scholarly journals A Population Pharmacokinetic Model of Intravenous Dexmedetomidine for Mechanically Ventilated Children after Neurosurgery

2019 ◽  
Vol 8 (10) ◽  
pp. 1563 ◽  
Author(s):  
In-Kyung Song ◽  
SoJeong Yi ◽  
Hyeong-Seok Lim ◽  
Ji-Hyun Lee ◽  
Eun-Hee Kim ◽  
...  
Keyword(s):  
Body Weight ◽  
Dose Group ◽  
Adverse Reactions ◽  
Low Dose ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Loading Dose ◽  
Mechanically Ventilated

Dexmedetomidine is a selective alpha-2 adrenergic agonist with concurrent sedative and analgesic effects, and it is being increasingly used in pediatric anesthesia and intensive care. This study aimed to investigate the pharmacokinetics of intravenous dexmedetomidine in mechanically ventilated children in the intensive care unit (ICU) after neurosurgery. Pediatric patients aged 2–12 years, who were mechanically ventilated in ICU after neurosurgery, were allocated into a low-dose (n = 15) or high-dose (n = 14) group. The low-dose group received dexmedetomidine at a loading dose of 0.25 µg/kg for 10 min, followed by a maintenance dose of 0.25 µg/kg/h for 50 min, whereas the high-dose group received dexmedetomidine at a loading dose of 0.5 µg/kg for 10 min, followed by a maintenance dose of 0.5 µg/kg/h for 50 min. Serial blood samples were collected for a pharmacokinetic analysis up to 480 min after the end of the infusion. The sedative effect of dexmedetomidine was assessed using the Bispectral Index and University of Michigan Sedation Scale. Adverse reactions, electrocardiography findings, and vital signs were monitored for a safety assessment. A population pharmacokinetic analysis was performed using non-linear mixed effects modeling. Dexmedetomidine induced a moderate-to-deep degree of sedation during infusion in both groups. The pharmacokinetics of dexmedetomidine were best described by a two-compartment disposition model with first-order elimination kinetics. The parameters were standardized for a body weight of 70 kg using an allometric power model. The population estimates (95% confidence interval) per 70 kg body weight were as follows: clearance of 81.0 (72.9–90.9) L/h, central volume of distribution of 64.2 (50.6–81.0) L, intercompartment clearance of 116.4 (90.6–156.0) L/h, and peripheral volume of distribution of 167 (132–217) L. No serious adverse reactions or hemodynamic changes requiring the discontinuation of dexmedetomidine were observed. Dexmedetomidine had increased clearance and volume of distribution in mechanically ventilated children in ICU after neurosurgery, thereby indicating the need to adjust the dosage to obtain a target plasma concentration.

scholarly journals Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

2001 ◽  
Vol 45 (6) ◽  
pp. 1803-1809 ◽  
Author(s):  
Sanjeev Krishna ◽  
Nelamangala V. Nagaraja ◽  
Tim Planche ◽  
Tsiri Agbenyega ◽  
George Bedo-Addo ◽  
...  
Keyword(s):  
Body Weight ◽  
Severe Malaria ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Intravenous Route ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Loading Dose

ABSTRACT We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n = 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] = 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V 1] = 0.65 liter/kg; volume of distribution at steady state = 1.41 liter/kg; half-life at β phase = 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weight-normalized CL and V 1. Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.

scholarly journals “Repurposing” Disulfiram in the Treatment of Lyme Disease and Babesiosis: Retrospective Review of First 3 Years’ Experience in One Medical Practice

Antibiotics ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 868
Author(s):  
Jiachen Gao ◽  
Zhaodi Gong ◽  
Dawn Montesano ◽  
Erica Glazer ◽  
Kenneth Liegner
Keyword(s):  
Lyme Disease ◽  
Retrospective Review ◽  
Dose Group ◽  
Adverse Reactions ◽  
Low Dose ◽  
Psychiatric Symptoms ◽  
High Dose Group ◽  
High Dose ◽  
Net Benefit ◽  
Lost To Follow Up

