End Of Drug Infusion Research Articles

Intraoperative dexmedetomidine attenuates norepinephrine levels in patients undergoing transsphenoidal surgery: a randomized, placebo-controlled trial

BackgroundDexmedetomidine has sympatholytic effects. We investigated whether dexmedetomidine could attenuate stress responses in patients undergoing endoscopic transnasal transseptal transsphenoidal surgery.MethodsForty-six patients were randomized to receive a continuous infusion of 0.9% saline (n = 23) or dexmedetomidine (n = 23). Immediately after general anesthesia induction, the dexmedetomidine group received a loading dose of 1 mcg/kg dexmedetomidine over 10 min, followed by a maintenance dose of 0.2–0.7 mcg/kg/h and the control group received 0.9% saline at the same volume until 30 min before the end of surgery. Serum levels of epinephrine, norepinephrine, and glucose were assessed before surgery (T1) and the end of drug infusion (T2). The primary outcome was the change in norepinephrine levels between the two time points.ResultsChanges (T2-T1 values) in perioperative serum norepinephrine levels were significantly greater in the dexmedetomidine group than in the control group (median difference, 56.9 pg/dL; 95% confidence interval, 20.7 to 83.8 pg/dL; P = 0.002). However, epinephrine level changes did not show significant intergroup differences (P = 0.208). Significantly fewer patients in the dexmedetomidine group than in the control group required rescue analgesics at the recovery area (4.3% vs. 30.4%, P = 0.047).ConclusionsIntraoperative dexmedetomidine administration reduced norepinephrine release and rescue analgesic requirement. Dexmedetomidine might be used as an anesthetic adjuvant in patients undergoing transnasal transseptal transsphenoidal surgery.Trial registrationClinical Trial Registry of Korea, identifier: KCT0003366; registration date: 21/11/2018; presenting author: Ji Seon Jeong.

Evaluation of the effects of dexmedetomidine infusion on oxygenation and lung mechanics in morbidly obese patients with restrictive lung disease

BackgroundDexmedetomidine infusion improves oxygenation and lung mechanics in patients with chronic obstructive lung disease; however, its effect in patients with restrictive lung disease has not been thoroughly investigated yet. The aim of this work was to evaluate the effects of dexmedetomidine infusion on oxygenation and lung mechanics in morbidly obese patients with restrictive lung disease.MethodsForty-two morbidly obese patients scheduled for bariatric surgery were included in the study. Patients were randomized to receive either dexmedetomidine infusion at a bolus dose of 1mcg/Kg followed by infusion at 1 mcg/Kg/hour for 90 min (Dexmedetomidine group), or normal saline infusion (Control group). Both groups were compared with regard to: oxygenation {P/F ratio: PaO2/fraction of inspired oxygen (FiO2)}, lung compliance, dead space, plateau pressure, blood pressure, and heart rate.ResultsDexmedetomidine group showed significant improvement of the PaO2/FiO2 ratio, and higher lung compliance compared to control group by the end of drug infusion. Dexmedetomidine group demonstrated decreased dead space, plateau pressure, blood pressure, and heart rate compared to control group by the end of drug infusion.ConclusionA 90-min dexmedetomidine infusion resulted in moderate improvement in oxygenation and lung mechanics in morbidly obese patients with restrictive lung disease.Trial registrationclinicaltrials.gov: NCT02843698 on 20 July 2016.

