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Biomedical subjects

D J Cutler

Publications and source records attributed to D J Cutler.

At least 55 records · Page 3Linked to original sources
PubMed1993

Possible mechanisms of action of antimalarials in rheumatic disease.

Understanding of the mechanism of action of the antimalarials in rheumatoid arthritis remains limited in spite of knowledge of a wide range of potentially relevant effects at the cellular level. Among the difficulties with proposed mechanisms of action are a lack of specificity, doubt about demonstrable effects at appropriate concentrations and a failure to explain the slow onset of action. It is possible that pharmacokinetic factors, or the slow change in the underlying disease pathology, might account for the slow onset.

Cells↗
PubMed1992

Sensitive stereospecific assay of warfarin in plasma: reversed-phase high-performance liquid chromatographic separation using diastereoisomeric esters of (-)-(1S,2R,4R)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]-hept-5- ene-2-carboxylic acid.

A stereospecific reversed-phase high-performance liquid chromatographic (HPLC) assay for warfarin in plasma has been developed. The assay involves a rapid, simple clean-up procedure which separates warfarin from plasma constituents and warfarin metabolites. Warfarin enantiomers were assayed as their (-)-(1S,2R,4R)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene -2- carboxylic acid diastereoisomeric esters by reversed-phase HPLC. Excellent resolution of the diastereoisomers was achieved in less than 10 min. Sensitivity of the assay was approximately 5-10 ng/ml for each isomer.

Bridged Bicyclo Compounds↗
PubMed1992

Bioavailability of hydroxychloroquine tablets assessed with deconvolution techniques.

Four deconvolution methods (staircase, delta function, and least squares methods using single and sequential first-order input functions) were used to assess the absolute bioavailability of hydroxychloroquine tablets in nine healthy fasting volunteers. The volunteers received, in a random crossover design, a 155-mg oral tablet and a 155-mg iv infusion of racemic hydroxychloroquine. The mean fractions of the dose absorbed, calculated using the four deconvolution methods, were not statistically different (p = 0.70). The mean fraction absorbed (+/- SD) was 0.67 +/- 0.12, which was not significantly different from that reported previously in a conventional bioavailability study (p = 0.22). The mean absorption half-life was calculated to be 4.0 +/- 1.3 h. The mean lag time before absorption commenced was 0.57 +/- 0.30 h. The fraction of the dose absorbed ranged from 0.44 to 0.86. Low and/or variable bioavailability of hydroxychloroquine may be a cause of therapeutic failure in some patients. Validation of the deconvolution methods means that these techniques may now be used to assess the bioavailability of hydroxychloroquine in patients. An advantage of these methods is that samples need only be collected over the expected time period of absorption, rather than the whole time drug can be detected in the body, as is required in conventional area under the concentration-time curve ratio methods. Deconvolution studies may be completed in 2 weeks rather than the 10 months required for a conventional bioavailability study of hydroxychloroquine.

Adult↗
PubMed1992

Chloride-37 nuclear magnetic resonance spectroscopic study of binding of salicylic acid and other hydroxybenzoic acids to the band 3 anion transport protein of human erythrocytes.

Chloride-37 nuclear magnetic resonance spectroscopy was used to investigate the displacement of chloride (Cl-) from binding sites on band 3 anion transport protein in human erythrocytes by salicylic acid and five other hydroxybenzoic acids (HAs). All the HAs studied displaced Cl- from these binding sites. The association constants for binding of the HAs to band 3 anion transport protein were larger than that for Cl- and dependent on the specific structural features of the molecule, rather than general physicochemical characteristics.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1992

A kinetic study of the role of band 3 anion transport protein in the transport of salicylic acid and other hydroxybenzoic acids across the human erythrocyte membrane.

The mechanism of transport of salicylic acid and five other hydroxybenzoic acids across the human erythrocyte membrane was investigated. The specific anion transport inhibitor, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, reduced but did not totally abolish transport of these acids. This observation suggests that these acids are transported by two parallel processes, one involving the band 3 anion transport protein channel and the other probably involving passive diffusion of the un-ionized molecule. The activation energies for membrane transport were large (99-127 kJ.mol-1), an observation that is consistent with the rate-limiting step for anion transport being the conformational change of the band 3 anion transport protein.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

Gentamicin clearance during continuous arteriovenous hemodiafiltration.