A total of 71 patients with Lyme disease were identified for analysis in whom treatment with disulfiram was initiated between 15 March 2017 and 15 March 2020. Four patients were lost to follow-up, leaving 67 evaluable patients. Our retrospective review found patients to fall into a “high-dose” group (≥4 mg/kg/day) and a “low-dose” group (<4 mg/kg/day). In total, 62 of 67 (92.5%) patients treated with disulfiram were able to endorse a net benefit of the treatment with regard to their symptoms. Moreover, 12 of 33 (36.4%) patients who completed one or two courses of “high-dose” therapy enjoyed an “enduring remission”, defined as remaining clinically well for ≥6 months without further anti-infective treatment. The most common adverse reactions from disulfiram treatment in the high-dose group were fatigue (66.7%), psychiatric symptoms (48.5%), peripheral neuropathy (27.3%), and mild to moderate elevation of liver enzymes (15.2%). We observed that although patients on high dose experienced a higher risk for adverse reactions than those on a low dose, high-dose patients were significantly more likely to achieve enduring remission.

scholarly journals Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4237-4239 ◽  
Author(s):  
José Hermida ◽  
José Zarza ◽  
Ignacio Alberca ◽  
Ramón Montes ◽  
Marı́a Luz López ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Odds Ratio ◽  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Loading Dose ◽  
Dose Requirement ◽  
Cytochrome P 450 ◽  
Reduced Risk ◽  
Medium Dose

The 2C9*3 and 2C9*2 polymorphisms of cytochrome P-450 CYP2C9 are associated with hypersensitivity to warfarin and bleeding. The effect of these polymorphisms on sensitivity to acenocoumarol is unknown. Three groups of patients, with low, medium, or high acenocoumarol-dose requirements, were studied. Age influenced the acenocoumarol sensitivity. Bearing the 2C9*3 allele was associated with the need for a lower acenocoumarol dose (odds ratio [OR], 6.02; 95% confidence interval [CI], 1.50-24.18); 80% of carriers of the 2C9*3 allele required a low dose. The 2C9*2 allele was associated with a lower acenocoumarol-dose requirement (OR, 2.70; 95% CI, 1.11-6.58) because of a reduced risk of the need for a high acenocoumarol dose (4.8% of the patients in the high-dose group carried the 2C9*2 allele versus 34.1% and 30.2%, respectively, in the medium-dose and low-dose groups). Therefore, carriers of 2C9*3 may need a low initial loading dose of acenocoumarol. Because acenocoumarol sensitivity with the 2C9*2 variant does not seem to be clinically relevant, the drug could be an alternative to warfarin in 2C9*2 carriers.

scholarly journals Double-Blind, Randomized, Three-Armed, Placebo-Controlled, Clinical Investigation to Evaluate the Benefit and Tolerability of Two Dosages of IQP-AE-103 in Reducing Body Weight in Overweight and Moderately Obese Subjects

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ralf Uebelhack ◽  
Udo Bongartz ◽  
Stephanie Seibt ◽  
Gordana Bothe ◽  
Pee Win Chong ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Placebo Group ◽  
Body Fat ◽  
Dose Group ◽  
Low Dose ◽  
Clinical Investigation ◽  
Controlled Trial ◽  
High Dose ◽  
Double Blind

Objective. This study was performed to determine the efficacy and tolerability/safety of IQP-AE-103 on body weight reduction in overweight to moderately obese adults. Methods. A double-blind, randomized, placebo-controlled trial involved one hundred and eight subjects (BMI between 25 and 35 kg/m2) that were randomly assigned to either the low-dose or the high-dose IQP-AE-103 group, or the placebo group. Following a 2-week run-in period, subjects received two capsules of investigational product after three daily main meals for 12 weeks. Subjects were instructed to maintain a nutritionally balanced hypocaloric diet according to the individual’s energy requirement. Body weight, body fat, and waist and hip circumference were measured at baseline, and after 2, 4, 8, and 12 weeks. Subjects also rated their feelings of hunger and fullness using visual analogue scales, and food craving on a 5-point scale at the same time intervals. Blood samplings for safety laboratory parameters were taken before and at the end of the study. Results. After 12 weeks of intake, the high-dose IQP-AE-103 group had a significantly greater weight loss compared with the placebo (5.03 ± 2.50 kg vs. 0.98 ± 2.06 kg, respectively; p<0.001) and the low-dose group (3.01 ± 2.19 kg; p=0.001). The high-dose group experienced a decrease in body fat of 3.15 ± 2.41 kg compared with a decrease of 0.23 ± 2.74 kg for the placebo group (p<0.001). High-dose IQP-AE-103 also decreased the feeling of hunger in 66% subjects. A beneficial effect of IQP-AE-103 on the lipid metabolism was also demonstrated in the subgroup of subjects with baseline total cholesterol levels above 6.2 mmol/L. No side effects related to the intake of IQP-AE-103 were reported. Conclusions. These findings indicate that IQP-AE-103 could be an effective and safe weight loss intervention. This trial is registered with NCT03058367.