381 Pharmacokinetics and Pharmacodynamics of Voriconazole in Burn Patients: A Case Series

Optimizing pharmacokinetics (PK) and pharmacodynamics (PD) of antifungals used to treat burn-associated fungal infection may improve survival in burn patients. In this population, altered organ function, various physiologic changes, and use of continuous renal replacement therapy (CRRT) can affect PK/PD. The objective of this study was to measure PK/PD adequacy of voriconazole (VOR), a common antifungal, in burn patients. This was an IRB-approved, prospective, observational study of antimicrobial PK/PD in critically ill burn patients. One patient was treated concurrently with CRRT, while two patients had preserved renal function (non-CRRT). Venous or arterial blood was sampled at pharmacologic steady-state prior to dose administration, at 0, 0.5, 1, 2, 4, and 8 hours after the end of drug infusion, and prior to the next dose. Total drug plasma concentrations were determined by high-performance liquid chromatography (HPLC). PK/PD parameters were estimated by non-compartmental analysis (NCA) using WinNonLin (Certara, Inc). The VOR PK/PD target was defined as an AUC24:MIC ≥ 25. Three burn patients (one on CRRT, age 38 years, 29% TBSA; two non-CRRT, aged 24 and 50 years, 79.9 ± 7.6% TBSA) receiving VOR (3.6 ± 0.059 mg/kg IV q12h) were analyzed. VOR PK/PD parameters were determined (Table 1). The patient receiving CRRT (patient 3) had lower Cmax (1.5 vs. 10.7 ± 1.2) and AUC (13.5 vs. 92.5 ± 16.3), and higher CLss (17.8 vs. 5.7 ± 3) than non-CRRT patients. Patient 2 had lower Vss (44.8 vs. 396 ± 34.6), and patient 1 had higher t1/2 (35.1 vs. 11.8 ± 1.45) than other patients. PK/PD target was met for MIC ≤ 1 for all patients. PK parameters for VOR varied widely in three critically ill burn patients. Because VOR is hepatically metabolized, it is unknown whether this variability is due to CRRT, or individual in metabolic activity. Additional data are needed to guide dosage selection and understand the impact of CRRT in this patient population. Ensuring optimal PK/PD of antifungal agents in critically ill burn patients may improve survival in this population with many physiologic disturbances which can undermine the effectiveness of therapy.

Effect of dexmedetomidine on spinal p38MAPK expression during remifentanil-induced postoperative hyperalgesia in rats with incisional pain

Objective To evaluate the effect of dexmedetomidine on spinal p38 mitogen-activated protein kinase (p38MAPK) expression during remifentanil-induced hyperalgesia in rats with incisional pain. Methods Forty-eight healthy male Sprague-Dawley rats, aged 6 weeks, weighing 220-250 g, were randomly divided into 4 groups (n= 12 each) using a random number table: control group (group C), incision pain group (group IP), incision pain + remifentanil group (group IP+ R), and incision pain + remifentanil + dexmedetomidine group (group IP+ R+ D). After successful establishment of the model of incisionsal pian, remifentanil 1.0 μg/kg was infused for 4 h via the tail vein in group IP+ R; remifentanil 1.0 μg/kg was infused for 4 h via the tail vein, and dexmedetomidine 10 μg/kg was simultaneously infused for 4 h via the jugular vein in group IP+ R+ D; the equal volume of normal saline was infused for 4 h via the tail and jugular veins in C and IP groups.The mechanical paw withdrawal threshold (MWT) was measured at 24 h before operation (T0), and at 4, 6, 24 and 48 h after the end of drug infusion (T1-4). After measurement of MWT at T4, the expression of p38MAPK was determined using immuno-histochemistry. Results Compared with group C, the MWT was significantly decreased at T1-4, and the expression of p38MAPK was up-regulated at T4 in IP and IP+ R groups (P 0.05). Compared with group IP, the MWT was significantly decreased at T1-4, and the expression of p38MAPK was up-regulated at T4 in group P+ R, and the MWT was significantly increased at T1-4, and the expression of p38MAPK was down-regulated at T4 in group IP+ R+ D (P<0.05). Compared with group IP+ R, the MWT was significantly increased at T1-4, and the expression of p38MAPK was down-regulated at T4 in group IP+ R+ D (P<0.05). Conclusion The mechanism by which dexmedetomidine reduces hyperalgesia induced by remifentanil is related to down-regulation of spinal p38MAPK expression in the rats with incisional pain. Key words: Dexmedetomidine; Pain, postoperative; Hyperalgesia; p38 mitogen-activated protein kinases; Spinal cord

