Anaesthesia medical workforce in New Zealand.

This survey was conducted in all 28 New Zealand District Health Boards with a response rate of 100%. The Clinical Directors of Departments of Anaesthesia were asked to quantify their current anaesthesia service delivery and to assess their workforce level. Over half of the District Health Boards reported understaffing, fifty percent occurring in hospitals of provincial cities or towns with an inability to attract specialist anaesthesia staff. Financial constraint was the other main reason for understaffing. With the information from the survey, an attempt was made to predict future New Zealand anaesthesia workforce requirements. A model for Australasia established by Baker in 1997 was used. In comparing this survey to previous studies, there is evidence that the nature and expectations of the anaesthesia workforce are changing as well as the work environment. Currently, there is no indication that anaesthesia specialist training numbers should be reduced. Close, ongoing monitoring and planning are essential to ensure future demands for anaesthesia services can be met.

New Zealand anaesthesia trainees and implications for the future workforce.

Attempting to ensure an adequate anaesthesia workforce for New Zealand requires many variables to be taken into consideration. The difficulty lies in trying to predict and match the future needs of the population and the future needs of the workforce itself. This paper examines variables that affect anaesthesia trainees' decisions in regard to future work plans which will affect anaesthesia distribution and manpower in New Zealand, particularly in smaller hospitals. It is already apparent that with distribution problems and/or actual shortages, the gaps in workforce availability for any professional group tend to be in the smaller centres. All New Zealand anaesthesia trainees were sent a questionnaire in 2002, with 110 of 138 trainees responding (79.7%). It appears enough specialists are being trained, with 80% indicating a desire to remain in New Zealand and 13% stating Australia as their choice of destination. The influence of student debt or encouragement of overseas training experience did not appear to be important in their decisions. Having a rotation during training to smaller hospitals had a positive effect on attitudes to working in smaller hospitals as specialists. The recruitment of these future specialists into smaller hospitals also depends upon broader lifestyle choices. Selection of smaller hospitals for anaesthesia practice is encouraged by good financial incentives, adequate professional support, including support by junior doctors, access to ongoing professional development and inclusion into a wider rotation with a larger hospital.

Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies.

Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.

Phase I safety and pharmacokinetic studies of brequinar sodium after single ascending oral doses in stable renal, hepatic, and cardiac allograft recipients.

Brequinar sodium (BQR), a substituted 4-quinoline carboxylic acid, was in clinical development in combination with cyclosporine (CsA) as a potentially effective therapy for the treatment and prophylaxis of rejection in organ transplant patients. This phase I study was performed in stable renal, hepatic, and cardiac transplant patients receiving CsA and prednisone maintenance therapy for immunosuppression. The pharmacokinetic objectives of this study were to characterize the pharmacokinetics of (a) single oral 0.5- to 4-mg/kg doses of BQR when given in combination with CsA and prednisone to stable renal, hepatic, and cardiac transplant patients and (b) steady-state oral doses of CsA, with and without single oral doses of BQR. In all three patient populations, the pharmacokinetics of BQR were characterized by a lower oral clearance (12-19 mL/min) than that seen in previous studies in patients with cancer (approximately 30 mL/min at similar doses) and a long terminal half life (13-18 hrs). This slower oral clearance for BQR could be due either to a drug interaction between BQR and CsA or to altered clearance or metabolic processes in patients with transplants. Steady-state CsA trough levels and the oral clearance of CsA were not affected by BQR coadministration. Among the three transplant populations, the cardiac transplant patients had lower oral clearance values of BQR and of CsA. The cause of this lower clearance is not known. Safety results indicate that BQR was well tolerated by this patient population.

Dose-dependent pharmacokinetics of warfarin in healthy volunteers.

