Hydrolysis Influence on Phytochemical Composition, Antioxidant Activity, Plasma Concentration, and Tissue Distribution of Hydroethanolic Ilex paraguariensis Extract Components

The infusion of aerial parts of Ilex paraguariensis is widely consumed. Its antioxidant activity suggests an important role of this plant in the treatment/prevention of oxidative stress related diseases. Plant extract active compounds are frequently found in esterified form that may be poorly absorbed. Hydrolysis of the extract is a possible approach to increase its bioavailability. The aim of this study was to perform a phytochemical analysis and evaluate in rats the plasma concentration and tissue distribution of antioxidant compounds in the hydroethanolic extract of Ilex paraguariensis, before and after enzymatic hydrolysis. Both extracts presented high antioxidant activity and phenolic content. Rats given single or repeated doses of the hydrolyzed extract showed increased plasma antioxidant activity and higher plasma levels of caffeic acid. However, no changes of endogenous antioxidants were observed. In conclusion, hydrolysis of the extract of Ilex paraguariensis is a strategy to improve its bioavailability and in vivo antioxidant activity.

Correlation between plasma concentration of cilazapril and haemodynamic and hormonal effects in healthy man.

1. The haemodynamic and humoral effects of cilazapril, a new angiotensin converting enzyme (ACE) inhibitor, were evaluated in normotensive healthy volunteers. 2. Single oral doses of 1.25, 2.5, 5 and 10 mg of cilazapril inhibited ACE by greater than or equal to 90% and induced the expected pattern of changes of the renin-angiotensin-aldosterone-system. 3. Cilazapril had a long duration of action, since some ACE inhibition was still present 72 h after drug intake. 4. Cilazapril administered intravenously at doses of 5 and 20 micrograms kg-1 for 24 h did not produce any significant effects. 5. During repeated administration of cilazapril for 8 days, no accumulation of cilazaprilat was observed and the clinical tolerance was excellent. 6. In normal volunteers, cilazapril administered orally acts as a potent inhibitor of converting enzyme.

Usefulness of methadone plasma concentration measurement in patients receiving nevirapine or efavirenz.

Objective: To determine methadone plasma trough and peak concentrations in patients presenting opiate withdrawal symptoms after introduction of nevirapine or efavirenz. To describe the disappearance of these symptoms after methadone titration based on plasma concentrations rather than on the symptoms. Methods: Nine patients undergoing highly active antiretroviral therapy (HAART) and either nevirapine or efavirenz treatment were monitored daily for opiate withdrawal in a specialized drug addiction center. Methadone dose was titrated daily, and plasma concentrations were measured. The data are retrospective (case series). Results: Several patients complained of symptoms such as nausea, vomiting, accelerated intestinal transit, or insomnia. Even after methadone titration based on clinical symptoms, patients and health-care providers trained in infectious disease did not classify these as withdrawal symptoms and considered them as the side effects of HAART or anxiety. Methadone plasma trough concentration showed low levels of (R)- and (R,S)-methadone. Further methadone dose adjustment according to plasma level resulted in the disappearance of these withdrawal symptoms. The daily methadone dose was split when the peak/trough (R)-methadone ratio was more than 2. Conclusions: When introducing efavirenz or nevirapine to patients undergoing methadone treatment, withdrawal symptoms should be monitored, especially those such as insomnia, vomiting, or nausea. Methadone plasma trough and peak measurements can be of value in preventing unnecessary side effects of HAART.

Orosomucoid (alpha1-acid glycoprotein) plasma concentration and genetic variants: effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation.

BACKGROUND AND OBJECTIVE: Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug. METHODS: Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined. RESULTS: Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics. CONCLUSION: ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.

Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study.

PURPOSE: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. METHODS: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. RESULTS: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. CONCLUSION: Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Valganciclovir in adult solid organ transplant recipients: pharmacokinetic and pharmacodynamic characteristics and clinical interpretation of plasma concentration measurements.

