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Annamycin (Ann) is a lipophilic and non-cross-resistant anthracycline antibiotic currently in clinical development as a liposomal formulation (L-Ann) composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG). Previous studies have demonstrated that the incorporation of Ann into these liposomes prolongs its terminal serum half-life and increases the tumor levels of the drug. However, an explanation for the altered pharmacokinetics and pharmacodynamics of doxorubicin and Ann when entrapped into these multilamellar lipid vesicles remains unknown. Since the distribution of lipophilic compounds within plasma lipoproteins has been shown to influence the pharmacokinetics and organ distribution of a number of lipophilic compounds and this distribution appears to be regulated by lipid transfer protein (LTP), we studied the distribution of Ann and L-Ann among plasma lipoproteins and the influence of LTP on the distribution of Ann and L-Ann among plasma lipoproteins. Our results concluded that when Ann was incorporated into liposomes composed of DMPC and DMPG, over 65% of the initial Ann concentration would distribute into the high density lipoprotein (HDL) fraction and that free Ann and L-Ann distribution within human plasma was independent of LTP activity. In addition, we observed that the increase in total plasma triglyceride (TG) concentrations (through the increase of very low-density lipoproteins (VLDL)) resulted in the increase distribution of Ann and L-Ann within the TG-rich VLDL fraction. However, increasing the VLDL core TG/cholesterol ratio decreased Ann distribution into VLDL. These findings suggest that initial Ann distribution is regulated by a mechanism that does not involve LTP, but through its interaction with plasma VLDL-TG.(ABSTRACT TRUNCATED AT 250 WORDS)
A method for plasma prekallikrein determination utilizing a chromogenic tripeptic substrate is presented. The method has a good reproducibility and can easily be automized. Several parameters have been optimized. By using mixtures of deficient plasmas and pooled normal plasma or purified factors it was proved that prekallikrein was the factor determined and that more than 10% (of normal plasma concentration) of FXII and HMW kininogen were essential for the activation of prekallikrein in our method. Further experiments showed that the method was fairly selective and was not influenced by inhibitors present in normal plasma. The later finding was attributed to the high dilution of plasma made possible by using a potent activator and a sensitive substrate.
Recent studies have shown that technetium 99m mercaptoacetyltriglycine (MAG-3) is a suitable replacement for iodine 131 or 123 hippurate in gamma-camera renography. Also, the determination of its clearance is of value, since it correlates well with that of hippurate and thus may be an indirect measure of renal plasma flow. In order to simplify the clearance method we developed formulas for the estimation of plasma clearance of MAG-3 based on a single plasma sample and compared them with the multiple sample method based on 7 plasma samples. The correlation to effective renal plasma flow (ERPF) (according to Tauxe's method, using iodine 123 hippurate), which ranged from 75 to 654 ml/min per 1.73 m2, was determined in these patients. Using the developed regression equations the error of estimate for the simplified clearance method was acceptably low (18-14 ml/min), when the single plasma sample was taken 44-64 min post-injection. Formulas for different sampling times at 44, 48, 52, 56, 60 and 64 min are given, and we recommend 60 min as optimal, with an error of estimate of 15.5 ml/min. The correlation between the MAG-3 clearances and ERPF was high (r = 0.90). Since normal values for MAG-3 clearance are not yet available, transformation to estimated ERPF values by the regression equation (ERPF = 1.86 x CMAG-3 + 4.6) could be of clinical value in order to compare it with the normal values for ERPF given in the literature.
Experimental data suggest the possibility that common bronchodilators, such as the xanthines and beta 2-adrenoceptor agonists, may produce microvascular anti-permeability effects in the subepithelial microcirculation of the airways. In this study, we have examined the effect of bronchodilators given intravenously on exudation of different-sized plasma proteins (albumin and fibrinogen) and the generation of plasma-derived peptides (bradykinins) in human nasal airways challenged with histamine. In a double-blind, crossover, placebo-controlled and randomised trial, 12 normal volunteers were given i.v.infusions of terbutaline sulphate, theophylline and enprofylline to produce therapeutic drug levels. The effect of topical nasal provocation with histamine was closely followed by frequently nasal lavage with saline. The lavage fluid levels of albumin, fibrinogen and bradykinins increased significantly after each histamine provocation. The ratio of albumin-to-fibrinogen in plasma and the lavage fluid was 24 and 56, respectively, indicating that topical histamine provocation induced a largely non-sieved flux of macromolecules across the endothelial-epithelial barriers. The systemically administered drugs did not affect the nasal symptoms (sneezing, secretion and blockage), nor did they significantly reduce the levels of plasma proteins and plasma-derived mediators in the nasal lavage fluids. The present data suggest that systemic xanthines and beta 2-adrenoceptor agonists, at clinically employed plasma levels, may not affect the microvascular (and epithelial) exudative permeability and the bradykinin forming capacity of human airways.
