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D J Cutler

Publications and source records attributed to D J Cutler.

At least 37 records · Page 2Linked to original sources
PubMed1999

Differential distribution of orexin-A and orexin-B immunoreactivity in the rat brain and spinal cord.

The orexins are recently identified appetite-stimulating hypothalamic peptides. We used immunohistochemistry to map orexin-A and orexin-B immunoreactivity in rat brain, spinal cord, and some peripheral tissues. Orexin-A- and orexin-B-immunoreactive cell bodies were confined to the lateral hypothalamic area and perifornical nuclei. Orexin-A-immunoreactive fibers were densely distributed in the hypothalamus, septum, thalamus, locus coeruleus, spinal cord, and near the ventricles, but absent from peripheral sites investigated. In contrast, orexin-B-immunoreactive fibers were distributed sparsely in the hypothalamus. Orexin cells are strategically sited to contribute to feeding regulation, but their widespread projections suggest that orexins have other physiological roles.

Amino Acid Sequence↗
PubMed1999

Classic Weinstein: tetrad analysis, genetic variation and achiasmate segregation in Drosophila and humans.

A maximum-likelihood method for the estimation of tetrad frequencies from single-spore data is presented. The multilocus exchange with interference and viability (MEIV) model incorporates a clearly defined model of exchange, interference, and viability whose parameters define a multinomial distribution for single-spore data. Maximum-likelihood analysis of the MEIV model (MEIVLA) allows point estimation of tetrad frequencies and determination of confidence intervals. We employ MEIVLA to determine tetrad frequencies among 15 X chromosomes sampled at random from Drosophila melanogaster natural populations in Africa and North America. Significant variation in the frequency of nonexchange, or E(0) tetrads, is observed within both natural populations. Because most nondisjunction arises from E(0) tetrads, this observation is quite unexpected given both the prevalence and the deleterious consequences of nondisjunction in D. melanogaster. Use of MEIVLA is also demonstrated by reanalyzing a recently published human chromosome 21 dataset. Analysis of simulated datasets demonstrates that MEIVLA is superior to previous methods of tetrad frequency estimation and is particularly well suited to analyze samples where the E(0) tetrad frequency is low and sample sizes are small, conditions likely to be met in most samples from human populations. We discuss the implications of our analysis for determining whether an achiasmate system exists in humans to ensure the proper segregation of E(0) tetrads.

Animals↗
PubMed1998

Responses to neuropeptide Y in adult hamster suprachiasmatic nucleus neurones in vitro.

We investigated the effects of neuropeptide Y and related analogues on the extracellularly recorded spontaneous firing rate activity of adult Syrian hamster suprachiasmatic nucleus neurones in vitro. Sixty-seven neurones were tested with neuropeptide Y: 45% were suppressed, 4% were activated, and the remaining 51% were unresponsive. These responses were not blocked by the GABA receptor antagonist bicuculline, indicating that neuropeptide Y-evoked responses did not appear to be dependent on GABA(A) receptor activation. We tested the effects of the neuropeptide Y Y1 receptor agonist [Leu31, Pro34]neuropeptide Y and the neuropeptide Y Y2 receptor agonist neuropeptide Y-(13-36) on nine cells suppressed by neuropeptide Y in order to determine the receptor subtype(s) mediating the effects of neuropeptide Y. Four of nine cells were suppressed by [Leu31, Pro34]neuropeptide Y only, one of nine was suppressed by neuropeptide Y-(13-36) only, two of nine were suppressed by both compounds, while the remaining two cells did not respond to either compound. These data suggest that neuropeptide Y can modulate suprachiasmatic nucleus function directly, without recruitment of GABA(A) interneurones. Further, our results indicate that neuropeptide Y may act on more than one receptor subtype within the adult hamster suprachiasmatic nucleus.

Action Potentials↗
PubMed1998

Stability of finite difference deconvolution I: theoretical analysis.

Analysis of the stability of finite difference deconvolution (FDD) shows that it is dependent on the characteristics of the unit impulse response function and the sampling schedule of the input response function, and that stability properties are improved when the cumulative amount function is directly estimated rather than the rate function. The estimated input rate for an intravenous (iv) unit impulse response function and the release rate for an oral solution unit impulse response function are unstable for any sampling schedule of the input response function. However, for an iv unit impulse response function, the estimated cumulative amount absorbed is stable for any sampling schedule of the response function. For an oral unit impulse response function, the estimated cumulative amount released is unstable for all the sampling points of the input response function located before the time of the maximum of the oral unit impulse response function, but it can be made stable if an appropriately designed sampling schedule of the input response function is used. In addition, the theoretical basis for choosing a sampling schedule to overcome the instability of FDD has been established.

Algorithms↗
PubMed1998

Stability of finite difference deconvolution II: simulation studies.