PURPOSE: To examine the pharmacokinetics of warfarin after administration of single oral doses (2, 5, and 10 mg) to healthy male volunteers. METHODS: A sensitive reverse-phase HPLC method was used to quantify warfarin plasma concentrations as low as 6 ng/ml. Blood samples were collected for up to 120 hours following administration of these doses. RESULTS: As the dose decreased from 5 to 2 mg, the apparent volume of distribution (V/F) increased from 12 to 21 liters and the terminal half-life (t1/2) increased from 47 to 71 hours. Oral clearance remained unchanged over the examined dose range. These apparent dose-dependent changes in warfarin's t1/2 and V/F may be due to saturable tissue binding of this drug. It appears that a previously undetected and prolonged terminal phase may exist but can not be adequately characterized with the 120-hour sampling interval. To evaluate this long t1/2, a follow-up study was conducted to examine warfarin's pharmacokinetics for up to 21 days following a 10-mg dose. The prolonged terminal phase started to become apparent when plasma levels declined to less than 100 ng/ml. The t1/2 of this terminal phase was determined to be approximately one week. CONCLUSIONS: This is the first report that documents the dose-dependent pharmacokinetics of warfarin and the previously unreported long t1/2 of one week for warfarin in humans.

Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers.

Data describing the pharmacokinetics and pharmacodynamics of low dose aspirin (acetylsalicylic acid; ASA) are limited. This single-center study was designed to determine the rate and extent of oral absorption of 80-mg ASA tablets in healthy, young male subjects and to assess the intra- and inter-subject variability of ASA pharmacokinetics and platelet aggregation effects. Ten subjects each received a single, open-label, oral 80-mg ASA dose on three separate days. Each dose was separated by a 2-week washout interval. Blood samples for pharmacokinetic determinations of ASA and its metabolite, salicylic acid (SA) and platelet aggregation studies were obtained at scheduled timepoints before and up to 24 hours after each dose. Peak plasma ASA levels of 1 microgram/mL were achieved within 30 minutes. Peak plasma SA levels of approximately 4 micrograms/mL were attained in 1 hour. The terminal half-lives (t1/2) of ASA and SA were 0.4 and 2.1 hours, respectively. Both ASA and SA pharmacokinetics and the platelet aggregation response to ASA exhibited considerable intra- and inter-subject variability. Inhibition of platelet aggregation was found to relate with ASA area under the plasma concentration versus time curve (AUC).

Simultaneous quantification of an anti-inflammatory compound (DuP 697) and a potential metabolite (X6882) in human plasma and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method using fluorescence detection has been developed for the simultaneous analysis of low nanogram concentrations of an anti-inflammatory drug, 5-Bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (DuP 697), and a potential metabolite (X6882) in human plasma and of DuP 697 in human urine. This assay method used an EM Separations Lichrospher C18 endcapped column. The mobile phase was acetonitrile-water (75:25, v/v). The detection of DuP 697 and X6882 was by fluorescence at excitation and emission wavelengths of 256 and 419 nm, respectively. The chromatographic system could separate DuP 697 from X6882, the external standard (anthracene), and other endogenous substances present in human plasma. In human plasma the limits of quantification for DuP 697 and X6882 were 3 and 20 ng/ml, respectively; the limit of quantification for DuP 697 in human urine was 5 ng/ml. These compounds were shown to be stable in frozen (-20 degrees C) human plasma and urine for at least 9 weeks. The assay described has been used to characterize DuP 697 pharmacokinetics after oral administration in humans.

Protein binding of brequinar in the plasma of healthy donors and cancer patients and analysis of the relationship between protein binding and pharmacokinetics in cancer patients.

The protein binding of weakly acidic and basic drugs has been shown to be altered in cancer patients. Brequinar is a weakly acidic, low-clearance, and highly protein-bound (> 98% bound) antitumor agent. The pharmacokinetic parameters of brequinar are subject to large interpatient variability. This large interpatient variability may be related to brequinar's plasma protein-binding capacity (assuming no change in the intrinsic clearance of the unbound drug). The objectives of this study, therefore, were (a) to characterize brequinar's protein binding in the plasma of healthy donors and cancer patients and (b) to examine the relationships between brequinar's plasma protein binding and its pharmacokinetics in patients. Brequinar protein binding was determined in human serum albumin (HSA) solution, drug-free donor plasma, and brequinar-free, predose plasma samples obtained from a phase I cancer trial. Pharmacokinetic results from this study were used to examine relationships between plasma protein binding and drug disposition. In HSA solution and healthy donor plasma, brequinar's protein binding as determined using spiked samples was concentration-dependent. The unbound brequinar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4% HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor plasma as the brequinar concentrations increased from 0.1 to 2.3 mM in the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysis of brequinar binding characteristics using the binding ratio and Rosenthal binding plots showed that albumin was the primary protein for brequinar binding in human plasma. The addition of various concentrations of alpha 1-acid glycoprotein to 4% HSA solution did not affect the protein binding of brequinar to HSA. The protein binding determined in the plasma of cancer patients was not quantitatively different, except for variability, from that observed in the plasma of healthy donors. Examination of relationships between the unbound brequinar fraction and pharmacokinetics suggested that plasma protein binding was not a major determinant of brequinar disposition in cancer patients.

