Plasma in humans

Animal data serve as the springboard to estimating a safe and effective range of doses for human therapeutic purposes. Initial doses in phase 1 studies are based on preclinical pharmacokinetic and safety data. First estimates of safe and effective drug concentrations in plasma in human studies are also based on animal data. The Clinical Studies section in the product label includes information derived from tolerance studies of the drug (phase I), pivotal human data demonstrating efficacy at a defined dose or dose range, and a description of untoward effects observed in... 

Normal Concentrations of the Major Lipid Classes in Plasma in Humans... 

Several preclinical studies, originally designed to support the above clinical trials, have been carried out. From these it was determined that m-THPC is not metabolized in vivo and virtually all the drag is eliminated via the liver. Pharmacokinetic data derived from animal studies with m-THPC led to the prediction that this substance would show rapid clearance from plasma in humans. Surprisingly, however, this was only observed in the animal models (dog, rabbit, rat), not in the human populations. This dichotomy stands as a cogent reminder that caution must always be exercised in translating animal-model data into human-dosing decisions [225]. 

Esler MD, Wallin G, Dorward PR, Eisenhofer G, Westerman R, Meredith I, et al. Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans. Am J Physiol 1991 260 R817-23. 

The acyl derivatives of kallikrein were prepared from porcine pancreatic kallikrein. In our experiments we used benzoyl-kallikrein. By deacylation the enzymatically active kallikrein was generated in plasma from benzoyl-kallikrein demonstrated by means of its amidolytic activity. From the time course of reactivation of benzoyl-kallikrein, a half-time of reactivation of 54 minutes was calculated. Benzoyl- kallikrein was protected from being inactivated by plasma inhibitors. Therefore, the kallikrein activity in plasma was higher after incubation with benzoyl-kallikrein than after incubation with the free enzyme. A comparatively high kinin activity was found in rabbit plasma. In human plasma, this effect was prevented by rapid degradation of kinin [42]. 

Bobba, R, Venkataraman, B, V Pais, P. and Joseph, T. (1996). Correlation between the severity of. symptoms in organo-phosphorus poisoning and cholinesterase activity (RBC and plasma) in humans. Indian J. Physiol. Pharmacol 40, 249-252. 

Gweon, B., et al. Suppression of angiogenesis by atmospheric pressure plasma in human aortic endothelial cells. Applied Physics Letters 104(13), 133701 (2014)... 

Varieties of phosphoproteins are present in blood plasma, in human saliva and in brain tissue. Brain phosphoproteins have yet to be listed and fully defined, but some appear to have a high content of phosphorylated residues. Hyperphosphorylation of some brain proteins has been associated with Alzheimer s disease. 

Munro, a. F. and Robinson, R., The catecholamine content of the peripheral plasma in human subjects with complete transverse lesions of the spinal cord, /. Physiol. 154, 244 (1960). 

History. Methods for the fractionation of plasma were developed as a contribution to the U.S. war effort in the 1940s (2). Following pubHcation of a seminal treatise on the physical chemistry of proteins (3), a research group was estabUshed which was subsequendy commissioned to develop a blood volume expander for the treatment of military casualties. Process methods were developed for the preparation of a stable, physiologically acceptable solution of alburnin [103218-45-7] the principal osmotic protein in blood. Eady preparations, derived from equine and bovine plasma, caused allergic reactions when tested in humans and were replaced by products obtained from human plasma (4). Process studies were stiU being carried out in the pilot-plant laboratory at Harvard in December 1941 when the small supply of experimental product was mshed to Hawaii to treat casualties at the U.S. naval base at Pead Harbor. On January 5, 1942 the decision was made to embark on large-scale manufacture at a number of U.S. pharmaceutical plants (4,5). 

Plasma Collection. Human plasma is collected from donors either as a plasma donation, from which the red cells and other cellular components have been removed and returned to the donor by a process known as plasmapheresis, or in the form of a whole blood donation. These are referred to as source plasma and recovered plasma, respectively (Fig. 1). In both instances the donation is collected into a solution of anticoagulant (146) to prevent the donation from clotting and to maintain the stabiUty of the various constituents. Regulations in place to safeguard the donor specify both the frequency of donation and the volume that can be taken on each occasion (147). 

Histamine in the Blood. After its release, histamine diffuses rapidly into the blood stream and surrounding tissues (12). Histamine appears in blood within 2.5 min after its release, peaks at 5 min, and returns to baseline levels by 15 to 30 min. In humans, the diurnal mean of plasma histamine levels is 0.13 ng/g. In urine, elevations of histamine or metaboUtes are more prolonged than plasma elevations. Consequendy, abnormahties are more easily detected by urinary histamine assay. About one-half of the histamine in normal blood is in basophils, one-third in eosinophils, and one-seventh in neutrophils the remainder is distributed among all the other blood components. Increases in blood histamine levels occur in several pathological... 

