PRESYSTEMIC DEACETYLATION OF LOW DOSES OF ENTERIC COATED ASPIRIN IN A PIG MODEL

1987 ◽  
Author(s):  
J V Lloyd ◽  
S E Rodgers ◽  
D M Siebert ◽  
F Bochner ◽  
G H McIntosh ◽  
...  
Keyword(s):  
Single Dose ◽  
Platelet Aggregation ◽  
Portal Vein ◽  
High Performance ◽  
Time Curve ◽  
Before And After ◽  
Enteric Coated Aspirin ◽  
Thromboxane Production ◽  
Enteric Coated ◽  
Prostacyclin Production

The antithrombotic effect of aspirin might be enhanced if platelet cyclooxygenase could be inhibited in the portal ciculation while sparing cyclooxygenase in the systemic vascular endothelium. This might be achieved by modifying the dose and formulation to maximise presystemic aspirin clearance by the liver. To test this hypothesis low dose enteric coated aspirin (Astrix, 50mg single dose, lOOmg single dose and lOOmg daily for 1 week) was orally administered to pigs with permanent indwelling arterial and portal vein catheters. Plasma aspirin concentrations were measured by high performance liquid chromatography in blood obtained simultaneously from the artery and portal vein for 6 hours after dosage. Platelet aggregation and thromboxane generation were measured in 4 pigs before and after the lOOmg chronic dosage regimen. Aortic prostacyclin production was measured in aspirin treated (lOOmg daily for 1 week) and untreated pigs after sacrifice. After the 50mg single dose the arterial:portal areas under the plasma concentration versus time curve (AUC) ratio was 0.63±0.09 (n=6). In 3 pigs which received all 3 dosage regimens the arterial:portal AUC ratios were 0.48±0.05 after 50mg single dose, 0.52±0.02 after lOOmg single dose and 0.47+0.03 after lOOmg daily for 1 week. Platelet aggregation in response to sodium arachidonate (1.65mM) was completely abolished after chronic aspirin administration. Thromboxane production (pg/106 platelets) by this stimulus decreased from 536±117 before aspirin to 57±14 after aspirin (n=4; p=0.017). Aortic prostacyclin synthesis (ng/disc after 10 min incubation) was 1.66±0.28 (n=4) in untreated pigs and 0.97±0.25 (n=4) in treated pigs (p=0.06).With this slow release aspirin formulation there was substantial but incomplete clearance of aspirin by the liver. This may not be sufficient to spare cyclooxygenase in the systemic vessels from the effect of aspirin.

Measurement of Aspirin Concentrations in Portal and Systemic Blood in Pigs: Effect on Platelet Aggregation, Thromboxane and Prostacyclin Production

1989 ◽  
Vol 61 (02) ◽  
pp. 211-216 ◽  
Author(s):  
F Bochner ◽  
D M Siebert ◽  
S E Rodgers ◽  
G H McIntosh ◽  
M J James ◽  
...  
Keyword(s):  
Single Dose ◽  
Platelet Aggregation ◽  
Time Profile ◽  
Time Curve ◽  
Systemic Artery ◽  
Enteric Coated Aspirin ◽  
Study Support ◽  
Thromboxane Production ◽  
Enteric Coated ◽  
Prostacyclin Production

SummaryLow doses of enteric-coated aspirin were administered orally to pigs. Plasma aspirin concentrations measured in blood obtained simultaneously from permanent catheters in a systemic artery and portal vein for 6 hours after dosage showed a large variation in the plasma aspirin concentration : time profile between pigs. After 50 mg single dose the ratio of the arterial : portal area under the plasma concentration versus time curve (AUC) was 0.63 ± 0.08 (mean ± SE, n = 6). In three pigs which received all three dosage regimens, the arterial : portal AUC ratios were 0.48 ± 0.05 after 50 mg single dose, 0.52 ± 0.02 after 100 mg single dose and 0.47 ± 0.02 after 100 mg daily for 1 week. Platelet aggregation in response to sodium arachidonate (1.65 mM) was completely abolished after chronic aspirin administration of 100 mg daily. Thromboxane production (pg/ 106 platelets) induced by this stimulus decreased from 536 ± 117 before aspirin to 57 ± 14 after aspirin (mean ± SE, n = 4; p = 0.03). Aortic prostacyclin synthesis, measured as 6-keto PGF1α (ng/disc after 10 min incubation), was 1.66 ± 0.28 (mean ± SE, n = 4) in untreated pigs and 0.95 ± 0.25 (n = 5) in treated pigs (p = 0.07). Results from this study support the idea that a difference between aspirin concentrations in the portal and systemic circulations can be achieved. Whether this can be translated into a clinically useful differential effect on the vessel wall compared to the platelet remains to be determined.