Tetrahydrobiopterin is essential for brain cells to make monoamine neurotransmitters. It has been reported that the concentrations of tetrahydrobiopterin in plasma and urine are low in certain mental disorders and that oral supplements are beneficial. A group of Japanese investigators have been conducting clinical trials of the effect of administration of tetrahydrobiopterin to autistic children and reported that it is beneficial with no significant side effects. We, therefore, initiated a study to assess plasma and urinary levels of tetrahydrobiopterin in infantile autism to see if they are reduced. Besides tetrahydrobiopterin, we also determined plasma and urinary levels of neopterin and monapterin in these individuals in order to evaluate the status of dihydroneopterin triphosphate, a key biosynthetic precursor of tetrahydrobiopterin. Sixteen autistic children and 12 healthy controls were included in this study. Results indicated that the plasma and urinary levels of tetrahydrobiopterin are not statistically different between the two groups and, therefore, no simple explanation for the beneficial effects of administration of tetrahydrobiopterin on autistic children can be offered at the present time. In contrast, plasma and urinary levels of neopterin were depressed (.01 less than p less than .05) and plasma monapterin was also significantly depressed (p less than .01) in autistic subjects compared with controls. Levels of other pterins, including folate, were not statistically different between the two groups. The basis for this depression in neopterin and monapterin is unknown. It does not seem likely that this depression could be attributed to a difference in age or T-lymphocyte/macrophage activity. However, further studies are needed to investigate these possibilities.
In 16 experiments on 4 healthy subjects, the effect of procedures which alter blood glucose, ie, infusion of 0.2 units/kg body wt/hr insulin and/or 0.66 g/kg body wt/hr glucose, on gastric acid secretion, plasma gastrin, and plasma osmolality was studied, Each subject underwent four different experimental procedures, each lasting 4 hr. All had in common one basal hour and the infusion of insulin in the second hour, but differed in the time of infusion of glucose or isotonic saline. To control for order effects, the four procedures were applied to the subjects in the form of a Latin square. Acid output was measured continuously be means of intragastric titration and a telemetering capsule; blood glucose, plasma gastrin, and plasma osmolaity were determined in 15-min intervals. An inverse relationship between blood glucose and acid output was found: Low glucose levels were associated with high rates of acid secretion, high glucose levels with low acid secretion. No noticeable changes occurred in either plasma gastrin or plasma osmolality. These results reveal a determining influence of blood glucose levels on acid secretion. On the basis of earlier work in animals it is concluded that this influence is exerted via the reciprocal activities of the hypothalamic satiety and feeding centers.
This study examined the postoperative plasma endotoxin level, plasma endotoxin inactivation capacity and clinical outcome after administration of an enteral diet supplemented with glutamine, arginine and omega-3-fatty acid in patients undergoing gastrointestinal operations on an prospective, randomized and double-blind design. 40 patients undergoing gastrointestinal operations were randomized into two groups, with each having 20 patients. One group received standard enteral nutrition and the other was fed the formulation supplemented with glutamine, arginine and omega-3-fatty acid. The two groups were isonitrogenous. The infusion was started from day 1 after surgery and continued for 7 days. Blood samples were collected on the morning of day 1 before operation and on the morning of 1, 4 and 7 day(s) after operation and analyzed for plasma endotoxin level and endotoxin inactivation capacity (EIC). Our study found no differences between the two groups on plasma endotoxin level. After surgery a rapid reduction in plasma endotoxin inactivation capacity was observed in both groups, a significant recovery of the plasma endotoxin inactivation capacity was observed on morning of day 4 after surgery in the study group (0.12 +/- 0.02 EU/mL and 0.078 +/- 0.022 EU/mL respectively, P < 0.01). Shortened hospital stay was observed in the experimental group (11.7 +/- 2.0 days in the control group and 10.6 +/- 1.2 days in the experimental group respectively, P = 0.03). It is concluded that perioperative parenteral nutrition supplemented with glutamine, arginine and omega-3-fatty acid ameliorated postoperative immunodepression but without direct effect on endotoxemia.