Mifepristone. After oral adininistration, peak plasma levels of mifepristone (84) (RU 486) are reached in 1 h and over 95% was bound to plasma proteins (351,352). The plasma half-life of RU 486 is approximately 24 h (352,353). In humans, monodemethylated (98), didemethylated (99) and alcohoHc nondemethylated (100) metaboHtes of RU 486 have been identified (351). These metaboHtes show some progestin-binding affinity, approximately five to ten times lower than that of RU 486 itself. RU 486 and its metaboHtes can be measured by radioimmunoassay and hplc (353,354). 

Florfenicol has a wide tissue distribution, similar to that reported for chloramphenicol in calves and thiamphenicol in humans (43,44). Chloramphenicol attains concentrations higher than the corresponding plasma concentrations in bile and urine, as does florfenicol (43). Unlike florfenicol, chloramphenicol concentrations in the Hver, kidney, spleen, and lungs are less than corresponding plasma concentrations. However, chloramphenicol penetrates the brain and CSF much better than does florfenicol, reaching values equal to plasma concentrations in the brain. The distribution of thiamphenicol into the kidney, urine, and muscles of humans compared with corresponding plasma concentration is similar to what was observed for florfenicol in calves (44). The penetration of thiamphenicol into the CSF is much smaller than that of florfenicol in calves. 

An hplc assay was developed suitable for the analysis of enantiomers of ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory dmg (NSAID), in plasma and urine (59). Following the addition of racemic fenprofen as internal standard (IS), plasma containing the KT enantiomers and IS was extracted by Hquid-Hquid extraction at an acidic pH. After evaporation of the organic layer, the dmg and IS were reconstituted in the mobile phase and injected onto the hplc column. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (chiral AD) with hexane—isopropyl alcohol—trifluoroacetic acid (80 19.9 0.1) as the mobile phase pumped at 1.0 mL/min. The enantiomers of KT were quantified by uv detection with the wavelength set at 254 nm. The assay allows direct quantitation of KT enantiomers in clinical studies in human plasma and urine after adrninistration of therapeutic doses. 

Plasma levels of 3—5 p.g/mL are obtained two hours after adraiinistration of 200 mg ketoconazole. No accumulation in the bloodstream was noted after a 30-wk treatment with this dose. The half-life is approximately eight hours. When ketoconazole is taken with meals, higher plasma levels are obtained. Distribution studies using radioactive ketoconazole in rats show radioactivity mainly in the Hver and the connective tissue. Radioactivity is also present in the subcutaneous tissue and the sebaceous glands. After one dose of 200 mg in humans, ketoconazole is found in urine, saUva, sebum, and cenimen. Like miconazole, the mode of action is based on inhibition of the cytochrome P-450 dependent biosynthesis of ergosterol. This results in disturbed membrane permeabiUty and membrane-bound enzymes (8,10,23,25). 

Erythrocyte Entrapment of Enzymes. Erythrocytes have been used as carriers for therapeutic enzymes in the treatment of inborn errors (249). Exogenous enzymes encapsulated in erythrocytes may be useful both for dehvery of a given enzyme to the site of its intended function and for the degradation of pathologically elevated, diffusible substances in the plasma. In the use of this approach, it is important to determine that the enzyme is completely internalized without adsorption to the erythrocyte membrane. Since exposed protein on the erythrocyte surface may ehcit an immune response following repeated sensitization with enzyme loaded erythrocytes, an immunologic assessment of each potential system in animal models is required prior to human trials (250). 

DETERMINATION OF CLARITHROMYCIN IN HUMAN PLASMA USING RP-LC WITH ELECTROCHEMICAL DETECTION... 

A selective, sensitive and stability indicating reversed phase-HPLC method was developed for the determination of clarithromycin antibiotic in human plasma. 

Human exposure to environmental contaminants has been investigated through the analysis of adipose tissue, breast milk, blood and the monitoring of faecal and urinary excretion levels. However, while levels of persistent contaminants in human milk, for example, are extensively monitored, very little is known about foetal exposure to xenobiotics because the concentrations of persistent compounds in blood and trans-placental transmission are less well studied. Also, more information is needed in general about the behaviour of endocrine disruptive compounds (and their metabolites) in vivo, for example the way they bind to blood plasma proteins. 

Figure S.S Amino acid sequence of p strands 2 3 4 in human plasma retinol-binding protein. The sequences are listed in such a way that residues which point into the barrel are aligned. These hydrophobic residues are arrowed and colored green. The remaining residues are exposed to the solvent.

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