Single-Dose Effect of Enteric-Coated Aspirin on Platelet Function and Thromboxane Generation in Middle-Aged Men

1993 ◽  
Vol 27 (4) ◽  
pp. 405-410 ◽  
Author(s):  
Hiroshi Mohri ◽  
Takao Ohkubo
Keyword(s):  
Single Dose ◽  
Platelet Aggregation ◽  
Bleeding Time ◽  
Adenine Nucleotides ◽  
Adenosine Diphosphate ◽  
Platelet Factor 4 ◽  
Middle Aged ◽  
Platelet Factor ◽  
Enteric Coated Aspirin ◽  
Enteric Coated

OBJECTIVE: To evaluate the effect of a single dose of enteric-coated aspirin (ECA) in three different dosages on platelet function and thromboxane generation in middle-aged men. DESIGN AND METHODS: In a nonblind, nonplacebo-controlled, crossover study, a single dose of ECA (50, 250, or 1000 mg) was given in a tablet form to a group of healthy, middle-aged men. Ten subjects, aged 50–67 years, volunteered to participate in this study. Platelet functions including bleeding time, platelet aggregation, adenine nucleotides, beta-thromboglobulin, platelet factor 4, thromboxane generation, and aspirin measurement were determined. RESULTS: Before ECA ingestion, the intracellular adenine nucleotides (adenosine triphosphate, adenosine diphosphate) were decreased, and both beta-thromboglobulin and platelet factor 4 were increased. These observations suggested that platelets were activated in vivo in middle-aged men. These findings returned to normal within 8 hours after the ingestion of ECA, and maintained normal for at least two days. Bleeding time was significantly prolonged at 8 and 24 hours compared with that before ingestion of ECA 1000 mg (p<0.05). The generation of platelet thromboxane was maximally inhibited by approximately 40 percent in the samples 8 hours after ECA ingestion. Abnormal values of adenine nucleotides, beta-thromboglobulin, and platelet factor 4 returned to normal within 8 hours. Arachidonic acid-induced platelet aggregation was inhibited compared with that before treatment (p<0.01) and the inhibitory effect was maintained for at least three days. Adenosine diphosphate- and epinephrine-induced aggregations were less inhibited than those induced by arachidonic acid. Inhibitory effects of ECA on platelet aggregation were dose dependent. CONCLUSIONS: Our study indicates that platelets are activated in middle-aged men and that a single dose of ECA 50 mg is safe and can inhibit thromboxane synthesis and platelet aggregation. These results suggest that a daily dose of ECA 50 mg may be useful for blocking platelet activation and preventing thrombosis.

scholarly journals Rifampin Reduces Concentrations of Trimethoprim and Sulfamethoxazole in Serum in Human Immunodeficiency Virus-Infected Patients

2001 ◽  
Vol 45 (11) ◽  
pp. 3238-3241 ◽  
Author(s):  
Esteban Ribera ◽  
Leonor Pou ◽  
Antoni Fernandez-Sola ◽  
Francisco Campos ◽  
Rosa M. Lopez ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
High Performance Liquid Chromatography ◽  
High Performance ◽  
Parent Drug ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Antituberculosis Treatment ◽  
Immunodeficiency Virus ◽  
Before And After

ABSTRACT To determine whether rifampin reduces concentrations of trimethoprim (TMP) and sulfamethoxazole (SMX) in serum of human immunodeficiency virus (HIV)-infected persons, levels of these agents were determined by high-performance liquid chromatography before and after more than 12 days of standard antituberculosis treatment for 10 patients who had been taking one double-strength tablet of co-trimoxazole once daily for more than 1 month. Statistically significant, 47 and 23% decreases in TMP and SMX mean areas under the concentration-time curve from 0 to 24 h (AUC0–24), respectively, were observed after administration of rifampin.N-Acetyl-SMX profiles without and with rifampin were similar. The steady-state AUC0–24 metabolite/parent drug ratio increased by 32% with rifampin administration. Our study shows that rifampin reduces profiles of TMP and SMX in serum of HIV-infected patients.

scholarly journals Pharmacokinetics and Safety of Ascending Single Doses of DZ-2640, a New Oral Carbapenem Antibiotic, Administered to Healthy Japanese Subjects

2000 ◽  
Vol 44 (3) ◽  
pp. 578-582 ◽  
Author(s):  
Makoto Tanaka ◽  
Kinuyo Kato ◽  
Hideo Hakusui ◽  
Yoichi Murakami ◽  
Kenichi Sato ◽  
...  
Keyword(s):  
Single Dose ◽  
Food Intake ◽  
Half Life ◽  
High Performance ◽  
Parent Compound ◽  
Tubular Secretion ◽  
Active Metabolites ◽  
Time Curve ◽  
Chromatography Method ◽  
The Mean