OBJECTIVE: To investigate the feasibility of predicting gentamicin dosing requirements during continuous arteriovenous hemodiafiltration (CAVHD). DESIGN: Prospective study. SETTING: General intensive therapy unit in a university teaching hospital. PATIENTS: Five adult patients with acute renal failure in whom both dialytic and gentamicin therapy were indicated. MEASUREMENTS AND MAIN RESULTS: CAVHD clearance and total body clearance of gentamicin were estimated from serial gentamicin concentrations in the blood and the combined ultrafiltrate and dialysate. Results (mean +/- SD) were: CAVHD clearance of gentamicin 5.2 +/- 1.8 mL/min; total body clearance of gentamicin 20.5 +/- 6.9 mL/min; ultrafiltrate flow rate 7.0 +/- 2.4 mL/min (420 +/- 146 mL/hr). CAVHD clearance of gentamicin was small and represented approximately 25% of total body clearance of gentamicin, although significant interpatient variation existed in these measurements and in the proportion of total gentamicin clearance attributable to CAVHD. CAVHD clearance of gentamicin was related to the ultrafiltrate flow rate (r2 = .81). CONCLUSIONS: CAVHD clearance of gentamicin may be predicted for variable ultrafiltrate flow rates. However, due to its minor and variable contribution to total body clearance of gentamicin, prediction of gentamicin dosing requirements based on estimates of CAVHD clearance of gentamicin would be precluded and close monitoring of circulating gentamicin concentrations during CAVHD is necessary.

Acute Kidney Injury↗
PubMed1991

Simulation of kinetic data on the influx and efflux of chloroquine by erythrocytes infected with Plasmodium falciparum. Evidence for a drug-importer in chloroquine-sensitive strains.

Literature data on influx and efflux kinetics of chloroquine (CQ) with erythrocytes infected with the malaria parasite Plasmodium falciparum were simulated using a four-compartment model with first-order exchange between the compartments. The four compartments represent (1) the buffer surrounding the infected erythrocyte; (2) the cytosol of the host erythrocyte; (3) the parasite cytosol; and (4) the food vacuole. Simulations showed that basal membrane transport of CQ, estimated from data on influx of CQ into uninfected red cells, largely accounts for uptake and release of CQ by erythrocytes infected with two different CQ-resistant (CQ-R) parasite strains. In contrast, the rate of uptake of CQ by erythrocytes infected with a CQ-sensitive (CQ-S) strain is substantially higher than predicted by uptake with membrane transfer by basal diffusion of CQ. Simulations also indicate that the difference in kinetics of CQ uptake by erythrocytes infected with the CQ-S and CQ-R strains can be explained by a net increase in the inward permeability coefficient at the host erythrocyte membrane, the composite membrane surrounding the parasite or the food vacuole membrane. The results are consistent with the presence of a drug-importer for CQ in erythrocytes infected with sensitive strains, which is absent in those infected with resistant strains. They are not consistent with the hypothesis that CQ resistance is attributable to a drug-exporter in resistant cells which is lacking in sensitive cells.

Animals↗
PubMed1991

High-performance liquid chromatographic separation of the enantiomers of hydroxychloroquine and its major metabolites in biological fluids using an alpha 1-acid glycoprotein stationary phase.

An enantioselective two-stage off-line assay has been developed for the analysis of hydroxychloroquine and its three major metabolites in biological fluids. The first non-stereoselective stage of the assay (PRP-1 column) separates and quantitates parent drug and metabolites. Fractions containing hydroxychloroquine and each of the metabolites are collected manually, evaporated, reconstituted in mobile phase and re-injected onto an alpha 1-acid glycoprotein column to separate and determine proportions of individual enantiomers. Preliminary results from patients samples indicate that the disposition of hydroxychloroquine and its major metabolites is enantioselective. p6

Body Fluids↗
PubMed1991

Kinetics and thermodynamics of chloroquine and hydroxychloroquine transport across the human erythrocyte membrane.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have almost identical molecular volumes but showed very different permeability characteristics. The permeability coefficient for the unionised species of CQ (2.0 cm/sec at 25 degrees) was about fifty times that of HCQ (0.039 cm/sec at 25 degrees), but the apparent activation energy for transport (85 kJ/mol for CQ, 81 kJ/mol for HCQ) was almost identical for the two drugs. The partition coefficient of CQ into various organic solvents was much higher than for HCQ, but the different permeability behaviour cannot be quantitatively explained by partitioning behaviour into hexane or octanol, two solvents commonly used to mimic the membrane interior. A comparison of permeability and partitioning characteristics suggests that the barrier phase for these drugs within the membrane can be modelled by a mixed solvent of 5% octanol in hexane. The results suggest that interactions with hydrogen bonding groups within the membrane are important in the membrane transport of these drugs, and that the membrane does not behave functionally as a simple hydrocarbon barrier.

