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Peak Plasma Rivaroxaban Levels in Individuals Weighing over 120 Kilograms

BackgroundRivaroxaban, a direct oral anticoagulant (DOAC), has been shown to be an efficacious and safe agent for treatment and secondary prevention of thromboembolism (TE). Currently, there is limited evidence available regarding its use in individuals weighing > 120 kg. Given the increasing prevalence of obesity in the general population, and that elevated weight itself is a risk factor for TE, this lack of data is a substantial issue. Theoretically, the greater volume of distribution in obesity may decrease DOAC peak drug concentration and half-life, potentially resulting in sub therapeutic anticoagulation. In fact, current ISTH guidelines recommend against empiric use of DOACs in patients over 120 kg, with the caveat that their use may be considered if drug specific peak and trough levels fall within the expected range (Martin et al. J Thromb Haemost. 2016). Additional data is required to guide the clinician regarding DOAC use for the management of TE in this growing demographic.ObjectivesOur primary objective was to assess peak rivaroxaban plasma levels (PRPL) in patients weighing > 120 kg on the standard 20 mg daily dose for treatment or secondary prevention of VTE and to compare these values to the expected range derived from pharmacokinetic studies in non-obese patients. The secondary objective was to assess for TE complications in this cohort.MethodsElectronic patient records were retrospectively reviewed at a thrombosis clinic at a single center from January 1, 2014 to May 31, 2017. Patients of age > 18, on rivaroxaban for treatment or secondary prevention of VTE, of weight > 120kg, and with at least one PRPL, measured 2-4 hours post drug ingestion at steady state, were included in the study. Patients with decreased renal function (creatinine clearance < 30mL/min), liver dysfunction (Child-Pugh score B or C), on concomitant strong P-glycoprotein or CYP 3A4 inducers or inhibitors, or with an additional indication for anticoagulation were excluded. Reference ranges for PRPL were extracted from pharmacokinetic studies (Buller et al. Blood. 2008). PRPL were measured using an anti-Xa assay calibrated to rivaroxaban (BIOPHENTM DiXal, HYPHEN BioMed).ResultsThere were 17 unique patients, each with a PRPL, weighing > 120kg, on rivaroxaban for treatment or secondary prevention of TE, over our study period. Six were female. The mean weight was 146.75 (SD +/- 20.19) kg. The mean calculated creatinine clearance (Cockcroft-Gault) was 208.53 (SD +/- 57.36) mL/min. The mean length of follow up from measurement of PRPL was 312.29 (SD +/- 265.47) days.The mean PRPL was 248.51 (5th to 95th percentile 174.6-380.4) ng/mL compared to the reference of 5th to 95th PRPL percentile of 175-360 ng/mL in non obese patients. Only 1 PRPL was found to be below the expected range at 161ng/mL (see figure 1). There were no recurrent TE events in any of the patients during the study.ConclusionsWe found that the majority of individuals weighing > 120 kg on standard dose rivaroxaban for treatment and secondary prevention of TE had a PRPL within the expected range, with only one value out of the seventeen falling below that range. There were no recurrent TE events in any of the patients. It is possible that the increased volume of distribution in obesity played a lesser role in decreasing PRPL given the lower lipophilicity of rivaroxaban compared to apixaban and dabigatran, although similar to edoxaban (Remko. Journal of Molecular Structure: THEOCHEM. 2009, Remko et al. Molecules. 2016). Despite the small sample size and lack of other pharmacokinetic values, this preliminary data is clinically reassuring that the use of rivaroxaban in patients weighing > 120kg seems to be safe. Further studies are required to fully elucidate the efficacy and safety of DOACs in the treatment of TE in morbidly obese patients. [Display omitted] DisclosuresSholzberg:Shire: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; NovoNordisk: Honoraria. Yeo:Bayer: Membership on an entity's Board of Directors or advisory committees.

Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer.

BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients.