Oral Cryotherapy For The Prevention Of Mucositis Following Myeloablative Conditioning and Hematopoietic Stem Cell Transplantation

PurposeTo investigate the effect of oral cryotherapy for the prevention of oral mucositis in recipients of Hematopoietic Stem Cell Transplantation(HSCT) after myeloablative conditioning and to specify its best timing and duration. MethodsThis study was a prospective randomized controlled clinical study, involving 37 patients from the bone marrow transplantation unit of the First Affiliated Hospital of Soochow University. In addition to the basic oral care given to all patients, study participants were divided into two experimental groups given oral cryotherapy and one control group. Optimal timing of the oral cryotherapy intervention was explored, based on pharmacokinetics of drug elimination. During the period of conditioning, experimental group 1(Exp.1) received oral cryotherapy from the beginning of drug infusion continuously until the end of drug infusion; experimental group 2 (Exp.2) received oral cryotherapy starting half way through the infusion of the drug. The rate and severity of mucositis was evaluated according to the National Cancer Institute-Common Toxicity Criteria. Data were then analyzed using SPSS15.0. ResultsOral mucositis occurred on cheeks (43.9%), tongue (27.57%) and lips (15.7%). There was no difference regarding the incidence of severe mucositis ≥ Grade 3 (33% in Exp.1 group, 15% in Exp.2 group, and 25% in the control group, p = ns) and its duration (8 days in Exp.1 group, 2.5 days in Exp.2 group, and 7 days in the control group, p = ns). However, the frequency of vomiting episodes was significantly reduced in Exp.2 with 10 episodes (2-28) versus 21 (2-60) in the control group (p=0.01) and 12.5 (2-39) in exp 1. [Conclusions] A short duration of oral cryotherapy beginning at midpoint of infusing the chemotherapy schedule significantly reduced vomiting associated with myeloablative conditioning. These preliminary results in view of the low statistical power of the study justify further trials. Disclosures:No relevant conflicts of interest to declare.

Light-induced Deterioration Test of Carboplatin under Clinical Settings

Chemotherapeutic drug dosages are calculated precisely based on the patient's height, body weight, and renal function, etc. To ensure safe and favorable outcomes of treatment, dosing solutions are prepared by appropriate mixing of the drug solutions based on such calculations. The package inserts for many injectable preparations include a warning for storing the product "shielded from light." However, there are no reports of stability assessment of a mixed product against light exposure or the residual amount of active ingredient in the dosing solution during or at the end of treatment. We evaluated the stability of carboplatin from the time of mixing of the dosing solution until the end of drug infusion in a clinical-like setting. With 4-hour exposure to outdoor scattered light, the dosing solution began to show discoloration by 1 hour, becoming dark yellow by 4 hours, with reduction of the percent residual carboplatin to about 23%. To identify the optimal light-shielding shade, the dosing solution was shielded from outdoor scattered light with 1 of 3 protective covers: aluminum foil, yellow plastic shade, and brown plastic shade. The yellow plastic shade prevented any changes of the appearance of the dosing solution during the 4-hour exposure period. The percent residual carboplatin, determined by HPLC, in the dosing solution shielded with a yellow plastic shade was about 85.2% at 2 hours and 78.6% at 4 hours. Thus carboplatin dosing solution should be completely shielded from light until infusion is completed.

Comparison of ketamine and fentanyl with propofol in total intravenous anesthesia: a double blind randomized clinical trial