The effects of starvation and refeeding on intestinal cell proliferation at several sites of the rat gastrointestinal tract were studied and used as a model of altered cell proliferation in order to investigate the relationship between the rate of cell production and plasma gastrin and enteroglucagon. There was a marked fall in crypt cell production rate after four days starvation, with the proximal sites of the gut being most affected. The response to refeeding varied with site, suggesting that there was more than one mechanism for the control of intestinal cell proliferation. Plasma gastrin and enteroglucagon both fell to one fifth of their control level after starvation. Plasma gastrin increased slowly after refeeding, whilst plasma enteroglucagon increased rapidly to values significantly above control. Plasma gastrin was only correlated with crypt cell production in the duodenum, while plasma enteroglucagon was correlated with crypt cell production rate at several sites, indicating that enteroglucagon may be involved in the control of intestinal cell production.
In mammals the composition of milk changes during early lactation, with a rapid decline of fat-soluble vitamins and a continuous increase in total lipids. The mechanisms underlying this phenomenon are not well understood, but might involve selective mechanisms related to mammary uptake or secretion into the milk. Since carotenoids are specifically distributed among the lipoprotein fractions in plasma, the simultaneous determination of carotenoids in plasma, lipoprotein fractions and milk might offer an opportunity to gain insight into this phenomenon. In 21 healthy mothers carotenoids in plasma and lipoprotein fractions were investigated at day 2 and 19 and milk on day 4 and 19 after delivery. Plasma levels of alpha-tocopherol and cholesterol as well as lutein, zeaxanthin and cryptoxanthin were significantly lower later in lactation (day 19) than shortly after birth (P < 0.01). The stage of lactation had no effect on the distribution of carotenoids and alpha-tocopherol among the plasma lipoprotein fractions. In milk, triacylglycerol increased (P < 0.01). In contrast, levels of carotenoids, alpha-tocopherol and vitamin A were highest in colostrum and declined (P < 0.01). Because the magnitude of decrease was not the same in all carotenoids, the carotenoid pattern changed substantially. In colostrum the carotenoid pattern resembled those of plasma and the low-density lipoprotein fraction. In mature milk it was similar to the pattern found in the high density lipoprotein fraction. Based on these observations a selective mechanism might be responsible for the transfer of these components in milk involving different lipoprotein fractions at specific times of lactation.
The intensity of a drug's action is related to its concentration in plasma water. Since the analytical methods for determining concentrations of drugs in plasma measure this as well as the drug bound to plasma proteins, evaluation of the binding of drugs to plasma proteins is needed for proper interpretation of drug level measurements. Anionic drugs have decreased binding in plasma from patients with renal failure. With some, such as phenytoin, a reduction is required in the levels usually considered "therapeutic" for uremic patients. Basic drugs may have normal or decreased binding. Propranolol, quinidine and tricyclic antidepressants are drugs in this class that have normal binding and that do not require changes in the plasma levels usually considered "therapeutic" for these patients.
