Changes in blood glucose and insulin after an oral palatinose administration in normal subjects

Changes in plasma glucose and insulin concentration in response to palatinose ingestion were compared with those to sucrose in eight normal volunteers. When 50 g of palatinose was administered, the plasma glucose gradually increased to its peak of 110.9 +/- 4.9 mg/dl at 60 min after administration and maintained a plateau during the 120 min of the experiment. The peak value of plasma glucose to 50 g sucrose in the same group was 143.3 +/- 8.8 mg/dl at 30 min after administration and then the value sharply decreased to the fasting level. The cumulative increase in plasma glucose (sigma delta PG) to palatinose was significantly smaller than that to sucrose. The changes in the plasma insulin level almost paralleled those in the plasma glucose level. These results indicate that palatinose is more slowly absorbed than sucrose and therefore useful as a sweetener for diabetic patients.     

Plasma kinetics and urine profile of ethyl glucosides after oral administration in the rat

In this in vivo study, the time course of plasma concentration and the urinary excretion of ethyl alpha-D-glucoside (alpha-EG) and ethyl beta-D-glucoside (beta-EG) were investigated in rats after a single oral dose of 4 mmol/kg body weight. Maximal plasma concentrations of both alpha-EG and beta-EG (EGs) reached approximately 3 mM at 1 h after oral administration and then decreased rapidly. Approximately 80% of EGs administered were excreted into the urine during the first 6 h. Within 24 h, cumulative urinary alpha-EG and beta-EG excretions were estimated to be 87.2+/-7.9% and 85.4+/-5.0%, respectively. Traces of both EGs were detected in plasma and urine 24 h after oral ingestion. The results of this study indicate that almost all of both EGs was rapidly absorbed into the blood stream and easily excreted into the urine after oral administration, and that a small amount of them remained in the rat body 24 h after administration.     

Bioequivalence of two fexofenadine formulations in healthy human volunteers after single oral administration

AIM: A randomized, two-way, crossover, bioequivalence study was conducted in 25 fasting, healthy, male volunteers to compare two brands of fexofenadine 180 mg tablets, FEXOFENADINE 180 mg Film Tablet (Drogsan A.S., Ankara, Turkey) as test and Telfast 180 mg Tablet (Aventis Pharma, Frankfurt am Main, Germany) as a reference product. METHOD: One tablet of either formulation was administered after 10 h of overnight fasting. After dosing, serial blood samples were collected during a period of 48 hours. Plasma samples were analysed for fexofenadine by a validated HPLC method. The pharmacokinetic parameters AUC(0-48), AUC(0-alpha), C(max), T(max), K(el), T(1/2), and CL were determined from plasma concentration-time profiles for both formulations and were compared statistically. RESULTS AND CONCLUSIONS: The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range, satisfying the bioequivalence criteria of the FDA. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetics profiles and that Drogsan's Fexofenadine is equivalent to Telfast of Aventis Pharma, Frankfurt am Main, Germany.     

Quantitative determination of nystatin in human plasma using LC-MS after inhalative administration in healthy subjects

The antifungal polyene antibiotics nystatin was tested in a clinical trial to describe pharmacokinetics and safety after repeated administration of Nystatin "Lederle" sterile powder in healthy volunteers. To monitor the nystatin concentration-time profile in plasma we developed a sensitive method in the range of 1-100ng/ml based on liquid chromatography coupled with tandem mass spectrometry. The target substance was separated from the biological matrix on C(18) solid-phase extraction cartridges with methanol. The Chromatography was performed isocratically using a reversed phase Caltrex Resorcinearene column. The mobile phase consisted of 5mM ammonium formate buffer and acetonitrile (40:60, v/v). The mass spectrometer works with electrospray ionization in its positive selected ion monitoring (SIM) mode using the respective MH(+) ions, m/z 926.6 for nystatin and m/z 924.4 for amphotericin B as internal standard. The method validation was performed according to the demands and international criteria for validation of bioanalytical methods and was successfully applied to the quantification of nystatin in human plasma in the pharmacokinetic trial.     

