scholarly journals Influence of Cytochrome P450 2C19 on the pharmacokinetics of lansoprazole administered by single and successive intravenous infusion in healthy Chinese volunteers

2012 ◽  
Vol 2 (1) ◽  
pp. 3 ◽  
Author(s):  
Yongqing Wang ◽  
Peipei Zhang ◽  
Ningling Jiang ◽  
Xiaojian Gong ◽  
Dewang Wang ◽  
...  
Keyword(s):  
Intravenous Infusion ◽  
High Performance ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Linear Increase ◽  
Cytochrome P450 2C19 ◽  
Repeated Doses ◽  
Healthy Chinese ◽  
To Receive ◽  
Single Intravenous Infusion

This study aimed to explore the effect of CYP2C19 polymorphisms on the pharmacokinetics of lansoprazole administered by single and successive intravenous (iv) infusions in healthy Chinese volunteers. A total of 30 subjects, including 20 extensive metabolizers (EMs) and 10 poor metabolizers (PMs) were recruited and randomly assigned to three groups receiving doses of 15, 30 and 60 mg. All subjects received a single dose of lansoprazole during a 60-min period, and only the 30 mg dose group continued to receive the same dose iv for the next seven days (twice daily). Plasma concentrations of lansoprazole were monitored by high performance liquid chromatography (HPLC) at the following times: 15, 30, 45, 60, 75, 105, 165, 225, 300, 390, 480, 600 and 720 min after lansoprazole administration. After a single intravenous infusion in the three groups, AUC, Cmax and t½ were significantly higher in PMs than in EMs, while total clearance (Cltotal) in PMs was significantly lower than that in EMs. Mean AUC and Cmax ratios in EMs and PMs were 2.1:1 and 1.4:1, respectively. After repeated doses of 30 mg, the AUC, Cmax, and t½ increased significantly, while the Cltotal decreased significantly in EMs. Mean AUC and Cmax ratios in EMs and PMs amounted to 2.2:1.4 and 1.5:1.2, respectively. Lansoprazole displays a linear increase in AUC and Cmax over a dose range of 15-60 mg, and these were dependent on individual CYP2C19 status.

Phase I and Pharmacokinetic Study of the Camptothecin Analog DX-8951f Administered as a 30-Minute Infusion Every 3 Weeks in Patients With Advanced Cancer

2000 ◽  
Vol 18 (23) ◽  
pp. 3986-3992 ◽  
Author(s):  
Valérie Boige ◽  
Eric Raymond ◽  
Sandrine Faivre ◽  
Michel Gatineau ◽  
Kathleen Meely ◽  
...  
Keyword(s):  
Phase I ◽  
Intravenous Infusion ◽  
Topoisomerase I ◽  
High Performance ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Phase Ii Studies ◽  
Heavily Pretreated ◽  
Dose Limiting Toxicity

PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks. PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m2. All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography. RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h·m2. The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m2. CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m2 every 3 weeks in patients previously treated with chemotherapy.

Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients.

1997 ◽  
Vol 15 (4) ◽  
pp. 1492-1501 ◽  
Author(s):  
C H Takimoto ◽  
W Dahut ◽  
M T Marino ◽  
H Nakashima ◽  
M D Liang ◽  
...  
Keyword(s):  
Steady State ◽  
Topoisomerase I ◽  
High Performance ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Drug Dose ◽  
Clinical Activity ◽  
Elimination Kinetics ◽  
Dose Levels

PURPOSE To investigate the pharmacokinetics and pharmacodynamics of 9-aminocamptothecin (9-AC) infused over 72 hours at doses of 5 to 74 micrograms/m2/h. PATIENTS AND METHODS 9-AC lactone and total (lactone plus carboxylate) plasma concentrations were measured in 44 patients with solid tumors using a high-performance liquid chromatography (HPLC) assay. Fifteen patients underwent extended pharmacokinetic sampling to determine the distribution and elimination kinetics of 9-AC. RESULTS At steady-state, 8.7% +/- 4.7% (mean +/- SD) of the total drug circulated in plasma as the active 9-AC lactone. Clearance of 9-AC lactone was uniform (24.5 +/- 7.3 L/h/m2) over the entire dose range examined; however, total 9-AC clearance was nonlinear and increased at higher dose levels. In 15 patients treated at dose levels > or = 47 micrograms/m2/h, the volume of distribution at steady-state for 9-AC lactone was 195 +/- 114 L/m2 and for total 9-AC it was 23.6 +/- 10.6 L/m2. The elimination half-life was 4.47 +/- 0.53 hours for 9-AC lactone and 8.38 +/- 2.10 hours for total 9-AC. In pharmacodynamic studies, dose-limiting neutropenia correlated with steady-state lactone concentrations (Css) R2 = .77) and drug dose (R2 = .71). CONCLUSION Plasma 9-AC concentrations rapidly declined to low levels following the end of a 72-hour infusion and the mean fraction of total 9-AC circulating in plasma as the active lactone was less than 10%. The pharmacokinetics of 9-AC may have a great impact on its clinical activity and should be considered in the design of future clinical trials of this topoisomerase I inhibitor.

