Hours In Plasma Research Articles

Colchicine disposition in human leukocytes after single and multiple oral administration.

Inasmuch as leukocytes were reported to be an active pharmacologic compartment, colchicine disposition was determined in plasma, granulocytes, and mononuclear cells in healthy volunteers after 1 mg oral single and multiple doses. After the single dose, maximal colchicine concentration was observed at 1 hour in plasma and 47 hours later in leukocytes. This delay was confirmed by the slow accumulation of colchicine by lymphocytes in culture. In the multiple-dose study, mean granulocyte colchicine concentration (20 to 53 ng/10(9) cells) were twofold higher than in mononuclear cells (9 to 24 ng/10(9) cells). Mean predicted colchicine multiple-dose granulocyte and mononuclear cell concentrations were 2.5-fold and ninefold higher, respectively, than those measured. After the last dose, colchicine decreased, with half-life values between 41 and 46 hours for leukocytes and 49 hours for plasma. This study validates leukocytes as a microcompartment whose kinetics correlates with colchicine biologic effects.

Intestinal ischemia-reperfusion injury causes pulmonary endothelial cell ATP depletion.

Intestinal ischemia-reperfusion is a common clinical event associated with both clinical and experimental distant organ injury. In particular, the pulmonary microvasculature appears to be susceptible to injury resulting from systemic inflammatory mediator activation. This study was designed to evaluate the hypothesis that noncellular humoral factors associated with intestinal ischemia-reperfusion result in pulmonary endothelial cell adenosine triphosphate (ATP) depletion. Male Sprague-Dawley rats had intestinal ischemia induced by microvascular clip occlusion of the superior mesenteric artery (SMA) for 120 minutes. Reperfusion resulted from superior mesenteric artery clip removal. After reperfusion for 0, 15, or 30 minutes, plasma samples were obtained from the portal vein. Monolayers of cultured rat pulmonary artery endothelial cells then were incubated with the plasma samples. Adenosine triphosphate levels were determined using a luciferin-luciferase assay. A 51Cr-release assay using labeled endothelial cells was performed under identical conditions to assess cytotoxicity. Potential mechanisms of ATP depletion were evaluated by analysis of cellular energy charge and assessment of microfilament architecture. Endothelial cell ATP levels decreased from 2.23 +/- 0.16 x 10(-11) moles/microgram DNA in sham preparations to 1.23 +/- 0.09 x 10(-11) moles/microgram DNA (p < 0.001) after 4 hours in plasma from animals undergoing 120 minutes of intestinal ischemia. For plasma obtained after 15 minutes of reperfusion, the decrease in cellular ATP concentration persisted (1.23 +/- 0.27 x 10(-11) moles/microgram DNA, p < 0.001 vs. sham). After 30 minutes' reperfusion, cellular ATP levels increased only slightly after the 4-hour incubation (1.39 +/- 0.26 x 10(-11) moles/microgram DNA, p < 0.005 vs. sham). No significant cytotoxic injury occurred in any group when compared with controls. Cellular energy charge was unchanged, and microfilament architecture was preserved. These data confirm the hypothesis that humoral factors, independent of the neutrophil, result in endothelial cell ATP depletion without metabolic inhibition or cell death. Depletion of energy stores by noncellular humoral factors may represent an early event that predisposes the cell to more severe injury by other mediators of the endogenous inflammatory response.

In vivo tissue pharmacokinetics by fluorine magnetic resonance spectroscopy: A study of liver and muscle disposition of fleroxacin in humans

Magnetic resonance spectroscopy of fluorine (19F) has been used to noninvasively study the in vivo pharmacokinetics of a model drug, fleroxacin (a fluoroquinolone antibiotic agent), in healthy human subjects. After oral administration, fleroxacin was detected in 19F magnetic resonance spectra from both liver and calf muscle and four magnetic resonance examinations were undertaken during a 24-hour period. By combining plasma analysis by high performance liquid chromatography with the magnetic resonance data, the following pharmacokinetic parameters (mean values) were obtained: tmax, 1.4, 4.6, and 5.6 hours in liver, plasma, and muscle, respectively; Cmax, 53, about 250, and about 60 mumol/L in plasma, liver, and muscle, respectively; t1/2, 4.4 hours (fast phase) and 10.8 hours (slow phase) in liver and 14.2 hours in plasma. The study documents for the first time the potential use of 19F magnetic resonance spectroscopy to noninvasively observe the time-related changes of a fluorine-containing drug in human tissues after oral administration.