Valganciclovir and ganciclovir are widely used for the prevention of cytomegalovirus (CMV) infection in solid organ transplant recipients, with a major impact on patients' morbidity and mortality. Oral valganciclovir, the ester prodrug of ganciclovir, has been developed to enhance the oral bioavailability of ganciclovir. It crosses the gastrointestinal barrier through peptide transporters and is then hydrolysed into ganciclovir. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of therapeutic drug monitoring. Based on currently available literature, ganciclovir pharmacokinetics in adult solid organ transplant recipients receiving oral valganciclovir are characterized by bioavailability of 66 +/- 10% (mean +/- SD), a maximum plasma concentration of 3.1 +/- 0.8 mg/L after a dose of 450 mg and of 6.6 +/- 1.9 mg/L after a dose of 900 mg, a time to reach the maximum plasma concentration of 3.0 +/- 1.0 hours, area under the plasma concentration-time curve values of 29.1 +/- 5.3 mg.h/L and 51.9 +/- 18.3 mg.h/L (after 450 mg and 900 mg, respectively), apparent clearance of 12.4 +/- 3.8 L/h, an elimination half-life of 5.3 +/- 1.5 hours and an apparent terminal volume of distribution of 101 +/- 36 L. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Unexplained interpatient variability is limited (18% in apparent clearance and 28% in the apparent central volume of distribution). There is no indication of erratic or limited absorption in given subgroups of patients; however, this may be of concern in patients with severe malabsorption. The in vitro pharmacodynamics of ganciclovir reveal a mean concentration producing 50% inhibition (IC(50)) among CMV clinical strains of 0.7 mg/L (range 0.2-1.9 mg/L). Systemic exposure of ganciclovir appears to be moderately correlated with clinical antiviral activity and haematotoxicity during CMV prophylaxis in high-risk transplant recipients. Low ganciclovir plasma concentrations have been associated with treatment failure and high concentrations with haematotoxicity and neurotoxicity, but no formal therapeutic or toxic ranges have been validated. The pharmacokinetic parameters of ganciclovir after valganciclovir administration (bioavailability, apparent clearance and volume of distribution) are fairly predictable in adult transplant patients, with little interpatient variability beyond the effect of renal function and bodyweight. Thus ganciclovir exposure can probably be controlled with sufficient accuracy by thorough valganciclovir dosage adjustment according to patient characteristics. In addition, the therapeutic margin of ganciclovir is loosely defined. The usefulness of systematic therapeutic drug monitoring in adult transplant patients therefore appears questionable; however, studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens.

Relationship between photoperiod, plasma concentration of ionic calcium and the histology of the prolactin-secreting cells of the rostral pars distalis of the pituitary gland, the corpuscles of stannius and the ultimobranchial gland in the goldfish, Carassius auratus L. /

The relationship between photoperiod, plasma concentration of ionic calcium and the histology of the prolactin-secreting cells of the rostral pars distalis of the pituitary gland, the Corpuscles of Stannius and the Ultimobranchial gland were investigated. Neither the plasma concentration of ionic calcium nor histologically apparent prolactin cell activity could be correlated with photoperiod. Some evidence of a photoperiodic effect on both the Corpuscles of Stannius and the Ultimobranchial gland was obtained. The expected reciprocal relationship between the activity of these glands was not obvious at the histological level . Quantitative and qualitative analysis at the light microscope level revealed, however, that the hormone prolactin-secreting eta cells of the rostral pars distalis and the hypocalcin-secreting cells of the Corpuscles of Stannius may be arranged in a lamellar pattern comprized of synchronous bands of cells in like-phase of a secretory cycle consisting of four stages - synthesis, storage, release and reorganization. Such synchronized cell cycles in these glands have not heretofore been described in literature. It is suggested that the maintenance of at least 255? of the cells in any one phase of the cycle ensures a supply of the required hormone at all times.

Short communication: plasma concentration of glucose-dependent insulinotropic polypeptide may regulate milk energy production in lactating dairy cows

In dairy cows, an increase in plasma concentration of glucose-dependent insulinotropic polypeptide (GIP) is associated with an increase in metabolizable energy intake, but the role of GIP in energy partitioning of dairy cattle is not certain. The objective of this study was to examine the relationship between plasma GIP concentrations and energy partitioning toward milk production. Four mid-lactation, primiparous, rumenfistulated Holstein-Friesian cows were fed a control diet of 55% forage and 45% concentrate [dry matter (DM) basis] in a 4 × 4 Latin square design with 4-wk periods. The 4 treatments were (1) control diet fed at 1000 and 1600 h, and (2) once-daily (1000 h) feeding, (3) twice daily (1000 and 1600 h) feeding, and (4) 4 times/d (1000, 1600, 2200 and 0400 h) feeding of the control diet plus 1 dose (1.75 kg on a DM basis at 0955 h) into the rumen of supplemental vegetable proteins (Amino Green; SCA NuTec Ltd., Thirsk, UK). Measurements of respiratory exchange and energy balance were obtained over 4 d during the last week of each period while cows were housed in open-circuit respiration chambers. Blood was collected from the jugular vein every 30 min for 12 h, using indwelling catheters, starting at 0800 h on d 20 of each period. Plasma GIP concentration was measured in samples pooled over each 5 consecutive blood samplings. The relationships between plasma GIP, DM intake, heat production, respiratory quotient, milk yield, and milk energy output were analyzed using linear correlation procedures, with metabolizable intake as a partial variant. Plasma GIP concentration was not correlated with heat production, or milk yield, but was positively correlated with milk energy yield (correlation coefficient = 0.67) and negatively correlated with RQ (correlation coefficient = −0.72). The correlations between GIP and RQ and milk energy output do not imply causality, but suggest that a role for GIP may exist in the regulation of energy metabolism in dairy cows.

