Pharmacokinetics and Excretion of Hydroxysafflor Yellow A, a Potent Neuroprotective Agent from Safflower, in Rats and Dogs
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Studies were conducted to characterize the pharmacokinetics and excretion of hydroxysafflor yellow A (HSYA) in rats and dogs after administration by intravenous injection or infusion. Plasma, urine, feces and bile concentrations of HSYA were measured using five validated mild HPLC methods. Linear pharmacokinetics of HSYA after the intravenous administrations were found at doses ranging from 3 to 24 mg/kg in rats and from 6 to 24 mg/kg in dogs. At a dose of 3 mg/kg, HSYA in urine, feces and bile was determined. For 48 h after dosing, the amount of urinary excretion accounted for 52.6 ± 17.9 % (range: 31.1 - 78.7 %, n = 6) of the dose, and the amount of fecal amount accounted for 8.4 ± 5.3 % (range 1.7 - 16.4 %, n = 6) of the dose. Biliary excretion amount accounted for 1.4 ± 1.0 % (range 0.4 - 2.9 %; n = 6) of the dose for 24 h after dosing. Percent plasma protein binding of HSYA ranged from 48.0 to 54.6 % at 72 h. In summary, five mild HPLC methods for the determinations of HSYA in rat plasma, urine, feces, bile and dog plasma have been developed and successfully applied to preclinical pharmacokinetics and excretion of HSYA in rats and dogs. The results of excretion studies indicated that HSYA was rapidly excreted as unchanged drug in the urine. In view of previous pharmacological work, the concentration-dependent neuroprotective effect of HSYA in rats was defined.One group of rabbits were injected intraperitoneally with diethyllead dichloride (7.7 mg Pb/kg) and another group of rabbits were likewise injected with an equivalent lead dose of lead acetate. These rabbits were followed up for changes in the lead amounts excreted daily in the urine and feces from 24 h through 7 d after the injection, respectively. In the group of rabbits injected with diethyllead dichloride (one of 3 rabbits died during the observation), an amount of lead equivalent to about 25% of the injected dose was excreted in the urine during the first 24 h after the injection. Also, an amount of lead equivalent to about 28% of the injected lead was excreted in the feces during the first 3 d, and the total lead excretion during the 7 d after the injection corresponded to about 60% of the injected dose of diethyllead. One day after dosing, the total lead in the urine was made up of about 92% diethyllead, about 7% inorganic lead and about 1% triethyllead. One day after dosing, the total lead in the feces consisted of about 63% inorganic lead, about 28% diethyllead and about 9% triethyllead. Three days after dosing, the total lead in feces comprised about 98% inorganic lead, about 1% diethyllead and about 1% triethyllead. In the group of 3 rabbits injected with lead acetate, the total lead amount excreted in both the urine and feces during the 7 d after the injection corresponded to only about 9% of the injected dose of lead acetate. This study revealed that the administration of diethyllead dichloride was followed by earlier excretion of a larger amount of lead in the urine and feces than that of lead acetate.Very small amounts of triethyllda were detected in the liver, kidney, bile and urine of the rabbits injected with diethyllead dichloride 7 d after the injection. In the liver, the triethyllead accounted for about 50% of the total lead amount. The triethyllead was derived from the diethyllead in vivo. The detection of triethyllead in organs 7 d after the injection of diethyllead was assumed to have resulted from the slow excretion of triethyllead, compared to diethyllead.
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Long term daily dosing for patients and families may be challenging due to food aversions, dosing protocols, and age of the patient. The few long term studies suggest that low quantity daily dosing is associated with passing higher dose challenges over the long term, whereas high dose maintenance may protect for longer avoidance intervals. We review the data for peanut and suggest several strategies for your patients.
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This chapter explains the rational behind the concept of pharmacokinetics-guided dosing and dashboards, and the expected benefit of dashboards in improving therapy with monoclonal antibodies in inflammatory disease. It outlines a brief description of the various dosing strategies (both the induction and maintenance phases). In four dosing strategies, induction phase doses were administered as a two-hour intravenous infusion fixed at 5 mg kg-1 at Weeks 0, 2, and 6 as per label recommendations. Maintenance phase doses varied depending on the strategy: label dosing, stepwise adaptive dosing, proportional adaptive dosing, and Bayesian adaptive dosing. The goal of adaptive dosing strategies using Bayesian systems is to identify a dose/dosing frequency that maximizes the likelihood of an individual patient achieving a target exposure associated with an improved clinical outcome. The development of Bayes dosing systems in inflammatory bowel diseases currently presents challenges in defining how the development and implementation of such devices are funded, reimbursed, and implemented clinically.
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Four lambs were placed on metabolism studies and fed two different levels of stilbestrol. At the 1 mg. level per lamb per day, 51% of the stilbestrol appeared in the feces and 25% in the urine. At the 2 mg. level, 45% appeared in the feces and 39% in the urine. Combining both levels of feeding, 80% of the fed stilbestrol was recovered in the urine and feces. The possible fate of the remaining 20% is briefly discussed.