Abstract B70: Combination of AT1R blockade with CD40 activation provides enhanced therapeutic efficacy for mouse pancreatic adenocarcinoma

Abstract B70: Combination of AT1R blockade with CD40 activation provides enhanced therapeutic efficacy for mouse pancreatic adenocarcinoma

Longitudinal Evaluation of Sympathetic Nervous System and Perfusion in Normal and Spontaneously Hypertensive Rat Hearts with Dynamic Single-Photon Emission Computed Tomography

The objective of this work was to evaluate the sympathetic nervous system and structure remodeling during the progression of heart failure in a rodent model using dynamic cardiac single-photon emission computed tomography (SPECT). The spontaneously hypertensive rat (SHR) model was used to study changes in the nervous system innervation and perfusion in the left ventricular (LV) myocardium with the progression of left ventricular hypertrophy (LVH) to heart failure. Longitudinal dynamic SPECT studies were performed with seven SHR and seven Wistar-Kyoto (WKY) rats over 1.5 years using a dual-head SPECT scanner with pinhole collimators. Time-activity curves (TACs) of the 123I-MIBG and 201Tl distribution in the LV blood pool and myocardium were extracted from dynamic SPECT data and fitted to compartment models to determine the influx rate, washout rate, and distribution volume (DV) of 123I-MIBG and 201Tl in the LV myocardium. The standardized uptake values (SUVs) of 123I-MIBG and 201Tl in the LV myocardium were also calculated from the static reconstructed images. The influx and washout rates of 123I-MIBG did not show a significant difference between SHRs and WKY rats. The DVs of 123I-MIBG were greater in the SHRs than in the WKY rats (p = .0028). Specifically, the DV of 123I-MIBG became greater in the SHRs by 6 months of age (p = .0017) and was still significant at the age of 22 months. The SUV of 123I-MIBG in SHRs exhibited abnormal values compared to WKY rats from the age of 18 months. There was no difference in the influx rate and the washout rate of 201Tl between the SHRs and WKY rats. The SHRs exhibited greater DV of 201Tl than WKY rats after the age of 18 months (p = .034). The SUV of 201Tl in SHRs did not show any significant difference from WKY at all ages. The higher DV of 123I-MIBG in the LV myocardium reveals abnormal nervous system activity of the SHRs at an age of 6 months, whereas a greater DV of 201Tl in the LV myocardium can only be detected at an age of 18 months. The results show that the abnormal nervous system activity appears earlier than perfusion. Furthermore, the comparison between the DV and the SUV indicates that dynamic SPECT with 123I-MIBG and 201Tl with the kinetic parameter DV is capable of detecting abnormalities of the LV at an early age.

Regional anaesthesia in neonates, infants and children: an educational review.

Prophylactic analgesia with local anaesthesia is widely used in children and has a good safety record. Performing regional blocks in anaesthetised children is a safe and generally accepted practice. When compared with adults, lower concentrations of local anaesthetics are sufficient in children; the onset of a block occurs more rapidly but the duration is usually shorter. Local anaesthetics have a greater volume of distribution, a lower clearance and a higher free (non-protein-bound) fraction. The recommended maximum dose has to be calculated for every individual. Peripheral blocks provide analgesia restricted to the site of surgery, and some of them have a very long duration of action. Abdominal wall blocks, such as transverse abdominis plane or ilio-inguinal nerve block, should be performed with the aid of ultrasound. Caudal anaesthesia is the single most important technique. Ropivacaine 0.2% or levobupivacaine 0.125 to 0.175% at roughly 1 ml kg⁻¹ is adequate for most indications. Clonidine and morphine can be used to prolong the duration of analgesia. Ultrasound is not essential for performing caudal blocks, but it may be helpful in case of anomalies suspected at palpation and for teaching purposes. The use of paediatric epidural catheters will probably decline in the future because of the potential complications.