Biological Transport↗
PubMed1990

Uptake of chloroquine by human erythrocytes.

Analysis of studies of the pH dependence of the kinetics of chloroquine (CQ) uptake by human erythrocytes indicates that the unionised CQ species is the major membrane permeant at physiological pH even though the concentration of this species as a fraction of the total CQ concentration in solution is extremely small (0.01% at pH 7.4). CQ concentration-dependence studies and studies performed in the presence of various substrates and inhibitors of erythrocyte membrane transport failed to provide evidence of saturation or inhibition of CQ transport, which suggests that the likely mechanism of CQ transport across human erythrocyte membranes is by passive diffusion. Results of equilibrium binding studies of CQ to intact and lysed human erythrocytes indicated that the mechanism of CQ accumulation in intact human erythrocytes appears to be by a combination of ion trapping (a consequence of the basic nature of the drug and the pH gradient across the human erythrocyte membrane) and binding of CQ to cell components.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1989

Bioavailability of hydroxychloroquine tablets in healthy volunteers.

1. Five healthy volunteers received, in a randomised crossover design study, a 155 mg oral tablet and an intravenous infusion of 155 mg racemic hydroxychloroquine (200 mg hydroxychloroquine sulphate) to assess the bioavailability of the commercially available tablet (Plaquenil, Winthrop Laboratories, Australia). 2. The terminal elimination half-life of hydroxychloroquine is more than 40 days, thus blood and urine samples were collected for 5 months following each dose to characterise adequately the terminal elimination phase and obtain accurate estimates of the areas under the concentration-time curves. 3. The mean (+/- s.d.) fraction of the oral dose absorbed, estimated from the blood and urine data, was 0.74 (+/- 0.13). A wide range of estimates of the fraction of the oral dose absorbed was calculated from the plasma data (0.41 - 1.53), reflecting the difficulties of accurate measurement of hydroxychloroquine in plasma. 4. A period of 6 months is required to achieve 96% of steady-state levels of hydroxychloroquine with the usual once daily, oral dosage regimen. Pharmacokinetic factors may thus be partly responsible for the delayed action of the drug in rheumatic conditions. 5. Haemodialysis will not aid in the case of oral overdose with hydroxychloroquine. Although the proportionate increase in clearance may be large, the increase in the fraction of the dose excreted will be negligible. The extensive sequestration of the drug by tissues limits effectiveness of haemodialysis.

Biological Availability↗
PubMed1989

Thrombosis: the major Hickman catheter complication in patients with solid tumor.

Major complications of Hickman catheter placement (thrombosis and infection) were determined in 168 patients with solid tumor (lung, 79; head and neck, 56; esophagus, 24; and miscellaneous, 9). Catheter-related thrombosis was clinically detected in 22 individuals and was detected at autopsy in six (total 17 percent). The 17 percent figure underestimates the true incidence of thrombosis since only 25 percent of study patients had autopsies. Patients with adenocarcinoma of the lung constituted a high risk group. Nine of 20 (45 percent) of these patients had thrombosis compared to 25, 9, and 16 percent of patients with squamous cell cancers of lung, head and neck and esophagus, respectively (p less than 0.002). Three patients with thrombosis had pulmonary emboli and two died. Thrombosis occurred despite daily heparin catheter flushing. INfections occurred in 11 patients. One had suspected endocarditis, one had a subcutaneous tunnel infection, and nine had exit site infections. All responded to local or systemic antibiotics. Better methods to prevent thrombosis are needed.

Adenocarcinoma↗
PubMed1988

Role of lysosomes in hepatic accumulation of chloroquine.