Cytotoxicity of Dimethylacetamide and Pharmacokinetics in Children Receiving Intravenous Busulfan

2007 ◽  
Vol 25 (13) ◽  
pp. 1772-1778 ◽  
Author(s):  
Georg Hempel ◽  
Doris Oechtering ◽  
Claudia Lanvers-Kaminsky ◽  
Thomas Klingebiel ◽  
Josef Vormoor ◽  
...  
Keyword(s):  
Safety Concern ◽  
Plasma Concentrations ◽  
Leukemic Cell ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Leukemic Cell Lines

PurposeTo assess the cytotoxicity and the exposure of N,N-dimethylacetamide (DMA) in children during high-dose therapy with an intravenous (IV) formulation of busulfan containing the potentially hepatotoxic and neurotoxic DMA as a solvent.Patients and MethodsEighteen children aged 0.9 to 17.3 years (median age, 4.0 years) received IV busulfan in 15 doses of 0.7 to 1.0 mg/kg busulfan containing overall DMA amounts of between 5 mmol (437 mg) and 70.5 mmol (6,142 mg) per dose. Plasma concentrations of DMA and busulfan were quantified and analyzed using nonlinear mixed-effects modeling. Four different leukemic cell lines were incubated with DMA, and cytotoxicity was assessed in comparison with busulfan as well as in a combination reflecting the ratio in the formulation.ResultsMaximal plasma concentrations of DMA up to 3.09 mmol/L were observed. No accumulation of the solvent occurred. Instead, the trough levels decreased over the 4 treatment days. The population pharmacokinetic analysis revealed a clearance of 86.9 mL h−1kg−1± 27% that increased to 298 mL h−1kg−1on the fourth day and a volume of distribution of 469 mL kg ± 22% (population mean ± interindividual variability). DMA volume of distribution correlated with the volume of distribution of busulfan. The cytotoxicity of DMA in vitro was 3 orders of magnitude lower than that of busulfan. No synergism was observed.ConclusionThe lack of accumulation of DMA confirms that there is no safety concern related to the DMA content in this IV busulfan formulation. The contribution of DMA to the antileukemic effect of the formulation seems to be limited.

scholarly journals Ovarian profile of Wistar rats treated with Theobroa cacao extract.

2019 ◽  
Vol 8 (2) ◽  
pp. 1570-1576
Author(s):  
Kebe E. Obeten ◽  
Victor A. Fischer ◽  
Ugwuja O. Jennifer ◽  
Akim Bonaventure
Keyword(s):  
Body Weight ◽  
Theobroma Cacao ◽  
Dose Group ◽  
Low Dose ◽  
Research Work ◽  
Wistar Rat ◽  
Female Rats ◽  
Control Group ◽  
High Dose ◽  
Test Substance

The study was aimed at determining the effect of aqueous extract of Theobroma cacao on the histology of the ovary of female albino wistar rat. Twenty-four (24) adult wistar female rats weighting about 100- 160g were used for this research work and were divided into three (3) groups of eight (8) animals each. Group A; control, Group B; low dose and Group C; high dose with eight (8) animals in each group. Control group received vital feed; the low dose group was administered 240mgkg body weight of Theobroma cacao extract and the high dose group was administered 500mgkg body weight of the test substance. Extract was given daily by oral gavage method for twenty-one (21) days. Twenty-four hours after the last administration, all animals in each group were sacrificed under chloroform anesthesia. The ovaries were harvested, weighed and fixed in 10% buffered formalin for histological studies. Results showed that following administration of extract of Theoboma cacao at these doses, an insignificant decrease in organ weight was observed. Histological observation showed few follicles as well as loss of the substance of granulose cell this could possibly suggest decrease in production of sex steroids in the ovary.Keywords: Theobroma Cacao, Ovary, Histology

scholarly journals The Effect of Ethanolic Extract of Cannabis sativa Leaves from Nigeria on the Antioxidants Markers in Albino Wistar Rats