Pharmacokinetic evaluation and antitumor activity of 2-methoxyestradiol nanosuspension

The aim of the present study was to evaluate the pharmacokinetic and antitumor activity of 2-methoxyestradiol (2-ME) nanosuspension relative to 2-ME solution both in vitro and in vivo. The pharmacokinetics of 2-ME administered either as a nanosuspension or as a solution were compared after I.V. administration to rats. In plasma, 2-ME nanosuspension exhibited a significantly (p < 0.01) reduced Cmax (1022.8 ± 467.4 ng/mL versus 2559.2 ± 775.8 ng/mL) and AUC0–240min (41566.8 ± 965.5 ng/mL min versus 79557.7 ± 256.2 ng/mL min), and a significantly (p < 0.01) greater volume of distribution (3.18-fold), clearance (1.85-fold), and elimination half-life (156.6 ± 33.5 min versus 70.0 ± 22.6 min) compared to the 2-ME solution. Methyl tetrazolium (MTT) assay showed that nanosuspension could significantly enhance the cytotoxicity of 2-ME on EC9706 cells in vitro. After 72 h exposure, the IC50 value of 2-ME nanosuspension was much lower than that of 2-ME solution (1.81 ± 0.15 μmol/L versus 4.14 ± 0.30 μmol/L). Studies on BALB/c mice with EC9706 solid tumors demonstrated significantly greater inhibition of tumor growth following treatment with 2-ME nanosuspension than 2-ME solution at the same dosage. These results suggest that the delivery of 2-ME nanosuspension is a promising approach for the treatment of tumors.

Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats

Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic–pharmacodynamic (PK–PD) modeling.Male Sprague–Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1–3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK–PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis.A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK–PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats.Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.

Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in aNG-nitro-l-arginine methyl ester rat model of secondary hypertension

The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic-pharmacodynamic (PK-PD) modelling. Male Wistar rats were randomly divided into two groups: control rats received tap water to drink for 2 weeks while L-NAME rats received L-NAME solution to drink for 2 weeks. The effects of carvedilol (1 and 5 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics were studied by means of traditional blood sampling. The relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by means of PK-PD modelling. Vascular sympatholytic activity of carvedilol was assessed by the estimation of drug effects on low frequency blood pressure variability by means of spectral analysis. A dose-dependent increase in volume of distribution, as well as a greater volume of distribution and clearance of S-carvedilol as compared with the R-enantiomer was found in both experimental groups. Although the PK-PD properties of the S-carvedilol chronotropic effect were not altered in L-NAME rats, hypertensive rats showed greater potency and efficacy to the carvedilol hypotensive response. Greater potency of carvedilol for inhibition of sympathetic vascular activity was found in L-NAME rats. Carvedilol showed enantioselective non-linear pharmacokinetic properties in both groups. An enhanced hypotensive activity of carvedilol was found in L-NAME hypertensive rats compared with control rats, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition.

Farmacocinética y farmacodinamia. Interacciones y efectos secundarios. Comparación con otras equinocandinas

New drugs will soon be incorporated into the echinocandin class of antifungals. The first to be released on to the market will be anidulafungin. The pharmacokinetic characteristics of this drug clearly distinguish it from the only representative of this family of antifungal agents available to date: caspofungin. Specifically, this new drug has a greater volume of distribution, a higher elimination half-life and, moreover, an elimination system -- spontaneous degradation --, thus avoiding interactions with other drugs and allowing its use without dosage adjustments in patients with renal or liver impairment. These are the main pharmacological differences between anidulafungin and caspofungin, since the latter requires dosage adjustments in patients with hepatic insufficiency, in patients under treatment with inducers of cytochrome P450 activity and in obese patients. Moreover, plasma concentration monitoring is recommended in patients requiring caspofungin who are also under treatment with cyclosporin A or tacrolimus. Clinical experience suggests that there are few differences in the tolerability profiles of the two drugs, both of which are excellent.

Pharmacokinetic characteristics and anticancer effects of 5-Fluorouracil loaded nanoparticles