DAILY VARIATION IN PLASMA-CONCENTRATION OF FENCAMFAMINE AND STRIATAL DOPAMINE-RECEPTORS IN RATS

Fencamfamine (FCF) is a psychostimulant drug classified as an indirect dopamine agonist. In the present study we evaluated the daily variation in plasma FCF concentration and in striatal dopamine receptors. Adult male Wistar rats (250-300 g) maintained on a 12-h light/12-h dark cycle (lights on at 07:00 h) were used. Rats received FCF (10.0 mg/kg, ip) at 09:00, 15:00, 21:00 or 03:00 h and blood samples were collected 30 (N = 6) or 60 (N = 6) min after the injections. Plasma FCF was measured by gas chromatography using an electron capture detector. Two-way ANOVA showed significant differences in FCF concentration when blood samples were collected 30 min after the injection, and the highest value was obtained following injection 21:00 h. Moreover, at 15:00, 21:00 and 03:00h, plasma FCF levels were significantly lower 60 min after injection when compared to the 30-min interval. Two other groups of rats (N = 6) were decapitated at 09:00 or 21:00 h and the striata were dissected for the binding assays. The Bmax for [H-3]-spiroperidol binding to striatal membranes was higher at 21:00 h, without changes in affinity constant (Kd). In conclusion, plasma FCF levels and dopamine receptors undergo daily variation,a phenomenon that should be considered to explain the circadian time-dependent effects of FCF.

Tumescent local anesthesia with ropivacaine in different concentrations in bitches undergoing mastectomy: plasma concentration and post-operative analgesia

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Influence of cardiopulmonary bypass on cefuroxime plasma concentration and pharmacokinetics in patients undergoing coronary surgery

The aims of this study were to evaluate the influence of cardiopulmonary bypass (CPB) on the plasma concentrations and pharmacokinetics of cefuroxime and to assess whether the cefuroxime dose regimen (a 1.5 g dose, followed by 750 mg every 6 h for 24 h) is adequate for cardiac surgery antibiotic prophylaxis. A prospective, controlled, observational study compared patients undergoing coronary surgery with CPB (CPB group, n = 10) or off-pump surgery (off-pump group, n = 9). After each cefuroxime dose, blood samples were sequentially collected and analysed using high-efficiency chromatography. For demographic data and pharmacokinetic parameters, the authors used Fisher's exact test for nominal variables and Student's t-test and the Mann-Whitney U-test for parametric and non-parametric variables, respectively. Plasma concentrations were compared using ANOVA, and the percentage of patients with a remaining plasma concentration of > 16 mg/l within 6 h after each bolus was quantified in tabular form. After each cefuroxime bolus was administered, both groups presented a significant decrease in plasma concentration over time (P < 0.001), without differences between the groups. The mean CPB time of 59.7 +/- 21.1 min did not change cefuroxime plasma concentrations or pharmacokinetics. The mean clearance +/- SD (ml/kg/min) and median elimination half-life (h) of the CPB group versus the off-pump group were 1.7 +/- 0.7 versus 1.6 +/- 0.6 (P = 0.67), respectively, and 2.2 versus 2.3 (P = 0.49), respectively. Up to 3 h following the first bolus of 1.5 g, but not after 6 h, all patients had plasma concentrations > 16 mg/l (CPB group = 20% and off-pump group = 44%). However, after all 750 mg boluses were administered, concentrations < 16 mg/dl were reached within 3 h. CPB does not influence cefuroxime plasma concentrations. The dosing regimen is adequate for the intraoperative period, but in the immediate postoperative period, it requires further review.

Orosomucoid (alpha1-acid glycoprotein) plasma concentration and genetic variants: effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation

BACKGROUND AND OBJECTIVE: Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug. METHODS: Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined. RESULTS: Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics. CONCLUSION: ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.

Prospective determination of imipenem concentration of the plasma of critically-ill children

ABSTRACT Imipenem plasma-concentrations were measured in 19 critically-ill children (median 0.8 year, range 0.02-12.9 years). Wide inter-individual variations (2-4x at peak and >10x at through concentrations) resulted in unpredictable plasma-levels in several children. To avoid subtherapeutic drug levels we recommend at least 100 mg/kg/day of imipenem-cilastatin in critically-ill children requiring such therapy.