2020 ◽  
pp. 58-65
Author(s):  
E. B. Umoren ◽  
I. Wopara ◽  
O. G. Adebayo ◽  
U. A. Ezike ◽  
A. O. Obembe
Keyword(s):  
Body Weight ◽  
Wistar Rats ◽  
Dose Group ◽  
Low Dose ◽  
Cannabis Sativa ◽  
Ethanolic Extract ◽  
High Dose Group ◽  
High Dose ◽  
Control Groups ◽  
And Control

Background: Cannabis sativa is an annual herbaceous plant in the Cannabis genus. The cannabis plant is widely regarded as a potent psychoactive, medicinal plant. Reportedly used for recreation and as intoxicant. The medical uses of the plant include effective control and management of chronic health problems such as HIV/AIDs, cancer, cachexia, nausea and vomiting, asthma and hypertension. C. sativa is known to possess antioxidative properties. This study therefore investigated the effects of C. sativa on antioxidant concentrations in albino Wistar rats. Materials and Methods: Thirty (30) rats used for this study were divided into three groups of 10 rats each. Group 1 received distilled water and served as control. Group 2 received C. sativa extract (100 ml/Kg body weight) by gavage and served as low dose group. Group 3 received C. sativa (250 ml/Kg body weight) by gavage and served as high dose group once daily for 28 days. Results: Catalase (CAT) concentration was significantly lower (P<0.05) in the low dose group as compared with control. In the high dose group, CAT concentration was significantly lower (P<0.05) when compared with the low and control groups respectively. Glutathione peroxidase (GPx) and Superoxide dismutase (SOD) concentrations were significantly higher (P<0.05) in the low dose group as compared with their respective control. GPx and SOD concentrations were significantly higher (P<0.05) in the high dose groups as compared to low dose and control groups respectively. Conclusion: CAT concentration decreased dose-dependently, while GPx and SOD concentrations increased dose-dependently among treated groups. Treatment with C. sativa revealed a paradoxical effect on CAT concentration with respect to GPx and SOD concentrations. Therefore, oral ingestion of ethanolic extract of C. sativa may not have significant effect on the body’s antioxidant stores due to the balance created for CAT deficiency by increased GPx and SOD concentrations.

scholarly journals Antiviral Efficacy and Pharmacokinetics of Oral Adefovir Dipivoxil in Chronically Woodchuck Hepatitis Virus-Infected Woodchucks

2001 ◽  
Vol 45 (10) ◽  
pp. 2740-2745 ◽  
Author(s):  
John M. Cullen ◽  
Daniel H. Li ◽  
Cynthia Brown ◽  
Eugene J. Eisenberg ◽  
Kenneth C. Cundy ◽  
...  
Keyword(s):  
Body Weight ◽  
Oral Bioavailability ◽  
Adefovir Dipivoxil ◽  
Dose Group ◽  
Low Dose ◽  
Hepatitis Virus ◽  
High Dose Group ◽  
Woodchuck Hepatitis Virus ◽  
High Dose ◽  
Antiviral Efficacy