Theoretical analysis of the stability of finite difference deconvolution (FDD) indicates that if the cumulative amount function is used to characterize the drug input the method is stable for any sampling schedule for an intravenous unit impulse response function. The analysis also indicates that the method is stable for an oral unit impulse response only for well designed sampling schedules. This article confirms these results through numerical simulation experiments. It is shown that the assumption that the unit impulse response is error-free has an influence on the performance of FDD which is generally of no practical significance, except possibly for the first few points estimated. It is also shown that there is no significant interaction between the statistical error due to data noise and the deterministic algorithm error. The major source of error in practice is likely to be the data noise in the input response function. The simulations confirm that, with the estimated cumulative amount function as the quantity estimated and, with a well designed sampling schedule for the case of an oral unit impulse response, FDD is in practice an accurate and stable method with acceptable precision under a typical error disturbance.

Algorithms↗
PubMed1997

Pharmacokinetics of dexamethasone and its relationship to dexamethasone suppression test outcome in depressed patients and healthy control subjects.

The pharmacokinetics of dexamethasone (DEX) were studied in 9 drug-free melancholically depressed patients and 10 healthy control subjects matched by sex and age. Each subject received 1 mg of DEX administered orally and by the (i.v.) route at 11:00 PM and serial blood samples were collected over the next 17 hours until 4:00 PM. There were no significant differences between the diagnostic groups and DEX bioavailability, peak plasma level, time to maximum concentration, or in elimination half-life after oral administration. Bioavailability estimates indicated that DEX absorption was incomplete and variable mean = 61%, SD = 14) in controls as well as depressed patients. In both groups there was a wide interindividual variability in plasma DEX levels following both oral and i.v. routes of administration. This variability could not be reliably predicted by differences in age, sex, or weight between subjects. The factors that accounted for most the variability in 4:00 PM plasma DEX levels after oral administration were clearance, bioavailability, and time to reach maximum concentration. Plasma DEX levels were lower in 3 depressed nonsuppressors compared to 3 matched controls who suppressed. No single pharmacokinetic factor was shown to be responsible for the lower DEX levels in the depressed nonsuppressors. These results indicate that plasma DEX levels need to be measured in each individual during the DST procedure so that this information may be taken into consideration when interpreting DST results.

Administration, Oral↗
PubMed1995

Ionophoretically applied substance P activates hamster suprachiasmatic nucleus neurons.

ionophoretic ejection of substance P (SP) activated 31% and suppressed 9% of hamster suprachiasmatic nucleus (SCN) cells in vitro. Hamster SCN cells did not demonstrate variation in sensitivity to SP across the circadian phases tested. SP modulated the response of 47% of hamster SCN cells to the excitatory amino acid (EAA) agonists glutamate and N-methyl-D-aspartate (NMDA). The results indicate that SP can alter both the spontaneous and EAA-evoked firing rate characteristics of hamster SCN neurons.

Action Potentials↗
PubMed1994

Effects of ionophoretically applied bombesin-like peptides on hamster suprachiasmatic nucleus neurons in vitro.

Ionophoresis of the smaller bombesin-like peptides (gastrin releasing peptide [GRP]-(18-27), neuromedin B, and bombesin) evoked responses from 30-60% of hamster suprachiasmatic nucleus cells recorded in a hypothalamic slice preparation, depending on the circadian phase. We also demonstrated for the first time that the putative bombesin-like peptide receptor antagonists [D-F5,D-Phe6,D-Ala11]bombesin-(6-13)methyl ester (BIM 26226) and [D-Phe6,Des-Met14]bombesin-(6-14)ethyl amide can be applied ionophoretically to block physiological responses to bombesin-like peptides. Together with earlier findings, these results show that bombesin-like peptides administered by several methods can potently alter the firing rates of hamster suprachiasmatic nucleus neurons in vitro. These results indicate that bombesin-like peptides affect suprachiasmatic nucleus cells and could play a role in modulating suprachiasmatic nucleus-mediated circadian rhythm entrainment.

Animals↗
PubMed1994

Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate.

Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (-)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration-effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease.

Arthritis, Rheumatoid↗
PubMed1994

Disposition and absorption of hydroxychloroquine enantiomers following a single dose of the racemate.