BackgroundIt is expected that prolonged circulation of anticancer drugs will increase their anticancer activity while decreasing their toxic side effects. The purpose of this study was to prepare 5-fluorouracil (5-FU) loaded block copolymers, with poly(γ-benzyl-L-glutamate) (PBLG) as the hydrophobic block and poly(ethylene glycol) (PEG) as the hydrophilic block, and then examine the 5-FU release characteristics, pharmacokinetics, and anticancer effects of this novel compound.Methods5-FU loaded PEG-PBLG (5-FU/PEG-PBLG) nanoparticles were prepared by dialysis and then scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to observe the shape and size of the nanoparticles, and ultraviolet spectrophotometry was used to evaluate the 5-FU in vitro release characteristics. The pharmacokinetic parameters of 5-FU/PEG-PBLG nanoparticles in rabbit plasma were determined by measuring the 5-FUby high-performance liquid chromatography (HPLC). To study in vivo effects, LoVo cells (human colon cancer cell line) or Tca8113 cells (human oral squamous cell carcinoma cell line) were implanted in BALB/c nude mice that were subsequently treated with 5-FU or 5-FU/PEG-PBLG nanospheres.Results5-FU/PEG-PBLG nanoparticles had a core-shell spherical structure with a diameter of 200 nm and a shell thickness of 30 nm. The drug loading capacity was 27.1% and the drug encapsulation was 61.5%. Compared with 5-FU, 5-FU/PEG-PBLG nanoparticles had a longer elimination half-life (t1/2, 33.3 h vs. 5 min), lower peak concentration (C, 4563.5 μg/L vs. 17047.3 μg/L), and greater distribution volume (VD, 0.114 L vs. 0.069 L). Compared with a blank control, LoVo cell xenografts and Tca8113 cell xenografts treated with 5-FU or 5-FU/PEG-PBLG nanoparticles grew slower and had prolonged tumor doubling times. 5-FU/PEG-PBLG nanoparticles showed greater inhibition of tumor growth than 5-FU (p < 0.01). In the PEG-PBLG nanoparticle control group, there was no tumor inhibition (p > 0.05).ConclusionIn our model system, 5-FU/PEG-PBLG nanoparticles changed the pharmacokinetic behavior of 5-FU, thus increasing its anticancer activity. 5-Fluorouracil loaded nanoparticles have potential as a novel anticancer drug that may have useful clinical applications.

Convection-enhanced delivery for treatment of brain tumors

Recently, innovative therapies have been developed for the treatment of malignant gliomas. Unfortunately, adequate delivery of these therapies has been a major obstacle to clinical success. Intravenous administration is restricted by the presence of the blood–brain barrier while local delivery, such as with drug-impregnated wafers, results in limited parenchyma penetration. Convection-enhanced delivery is a promising method for the delivery of macromolecules to the CNS. Convection-enhanced delivery involves the infusion of therapeutic agents via surgically implanted catheters and uses a pressure gradient to achieve a greater volume of distribution compared with that seen with diffusion alone. This article will review the development of convection-enhanced delivery and its use in the treatment of malignant gliomas.

Randomized controlled comparative clinical pharmacokinetic study of nab-paclitaxel and solvent-based paclitaxel in Chinese patients (pts) with metastatic breast cancer (MBC)

11505 Background: nab-paclitaxel is a novel solvent-free, 130-nM albumin-bound (nab™) formulation of paclitaxel. In previous studies, nab-paclitaxel demonstrated higher volume of distribution and clearance than that of paclitaxel formulated with Cremophor (Cr-PAC) in Caucasian patients (Sparreboom, Clin Cancer Res 2005;11:4136) and had greater response rate and favorable safety profile in pts with MBC (Gradishar et al., JCO, 2005;23:7794) . The aim of this study was to evaluate nab-paclitaxel blood pharmacokinetics (PK) and compare it with that of Cr-PAC in Chinese MBC patients.Methods: In this randomized controlled, open-label study, patients were assigned to either nab-paclitaxel 260 mg/m2 intravenously (iv) over 30 minutes q3w or Cr-PAC 175 mg/m2 iv over 3 hours q3w. At cycle 1, 12 patients in each treatment group participated in the PK study and then continued treatment until PD or unacceptable toxicity. Plasma samples from pts were analyzed for PK parameters. The primary clinical endpoints were ORR and toxicity (Guan et al; submitted, ASCO, 2007). Results: 24 female pts (median age 44.5 years) participated. No statistically significant between group differences were noted in age, height, weight, or baseline liver function. Paclitaxel blood PK parameters in 2 treatment groups are summarized in the Table. ORR: nab-paclitaxel, 75%; Cr-PAC, 25% (P = 0.018). The maximum grade (G) of neutropenia and neuropathy in the nab-paclitaxel and Cr-PAC groups were G3 and G2, respectively, with no significant between-group difference. Conclusion: nab-Paclitaxel had a greater distribution volume, clearance, and smaller dose adjusted AUC0-inf compared with that of Cr-PAC. There was no significant difference in T1/2 in the 2 groups. PK results in Chinese pts are identical to data reported in Caucasian pts. The lower CL and Vz for Cr-PAC are probably related to sequestration of paclitaxel in the blood by Cremophor. * dose adjusted AUC0-inf [Table: see text] [Table: see text]