Background: Propofol has emerged as a gold-standard for total inrtravenous anesthesia (TIVA) for short surgical interventions but lack of analgesia remains it’s main shortcoming therefore it is always combined with an analgesic. Ketamine and fentanyl are the popular analgesic in this context. This study was carried out to compare these drugs with propofol to assess hemodynamic and recovery profile of either combination.Methods: Hundred consenting patients undergoing short elective surgeries were randomly allocated into two groups of fifty each: group PF received propofol 2 mg/kg + fentanyl 2 μg/kg for induction and propofol 4 mg/kg/hr + fentanyl 1μg/kg/hr for maintenance of anesthesia and group PK received propofol 2mg/kg + ketamine 1mg/kg for induction and propofol 4mg/kg/hr + ketamine 1 mg/kg/hr for maintenance of anesthesia. Hemodynamic variables were recorded pre, intra and postoperatively at regular intervals. At the end of drug infusion(s), time to spontaneous eye opening and response to postoperative questionnaire was noted to assess recovery. All the data presented as mean + standard deviation and number of patients. Results: Patients in both did not differ significantly in demographic and hemodynamic profile. Time to spontaneous eye opening was similarly comparable in both the groups (8±3 min and 8±2 min) (p=0.53). Response to postoperative questionnaire at 30 minutes after anesthesia was good in both the groups. Incidence of postoperative nausea and vomiting was also insignificant statistically between both the groups. (p=0.74)Conclusion: We concluded that both ketamine and fentanyl are equally safe and efficacious with propofol for short surgical procedures.

Pharmacokinetics of intravenously administered moxifloxacin in eye compartments: an experimental study

The purpose of this study was to evaluate the pharmacokinetics of intravenously administered moxifloxacin, a fourth-generation fluoroquinolone, in different parts of the non-inflamed eye. Moxifloxacin was administered intravenously at a dose of 20 mg/kg moxifloxacin over 30 min. Sampling of peripheral blood, aqueous humour and vitreous was performed at standard time intervals post infusion once in each animal. Moxifloxacin levels were estimated by high-performance liquid chromatography with fluorescence detection. Mean serum concentrations were 3.43, 2.74, 1.48 and 1.12 μg/mL at 0.5, 3, 6 and 24 h after the end of drug infusion, respectively. Respective concentrations in aqueous humour were 2.44, 2.03, 1.30 and 1.09 μg/mL and in vitreous body they were 1.68, 1.87, 1.78 and 1.15 μg/mL. It is concluded that systemic administration of moxifloxacin in rabbits was accompanied by efficient penetration into both the aqueous humour and the vitreous body at concentrations well above the minimum inhibitory concentration for most causative pathogens of endophthalmitis. Further research is mandatory to clarify the clinical significance of these findings.

Pharmacokinetics of Fusidic Acid and Cefepime in Heart Tissues: Implications for a Role in Surgical Prophylaxis

The pharmacokinetic profiles of fusidic acid and cefepime in heart tissues were assessed in 30 patients undergoing elective valve replacement and cardiopulmonary by-pass. Single doses of 1 g of fusidic acid and 2 g of cefepime were administered intravenously to two groups of 15 and 15 patients respectively upon initiation of anes-thesia. Samples of serum, heart valves, myocardium, pericardium, mediastinal fat and sternum were collected within <1 hour, 1-2 h and 2-4 h after the end of drug infusion. Drug concentrations were estimated by a microbiological assay. It was found that con-centrations of fusidic acid in all specimens were 20-fold higher than the MIC90s of methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, being at such levels throughout all period of sampling. Cefepime concentrations in heart valves collected 1-2 h after drug infusion were higher than the MIC90s of multidrug-resistant Enterobacteriaceae. It is concluded that both fusidic acid and cefepime penetrated heart tissues adequately; however only fusidic acid could also accumulate in the mediastinum. These data suggest that both antibiotics may be a good alternative for prophylaxis in open heart surgery.

Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone

We previously demonstrated that peak microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) occurs at the end of drug infusion and correlates with drug pharmacokinetics (PK). In the current study, a new expanded evaluation of drug target effect was undertaken. Patients with advanced solid malignancies were treated with ixabepilone 40 mg/m2 administered as a 1-h i.v. infusion every 3 weeks. Blood, plasma, and tumor tissue sampling was carried out to characterize pharmacodynamics and PK. Forty-seven patients were treated with 141 cycles of ixabepilone. In both PBMCs (n=27) and tumor cells (n=9), peak MBF occurred at the end of infusion; however, at 24-72 h after drug infusion, the number of cells with MBF was significantly greater in tumor cells, relative to PBMCs. A Hill model (EC50=109.65 ng/ml; r2=0.94) was fitted, which demonstrated a relationship between percentage of PBMCs with MBF and plasma ixabepilone concentration. The percentage of PBMCs with MBF at the end of infusion also correlated with severity of neutropenia (P=0.050). Plasma ixabepilone concentration and severity of neutropenia correlate with the level of MBF in PBMCs. Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents.