Impaired thromboxane synthesis in preactivated human blood platelets: Agonist-specific, irreversible desensitization to thrombin

The causes for reduced platelet thromboxane synthesis in patients with acquired platelet storage pool disease are incompletely understood. The present study was designed to define the nature of the defect(s) underlying diminished thromboxane synthesis in human platelets previously exposed to thrombin in vitro. Platelets pretreated with high concentrations of thrombin were unable to form measurable amounts of thromboxane in response to a second stimulation with thrombin. In contrast, thrombin-pretreated platelets formed additional thromboxane in response to arachidonate, collagen, or A23,187. Thrombin pretreated platelets did not recover with respect to thrombin inducible thromboxane synthesis when incubated for two hours in plasma either in the presence or absence of added arachidonic acid. These observations suggest that neither inactivation of cyclooxygenase nor depletion of endogenous arachidonic acid is responsible for the impaired thrombin-induced thromboxane synthesis in thrombinprestimulated platelets. Impaired thrombin-induced thromboxane synthesis in these platelets may be due to agonist-specific, irreversible receptor uncoupling.

Pharmacokinetics of streptomycin with particular reference to its distribution in plasma, milk and uterine fluid of she-buffaloes.

The study elucidated the pharmacokinetics of streptomycin in healthy lactating she-buffaloes after a single intramuscular (IM) injection (10 mg/kg). The drug attained its peak concentrations of 24.39 +/- 2.67, 0.45 +/- 0.05 and 5.06 +/- 0.18 micrograms/ml at 1, 4 and 1 hour in plasma, milk and uterine fluid respectively. Calculations based on the assumption of a 2-compartment model gave a plasma t1/2 (beta) of 4.01 +/- 0.44 h and an apparent volume of distribution [Vd(area)] of 0.47 +/- 0.06 1/kg. The drug was detectable in the plasma, milk and uterine fluid for 30, 8 and 12 hours, respectively. A therapeutic concentration of the drug was maintained for 6 to 7 hours in the plasma and for around 1 hour only in the uterine fluid. However, a therapeutic level could not be achieved in milk at any time. The results suggest that the drug can be used clinically by the IM route against streptomycin susceptible systemic infections but not those in the uterus and mammary gland.

The disposition of 14C-indapamide in man.

The metabolism of 14C-indapamide labeled in the indoline ring was determined after a single oral administration of a solution (4.99 mg, 90.47 microCi) to four fasted adult male volunteers. 14C-Indapamide was rapidly absorbed, and peak blood concentrations of radioactivity occurred by 0.5 hour in three subjects and at 2 hours in one subject. The mean elimination half-lives of total radioactivity were 27.0 hours in blood and 24.5 hours in plasma. The concentration of total radioactivity in blood was 5.7 times greater than in plasma, indicating extensive binding to red blood cells. Unchanged drug, as analyzed in one subject, reached a peak concentration by 0.5 hour, and had a blood half-life of 15.8 hours. Radioactivity was primarily excreted in the urine, and more than 50 per cent of the administered radioactivity was eliminated by this route in 48 hours. By eight days, 92.8 per cent of the radioactivity was recovered, with 70.3 per cent in the urine and 22.5 per cent in the feces. 14C-Indapamide was shown to be extensively metabolized, with only 7.3 per cent of the dose excreted as unchanged drug in the urine. Systemic and renal clearances of total radioactivity were 12.8 +/- 1.3 and 8.6 +/- 0.8 ml/min, respectively, while the renal clearance of unchanged indapamide, determined for one subject, was substantially lower (1.71 ml/min).

Fibrin epsilon-(gamma-glutamyl)lysine crosslink acceleration by red blood cells.