Plasma membranes were isolated from rat liver mainly under isotonic conditions. As marker enzymes for the plasma membrane, 5'-nucleotidase and (Na+ + K+)-ATPase were used. The yield of plasma membrane was 0.6-0.9 mg protein per g wet weight of liver. The recovery of 5'-nucleotidase and (Na+ +K+)-ATPase activity was 18 and 48% of the total activity of the whole-liver homogenate, respectively. Judged from the activity of glucose-6-phosphatase and succinate dehydrogenase in the plasma membrane, and from the electron microscopic observation of it, the contamination by microsomes and mitochondria was very low. A further homogenization of the plasma membrane yielded two fractions, the light and heavy fractions, in a discontinuous sucrose gradient centrifugation. The light fraction showed higher specific activities of 5'-nucleotidase, alkaline phosphatase, (Na+ +K+)-ATPase and Mg2+-ATPase, whereas the heavy one showed a higher specific activity of adenylate cyclase. Ligation of the bile duct for 48 h decreased the specific activities of (Na2+ +K+)-ATPase and Mg2+-ATPase in the light fraction, whereas it had no significant influence on the activities of these enzymes in the heavy fraction. The specific activity of alkaline phosphate was elevated in both fractions by the obstruction of the bile flow. Electron microscopy on sections of the plasma membrane subfractions showed that the light fraction consisted of vesicles of various sizes and that the heavy fractions contained membrane sheets and paired membrane strips connected by junctional complexes, as well as vesicles. The origin of these two fractions is discussed and it is suggested that the light fraction was derived from the bile front of the liver cell surface and the heavy one contained the blood front and the lateral surface of it.
The specificity of human plasma lecithin-cholesterol acyltransferase for molecular species of phosphatidylcholine (PC) was studied by determining the molecular species composition of whole plasma before and after incubation at 37 degrees C. Since the disappearance of PC under the conditions employed is entirely due to the activity of lecithin-cholesterol acyltransferase, its specificity can be determined from the decrease in the concentration of each species after the reaction. The selectivity factor for each species was calculated by dividing its observed contribution by its concentration at zero time. The major species contributing to cholesterol esterification in whole plasma were 16:0-18:2 (46%), 18:0-18:2 (16%), 16:0-18:1 (15%), 16:0-20:4 (10%), 18:0-20:4 (5%) and 18:1-18:2 (5%). The specificity, as determined from the selectivity factors for whole plasma, was in the order: 16:0-18:2 greater than 18:1-18:2 greater than 16:0-18:1 greater than 18:0-18:2 greater than 16:0-22:6 greater than 18:0-20:4 greater than 16:0-20:4. The high-density lipoproteins (HDL) contained a significantly higher percentage of 16:0-20:4 and 18:0-20:4 and a lower percentage of 16:0-18:1 and 18:0-18:1 compared to the very-low and low-density lipoproteins. These differences disappeared after incubation of the plasma for 24 h. Using selectivity factors for HDL PCs only, the specificity of the enzyme was found to be in the order: 16:0-18:2 greater than 18:1-18:2 greater than 18:1-18:1 greater than 16:0-22:6 greater than 18:0-18:2 greater than 16:0-18:1 greater than 16:0-20:4. These results indicate that in native plasma, lecithin-cholesterol acyltransferase prefers 16:0 greater than 18:1 greater than 18:0 at the 1-position and 18:2 greater than 18:1 greater than 22:6 greater than 20:4 at the 2-position of PC.
Polyunsaturated fatty acid (PUFA) profiles and alpha-tocopherol levels were studied in human plasma and whole blood incubated with copper under air or nitrogen. In plasma, both PUFAs and alpha-tocopherol disappeared. The results were completely different in whole blood: (i) in plasma, while alpha-tocopherol decreased in the same manner as in plasma incubated alone, profiles of PUFA were only slightly modified. So, in spite of the absence of alpha-tocopherol, lipoperoxidation was not very marked. That is why the release of a protective factor from erythrocytes during hemolysis was under consideration. This was confirmed by the complete inhibition of degradation of PUFAs in plasma when hemolysate was added; (ii) In erythrocytes, no modification in PUFA profiles could be detected while alpha-tocopherol decreased slightly. Thus, not only do erythrocytes resist the copper-dependent oxidative stress in an incredible manner, but they also seem to protect plasma at the time of hemolysis.