DY-9760e, a Calmodulin Antagonist, Reduces Brain Damage after Permanent Focal Cerebral Ischemia in Cats

DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate), a calmodulin antagonist, provides protection against Ca(2+) overload-associated cytotoxicity and brain injury after cerebral ischemia in rats. In this study, we assessed the effect of DY-9760e on ischemic infarct volume in cats subjected to permanent focal cerebral ischemia. DY-9760e was infused for 6 h, beginning 5 min after occlusion of the middle cerebral artery. The infarct volume was measured at the end of drug infusion. DY-9760e, at the dose of 0.25 but not 0.1 mg/kg/h, significantly reduced cerebral infarct volume without affecting any physiological parameters, and its protective effect was mainly evident in the cerebral cortex, where the penumbra, a salvageable zone, exists. The present study demonstrates that DY-9760e protects against brain injury after focal ischemia in a gyrencephalic animal as well as in the rodents reported previously and suggests its therapeutic value for the treatment of acute stroke.

Continuous Intrathecal Infusion of Hydromorphone: Safety in the Sheep Model and Clinical Implications

To determine the safety of hydromorphone delivered by continuous intrathecal infusion via implanted delivery systems in sheep. Sheep implanted with intrathecal infusion systems were randomly assigned to receive either 1.5, 3, or 6 mg/day hydromorphone HCl or saline control (3 sheep/dose level) at a fixed infusion rate of 1.92 mL/day for 28-31 days. Infusions were initiated approximately 5 days after surgical implantation of the delivery systems (pumps and intrathecal catheters), and investigators were blinded to doses administered. An additional group of sheep (N=3) received hydromorphone (open label) at a dose of 12 mg/day. All animals were examined daily during drug infusion for changes in behavior and neurologic function. Cerebrospinal fluid was analyzed for protein, cytology, and hydromorphone concentration in samples collected prior to and at the end of drug infusion. The spinal cord with the catheter in situ was removed en bloc and fixed in formalin for microscopic analysis. All sheep receiving intrathecal hydromorphone exhibited gaiting deficits and biting behavior over the caudal lumbar area above the infusion site. Animals treated with 12 mg/day were sedate and lethargic, and exhibited repeated biting behavior over the caudal lumbar area during the study. No lesions were noted in any animal upon gross evaluation of the spinal cord. Microscopic changes were comparable between hydromorphone- and saline-treated animals with one exception. Mild inflammation 5 cm cranial to the catheter tip was present in two of three sheep receiving 12 mg/day and in one of three sheep receiving 1.5 mg/day. Mild chronic inflammation hydromorphone in the vicinity of the catheter was also presented in saline-treated animals. Hydromorphone was not associated with inflammatory mass formation in the sheep model. Further studies are necessary to determine whether hydromorphone is a safer alternative to morphine for continuous intrathecal infusion for the treatment of chronic pain.