The disposition of hydroxychloroquine enantiomers has been investigated in nine patients with rheumatoid arthritis following administration of a single dose of the racemate. Blood concentrations of (-)-(R)-hydroxychloroquine exceed those of (+)-(S)-hydroxychloroquine following both an oral and intravenous dose of the racemate. Maximum blood concentrations of (-)-(R)-hydroxychloroquine were higher than (+)-(S)-hydroxychloroquine after oral dosing (121 +/- 56 and 99 +/- 42 ng/ml, respectively, P = 0.009). The time to maximum concentration and the absorption half-life, calculated using deconvolution techniques, were similar for both enantiomers. The fractions of the dose of each enantiomer absorbed were similar, 0.74 and 0.77 for (-)-(R)- and (+)-(S)-hydroxychloroquine, respectively (P = 0.77). The data suggest that absorption of hydroxychloroquine is not enantioselective. The stereoselective disposition of hydroxychloroquine appears to be due to enantioselective metabolism and renal clearance, rather than stereoselectivity in absorption and distribution.

Absorption↗
PubMed1994

Bioavailability of hydroxychloroquine tablets in patients with rheumatoid arthritis.

Nine patients with RA received two doses of 155 mg racemic hydroxychloroquine each, as a tablet and by i.v. infusion, in a randomized cross-over design study. Blood concentrations over the first 32 h following each dose were determined. Bioavailability was estimated using a sequential exponential least squares deconvolution method. The mean fraction absorbed from the tablet was 0.79 (range 0.39 to 1.27). The mean absorption lag-time was 1.3 h (range 0.5 to 3.7 h) and the mean time for 50% absorption was 4.3 h (range 1.9 to 10.3 h). Mean rate and extent of hydroxychloroquine absorption were not significantly different from that previously reported for healthy volunteers, although the interindividual variability in absorption parameters was greater in the patient group. Variability in the extent of absorption would lead to differences in steady-state hydroxychloroquine concentrations between patients, potentially contributing to the variability in response observed in clinical practice.

Adult↗
PubMed1993

Blood to plasma ratio of mefloquine: interpretation and pharmacokinetic implications.

The blood to plasma ratio of the antimalarial mefloquine has been reported to be close to 1, while other reports indicate extensive accumulation in erythrocytes. This apparent contradiction has been resolved by a quantitative examination of the compensating effects of plasma protein binding of mefloquine which almost exactly matches the extent of mefloquine accumulation in erythrocytes. The observed blood to plasma ratio of about 1 arises as the result of a balance between extensive red cell uptake and extensive plasma protein binding. Some pharmacokinetic implications of the distribution of mefloquine within blood are outlined.

Erythrocytes↗
PubMed1993

Kinetics of chloroquine uptake into isolated rat hepatocytes.

The kinetics of uptake of chloroquine into isolated rat hepatocytes were studied to further investigate whether they are consistent with accumulation of chloroquine at therapeutic concentrations that is predominantly due to lysosomal trapping. A mathematical model describing the disposition of weak bases in isolated hepatocytes was developed and fitted to the chloroquine uptake data, allowing estimation of permeability coefficients for un-ionized chloroquine transport across rate-limiting membranes (p0 = 5.9 +/- 0.5 cm. s-1). The results of these studies suggest that the lysosomal membrane is the rate-limiting membrane in uptake of chloroquine in isolated hepatocytes. The rate and extent of accumulation of chloroquine in isolated hepatocytes in the presence of 10 mM NH4Cl were decreased. These results are consistent with a reduction in lysosomal pH caused by NH4Cl. The kinetics of uptake of hydroxychloroquine, which is structurally similar to chloroquine, were also investigated. The results of these studies were also consistent with lysosomal trapping, although the p0 value for un-ionized hydroxychloroquine (p0 = 0.28 +/- 0.02 cm.s-1) was much lower than that for un-ionized chloroquine. The estimated p0 value for un-ionized chloroquine and hydroxychloroquine transport across the lysosomal membrane are of a similar magnitude to those reported for transport of these compounds across human erythrocyte membranes, suggesting a similar transport mechanism.

Animals↗
PubMed1993

Plasma protein binding of the enantiomers of hydroxychloroquine and metabolites.

The in vitro binding of the enantiomers of hydroxychloroquine and its three major metabolites in pooled plasma obtained from four healthy volunteers and the binding of the enantiomers of hydroxychloroquine to purified plasma proteins has been investigated. The plasma protein binding of hydroxychloroquine was found to be stereoselective. The (S)-enantiomer of hydroxychloroquine was 64% bound in plasma, while (R)-hydroxychloroquine was 37% bound. Fifty% of (S)-hydroxychloroquine was bound to a 40 g.l-1 solution of human serum albumin, while only 29% of the (R)-enantiomer was bound. The enantioselectivity of hydroxychloroquine binding was reversed in a 0.7 g.l-1 solution of alpha 1-acid glycoprotein with (R)-hydroxychloroquine being bound to a greater extent than its optical antipode (41% versus 29%). The enantiomers of the metabolites of hydroxychloroquine were bound to a similar extent to plasma and purified plasma proteins. Binding of hydroxychloroquine to plasma and purified proteins was found to be linear over the racemic concentration range of 50 to 1000 ng.ml-1 and hydroxychloroquine metabolite binding to plasma was linear over the range 25 to 500 ng.ml-1.