ELISA determination and preliminary pharmacokinetics of modified human rIL-1 beta in dogs.

A single dose pharmacokinetic study with modified human Interleukin-1 Beta (IL-1 beta or DuP 118) was performed by injecting 5 micrograms/kg of drug into the jugular vein of three beagle dogs. Serial 5-ml plasma samples were removed from the dogs over a 120-minute period. DuP 118 plasma levels were measured using a sandwich ELISA technique capable of measuring concentrations ranging from 0.25 to 2 ng/ml with accuracy and precision constraints of less than +/- 20% variability. DuP 118 stored at -20 degrees C in dog plasma was stable for at least 1 month. Pharmacokinetic parameters were determined for the three dogs by standard model independent or non-compartmental methods. DuP 118 was rapidly distributed in the dog. The volume of distribution was approximately two-fold higher than the total body water of a lean dog. The terminal half-life was short, less than 30 minutes. Within approximately an hour after dosing, DuP 118 plasma levels were reduced 20-fold and were below the quantifiable limit of the assay.

Nanogram level quantitation of oxycodone in human plasma by capillary gas chromatography using nitrogen-phosphorus selective detection.

A sensitive and specific capillary gas chromatographic assay is reported for the quantitation of oxycodone in human plasma. The technique involves a single extraction of oxycodone and internal standard (hydrocodone) from plasma by toluene containing 1% isopropanol. Separation is achieved on a methyl silicone (HP-1) fused-silica capillary column (25 m x 0.2 mm I.D., 0.33 microns film thickness) and detection is by nitrogen-phosphorus selective mode. The minimum quantifiable limit is 1.8 ng/ml using 2 ml of plasma. The method is applicable to characterize the plasma profile of oxycodone in humans after a single oral 5-mg oxycodone hydrochloride tablet.

Effect of moricizine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

Moricizine HCl, a new orally active antiarrhythmic agent, induces its own hepatic metabolism and consequently may interfere with the metabolism of warfarin, a drug used commonly by cardiac patients that also is subject to extensive hepatic metabolism. Both drugs are also highly protein bound in plasma. To assess the possibility of an interaction, single-dose sodium warfarin (25 mg oral Coumadin, Du Pont Pharmaceuticals, Wilmington, DE) pharmacokinetics, pharmacodynamics; and plasma protein binding were examined in 12 healthy male volunteers 14 days before and 14 days after starting chronic oral moricizine HCl administration (250 mg every 8 hours). The terminal elimination rate constant of warfarin was increased by about 10% when measured in the presence of chronic moricizine administration. However, oral plasma clearance, apparent volume of distribution, maximum peak plasma concentration, time to reach peak concentration, and protein binding were unaffected. More importantly, there was no evidence of a pharmacodynamic interaction based on the prothrombin time profile. It was concluded that no clinically significant interaction occurs under these conditions.

Effects of multiple doses of moricizine hydrochloride on its pharmacokinetics and hepatic microsomal enzymes in rats.

We studied the influence of chronic moricizine hydrochloride (MRZ) treatment on the drug's pharmacokinetics and on drug metabolizing enzyme activities in rats. Separate groups of 8 rats (4 males and 4 females) were treated with 40 and 100 mg/kg oral MRZ once daily for 7 days and saline control for 7 days prior to the preparation of hepatic microsomal enzyme suspensions. Depending on the substrate, treatments with multiple oral MRZ increased or decreased hepatic microsomal enzyme activities. For the pharmacokinetic study, rats (4 males and 4 females) were treated with 40 mg/kg oral MRZ once daily for 7 days. A comparison of MRZ pharmacokinetics obtained on day 1 relative to day 7 revealed that both AUC0-t and AUC0-infinity increased about 7-fold in males and 2-fold in females. Cmax also increased about 5-fold from day 1 to day 7 in males. These increases in blood concentrations and AUC's are likely due to enzyme inhibition. Results obtained from female rats on days 1, 4 and 7 suggest that metabolic changes probably occur after the 4th day of dosing. Therefore, chronic MRZ treatment affected its pharmacokinetics and hepatic metabolizing enzyme activities in rats.