Flecainide Test in Brugada Syndrome: A Reproducible but Risky Tool

The flecainide test is widely used in Brugada syndrome. However, its reproducibility and safety remain ill-defined. This study included 22 patients (18 men, mean age 34 years). Mutations in the SCN5A gene were found in eight patients. Two patients had aborted sudden cardiac death, 8 had syncope/presyncope, and 12 were asymptomatic. The ECG was diagnostic in 19 patients and suggestive in 3. At baseline, 21 of 22 patients underwent a flecainide test (2 mg/kg IV bolus over 10 minutes). In 21 of 21 patients the test was diagnostic or amplified the typical ECG pattern. At the end of drug infusion, sustained VT lasting 7-10 minutes developed in two patients. A second flecainide test was performed within 2 months in 20 patients. The test was not repeated in the two patients with prior development of VT. The flecainide test was diagnostic in 20 of 20 patients. Sustained VT occurred in one patient and recurrent VF in another. The reproducibility of the flecainide test was 100%. In 4 (18%) of 22 patients major VAs were documented after the end of flecainide infusion. VA occurred in 3 (43%) of 7 patients with, versus 1 (7%) 15 without SCN5A gene mutation (P < 0.05). No diagnostic ECG changes or arrhythmias developed in 25 control patients without structural heart disease who underwent the same study protocol. This study shows a high flecainide reproducibility, supporting its diagnostic value in Brugada syndrome. However, the occurrence of major VA, significantly higher in patients with documented SCN5A gene mutation, including in asymptomatic patients, mandates the performance under appropriate medical supervision. Whether a slower rate of drug infusion can lower the risk of VA induction, while maintaining the sensitivity of the test should be explored.

Methotrexate concentration in cerebrospinal fluid of the space created by tumor removal.

This paper investigates the post-surgical pharmacokinetics of methotrexate (MTX) in the plasma, the cerebrospinal fluids (CSF), and the spaces created by tumor removal (STR) in patients with glioblastoma, during hyperosmotic disruption of the blood brain barrier (HODBBB) and intra-arterial chemotherapy with MTX. Eight Japanese patients with glioblastoma, three with open STRs and five with closed STRs, received a total of thirteen courses of HODBBB and intra-arterial combination chemotherapy with MTX. The patients were initially administered mannitol, then the anticancer drugs were infused into the carotid artery. Samples of blood and CSF from the STRs were obtained. MTX concentrations were measured by fluorescence polarization immunoassay and the pharmacokinetic parameters of MTX in plasma and CSF were estimated. The plasma concentrations of MTX peaked at the end of drug infusion, and then decayed bi-exponentially during the remainder of the treatment period. The CSF concentration of MTX in the STR peaked 2 h after drug administration, then mono-exponentially decreased. The area under the concentration-time curve (AUC) for plasma and CSF MTX concentrations increased in parallel with the MTX dose. In patients with open STRs, the mean AUC of MTX in CSF was 4.44% of that found in plasma, while in patients with closed STRs, the mean was 61.2% of that found in plasma. In the latter group, the MTX administered using HODBBB and intra-arterial chemotherapy was maintained in the STRs for long periods.

Pharmacokinetic characterization of the indole alkaloid ibogaine in rats

To investigate the pharmacokinetic properties of ibogaine, a putatively anti-addictive alkaloid, levels of this drug were quantified in plasma and tissues for up to 3 h following i.v. infusion in rats. Immediately following a 31-35 min infusion (20 mg/kg), mean plasma ibogaine levels were 373 ng/ml; these values declined rapidly thereafter in a biexponential manner. The plasma time course in 5 of 7 animals demonstrated an excellent fit to a two-compartment pharmacokinetic model, with alpha and beta half-lives of 7.3 min and 3.3 h, respectively. Drug clearance was estimated to be 5.9 l/h (n = 7). Ibogaine levels in brain, liver and kidney 3 h after the end of drug infusion were 143-170 ng/g, close to simulated values for the peripheral pharmacokinetic compartment. However, 3-h drug levels in adipose tissue were much higher (3,328 ng/g), implying the need for a more complex pharmacokinetic model. Mechanisms for the initial, rapid disappearance of plasma ibogaine are thought to include metabolic demethylation as well as redistribution to body stores. The sequestration of ibogaine by adipose tissue probably contributes to a protracted persistence of drug in the body. This persistence may be underestimated by the beta half-life reported in the present study.

Effects of rat brain kappa 1- and kappa 2-opioid receptors after chronic treatment with non-peptide kappa-agonists.