At therapeutic free concentrations (120-360 nM in rheumatoid arthritis), the accumulation ratio for chloroquine (7-chloro-4-[[4-(diethylamino)-1-methylbutyl]amino]-quinoline; CQ) in viable isolated rat hepatocytes is 795 +/- 33, which is of the same order of magnitude as in vivo hepatic uptake in the rat. The accumulation ratio is much lower in nonviable hepatocytes (12.4 +/- 0.5), showing that accumulation in membranes of hepatocytes accounts for a negligible proportion (less than 3%) of total accumulation at therapeutic free concentrations. This also indicates that the predominant mechanism of accumulation is dependent on structural integrity of cells and/or organelles. The accumulation ratio for CQ in viable hepatocytes is markedly reduced by NH4Cl and the metabolic inhibitors KCN and NaF. Since intralysosomal pH is known to be elevated in the presence of some weak bases (including NH4Cl and CQ) and metabolic inhibitors, this suggests that hepatic accumulation of CQ is a consequence of ion trapping in the acidic interior of lysosomes. Accumulation is linear at therapeutic free CQ concentrations; however, at CQ concentrations well above the therapeutic range, the accumulation ratio is markedly reduced. This is consistent with the known capacity of CQ to raise intralysosomal pH at these concentrations.

Animals↗
PubMed1988

A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers.

1. The pharmacokinetics of hydroxychloroquine were studied in five healthy volunteers following an intravenous infusion of 155 mg (2.47 +/- 0.25 mg kg-1) racemic hydroxychloroquine. Four of these volunteers also received a further 310 mg (4.92 +/- 0.45 mg kg-1) infusion of hydroxychloroquine and evidence of nonlinearities in the pharmacokinetics of hydroxychloroquine were sought. 2. No nonlinear elimination or distribution processes appeared to be operating at the doses of hydroxychloroquine used in this study, supporting the hypothesis that in the therapeutic dosing range the pharmacokinetics of hydroxychloroquine are linear. 3. Half-life and mean residence time were long (around 40 days) and large volumes of distribution were calculated (5,522 l from blood, 44,257 l from plasma). Sequestration into the tissues is an important feature of the disposition of hydroxychloroquine. The persistence of hydroxychloroquine in the body is due primarily to this extensive tissue distribution, rather than to low clearance (667 ml min-1 based on plasma data, 96 ml min-1 based on blood data). 4. Plasma data were more variable than blood data. Blood to plasma concentration ratios were not constant (mean +/- s.d.: 7.2 +/- 4.2). The data indicate that it is preferable to measure whole blood concentrations of hydroxychloroquine, rather than plasma concentrations, in pharmacokinetic studies. 5. The pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.

Adult↗
PubMed1988

Incidence and cardiac effects of systemic venous air embolism. Echocardiographic evidence of arterial embolization via noncardiac shunt.

Central nervous system dysfunction in venous air embolism may result from air entering the arterial circulation. Using two-dimensional and pulsed-wave Doppler echocardiography, this study not only documented the frequent presence of air in the right heart chambers of patients undergoing upright neurosurgery or pacemaker insertion, but also documented the presence of air in the left atrium and left ventricle of one patient via noncardiac shunt. Studies in dogs confirmed paradoxical air embolism in the absence of anatomic communications between right and left heart chambers. Systemic venous air also produced a dose-dependent increase in pulmonary artery pressure and diastolic flattening of the ventricular septum with increase in left ventricular filling pressure despite preserved systolic function.

Aged↗
PubMed1987

Temperature dependence of the acid dissociation constants of chloroquine.

The pKa values of the conjugate acids of the antimalarial drug chloroquine were determined at various temperatures using fluorescence spectrophotometry and nonlinear regression in the data analysis. Both pKa values decreased by approximately one unit with increasing temperature over the range 0-37 degrees C with enthalpy changes of 46 and 49 kJ X mol-1. The ionization of chloroquine was found to be mainly controlled by the change in enthalpy. The chloroquine monocation was shown to be almost exclusively in the alkylamino protonated form at all temperatures studied.

Chloroquine↗
PubMed1987

Apparent dose-dependence of chloroquine pharmacokinetics due to limited assay sensitivity and short sampling times.

We have shown that apparent nonlinearities in the pharmacokinetics of chloroquine and wide variability in reported kinetic values are possibly artefacts of experimental design. We have used simulated data based on linear equations to demonstrate that chloroquine kinetics may appear to be dose-dependent if samples are collected over a short period or if they are assayed with a method of low sensitivity.

Chloroquine↗