Plasma renin activity and aldosterone response to furosemide after chronic growth hormone administration to deficient subjects

The plasma renin activity (PRA) and aldosterone responses to furosemide-induced diuresis were measured in seven children with growth hormone deficiency prior to, during and after the admistration of clinical grade human growth hormone (hGH). The furosemide-stimulated increases in PRA were unchanged from baseline values after one and eight months of hGH administration, but the plasma aldosterone concentrations were significantly increased over control values after eight months of hGH administration.Plasma cortisol concentrations as determined by competitive protein binding assay were measured with the 30-minute cosyntropin (Cortrosyn) test. A normal response as defined by a final level of at least 20 ug/100 ml was found in all children. Resting cortisol concentrations were unchanged during treatment with hGH but the mean increment and final levels were significantly diminished after 8 months of hGH administration. These data have not elucidated the mechanism by which clinical grade hGH improves diuretic-induced aldosterone responsiveness but diminishes cosyntropin stimulation of the adrenal in childhood.     

Pupillary effects of leucine and methionine enkephalin in rats after intraperitoneal administration

Changes in pupil size after peripheral administration of met-enkephalin, leu-enkephalin, or morphine were studied in the rat. With a simple pupillographic technique, the pupil diameter of male, S.D. rats (250–300 g) was measured by a series of photographs taken every 60 sec for at least 45 min after the last drug injection. Morphine (8 mg/kg, SC) caused mydriasis characterized by rapid and marked fluctuations of pupil size. Mydriasis also occurred after leu-enkephalin (5 and 10 mg/kg, IP) and met-enkephalin (20 mg/kg, IP). Both peptides induced morphine-like fluctuations. When given 15 min after morphine, leu-enkephalin (5 and 10 mg/kg) increased the mydriatic effect of morphine from 172 percent of control to 224 and 272 percent, respectively. Met-enkephalin (20 mg/kg, but not 10 mg/kg) also enhanced the mydriatic response of morphine, to 244 percent of control. These interactions appear to represent simple addition rather than potentiation. The effects of both peptides were reversed by naloxone (1 mg/kg, SC), suggesting an opiate receptor interaction for the pupillary effects of the enkephalins. The rat pupil thus provides one of the few in vivo models permitting quantification of enkephalin action after parenteral administration.     

Plasma fibrinolysis after intraduodenal administration of urokinase in rats

Plasma fibrinolysis in rats rose above the level of physiological fluctuations in a curve with two peaks at 1 and 6 h, following intraduodenal administration of high-molecular-weight urokinase (HMW-UK; MW 53,000; 124,000 IU/mg protein). Activation of plasma fibrinolysis was also confirmed with insolubilized enzyme (glass-coupled UK), but lacked the first activity peak. Plasma fibrinolytic enzyme isolated by affinity chromatography revealed strong fibrinolytic (1,120 IU/dl), pyro-Glu-Gly-Arg-pNA amidolytic (3,200 nmol/dl) and Glu-plasminogen activating (24.5 IU/dl) activities. Using specific UK antibody, it appeared that the first peak originated from the administered UK, while the second one derived from endogenous plasminogen activator. Dose response of UK was not observed, and the maximal effect was at about 5,000 IU/kg body weight.     

The pharmacokinetic profile of crocetin in healthy adult human volunteers after a single oral administration

Crocetin, a unique carotenoid with a short carbon chain length, is an active compound of saffron and Gardenia jasminoides Ellis used as traditional herbal medicine. The present study was undertaken to investigate the pharmacokinetic profiles of crocetin in healthy adult subjects. The study was conducted as an open-label, single dose escalation with 10 Filipino volunteers (5 men and 5 women). The subjects received a single dose of crocetin at three doses (7.5, 15 and 22.5 mg) in one week interval. Blood samples were collected from the brachial vein before and at 1, 2, 4, 6, 8, 10 and 24 h after administration. Plasma concentrations of crocetin were determined by high-performance liquid chromatography (HPLC). Crocetin was rapidly absorbed and detected within an hour of administration with a mean time to reach maximum concentration (T_max) of crocetin ranging from 4.0 to 4.8 h. The mean values of C_max and AUC_0-24 h ranged from 100.9 to 279.7 ng/ml and 556.5 to 1720.8 ng^.h/ml respectively. C_max and AUC values increased with dose proportional manner. Crocetin was eliminated from human plasma with a mean elimination half life (T_1/2) of 6.1 to 7.5 h.In summary, there were no serious adverse events up to 22.5 mg dose of crocetin while crocetin was found to be absorbed more quickly than the other carotenoids such as β-carotene, lutein and lycopene.     