FIBRIN, the skeletal protein of thrombi, is derived from its soluble Pl.asma precursor, fibrinogen. Fibrinogen has a molecular weight of ∼340,000. It is composed of three pairs of subunit polypeptide chains, Aα, Bβ, and γ, of molecular weights 68,000, 56,000 and 49,000, respectively, joined by disulphide bonds. The serine protease thrombin releases fibrinopeptides A and B from the amino terminal end of the Aα- and Bβ-chains of fibrinogen to leave the α- and β-chains of fibrin monomer. Fibrin monomers then align by noncovalent interactions to give a fibrin polymer gel. Under the influence of thrombin-activated factor XIII (factor XHIa, activated fibrin stabilising factor, Plasma transglutaminase) and calcium ion, covalent e-(γ-glu-tamyl)lysine crosslinks are rapidly formed between γ-chains of adjacent fibrin monomers to give the γ-dimer subunit of partially crosslinked fibrin1. The γ-crosslinking transforms the clot into a covalently bonded polymer, rendering it insoluble in 3 M urea and other agents that disrupt noncovalent interactions2. Extensive crosslinking of the α-chain to give the α-polymer subunit of fully crosslinked fibrin requires several hours in Plasma and confers relative Plasmin resistance to the clot3. We report here an increased rate and extent of α-crosslinking when red blood cells are present in the fibrin clot.

Validity of screening methods for drugs of abuse in biological fluids. II. Heroin in plasma and saliva.

Five subjects received 3 single intravenous doses of heroin, 2.5, 5, andd 10 mg per 70 kg and 1 oral dose of dextromethorphan, 60 mg per 70 kg; another 4 subjects received morphine, 30 mg, subcutaneously, 4 times per day for 3 months. Saliva and plasma samples were collected at intervals for 48 hours following each single drug dose and hourly for 6 hours between chronic doses. Plasma samples were analyzed for opiate by RIA, and saliva samples by RIA, a modified FRAT, and the EMIT. The low dose of heroin was not consistently detectable at any sampling time in either the plasma or the saliva. The medium and high doses were detectable with high probability for 2 to 4 hours in plasma and 1 to 2 hours in saliva. Dextromethorphan was not detectable in plasma hut was detected with high probability in saliva for 30 minutes by EMIT and 2 hours by FRAT. During chronic administration there were high probabilities of detection of morphine in plasma for at least 6 hours and in saliva for 3 to 4 hours after the last morphine dose. While these fluids do not appear to be as useful as urine in routine screening for herOin, they may be useful in the detection of high‐dose chronic abuse.

Red cell cholesterol depletion and the formation of spiculated cells in vivo.

Abstract Red cell cholesterol readily exchanges with plasma cholesterol and red cell cholesterol loss has been produced in vitro by depletion of the pool of plasma-unesterified cholesterol. To examine the possibility that the capacity of the plasma to solubilize cholesterol may also influence red cell-plasma cholesterol exchange, studies have been performed in which plasma cholesterol solubility has been markedly enhanced by intravascular administration of the phospholipid, lecithin. Rats infused with a sonicated dispersion of pure phospholipid for 24 hours develop grossly lactescent plasma containing greatly increased amounts of phospholipid and unesterified cholesterol. After 24 hours of phospholipid infusion, red cells are markedly altered: cells appear spheroidal and spiculated, exhibit increased osmotic fragility, and contain significantly less cholesterol. The cholesterol loss is selective and results in almost a 50 per cent reduction in the red cell cholesterol to phospholipid ratio. When normal red cells are incubated for 20 hours in plasma of high phospholipid content, selective red cell cholesterol loss of similar magnitude is produced. In vitro, red cell cholesterol depletion occurs even though the medium for incubation contains, in addition to increased phospholipid, greatly increased amounts of unesterified cholesterol. These findings would suggest that, regardless of the absolute amounts of plasma-unesterified cholesterol, red cell cholesterol loss, and possibly uptake, may be more directly regulated by the availability of solubilizing plasma components.

Creatine and phosphocreatine in the human red cell.

In vitro experiments showed that the concentration of creatine in a mixed population of normal red cells was either unchanged or slightly diminished during incubation at 37° C. for 48 hours in plasma or a buffered medium. If young cells were present there was always a fall in creatine during the early stages of incubation. Creatine lost in this way appeared in the cell‐free supernatant fluid. The ability of the red cell to retain some creatine throughout its life span is due to the relative impermeability of the cell membrane to this substance.Traces of phosphocreatine and creatine phosphokinase were detected in a population of young cells but not in mature cells. It is unlikely, therefore, that creatine takes part in energy transformations in the non‐nucleated red cell, although it may do so in an earlier phase of its development. The origin of the red‐cell creatine is obscure. Synthesis of creatine by young, non‐nucleated, red cells was not detected in vitro and its derivation from plasma creatine is considered unlikely because of the impermeability of the cell membrane. It is suggested that the creatine is acquired by the cell at some stage in its development from nucleated precursors.