Linezolid treatment of vancomycin-resistant enterococcus faecium ventriculitis

The successful treatment of a 7-month-old infant with shunt-associated ventriculitis caused by vancomycin-resistant Enterococcus faecium is presented. Linezolid was administered intravenously every 8 h; children have a greater volume of distribution and total body clearance than adults and therefore require more frequent dosing. The patient tolerated the therapy without adverse effects.

Human recombinant erythropoietin in the prevention and treatment of anemia of prematurity.

Human recombinant erythropoietin has been studied extensively as treatment for a variety of anemias. Since in vitro studies showed the primary etiology of the anemia of prematurity to be insufficient serum erythropoietin concentrations, clinical trials have evaluated the administration of human recombinant erythropoietin to preterm infants to treat this indication. These studies were followed by pharmacokinetic determinations in animal models and preterm infants, which revealed that preterm infants required greater doses of human recombinant erythropoietin because of a more rapid clearance and greater volume of distribution. Recent studies have focused on the administration of human recombinant erythropoietin in the first weeks of life to alleviate the anemia caused by excessive phlebotomy losses, and to prevent the anemia of prematurity. In addition, human recombinant erythropoietin has been tried clinically in a variety of neonatal populations in an attempt to decrease or eliminate transfusions. Although much information has been accumulated about the clinical use of human recombinant erythropoietin in preterm infants over the last 15 years, many questions remain unanswered. The evolution of clinical practice in the care of extremely low birthweight infants continues to affect the number of transfusions. It is likely that human recombinant erythropoietin administration in combination with instituting rigorous transfusion guidelines and decreasing phlebotomy losses will have the greatest impact in decreasing transfusion requirements in all preterm and term neonates, regardless of the etiology of their anemia.

Feto-maternal distribution of ropivacaine and bupivacaine after epidural administration for cesarean section

Ropivacaine is a new amino amide local anesthetic less lipophilic and with a lower affinity for plasma proteins than bupivacaine. The purpose of this study was to examine the feto-maternal distribution of ropivacaine and bupivacaine after epidural administration for cesarean section. Healthy parturients were randomly allocated in a double-blinded manner to receive either 0.5% ropivacaine or 0.5% bupivacaine through a lumbar epidural catheter. The total and free concentrations of ropivacaine and bupivacaine were determined in the maternal and umbilical plasma. The total dose (mg/kg) required for adequate surgical anesthesia and the resulting maximum total concentrations did not differ significantly between ropivacaine and bupivacaine. The free plasma clearance of bupivacaine was higher than that of ropivacaine (7382 vs 3344 ml/min, P=0.0001). The apparent terminal elimination half-life of ropivacaine was shorter than that of bupivacaine (6.0 vs 8.8 h, P=0.007). At delivery, the maternal free plasma concentration of ropivacaine was more than twice that of the free concentration of bupivacaine (0.072 vs 0.032 μg/ml, P=0.002). The free concentration of ropivacaine was about twice that of bupivacaine in the umbilical venous (0.06 vs 0.03 μg/ml, P=0.001) and umbilical arterial (0.05 vs 0.02 μg/ml, P=0.007) plasma. The more rapid plasma clearance of bupivacaine compared to ropivacaine, leading to lower maternal plasma concentrations and hence to lower umbilical concentrations at delivery, could be explained by the higher lipid solubility, hence greater distribution volume, of bupivacaine.