Developmental toxicity of bropirimine in rats after oral administration

Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were orally (gastric intubation) dosed with bropirimine (an immunomodulator and inducer of interferon with antiviral and antitumor activities against experimental models) at 100, 200 or 400 mg/kg/day (first experiment), or at 25, 50, or 100 mg/kg/day (second experiment), on days 7-15 of gestation. In the first experiment, maternal toxicity occurred in all bropirimine-treated groups as evidenced primarily by significant decreases in weight gain, as compared to the vehicle control group. Embryotoxicity also occurred as evidenced by a dose-related increase in the number of dams with early implantation sites only. This pronounced effect on early embryonic development led to an insufficient number of offspring to access the developmental toxicity of bropirimine. This effect and the fact that all three doses were toxic to the dams dictated that a second experiment be carried out at lower doses. Significant effects on maternal weight gain also were observed in the second experiment, at least in the first 4 days of dosing, although only one dam in the 100 mg/kg/day group had early implantation sites only, in contrast to 11 such dams at this dosage in the first experiment. However, the fact that there were significant dose-related increases in the incidence of several variations in fetuses in this group indicated that there also was embryotoxicity at 100 mg/kg/day in the second experiment. Thus, although no biologically significant increases in the incidence of any malformation or major variation were found in this study, the results did indicate that bropirimine was embryotoxic at dosages which also produced significant maternal toxicity.     

The characterization of sulphated metabolites of norethindrone in human milk after oral administration of contraceptive steroids

The excretion of ethynyl steroids in milk from a lactating woman taking a daily dose of an oral contraceptive (Conlumin) containing 1 mg of norethindrone and 50 micrograms of mestranol has been studied. Milk was diluted with aq. triethylamine sulphate and steroids were extracted on a Sep-Pak C18 cartridge at 60-64 degrees C. Groups of unconjugated steroids, glucuronides, mono- and disulphates were separated on triethylaminohydroxypropyl Sephadex LH-20. Following hydrolysis and further purification, steroids possessing an ethynyl-substituent were isolated by chromatography on sulphohydroxypropyl Sephadex LH-20 in silver form. Gas chromatographic-mass spectrometric analysis of the O-methyloxime-trimethylsilyl ether derivatives of these steroids, showed the presence of norethindrone and mestranol in the free fraction and of tetrahydro metabolites of norethindrone with 3 alpha,5 alpha, 3 alpha,5 beta and 3 beta,5 alpha configurations in the mono- and disulphate fractions. The disulphate of the 3 alpha,5 alpha isomer was the most abundant ethynyl steroid in milk after 13 days of administration. The site of conjugation of the monosulphates was established by acetylation prior to solvolysis and analysis by gas chromatography-mass spectrometry. This showed that the 3 alpha,5 alpha isomer was conjugated mainly in the 17 beta-position while the 3 alpha,5 beta isomer was conjugated at C-3.     

Gas chromatography/mass spectrometry characterization of urinary metabolites of danazol after oral administration in human

Danazol (17alpha-pregna-2,4-dien-20-yno [2,3-d]-isoxazol-17beta-ol), is a synthetic derivative of ethisterone, structurally related to stanozolol. For this reason its use as doping agent has been investigated. Danazol (Runch) (200 mg) were orally administered to two healthy male volunteers. Urine samples were collected up to 1-week post-dose. Four new metabolites have been identified in addition to the five previously reported. We propose the monitorization of 6beta-hydroxy-2-hydroxymethyl-1,2-dehydroethisterone and 6beta,16epsilon-dihydroxy-2epsilon-hydroxymethyl-ethisterone by free fraction analysis. In a same way, we proposed to detect the principal isomer of a mono-hydroxylated metabolite of 6beta-hydroxy-2epsilon-hydroxymethylethisterone in the conjugated fraction. We conclude that new metabolites can be included for the detection of danazol abuse since the main metabolite ethisterone is excreted relatively fast in urine.     