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Sensitivity and specificity of dosing alerts for dosing errors among hospitalized pediatric patients
To determine the sensitivity and specificity of a dosing alert system for dosing errors and to compare the sensitivity of a proprietary system with and without institutional customization at a pediatric hospital.A retrospective analysis of medication orders, orders causing dosing alerts, reported adverse drug events, and dosing errors during July, 2011 was conducted. Dosing errors with and without alerts were identified and the sensitivity of the system with and without customization was compared.There were 47,181 inpatient pediatric orders during the studied period; 257 dosing errors were identified (0.54%). The sensitivity of the system for identifying dosing errors was 54.1% (95% CI 47.8% to 60.3%) if customization had not occurred and increased to 60.3% (CI 54.0% to 66.3%) with customization (p=0.02). The sensitivity of the system for underdoses was 49.6% without customization and 60.3% with customization (p=0.01). Specificity of the customized system for dosing errors was 96.2% (CI 96.0% to 96.3%) with a positive predictive value of 8.0% (CI 6.8% to 9.3). All dosing errors had an alert over-ridden by the prescriber and 40.6% of dosing errors with alerts were administered to the patient. The lack of indication-specific dose ranges was the most common reason why an alert did not occur for a dosing error.Advances in dosing alert systems should aim to improve the sensitivity and positive predictive value of the system for dosing errors.The dosing alert system had a low sensitivity and positive predictive value for dosing errors, but might have prevented dosing errors from reaching patients. Customization increased the sensitivity of the system for dosing errors.
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Studies have reported high prevalence of inappropriate dosing in patients with renal impairment, which was significantly reduced with pharmacists' interventions. The objective of this study was to assess the proportions of renal drug dosing errors following the implementation of pharmacists-led renal drug dosing adjustment program. This was a quasi-experimental study conducted at the King Abdul Aziz Medical City, a tertiary teaching hospital, Jeddah, Saudi Arabia. The study comprised of 3 phases. The pre-phase and post-phase evaluated drug orders for dosing appropriateness. During the intervention phase, a renal drug dosing adjustment program was implemented, which included educational sessions on dosing in renal insufficiency and a renal drug dosing guidance. The primary outcome was to assess the change in the proportions of dosing errors following the intervention. In the pre-phase, inappropriate dosing was noted in 20.1% (70/348) of orders that required dosing adjustment. Among the total dosing errors, 44.2% (31/70) were further corrected, and pharmacists have documented intervention in 48.3% (15/31) of the corrected orders. In the post-phase, inappropriate dosing was noted in 21.9% (76/346) of orders that required dosing adjustment. Among the total dosing errors, 39.4% (30/76) were further corrected, and pharmacists have documented intervention in 66.6% (20/30) of the corrected orders. There was no statistically significant difference in inappropriate drug dosing between pre-phase and post-phase with a P = 0.56. The intervention was not associated with significant reduction in renal dosing errors, although pharmacist involvement in the corrected orders orders increased after the implementation of the intervention. This may indicate the need to integrate renal dosing guidance into the hospital prescribing system to optimize drug dosing in renal patients.
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To study the feeding behavior of the guinea pigs, in terms of food consumption, con- sumption of cecotrophs and excretion of hard feces, was the objective of this study. For this purpose, 16 adult male type A1 guinea pigs were used, which were individually housed and fed a commercial pelleted diet. For 24 hours and with a frequency of approximately one hour, the rhythms of food consumption, excretion of faeces and excretion of cecotrophs were recorded. I record the data in three moments. At the time, only the consumption of food and the excretion of feces were measured. At time two and three, half of the ani- mals were given an Elizabethan collar to prevent them from cecrophilia. For the analysis of the results, a mixed model of repeated measures was used. In which the main effects were the treatment, the time and their interaction and the random effect was the animal nested to the treatment. The means were compared using a protected t-test. At time 1, for food consumption and stool excretion, no differences were detected between day and night (P ≥ 0,44). At time 2, avoid cecotrophy, reduced feed intake and excretion of feces at ap- proximately 50 % (P ≤ 0,05). While between day and night no differences were detected for the consumption of food, excretion of faeces and excretion of cecotrophs (P ≥ 0,08). No differences were detected between the time of day and allow cecotrophy (P ≥ 0,44). Additionally, it was observed that the animals that did not have the collar did not excrete cecotrophs. It is analysis of the food consumption rhythms showed peaks of food consum- ption at 12:00, 15:00 and 18:00 (P < 0, 001). On the other hand, the excretion of feces was reduced in the first hours of the morning, but after 15:00 the excretion of feces increases (P < 0,001). In the animals with Elizabethan collar, no differences were detected in the rates of excretion of cecotrophs (P = 0,241). In conclusion during the 24 hours peaks of food consumption are observed that shows a rhythm of food consumption and possibly in
the morning the animal spends time to consume cecotrofos.
Key words: nutritional behavior, cecotrophy, cecotropes
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Nivolumab has received regulatory approval to be given by weight-based or flat dosing every two weeks or by flat dosing every four weeks. However, flat dosing would lead to unnecessarily high doses for patients with lower body weight, increasing the drug usage and probability of toxicity. We review the rationale of using a four-weekly hybrid dosing strategy using weight-based and flat-dosing regimens adopted by some jurisdictions.
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