scholarly journals The pharmacokinetics and bioavailability of rabeprazole following single intravenous infusion and oral administration in healthy Chinese volunteers

2011 ◽  
Vol 1 (1) ◽  
pp. 4
Author(s):  
Yongqing Wang ◽  
Hongwen Zhang ◽  
Ling Meng ◽  
Nana Tang ◽  
Hongyu Yuan ◽  
...  
Keyword(s):  
Oral Administration ◽  
Intravenous Administration ◽  
Intravenous Infusion ◽  
Half Life ◽  
Total Body Clearance ◽  
Constant Infusion ◽  
Healthy Chinese ◽  
Total Body ◽  
To Receive ◽  
Body Clearance

To investigate the pharmacokinetics and bioavailability of rabeprazole administrated by intravenous infusion and oral administration in healthy Chinese volunteers. A total of 20 male subjects were recruited and randomly assigned at the beginning of the study to receive a single dose of rabeprazole (20 mg) administrated either intravenously or orally. Following a 7-day washout period, all subjects received another 20mg dose via the alternate route. Intravenous dose was given in constant infusion over 30 min, and the oral dose was given in two 10mg tablets. Intravenous administration yielded the following measurements: the terminal half-life was (62.4±10.7) min; the Cmax was (1308.6±266.4) ng·ml-1; the total body clearance was (0.21±0.05) L·min-1; the AUC0-τ and AUC0-∞ were (99.6±21.9) mg∙min∙L-1 and (102. 4±23.3) mg∙min∙L-1, respectively. Oral administration yielded the following measurements: the half-life was (64.2±15.5) min; the Cmax was (508.3±180.2) ng·ml-1; Tmax was attained at about 229.5 min; the total body clearance was (0.31±0.10) L·min-1; the AUC0-τ and AUC0-∞ were (69.5±20.0) mg∙min∙L-1 and (70.6±20.2) mg∙min∙L-1, respectively. The bioavailability of rabeprazole was estimated to be 70.1% in healthy Chinese volunteers. The total body clearance after oral administration was significantly higher than that measured following intravenous administration (P <0.01).

Potentiating effect of secretin on cholecystokinin-stimulated pancreatic secretion in dogs

1984 ◽  
Vol 246 (3) ◽  
pp. G248-G252 ◽  
Author(s):  
W. Y. Chey ◽  
K. Y. Lee ◽  
T. M. Chang ◽  
Y. F. Chen ◽  
L. Millikan
Keyword(s):  
Intravenous Infusion ◽  
Pancreatic Secretion ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Exocrine Pancreatic Secretion ◽  
Cholecystokinin Octapeptide ◽  
Postprandial State ◽  
Pancreatic Fistulas ◽  
Physiological Dose ◽  
Bicarbonate Output

A possible potentiating effect of cholecystokinin octapeptide (CCK-OP) on the action of secretin on exocrine pancreatic secretion was studied in five dogs with gastric fistulas and modified Herrera pancreatic fistulas. Secretin in a dose, 2.45 pmol (0.03 clinical units) X kg-1 X h-1, that mimics the plasma secretin level in the postprandial state increased pancreatic bicarbonate secretion, but the increase was not statistically significant. CCK-OP in graded doses, 26.2, 52.5, 109, and 219 pmol (0.03, 0.06, 0.125, and 0.25 microgram) X kg-1 X h-1, given intravenously produced a significant increase in both bicarbonate and protein secretion, and the increase was dose related. The plasma concentrations of immunoreactive CCK during intravenous infusion of CCK-OP in doses of 26.2 and 52.5 pmol X kg-1 X h-1 were found to mimic the postprandial plasma concentrations of immunoreactive CCK in eight dogs. When CCK-OP in four graded doses was added to intravenous infusion of secretin, 2.45 pmol X kg-1 X h-1, the actual bicarbonate output at each dose level of CCK-OP was greater than the sum of the bicarbonate outputs produced by secretin alone and CCK-OP alone in a corresponding dose. Thus, we conclude that the action of secretin in a physiological dose that mimics the plasma level of secretin after a meal is potentiated by CCK-OP in a dose range that produces a plasma CCK-OP level comparable with that in the postprandial state and vice versa. The study indicates that, like secretin, CCK-OP is another necessary agent for pancreatic secretion of bicarbonate during digestion.(ABSTRACT TRUNCATED AT 250 WORDS)

