish to have a child a shunt operation might perhaps be offered.

The hydrolysis and absorption of conjugated folates in man.

After ingestion of synthetic PteGlu3 in physiological doses, the folate forms were studied in plasma obtained from human vena portae blood. Plasma conjugase was inhibited by rapid heat-denaturation. The folate forms were assayed with L. casei and S. faecalis and identified by thin-layer chromatography (biautography). Mono- and diglutamic folate was demonstrated in the portal plasma, indicating that intestinal hydrolysis precedes the absorption of conjugated folates. The pteroylpolyglutamate hydrolase activity in the human gastrointestinal tract was investigated. The activity was demonstrated in gastric juice, pancreatic juice, and intestinal mucosa. The highest activity was found in the pancreatic juice with a pH-optimum of 4.5. In gastric juice the pH-optimum for the enzyme was 3 and the activity half of that found in pancreatic juice. However, in view of the volumes of these fluids produced every day, the activity at physiological pH might be enough to hydrolyse the daily intake of conjugated folates in amounts of about 500 mug.

Absorption of digoxin in man after oral and intrasigmoid administration studied by portal vein catheterization.

The absorption of digoxin has been studied in fasting patients undergoing transumbilical, portal catheterization for diagnostic purposes. A purely aqueous solution was administered orally in 4 patients and in the sigmoid colon in 2 patients. Blood samples were taken simultaneously from the portal and a peripheral vein. Plasma digoxin concentrations were determined by radioimmunoassay. Digoxin appeared early in the blood after oral administration; the average peak of porto-peripheral concentration differences was at 18 min. After intrasigmoid administration, absorption was slower, and no distinct peaks were found. Calculation of the mean amounts absorbed showed that half the dose had been absorbed via the portal vein during 2 hours in the oral study and during6 hours in the intrasigmoid test. Approximately 2/3 of the dose had been absorbed during 6 hours after oral dosing. The absorption rate was estimated taking into account the decreasing amount of drug left to be absorbed at different times. After cral administration, the mean peak rate was found to correspond to an absorption half-time of 0.78 h, which was more than 20 times faster than the rate after 6 h. The mean rate after intrasigmoid administration appeared to be about 1/3 of that after oral dosing. Physiological factors that might account for these differences in absorption rate are discussed.

Technique and complications of transumbilical catheterization of the portal vein and its tributaries.

In 120 patients who had 127 transumbilical catheterizations of the portal vein, 33 of pancreatic veins, and 15 for other portal tributaries, the surgical success rate was 91 per cent over-all, increasing to 95 per cent during the last year. Catheterization was made with the same technique as is used for arteriography. The most important complication was thrombosis of the portal vein, giving slight transient symptoms in 2 patients. Other complications were wound infection, suture granuloma, herniation in the linea alba, bleeding from the operative wound, and subintimal injections. As the technique may yield good results in studies of drug resorption, flow studies, detection of metastases, and investigation of pancreatic veins, it seems justified in suitable patients despite the complication rate. None of the complications produced lasting disability.

Superior mesenteric angiography and blood flow following intra-arterial injection of prostaglandin F2alpha.

The effect of intra-arterially administered prostaglandin F2alpha(PGF2alpha) on venous demonstration in angiography of the superior mesenteric artery was compared to that of bradykinin in 10 patients, and the flow increase in this vessel following PGF2alpha was measured by a dye dilution technique in another 8 patients. The angiographic demonstration of veins was similarly improved by the 2 drugs, the effect of 60 mug. of PGF2alpha being roughly equivalent to that of 10 mug. of bradykinin. The loss of arterial detail was less marked after PGF2alpha which, however, had a longer duration of action. The flow studies indicated that 80 mug. of PGF2alpha increased the superior mesenteric blood flow 103 +/- 16 per cent. There was no influecne on blood pressure or pulse rate. The patients experienced a sensation of warmth in the abdomen for a few seconds following the injection of drugs, but no other side effect was noted. It is concluded that PGF2alpha causes a rapid increase of the superior mesenteric blood flow in man making it suitable for pharmacoangiography of this vascular bed.