Lidocaine for the prevention of pain due to injection of propofol.

Propofol has a high incidence of pain with injection, particularly into small veins. We sought to determine whether concomitant administration of lidocaine could prevent this pain. In a randomized double-blind trial, 368 women were allocated to one of four groups to receive 19 mL of propofol mixed with either 1 mL of 0.9% saline, 1 mL of 0.5% (5 mg) lidocaine, 1 mL of 1% (10 mg) lidocaine, or 1 mL of 2% (20 mg) lidocaine. The pain of injection was scored as none, mild, moderate, or severe. There was a significant reduction in the overall incidence of pain from 73% with saline to 32% with 20 mg lidocaine. A highly significant negative dose-response relationship between the dose of lidocaine and the severity of pain was demonstrable, both at induction of anesthesia and as recalled in the recovery room (P less than 0.001 for both). Lidocaine (20 mg IV) will significantly reduce the incidence and severity of pain with propofol injection, but about 6% of patients will still suffer unpleasant pain if the dorsum of the hand is used.

Self-association and solubility behaviors of a novel anticancer agent, brequinar sodium.

To aid in the selection of appropriate excipients to formulate brequinar sodium [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxyli c acid sodium salt; DuP 785], studies were initiated to characterize thoroughly its solubility behavior. The measured solubilities at RT (approximately 23 degrees C) agreed with the theoretical values in the pH range from 0.5 to 7.2, but became significantly greater than theoretical values at pH values above 7.2. This deviation was likely due to the vertical stacking-type self-association between brequinar molecules in water. The NMR and pH methods determined a critical association concentration of 15 mg/mL. Sodium salicylate, which has been proven to interfere with molecular self-association, reduced drug solubility from 116 to 10 mg/mL. But urea, another deaggregative agent, gave about a twofold increase rather than a decrease in solubility. Addition of sodium chloride caused a 226-fold decrease in solubility. The apparent solubility product did not remain constant but decreased as sodium chloride concentration increased, suggesting that the added salt decreased the degree of self-association between brequinar molecules. Among four surfactants examined (a bile salt with a rigid fused ring versus three ordinary surfactants with a flexible chain structure), only sodium cholate significantly increased the aqueous solubility of brequinar sodium.

Pharmacokinetics of pentaerythritol tetranitrate following intra-arterial and oral dosing in the rat.

The pharmacokinetics of pentaerythritol tetranitrate (2,2-bis(hydroxymethyl)-1,3-propanediol tetranitrate, 1) were studied in rats following a single intra-arterial or oral dose (2 mg/kg) of the 14C-labeled drug. Blood levels of the tetranitrate and its metabolites were determined using a thin-layer radiochromatographic procedure. The apparent systemic clearance of 1 was 0.61 +/- 0.16 L/min/kg (mean +/- SD, n = 6) which exceeded the value of normal cardiac output in rats. The steady-state volume of distribution was 4.2 +/- 1.1 L/kg (n = 6), and the elimination half-life was estimated at 5.8 +/- 0.6 min (n = 6). Blood levels of 1 were only detectable (higher than 4.0 ng/mL) in three of the six rats examined after the oral dose. The trinitrate derivative (2,2-bis(hydroxymethyl)-1,3-propanediol trinitrate, 2) the active metabolite of 1, was not detectable following oral dosing with the tetranitrate. The oral bioavailability of 1 was in the range of 0-8%. In spite of the low water solubility of 1 (i.e., 1 microgram/mL), a rather high fraction of the radioactive oral dose [25.7 +/- 10.3% (n = 4) versus 62.4 +/- 14.5% (n = 4) from the intra-arterial dose] was recovered in the urine. A significant portion of the intra-arterial dose (32.7 +/- 11.0%, n = 4) was eliminated in feces, indicating enterohepatic recycling of radioactivity. Analysis of the metabolite pattern in urine indicated extensive metabolism of 1, 2, and the dinitrate derivative 3 (2,2-bis(hydroxymethyl)-1,3-propanediol dinitrate). Less than 0.2% of the dose was recovered as unchanged drug and 2 following either route of administration.