Blood Proteins↗
PubMed1993

Absorption and in vivo dissolution of hydroxycholoroquine in fed subjects assessed using deconvolution techniques.

1. Nine healthy subjects each received three doses of 155 mg rac-hydroxychloroquine, as a tablet, an oral solution and by intravenous infusion, in a randomised cross-over design study, 30 min after a standard high fat breakfast. 2. Four methods of deconvolution were used to assess the absolute bioavailability of the tablet and oral solution doses. These were the delta function method, the staircase approximation method, and two least squares methods using a single first-order input and a sequential first-order input. The mean (+/- s.d.) fraction absorbed estimated by the four methods was 0.64 +/- 0.14 after the tablet and 0.87 +/- 0.30 after the oral solution. Wide intersubject variability was observed (0.50-0.91 for the tablet; 0.30-1.37 for the solution). 3. The mean (+/- s.d.) absorption half-life was 3.7 +/- 2.0 h for the tablet and 3.3 +/- 1.6 h for the solution, suggesting that absorption following the tablet dose was not rate-limited by dissolution. 4. The in vivo dissolution rate, extent of release and lag-time were determined using cube-root law and first-order input functions. Dissolution was found to be rapid, after a significant lag-time, but incomplete in some subjects. 5. The rate and extent of absorption was similar to that reported previously for fasted subjects. The lag-time before absorption commenced in fed subjects (1.65 +/- 0.46 h) showed a significant three-fold increase over that reported previously in fasting subjects (0.63 +/- 0.33 h), but this difference is not likely to be of clinical significance.

Administration, Oral↗
PubMed1993

Disposition of the enantiomers of hydroxychloroquine in patients with rheumatoid arthritis following multiple doses of the racemate.

In eight patients with rheumatoid arthritis receiving racemic hydroxychloroquine, blood and urine concentrations of the enantiomers of hydroxychloroquine and its major metabolites were measured each month over the first 6 months of therapy. Plasma concentrations of hydroxychloroquine enantiomers were measured in five of these patients. In all patients, the blood concentration of (R)-hydroxychloroquine exceeded that of the (S)-enantiomer, the mean (R)/(S) ratio being 2.2 (range 1.6-2.9). A similar excess of (R)-hydroxychloroquine was found in the plasma, the mean (R)/(S) ratio being 1.6 (range 1.2-1.9). The mean enantiomer blood concentration ratio (R)/(S) for the metabolite desethylhydroxychloroquine was 0.45 (range 0.34-0.58) and for desethylchloroquine it was 0.56 (range 0.35-0.86) suggesting stereoselective metabolism of hydroxychloroquine. (S)-hydroxychloroquine had a mean (+/- s.d.) renal clearance from blood of 41 +/- 11 ml min-1, approximately twice that of (R)-hydroxychloroquine. The predicted unbound renal clearance was also higher for (S)-hydroxychloroquine. The clinical implications of enantioselective disposition of hydroxychloroquine are currently not known.

Adult↗
PubMed1993

Concentration-effect relationship of hydroxychloroquine in rheumatoid arthritis--a cross sectional study.

OBJECTIVE: To determine the relationship between hydroxychloroquine concentration and effect in patients with rheumatoid arthritis (RA). METHODS: Using a cross sectional study design, drug concentration and effect were measured at one time. Forty-three patients with RA, receiving hydroxychloroquine therapy for at least 6 months and not receiving glucocorticosteroids, gold or penicillamine therapy were enrolled. The main outcome measures were hydroxychloroquine concentration and disease activity measured as degree of synovitis, pain, duration and intensity of morning stiffness, impairment of activities of daily living, patients' and physicians' subjective assessment of disease, erythrocyte sedimentation rate, and rheumatoid factor (RF). Hemoglobin and albumin concentrations were also recorded. RESULTS: Patients with none or mild intensity of morning stiffness, those with stiffness lasting less than 0.5 h and those with negative RF had significantly higher hydroxychloroquine blood concentrations than those in whom these measures indicated a more active disease (Mann-Whitney U test, p < 0.05). Similar trends were recorded for 3 other disease activity measures (p = 0.12-0.24). Analysis of all 9 individual disease activity measures indicated that the groups with less active disease had higher mean blood concentrations of hydroxychloroquine than those with measures indicating more active disease (p < 0.01). CONCLUSION: Our data provide the first evidence of a concentration-response relationship for hydroxychloroquine in RA for individual disease activity measures. However, an unweighted summed score of disease activity did not correlate significantly with drug blood concentrations. A prospective study is necessary to confirm the relationship and to determine a therapeutic concentration range.

Adult↗