Antivenoms

The first advance on crude filtered immune serum or plasma for treating systemically envenomed bite victims was the use of IgG (predominantly equine) precipitated by salt treatment. This was followed by the development of F(ab')(2) antivenoms, prepared using pepsin digestion to remove both the highly reactive and nonspecific Fc part of the IgG molecule and also other non-antibody proteins from the material. Within normal limitations, both monospecific (raised against the venom of a single species) and polyspecific (raised against a mixture of venoms of different species) F(ab')(2) antivenoms have proved to be generally effective. Many preparations are poor for a wide range of reasons often not related to the method of preparation. The main problem associated with them is the high reaction rate in patients caused by complement-mediated anaphylactic reactions. The most significant recent development in immunotherapy has been the production of ovine Fab antivenoms prepared by replacing pepsin digestion with papain digestion. Theoretically, these possess advantages over F(ab')(2) antivenoms, such as a greater volume of distribution and more rapid kinetics. A major disadvantage of Fab antivenoms is, however, their shorter clearance time, which may result in inadequate blood antivenom concentrations for neutralising venom entering the system late from a venom depot at the bite site. Affinity purification of both Fab and F(ab')(2) antivenoms also results in a major increase in specific activity when compared with the original serum source, but this adds greatly to the cost of production, rendering its use prohibitive in the rural tropics where bites and stings are a major problem. The use of sheep as opposed to horses for immunisation also results in a cheaper product, due to the lower cost of animal maintenance; theoretically, sheep preparations should also be safer, causing fewer sensitivity reactions, due to the nature of ovine as opposed to equine protein. Additionally, it is a great advantage in the rural tropics to have a lyophilised, as opposed to a liquid, antivenom because of the longer shelf-life of the former at ambient tropical temperatures. However, lyophilisation does add considerably to the cost of production, involves additional testing and has also in the past been reported to result in some decrease in neutralising potency. There may well be a case for the development of a combined ovine Fab/F(ab')(2) antivenom which combines the advantages of each product. Alternatives to conventional antivenoms should also be explored in the future.

Plasma pharmacokinetics of 7-ethyl-10-hydroxycamptothecin (SN-38) after intravenous administration of SN-38 and irinotecan (CPT-11) to rats.

We studied the plasma pharmacokinetics of the lactone form and the carboxylate form of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan (CPT-11), after intravenous bolus administrations of each form of SN-38 and of CPT-11 to rats. After the SN-38 lactone injection, SN-38 lactone was predominant at first, and then the lactone to the carboxylate concentration ratio (LC ratio) was maintained from 30 to 90 min after the injection. The carboxylate was predominant throughout the period after the carboxylate dosing. Model-dependent analyses showed that the SN-38 lactone had greater plasma clearance and a greater distribution volume than the carboxylate. The CPT-11 administration resulted in a predominant plasma SN-38 lactone concentration. The contribution of the SN-38 lactone AUC to the total SN-38 AUC (57%) was independent of the dose of CPT-11. These results suggest that it is possible to estimate the SN-38 lactone concentration and AUC from the total SN-38 concentration without separate determination of the lactone and carboxylate. Our results showed that both SN-38 lactone and CPT-11 administration gave the predominant SN-38 lactone in plasma; however, only CPT-11 could sustain the lactone concentration at a high level, which is necessary for antitumor activity.

Repeated Doses of Rocuronium Bromide Administered to Cirrhotic and Control Patients Receiving Isoflurane