Examination of the in vitro degradation of [14C] pentaerythritol tetranitrate in rat and human blood with an improved thin-layer radiochromatographic procedure.

Improvements were made on a reported thin-layer radiochromatographic assay for the determination of [14C]pentaerythritol tetranitrate (PETN) and its metabolites in whole blood, using methanol instead of dioxane as the extracting solvent. Recovery of total radioactivity for the entire work-up procedure was greater than 90%, and the distribution of PETN and its metabolites in degraded blood samples was found to be reproducible. This modified method appeared simpler and yielded better recovery of radioactivity than the literature method. In vitro metabolism of [14C]PETN in rat and human blood was examined by incubation of the drug with fresh blood at 37 degrees C for 60 min. In rat blood, the half-life of PETN degradation was about 15 min producing the trinitrate, dinitrate and mononitrate metabolites. Human blood was also capable of degrading PETN in vitro, but at a lower rate than rat blood, yielding only the trinitrate metabolite in quantifiable amounts during the incubation period. Equilibrium of PETN between plasma and red blood cells was observed within 1 min after PETN addition to both rat and human blood. The apparent plasma/red blood cells partition ratios of PETN were 1.1 and 1.7 for rat and human blood, respectively. PETN degradation was approximately ten times slower in rat plasma than in rat blood, suggesting that enzymes in erythrocytes are important for PETN metabolism in rat whole blood.

Rapid microbial degradation of organic nitrates in rat excreta. Re-examination of the urinary and fecal metabolite profiles of pentaerythritol tetranitrate in the rat.

The in vitro stabilities of three organic nitrates, viz. pentaerythritol tetranitrate ( PETN ), nitroglycerin (NTG), and isosorbide dinitrate (ISDN) in rat urine, and of PETN in rat feces were examined. PETN , NTG, and ISDN degraded completely in rat urine following incubation for 24 hr at either 25 or 37 degrees C. Degradation of PETN , NTG, and ISDN was absent in sterilized urine under the same conditions. These data suggested that decomposition of organic nitrates in untreated urine was usually rapid and extensive, and was primarily of microbial origin. Stability of these organic nitrates could also be maintained when urine samples were stored in packed ice. Rapid and extensive microbial degradation of PETN was also found in rat fecal homogenates, suggesting the possibility of organic nitrate metabolism by intestinal microflora. The metabolic profiles of PETN in rat urine and feces following intra-arterial and oral dosing of this organic nitrate were then re-examined. The data confirmed a previous finding that in vivo PETN excretion in urine was minimal. However, contrary to data which showed about 8% fecal recovery after oral dosing, our results suggested a smaller (2%) fecal PETN recovery with oral dosing. It appeared likely then that unabsorbed PETN might be further metabolized by gut flora.

Statistical prediction of drug stability based on nonlinear parameter estimation.

The classical approach in Arrhenius prediction of drug stability uses two sequential steps of linear regression involving (a) a function of drug content versus time to obtain the rate constants (k) at several elevated temperatures and (b) the relationship of logarithm of mean k versus reciprocal temperature to predict the room temperature rate constant and hence the shelf-life of the drug. Uncertainties in drug content determinations are often neglected in the second regression. The classical approach also provides a wide and unsymmetrical 95% confidence interval for the predicted shelf-life. We have developed equations which allow for direct statistical prediction of shelf-life using observed values of drug content, time, and temperature. Nonlinear regression analysis was employed to provide parameter estimates of drug shelf-life and the energy of activation. The developed approach was shown to provide good estimates of shelf-life with meaningful statistics of reactions over a wide range of stability and energetics, with various kinetic orders, with different levels of noise in the data, and with different types of data structure. Comparison between the nonlinear approach and the classical approach showed that the nonlinear approach provided better mean estimates of shelf-life with much smaller and more symmetrical 95% confidence intervals than the classical approach. The method appears sufficiently robust and wide-ranging as to be potentially applicable for the prediction of the drug stability of pharmaceutical products.