Injection of kappa-agonist dynorphins and non-peptide kappa-agonists into the hippocampus induces a reduction in blood pressure. It has been postulated that kappa-opioid agonists and kappa-receptors are important in one mechanism of antihypertension and might have clinical potential for the treatment of hypertension. We have investigated whether chronic treatment with U-50488H and U-62066E, two non-peptide kappa-agonists, effects brain kappa 1- or kappa 2-receptor numbers or affinities in areas that might correlate with changes in blood pressure. kappa 1- and kappa 2-Opioid receptor affinities and densities were determined in cortex, hippocampus, hypothalamus, midbrain and pons after 14 days subcutaneous infusion of two non-peptide kappa-agonists, U-50488H and U-62066E, 9.6 mg kg day-1, by means of osmotic minipumps, to spontaneously hypertensive rats (SHR) and to Wistar-Kyoto (WKY) rats. This infusion significantly reduced blood pressure. Brains were removed within 48 h of the end of drug infusion and kappa-receptor binding studies were performed on homogenates from each brain area using [3H]U-69593 to assay kappa 1-receptors and [3H]bremazocine to assay kappa 2-receptors. U-62066E treatment seemed to cause a slight decrease in the number of [3H]bremazocine binding sites (kappa 2-receptors) from 98.2 +/- 9 to 74.9 +/- 8 fmol (mg protein)-1 in the hippocampus when compared with SHR controls. A small decrease in kappa 2-receptor density in the pons of WKY rats was also observed after U-50488H treatment (control, 51.2 +/- 5; U-50488H-treated, 24.3 +/- 9 fmol (mg protein)-1. Although SHR blood pressure values were consistently reduced by treatment with kappa-agonists, there was little if any significant change in apparent numbers of kappa 1- or kappa 2-receptors or their affinities in any of the brain regions examined. These data indicate that although chronic treatment with kappa-agonists reduces blood pressure in SHR, the treatment does not elicit major changes in brain kappa-receptors either in SHR or in WKY rats. The potential use of kappa-agonists for treating hypertension might not cause receptor changes in the brain and might, therefore, result in fewer side effects or negligible rebound hypertension.

The Pharmacokinetics of Acetyl Starch as a Plasma Volume Expander in Patients Undergoing Elective Surgery

Acetyl starch (ACS) is a new synthetic colloid solution for plasma volume expansion and is now undergoing phase 2 clinical trials.We compared the pharmacokinetics of ACS with those of hydroxyethyl starch (HES) in 32 patients (ASA physical status I and II) undergoing elective surgery. In this randomized, double-blind trial, patients received either 15 mL/kg ACS 6% (average molecular weight [Mw] 200,000/molar substitution [MS] 0.5) or HES 6% (Mw 200,000/MS 0.5) IV up to a maximal dose of 1000 mL. Plasma colloid concentrations were measured by repetitive arterial blood sampling over 24.5 h. Plasma colloid concentrations were detected using a high-pressure liquid chromatography controlled enzymatic test. Standard pharmacokinetics were calculated, including initial half-life (t1/2init), i.e., the time required for a 50% decline of the maximal plasma colloid concentration at the end of drug infusion. Whereas HES was eliminated by second-order kinetics, ACS followed first-order characteristics. In the first hours after IV administration, t1/2init and clearances were similar in both groups. However, the terminal half-life of HES was significantly longer than that of ACS (9.29 +/- 1.43 h vs 4.37 +/- 1.06 h). After 16.5 and 24.5 h, ACS showed significantly lower plasma concentrations than HES, which indicates that the final degradation of ACS by esterases and amylase was significantly more rapid. ACS might be an alternative plasma volume expander, which avoids the accumulation of persisting macromolecules. Implications: We studied the pharmacokinetics of acetyl starch, a newly developed colloid solution for plasma volume substitution, compared with hydroxyethyl starch in 32 surgical patients undergoing elective major general surgical procedures. In contrast to hydroxyethyl starch, this new agent undergoes rapid and nearly complete enzymatic degradation. (Anesth Analg 1998;86:856-60)

Plasma hydroxy metronidazole/metronidazole ratio in anti-HCV carriers with and without apparent liver disease