ABSTRACT The antiviral efficacy of orally administered adefovir dipivoxil was evaluated in an 18-week study (12 weeks of treatment and 6 weeks of recovery) conducted with woodchucks chronically infected with woodchuck hepatitis virus (WHV). Adefovir dipivoxil is a prodrug of adefovir designed to enhance its oral bioavailability. Following administration of 15 mg of adefovir dipivoxil per kg of body weight in four WHV-infected animals, the mean maximum concentration of adefovir in serum was 0.462 μg/ml, with an elimination half-life of 10.2 h, and the oral bioavailability of adefovir was estimated to be 22.9% (±11.2%). To study antiviral efficacy, the animals were divided into three groups. There were six animals each in a high-dose group (15 mg/kg/day) and a low-dose group (5 mg/kg/day). A vehicle control group consisted of five animals because WHV DNA was detectable only by PCR at the time of the study in one of the original six animals. Efficacy was evaluated by determining the levels of WHV DNA in serum. The geometric mean WHV DNA level for the high-dose group diminished by >40-fold (>1.6 log10) after 2 weeks of treatment and >300-fold (>2.5 log10) at 12 weeks. There was a >10-fold reduction in five of six low-dose animals by 2 weeks, but levels were unchanged in one animal. By 12 weeks of treatment there was a >45-fold (>1.6 log10) reduction of WHV DNA levels, and serum WHV DNA levels were below the limit of quantification in three of six animals. Viral DNA levels returned to pretreatment levels during the 6-week recovery period. There were no clinically significant changes in body weight, hematology, or serum chemistry values, including bicarbonate or lactate, in any of the treated animals. No histologic evidence of liver injury was apparent in the biopsies. Under the conditions of this study, adefovir dipivoxil was an effective antihepadnaviral agent.

The Subacute and Subchronic Oral Toxicity of 1,3-Dichloropropane in the Rat

1991 ◽  
Vol 10 (4) ◽  
pp. 421-430 ◽  
Author(s):  
James B. Terrill ◽  
Merrel Robinson ◽  
Gary W. Wolfe ◽  
Leonard H. Billups
Keyword(s):  
Body Weight ◽  
Food Consumption ◽  
Total Protein ◽  
Dose Group ◽  
Low Dose ◽  
Clinical Chemistry ◽  
High Dose Group ◽  
Blood Levels ◽  
High Dose ◽  
Dose Levels

1,3-Dichloropropane (DCP) was administered by gavage for 14 and 90 days to male and female Sprague-Dawley-derived rats (10/sex/group). In the 14-day study using dose levels of 200, 600, and 1800 mg/kg/day, all high-dose group animals died, and none died in the other two treatment groups. Other signs associated with treatment in high-dose animals included languid behavior, salivation (also seen in middose group animals), dyspnea, and prostration. No differences were found between animals in the low-dose or middose groups compared to the control animals for body weight, food consumption, hematology, and gross postmortem and histopathology data. Total protein and albumin blood levels were increased for low-dose and middose females, and middose females, respectively. The clinical chemistry findings appeared to be treatment-related, since they were accompanied by significantly increased liver weights (absolute and relative; both sexes of middose animals) and kidney weights (absolute and relative; middose males). The dose levels used in the 90-day study, chosen on the results of the 14-day study, were 50, 200, and 800 mg/kg/day. All animals survived to termination. Males in the high-dose group exhibited a significant decrease in body weight, whereas females in this group exhibited urine-stained fur. No treatment-related effects were found in food consumption or hematology data. Alkaline phosphatase, alanine aminotransferase (males only), albumin, and total protein for high-dose group animals were increased. These findings were accompanied by increases in liver weight for low-dose (females only), middose, and high-dose animals and kidney weights for middose and high-dose group animals. Microscopic evaluations revealed centrilobular hepatocellular hypertrophy for the high-dose group animals and an exacerbation of chronic progressive nephropathy for middose (males only) and high-dose animals.

Intensive Initial Oral Anticoagulation and Shorter Heparin Treatment in Deep Vein Thrombosis

1984 ◽  
Vol 52 (03) ◽  
pp. 276-280 ◽  
Author(s):  
Sam Schulman ◽  
Dieter Lockner ◽  
Kurt Bergström ◽  
Margareta Blombäck
Keyword(s):  
Deep Vein Thrombosis ◽  
Oral Anticoagulation ◽  
Dose Group ◽  
Low Dose ◽  
Clinical Signs ◽  
Coagulation Factor ◽  
High Dose ◽  
Vein Thrombosis ◽  
Heparin Treatment ◽  
Deep Vein

SummaryIn order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation (“low-dose”) and heparin or a more intense oral anticoagulation (“high-dose”) with a shorter period of heparin treatment.In the first part of the study 129 patients were randomized. The “low-dose” group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the “high-dose” group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis.In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 (“low-dose”) and 3.7 (“high-dose”) days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred.Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.

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