ABSTRACT DZ-2640 is the ester-type oral carbapenem prodrug of an active parent compound, DU-6681. The pharmacokinetics and safety of DU-6681 were investigated in six studies after oral administration of a single dose of DZ-2640 to healthy male Japanese volunteers at doses of 25, 50, 100, 200, and 400 mg (as the equivalents of DU-6681) in the fasted state. The same volunteers received the drug at a dose of 100 mg in the fasted and fed states to examine the effect of food intake on the bioavailability of DZ-2640. The concentrations of DU-6681 in plasma and urine were determined by a validated high-performance liquid chromatography method and a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of DU-6681 in plasma (C max) ranged from 0.263 μg/ml (25-mg dose) to 2.489 μg/ml (400-mg dose) and were reached within 1.5 h following drug administration. After reaching theC max, plasma DU-6681 concentrations declined in a monophasic manner, with a half-life of 0.47 to 0.89 h. The area under the concentration-time curve (AUC) andC max increased almost linearly with the dose up to the 200-mg dose. The AUC and C max increased less than proportionally after administration of the 400-mg dose, suggesting a reduction in drug absorption. The plasma protein binding of DU-6681 was in the range of 23.3 to 25.6%. The cumulative urinary recoveries (0 to 24 h) were in the range of 31.9 to 44.9%. The AUC was slightly but statistically significantly reduced by food intake. However, the C max, half-life, and recovery in urine were not affected by food intake. The renal clearance (402 to 510 ml/min) was much greater than the mean glomerular filtration rate (ca. 120 ml/min), which indicated active tubular secretion of the drug. A mild transient and moderate diarrhea was observed in two of six volunteers in the study with a single dose of 25 mg. Mild soft stools were observed in two of six volunteers who received a 400-mg dose of the drug.

Peripheral Venous Plasma Aspirin Concentrations and Platelet Aggregation Inhibition Produced by Enteric-Coated Aspirin Formulations

1986 ◽  
Vol 55 (02) ◽  
pp. 222-227 ◽  
Author(s):  
Roslyn A Brandon ◽  
J A G Emmett ◽  
M J Eadie ◽  
A C W Curran ◽  
I H Bunce
Keyword(s):  
Platelet Aggregation ◽  
Peripheral Circulation ◽  
Systemic Circulation ◽  
Inhibition Of Platelet Aggregation ◽  
Enteric Coated Aspirin ◽  
Aggregation Inhibition ◽  
Enteric Coated ◽  
Adult Volunteers ◽  
Chronic Use ◽  
Venous Plasma

SummaryIn a random cross-over design, six healthy consenting adult volunteers were given on separate occasions single doses of 300-650 mg of 3 different formulations of enteric-coated aspirin. Over various intervals for 48-54 h following dosage, plasma aspirin and salicylate concentrations were measured together with percentage inhibition of platelet aggregation activated by threshold concentrations of sodium arachidonate alone and combined with ADP and collagen. In all subjects each formulation delivered measurable quantities of aspirin to the peripheral circulation, the unchanged drug being detected at various times up to and including 28 h after dosage. Moreover, low aspirin concentrations were found to co-exist with unimpaired platelet aggregation. All 3 formulations yielded statistically significant (P <0.01) inhibition of platelet aggregation activated both by arachidonate and by the combination of aggregants when tested 24-29 and 48-54 h after dosage; there were no significant differences (P >0.05) between the 3 formulations in this regard. Two different patterns of delivery of unchanged aspirin to the systemic circulation from these enteric-coated formulations were apparent. These patterns may be important when considering which aspirin formulation might be most appropriate in chronic use for an antiplatelet effect. None of the enteric-coated formulations used in this study may be optimal in this regard.

scholarly journals Single-Dose Pharmacokinetics of Cidofovir in Continuous Venovenous Hemofiltration

2014 ◽  
Vol 58 (4) ◽  
pp. 1952-1955 ◽  
Author(s):  
Matthias G. Vossen ◽  
Klaus-Bernhard Gattringer ◽  
Walter Jäger ◽  
Stefanie Kraff ◽  
Florian Thalhammer
Keyword(s):  
Single Dose ◽  
High Performance ◽  
Life Time ◽  
Time Profile ◽  
Critically Ill Patient ◽  
Continuous Venovenous Hemofiltration ◽  
Time Curve ◽  
Dose Concentration ◽  
Total Body ◽  
The Right

ABSTRACTDosage recommendations for cidofovir are available for renally competent as well as impaired patients; however, there are no data for patients undergoing continuous renal replacement therapy. We determined the single-dose concentration-versus-time profile of cidofovir in a critically ill patient undergoing continuous venovenous hemofiltration (CVVH). One dose of 450 mg cidofovir (5 mg/kg) was administered intravenously due to a proven cytomegalovirus (CMV) infection and failure of first-line antiviral therapy. Additionally, 2 g of probenecid was administered orally 3 h prior to and 1 g was administered 2 h as well as 8 h after completion of the infusion. The concentrations of cidofovir in serum and ultrafiltrate were assessed by high-performance liquid chromatography. The peak serum concentration measured at 60 min postinfusion was 28.01 mg/liter at the arterial port. The trough serum level was 19.33 mg/liter at the arterial port after 24 h. The value of the area under the concentration-versus-time curve from 0 to 24 h was 543.8 mg · h/liter. The total body clearance was 2.46 ml/h/kg, and the elimination half-life time was 53.32 h. The sieving coefficient was 0.138 ± 0.022. Total removal of the drug was 30.99% after 24 h. Because of these data, which give us a rough idea of the concentration profile of cidofovir in patients undergoing CVVH, a toxic accumulation of the drug following repeated doses may be expected. Further trials have to be done to determine the right dosage of cidofovir in patients undergoing CVVH to avoid toxic accumulation of the drug.

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