The Measurement of Heparin and Other Therapeutic Sufphated Polysaccharides in Plasma, Serum and Urine

1985 ◽  
Vol 54 (03) ◽  
pp. 630-634 ◽  
Author(s):  
J Dawes ◽  
C V Prowse ◽  
D D Pepper
Keyword(s):  
Biological Fluids ◽  
Anticoagulant Activity ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Heparin Therapy ◽  
Competitive Binding Assay ◽  
First Order Kinetics ◽  
Activity Measurements ◽  
Heparin Activity ◽  
Dose Dependent

SummaryThe competitive binding assay described will specifically and accurately measure concentrations of administered heparin in biological fluids with a sensitivity of 60 ng ml-1. Neither endogenous glycosaminoglycans, nor plasma proteins such as ATIII and PF4 interfere in the assay. Semi-synthetic highly sulphated heparinoids and LMW heparin can also be measured. Using this assay heparin clearance followed simple first-order kinetics over the dose range 100-5,000 units, but the half-life was strongly dose-dependent. There was good correlation with heparin activity measurements by APTT and anti-Xa clotting assays. Plasma concentrations were measurable for at least 5 h following subcutaneous injection of 10,000 units of heparin. Excretion in the urine could be followed after all but the lowest intravenous dose. This assay, used in conjunction with measurements of heparin anticoagulant activity, will be valuable in the elucidation of mechanisms of action of heparin and the heparinoids, and in the assessment and management of problems related to heparin therapy.

scholarly journals Intranasal administration of the chemotherapeutic perillyl alcohol results in selective delivery to the cerebrospinal fluid in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Geetika Nehra ◽  
Shannon Andrews ◽  
Joan Rettig ◽  
Michael N. Gould ◽  
Jill D. Haag ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Tumors ◽  
Nasal Mucosa ◽  
Brain Cancer ◽  
Intranasal Administration ◽  
High Performance ◽  
Early Stage ◽  
Plasma Concentrations ◽  
Perillyl Alcohol ◽  
Systemic Absorption

AbstractPerillyl alcohol (POH) has been extensively studied for the treatment of peripheral and primary brain tumors. The intranasal route of administration has been preferred for dosing POH in early-stage clinical trials associated with promising outcomes in primary brain cancer. However, it is unclear how intranasal POH targets brain tumors in these patients. Multiple studies indicate that intranasally applied large molecules may enter the brain and cerebrospinal fluid (CSF) through direct olfactory and trigeminal nerve-associated pathways originating in the nasal mucosa that bypass the blood–brain barrier. It is unknown whether POH, a small molecule subject to extensive nasal metabolism and systemic absorption, may also undergo direct transport to brain or CSF from the nasal mucosa. Here, we compared CSF and plasma concentrations of POH and its metabolite, perillic acid (PA), following intranasal or intravascular POH application. Samples were collected over 70 min and assayed by high-performance liquid chromatography. Intranasal administration resulted in tenfold higher CSF-to-plasma ratios for POH and tenfold higher CSF levels for PA compared to equal dose intravascular administration. Our preclinical results demonstrate POH undergoes direct transport from the nasal mucosa to the CSF, a finding with potential significance for its efficacy as an intranasal chemotherapeutic for brain cancer.

scholarly journals Radioimmunoassay of plasma ouabain in healthy and pregnant individuals

2000 ◽  
Vol 165 (3) ◽  
pp. 669-677 ◽  
Author(s):  
O Vakkuri ◽  
SS Arnason ◽  
A Pouta ◽  
O Vuolteenaho ◽  
J Leppaluoto
Keyword(s):  
Pregnant Women ◽  
Human Plasma ◽  
High Performance ◽  
Chemical Nature ◽  
Solid Phase ◽  
Plasma Concentrations ◽  
First Trimester ◽  
Plasma Samples ◽  
Third Trimester ◽  
Endogenous Substances