Proteomic signatures of human oral epithelial cells in HIV-infected subjects

The oral epithelium, the most abundant structural tissue lining the oral mucosa, is an important line of defense against infectious microorganisms. HIV infected subjects on highly active antiretroviral therapy (HAART) are susceptible to comorbid viral, bacterial and fungal infections in the oral cavity. To provide an assessment of the molecular alterations of oral epithelia potentially associated with susceptibility to comorbid infections in such subjects, we performed various proteomic studies on over twenty HIV infected and healthy subjects. In a discovery phase two Dimensional Difference Gel Electrophoresis (2-D DIGE) analyses of human oral gingival epithelial cell (HOEC) lysates were carried out; this identified 61 differentially expressed proteins between HIV-infected on HAART subjects and healthy controls. Down regulated proteins in HIV-infected subjects include proteins associated with maintenance of protein folding and pro- and anti-inflammatory responses (e.g., heat-shock proteins, Cryab, Calr, IL-1RA, and Galectin-3-binding protein) as well as proteins involved in redox homeostasis and detoxification (e.g., Gstp1, Prdx1, and Ero1). Up regulated proteins include: protein disulfide isomerases, proteins whose expression is negatively regulated by Hsp90 (e.g., Ndrg1), and proteins that maintain cellular integrity (e.g., Vimentin). In a verification phase, proteins identified in the protein profiling experiments and those inferred from Ingenuity Pathway Analysis were analyzed using Western blotting analysis on separate HOEC lysate samples, confirming many of the discovery findings. Additionally in HIV-infected patient samples Heat Shock Factor 1 is down regulated, which explains the reduced heat shock responses, while activation of the MAPK signal transduction cascade is observed. Overall, HAART therapy provides an incomplete immune recovery of the oral epithelial cells of the oral cavity for HIV-infected subjects, and the toxic side effects of HAART and/or HIV chronicity silence expression of multiple proteins that in healthy subjects function to provide robust innate immune responses and combat cellular stress.     

Erythromycin pharmacokinetics in children after rectal and oral administration

Pharmacokinetics of erythromycin base was studied clinically in children not older than 14 years treated with new children dosage forms of the antibiotic i. e. 0.1 and 0.25 g enteric coated tablets and 0.06 and 0.125 g suppositories. It was noted that the new dosage forms were characterized by higher availability which was 2.5-3 times higher than that after using the erythromycin base tablets without the coating. Systematic increasing of erythromycin availability after the use of the rectal suppositories was observed with increasing of the children age. Absolute absorption in newborns, sucklings and children over 1 year amounted to 28, 36 and 54 per cent respectively.     

Metabolism of glycosaminoglycans in rats during methionine deficiency and administration of excess methionine

Methionine deficiency in rats caused significant decrease in the concentration of many sulphated glycosaminoglycans in the aorta and other tissues, while administration of excess methionine caused an increase in these constituents. The activity of some important biosynthetic enzymes decreased in methionine deficiency and increased on administration of excess methionine. No uniform pattern was observed in the changes in the activity of enzymes concerned with degradation of glycosaminoglycans. The concentration of 3′-phosphoade-nosine 5′-phosphosulphate and the activities of the sulphate activating system and sulpho-transferase were decreased in methionine deficiency, while feeding excess methionine did not affect these parameters as compared to controls.     

Increased micronucleus frequency after oral administration of cadmium in dogs

Cadmium (Cd) is a toxic heavy metal that has been classified as a human carcinogen by the International Agency for Research on Cancer. The genotoxic effects of cadmium oxide (CdO) were investigated in cultured dog lymphocytes after a short-term oral CdO administration by the micronucleus (MN) test. The dogs were given 10 mg CdO/kg body weight per day for 3 and 28 d, respectively group I (n=7) and group II (n=6). Blood samples were collected at the beginning of feeding and at 4 and 29 d after Cd administration and cultured for 72 h. Whereas no significant increase in the MN frequency in group I was observed (p=0.398), a significant MN induction with CdO was found in group II (p=0.028) when compared with initial MN frequencies of dogs in both groups. Our results suggest that CdO might be directly and/or indirectly genotoxic after a monthly oral administration of CdO in dogs.