Stereoselective hydrolysis at pH 7.5 and 37 degrees of C(+/-)P(+/-)-soman by liver homogenate and plasma from rat, guinea pig and marmoset, and by human plasma is studied by using the four single stereoisomers. The fast hydrolysis of the C(+/-)P(+)-isomers is monitored titrimetrically, whereas the decay of the much slower reacting C(+/-)P(-)-isomers is followed by gas chromatographic determination of the residual concentration. Values of Km and Vmax are evaluated for the enzymatic hydrolysis of the two relatively nontoxic C(+/-)P(+)-isomers. The plasma enzymes have a high affinity for these isomers (Km: 0.01-0.04 mM); the Km values of the liver enzymes vary between 0.04 and 0.7 mM. Except for rat liver homogenate, only first-order rate constants can be obtained for catalyzed hydrolysis (kc) of the highly toxic C(+/-)P(-)-isomers: most measurements with C(+/-)P(-)-isomer concentrations greater than 0.3 mM are complicated by epimerization to C(+/-)P(+)-isomers, which may conceal enzyme saturation with the C(+/-)P(-)-isomers. The first-order rate constants of catalyzed hydrolysis (Vmax/Km or kc) by all liver homogenates and plasmata decrease in the order: C(+)P(+)- greater than C(-)P(+)- much greater than C(-)P(-)- greater than C(+)P(-)-soman. The highest P(+)-/P(-)-stereoselectivity is found for rat plasma. Rat liver homogenate is more potent than the other liver homogenates in catalyzing the hydrolysis of both the C(+/-)P(+)- and the C(+/-)P(-)-isomers. Rat plasma shows the highest activity for degradation of the C(+/-)P(+)-isomers, but is approximately as active as marmoset and human plasma for degradation of the C(+/-)P(-)-isomers.
Electrolytic lesions of the parabrachial nucleus (PBN) caused significant increases in basal plasma renin activity (+433%) and basal plasma norepinephrine concentration (+98%) in conscious rats. Plasma epinephrine concentration, mean arterial pressure, heart rate, hematocrit, plasma osmolality and plasma sodium and potassium concentrations were not significantly affected by the lesions. Atenolol reduced the elevated plasma renin activity in the lesion group to a value similar to that of a control group (sham lesions or lesions in areas adjacent to the PBN). Captopril significantly lowered mean arterial pressure in the lesion group, but it had no effect on arterial pressure in the control group. Lesions of the PBN also increased the baroreflex-mediated bradycardia evoked by an abrupt elevation of arterial pressure. We propose that the PBN tonically inhibits sympathetic activity, sympathetically mediated renin release and baroreflex sensitivity.
Plasma lecithin:cholesterol acyltransferase (LCAT) concentration has been shown to be higher in women than in men, suggesting that sex hormones may influence LCAT metabolism. In order to explore this possibility, the associations of plasma LCAT concentration with the concentrations of total, free and protein-bound testosterone, 5 alpha-dihydrotestosterone and oestradiol in plasma, and with total androstenedione concentration in plasma, were examined in 88 men aged 52-67 yr. Total cortisol in plasma was also assayed. No statistically significant correlations were observed between LCAT and androgen or oestrogen concentrations, but a weak positive association was observed between LCAT and plasma cortisol concentration (r = +0.227, p less than 0.05).
The circulating levels of the plasma androgens, testosterone and 11-ketotestosterone, and their specific binding to skin cytosol, skin nuclear extract, and plasma were determined in mature male and immature male and female brown trout during a single spawning cycle. 11-Ketotestosterone was not bound by any of the fractions examined whereas testosterone was bound with high affinity to plasma (kD = 32.6 nM), skin cytosol (kD = 16.9 nM), and skin nuclear extract (kD = 2.6 nM). The binding capacity of each fraction varied independently with time. In mature male fish an increase in specific binding of testosterone to nuclear extract, from 77 to 269 fmol mg-1 protein, occurred between September and November, coincident with peak androgen levels. Following the spawning period and the decline in androgen levels, nuclear-binding capacity in mature fish dropped to a level similar to that of immature fish by June. Nuclear binding in immature fish remained in the range 25-75 fmol mg-1 protein throughout. Plasma-binding capacity of both mature and immature fish declined during the spawning period, from 190 to 125 nM in mature fish and from 360 to 125 nM in immature fish. Plasma-binding capacity in both mature and immature fish increased following spawning to reach levels of 340 nM (mature) and 250 nM (immature). Little change was observed in cytosol-binding capacity of either mature or immature fish. The results suggest that androgen-induced structural changes in the integument are predominantly testosterone stimulated, are initiated by an increase in the concentration of a specific testosterone-binding protein within the nucleus, may be potentiated by a drop in plasma testosterone-binding capacity, and that a cytosol-binding protein of intermediate affinity for testosterone may maintain a high intracellular concentration of steroid.