Ouabain was recently isolated from human plasma, bovine hypothalamus and bovine adrenal in attempts to identify endogenous substances inhibiting the cell membrane sodium pump. A number of radioimmunoassays have been developed in order to study the clinical significance of ouabain. The results have been controversial with regard to the presence and chemical nature of plasma ouabain-like immunoreactivity. We have now measured ouabain in healthy and pregnant individuals using solid-phase extraction of plasma samples followed by a new radioimmunoassay with the extraordinary sensitivity of at least 2 fmol/tube (5 pmol/l). Plasma extracts, a previously isolated human plasma ouabain-like compound and bovine hypothalamic inhibitory factor displaced the tracer in parallel and eluted identically with ouabain in high-performance liquid chromatography. Plasma ouabain immunoreactivity was found to be much lower than reported previously: 12.6+/-1.3 pmol/l in healthy men (mean+/-s.e., n=20) and 9.4+/-0.7 pmol/l in women (n=14). In pregnant women (n=28) plasma ouabain concentration was 16.3+/-4.0 pmol/l during the first trimester, 18.8+/-4.3 pmol/l during the second trimester and 24.3+/-4.0 pmol/l during the third trimester (all P<0.01 compared with non-pregnant women). Plasma ouabain 3-5 days after the delivery was 13.6+/-1.1 pmol/l (n=10, P<0.05-0.01 compared with second and third trimesters). The pregnancy-related changes in the plasma concentrations of ouabain resembled those of cortisol. Therefore cortisol was measured from the same plasma samples and a significant positive correlation was found (r=0.512, P=0.006). The similar profiles of plasma ouabain and cortisol during pregnancy and their rapid decreases postpartum are consistent with the adrenal cortical origin of ouabain and also show that the secretions of these hormones are possibly under the control of same factors.

Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (30) ◽  
pp. 7697-7702 ◽  
Author(s):  
Susan M. O'Brien ◽  
Charles C. Cunningham ◽  
Anatoliy K. Golenkov ◽  
Anna G. Turkina ◽  
Steven C. Novick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Intravenous Infusion ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Lymphocytic Leukemia ◽  
Complete Disappearance ◽  
Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

Role of routine fluid replacement in children undergoing tonsillectomy

1990 ◽  
Vol 104 (10) ◽  
pp. 801-802 ◽  
Author(s):  
P. S. Wilson ◽  
D. G. Snow ◽  
J. O'Connel ◽  
D. W. Proops ◽  
M. Barrow
Keyword(s):  
Blood Loss ◽  
Prospective Study ◽  
Intravenous Infusion ◽  
Intravenous Fluid ◽  
Fluid Replacement ◽  
Control Group ◽  
A Prospective Study ◽  
To Receive

AbstractIt has been suggested that children undergoing tonsillectomy would benefit from an intravenous infusion, to counteract the period of pre-operativefasting combined with the blood loss at operation.A prospective study of 50 children undergoing tonsillectomy was undertaken. The children were randomly allocated into two groups, one to receive an infusion and a control group.There were no significant differences between the two groups, although the children with an infusion had a longer mean post-operative stay.There would seem to be no role for routine intravenous fluid replacement in children undergoing uncomplicated tonsillectomy.

Continuation Therapy with Amitriptyline in Depression

1978 ◽  
Vol 133 (1) ◽  
pp. 28-33 ◽  
Author(s):  
A. Coppen ◽  
K. Ghose ◽  
S. Montgomery ◽  
V. A. Rama Rao ◽  
J. Bailey ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Antidepressant Medication ◽  
Depressive Illness ◽  
Continuation Therapy ◽  
One Year ◽  
To Receive

SummaryThirty-two patients who had responded to amitriptyline (150 mg daily) when suffering from a depressive illness were allocated either to receive placebo or to remain on the same medication for one year.Plasma concentrations of the drug were regularly estimated. There was no correlation between plasma concentration and subsequent residual affective morbidity. In spite of considerable encouragement, three of the patients did not take the prescribed amitriptyline and they all relapsed. Five out of sixteen patients who received placebo relapsed. None of the patients who continued to take amitriptyline relapsed.It is emphasized that the patients studied were selected, inasmuch as they were apparent responders to amitriptyline. It is concluded that this group of patients should continue to be treated with antidepressant medication for eight months after apparent recovery, and care should be taken to ensure the patients' compliance.

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