Steroid muscle relaxants often display pharmacodynamic changes in patients with cirrhosis because of alterations in elimination processes. Rocuronium is a new steroid muscle relaxant possibly eliminated through the liver. This study was designed to compare rocuronium pharmacodynamics and pharmacokinetics in cirrhotic and healthy patients. Rocuronium was administered to 26 cirrhotic patients and 24 control subjects anesthetized with isoflurane for an elective procedure. Patients were randomly allocated to received an initial dose of rocuronium: 120, 180, 250, or 300 micrograms.kg-1. Dose-response curves were established, and ED50 was calculated. Preselected maintenance doses (75, 150, or 225 micrograms.kg-1) were administered at 25% recovery of twitch height to compare clinical duration of action. At the end of the procedure, relaxation was reversed in half of the patients, and the time course of recovery was compared in the two groups. Blood samples drawn during the procedure and after the last maintenance dose allowed pharmacokinetic analysis in six cirrhotic patients and six control subjects. ED50 of the initial dose was 144 micrograms.kg-1 in cirrhotic patients and 60 micrograms.kg-1 in control subjects, related to a higher initial volume of distribution (cirrhotic 78.5 +/- 31.7 ml.kg-1, control 29.8 +/- 17.3 ml.kg-1). Time from complementary dose to 25% recovery was longer in cirrhotic patients (41.0 +/- 20.7 min vs 30.2 +/- 9.7 min), but time course of action during maintenance was not statistically different in the two groups. In cirrhotic patients receiving five maintenance doses or more, prolongation of the duration of action with successive maintenance doses could be statistically demonstrated. Spontaneous recovery was delayed in cirrhotic patients, because of impaired elimination processes: greater volume of distribution at steady-state (264 +/- 92 vs. 151 +/- 59 ml.kg-1); trend toward a lower clearance (189 +/- 60 vs. 296 +/- 169 ml.min-1). Rocuronium pharmacodynamics are moderately altered by cirrhosis, possible because of pharmacokinetic alterations. Individual variability in response to rocuronium is great, and dosage should be carefully titrated to that required.

Pharmacodynamics and pharmacokinetics of clentiazem and diltiazem in closed-chest anesthetized dogs.

In the present study we investigated the relationship between pharmacodynamic and pharmacokinetic properties of the benzothiazepine-like calcium antagonists, clentiazem and diltiazem. Experiments were carried out in closed-chest anesthetized dogs, instrumented for hemodynamic recording and blood sampling. Clentiazem and diltiazem bolus injections (400 micrograms/kg) were administered intravenously, and subgroups of animals were sacrificed at 15, 30, 60, or 120 minutes Clentiazem and diltiazem plasma and myocardial levels were determined by high performance liquid chromatography (HPLC). Clentiazem elicited a more marked reduction in mean arterial pressure (-17% for clentiazem vs. -12% for diltiazem), along with an attenuation of the expected positive reflex chronotropic response. Pharmacokinetic analysis revealed that clentiazem had a greater volume of distribution (33 +/- 16 l vs. 15 +/- 9 l for diltiazem), while the half-life of elimination (t1/2 beta) was similar (55 +/- 21 minutes vs. 59 +/- 23 minutes). The kinetic disposition profile of both drugs was analyzed through myocardial/plasma concentration ratios. In the distribution phase (0-15 minutes), this ratio was similar (26 +/- 2 for clentiazem vs. 18 +/- 5 diltiazem), suggesting that the myocardium was not a preferential site of distribution for either drugs. Data collected within the elimination phase indicate significant myocardial retention for clentiazem; at the end of the study period, the myocardial/plasma concentration ratio was twofold higher for clentiazem. The observed retention of clentiazem in the myocardium may be responsible for attenuation of the baroreflex. Clentiazem increased potency was confirmed by the fact that its hypotensive and cardioinhibitory effects were observed at lower plasma concentrations.

EFFECT OF I.V. LOW-DOSE ADRENALINE AND PHENYLEPHRINE INFUSIONS ON PLASMA CONCENTRATIONS OF BUPIVACAINE AFTER LUMBAR EXTRADURAL ANAESTHESIA IN ELDERLY PATIENTS

Thirty patients undergoing primary total hip replacement under lumbar extradural anaesthesia with 0.75% bupivacaine 25 ml were allocated randomly to receive either low-dose adrenaline or phenylephrine infusions i.v. throughout surgery. Haemodynamic measurements and arterial blood samples were obtained before the extradural injection and at 10, 20, 30, 40, 50, 60 and 90 min thereafter. Peak arterial plasma concentrations of bupivacaine were observed 10 min after extradural anaesthesia and were significantly lower in patients receiving adrenaline infusions. Cardiac output was significantly greater in patients receiving adrenaline infusions (P less than 0.01). It is postulated that the smaller circulating concentrations of bupivacaine observed in patients receiving adrenaline were caused by increased cardiac output and a greater volume of distribution than in patients receiving phenylephrine.