Aims To evaluate plasma hydroxy-metronidazole/metronidazole ratio as a dynamic liver function test in HCV-infected individuals with/without liver disease, in the absence of liver cirrhosis. Methods Metronidazole was administered intravenously in healthy volunteers, asymptomatic anti-HCV-positive blood donors, and in chronic hepatitis C patients. Serology to HCV was determined by a second generation assay and confirmed by gelatin particle agglutination test using recombinant antigens C22-3 and C200. Plasma concentration of metronidazole and hydroxy-metronidazole was measured by high performance liquid chromatography in samples collected 5, 10, 20 and 30 min following the end of metronidazole infusion. Results Chronic hepatitis C patients had abnormal liver enzymes, while healthy volunteers and anti-HCV-positive blood donors had normal liver biochemistry tests. Plasma metronidazole concentration was similar in all groups studied. Plasma hydroxy-metronidazole/metronidazole ratio was significantly reduced in HCV-infected subjects, an effect observed 10 min after the end of drug infusion. Conclusions Metronidazole clearance is impaired in anti-HCV-positive blood donors and chronic hepatitis C patients, indicating that HCV is capable of affecting liver function at early stages of the disease. The metronidazole clearance test can detect impaired liver function in HCV-infected individuals even in the absence of liver cirrhosis.

Pharmacokinetics of cyclophosphamide in patients with systemic necrotizing angiitis.

Cyclophosphamide pharmacokinetics were investigated following administration to patients with systemic necrotizing angiitis. Ten patients (eight women and two men) received cyclophosphamide as a 1-h-rate-constant intravenous infusion at doses ranging from 600 to 1200 mg. All patients received concomitant oral prednisone (1 mg/kg/d). Blood samples were collected at the end of drug infusion and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h later. Serum cyclophosphamide concentrations were assayed by high pressure liquid chromatography. The peak serum cyclophosphamide levels ranged from 15.7 to 29.4 mg/L. The mean cyclophosphamide elimination half-life was 6.2 +/- 1.3 h (mean +/- SD). The mean apparent volume of distribution and mean total plasma clearance were, respectively, 0.75 +/- 0.22 L/kg (mean +/- SD) and 83 +/- 22 mL/min (mean +/- SD). These results obtained in systemic vasculitic diseases were consistent with those observed in other studies with cancer patients receiving comparable doses of cyclophosphamide.

In vivo and ex vivo effects of adenosine A 1 and A 2 receptor agonists on platelet aggregation in the rabbit

We have investigated both in vivo and ex vivo antiaggregatory activity of three adenosine receptor agonists in the anesthetized rabbit: the non-selective, 5′- N-ethyl-carboxamidoadenosine (NECA), the selective adenosine A 1 receptor agonist 2-chloro-N 6-cyclopentyladenosine (CCPA) and the new selective A 2 receptor agonist, 2-hexynyl-NECA. The drugs were administered by 30-min intravenous infusion at a dose reducing mean blood pressure by 40–50%. NECA and CCPA also markedly decreased heart rate. In ex vivo experiments, NECA (10 μg/kg) adn 2-Hexynyl-NECA (10 μg/kg) maximally inhibited adenosine 5′-diphosphate (ADP)-induced platelet aggregation at the end of drug infusion by 26.7±2.9% and 25.2±3.5%, respectively. In in vivo studies, the inhibition of platelet aggregation was evaluated using the technique based on selective accumulation of 111In-labeled platelets in pulmonary microcirculation upon challenge with ADP 100 μg/kg. NECA (10 μg/kg) and 2-hexynyl-NECA (10 μg/kg) decreased peak values for platelet accumulation by 35.3 ±6.9% and 52.5 ± 5.9% and the area under curve values by 37.7 ± 8.7% and 41.2 ± 12.0% respectively. In comparison, CCPA (100 μg/kg) did not affect platelet responses to ADP in either of the experimental models. Thus, the present study clearly demonstrates for the first time the in vivo antiplatelet activity of adenosine A 2 receptor agonists, whereas the adenosine A 1 receptor agonist was inactive, in consonance with the in vitro data.