Slow Absorber Research Articles

Cyclosporin C2hour monitoring after renal transplantation.

Therapeutic drug monitoring of cyclosporin A (CsA) is essential because of its variable pharmacokinetics in individual patients and its narrow therapeutic window. In the past, standard trough level (C0) monitoring has been used, and although this method is currently the routine strategy, it has been shown that a single blood concentration measurement 2 hours after CsA administration (C2hour) is a significantly more accurate predictor of drug exposure and clinical events than trough concentrations. The CsA absorption profiling, in particular the measurement of C2hour, is a much more sensitive approach to assessing the pharmacokinetics and predicting the clinical effect in the individual patient. However, there are limited prospective data available examining the risks and benefits of C2hour monitoring in renal transplant recipients. Most studies focus on the early post-transplant phase, but there is little experience with C2hour monitoring in maintenance patients. Our experience in 127 stable long-term renal allograft recipients suggests that the therapeutic window for C2hour levels in patients during maintenance is lower than previously anticipated. Repeat determinations of both C0 and C2hour levels in 46 patients to determine precision of C2hour monitoring showed a high intrapatient variability. We observed only a slightly better coefficient of variation for C2hour than for C0 in repeat determinations. This suggests that drug monitoring using C2hour levels in transplant patients may provide a more accurate and reliable measure of drug exposure in the individual patient. However, CsA absorption showed only a weak correlation with dose during repeated measurements, suggesting high variability in absorption in these stable patients. We conclude that an adequate C2hour level soon after transplantation is associated with a reduced risk of acute rejection in adult renal transplant recipients. It is important to identify slow and poor absorbers in the initial phase after transplantation in order to avoid inappropriate increases in CsA dose. In maintenance patients, C2hour values between 500 and 600 ng/ml are effective and safe for providing effective rejection prophylaxis. Although mean C2hour levels do not seem to identify patients at risk of rejection, they may help to identify excessive immunosuppression and to improve long-term survival by reducing CsA toxicity.

Recommendations for the implementation of Neoral C(2) monitoring in clinical practice.

Recommendations for the implementation of Neoral C(2) monitoring in clinical practice.

The population pharmacokinetics of digoxin in dogs with heart disease.

Clinical monitoring of digoxin plasma concentration is recommended because of both a large inter-animal variation in digoxin pharmacokinetics and the small ratio of toxic/therapeutic concentrations. Digoxin concentration data from clinical therapeutic drug monitoring (TDM) are used to adapt dosage regimes. Hierarchical mixed effects modeling of TDM data can be used to identify factors that are covariables for pharmacokinetic model parameters. Knowledge of such pharmacokinetic model covariables may help to improve dose calculations and predictions and can also help to understand the pharmacodynamics of drug action and toxicity. Such models have been developed for digoxin in humans (Sheiner et al., 1977). The pharmacokinetics of digoxin in healthy dogs has been described previously (Button et al., 1980b) and dosage regimes have been examined in dogs with induced (Button et al., 1980a) or naturally occurring congestive heart failure (Tobias et al., 1989). These previous studies showed that dose adjustments made according to assumed covariables for digoxin pharmacokinetics did not accurately achieve the desired plasma concentrations in individual animals (Tobias et al., 1989). Individualized dosage regimes using TDM are necessary to achieve desired plasma digoxin concentration in dogs (Button et al., 1980a). We applied hierarchical mixed effects modeling to examine the pharmacokinetics of digoxin in 161 cases with naturally occurring heart disease in dogs. Of these, 32 were examined prospectively and 129 retrospectively. We aimed to describe the pharmacokinetics of digoxin in dogs with heart disease and to identify covariables, which could be used to predict an individual dog’s digoxin pharmacokinetics. Samples for digoxin analysis were taken at steady-state, after known but varying doses, dose intervals and dose-to-sample intervals, from routine clinical TDM cases. These samples were analyzed using commercial kit RIA or EMIT assays. Covariable data collected included serum creatinine, serum potassium, body weight (kg) x (x=0.75, 1), estimated body surface area, age and the formulation administered (Lanoxin tablets or pediatric elixir, Glaxo Wellcome). A one compartment open pharmacokinetic model for oral administration was applied to the data using proprietary software (PPharm v 1.51, Innaphase, France). Initial modeling identified two distinct populations of cases, one with a markedly slower absorption rate constant (ka) than the other (Fig. 1). Analysis for k-means clustering based on Euclidean differences identified two populations, one of 19 cases and one of 142 cases (Systat v 8.0, SPSS Inc. Chicago, IL, USA). The means of the two sample populations for ka differed statistically using Student’s t-test (PB0.01) (Table 1.). No correlation was identified between the 19 slow absorbing cases and any known covariable, including dose formulation (Fig. 1). All 19 slow absorbers were from the 32 cases (19/32=59%) which had been admitted to the hospital, a stressful event, within 2 h prior to dosing: in contrast, the remaining 129/142 (91%) cases had been dosed at home prior to sample collection. Acute stress has been associated with release of corticotrophin releasing factor (CRF) and intracerebroventricular infusion of CRF has been shown to delay total gastric emptying in dogs (Lee & Sarna, 1997). Therefore, we hypothesize that the slower absorption of orally administered digoxin was due to delayed gastric emptying in 59% cases admitted to hospital for dosing. Stress and pain have previously been shown to alter drug absorption and metabolism (Jamali & Kunz-Dober, 1999). Knowledge of a delay in absorption of drugs administered to patients by the oral route at the time of hospitalization, if confirmed, would influence selection of the route of drug administration for such patients. Multimodal populations violate the assumption of normal/ log-normal population distribution for parametric population pharmacokinetic analysis. Therefore, all 19 cases identified to have a low ka were deleted from further analyses. For the remaining 142 cases the number of observations per subject

Excited-state absorption studies of Cr/sup 4+/ ions in several garnet host crystals

An experimental study of saturable absorption and excited-state absorption (ESA) in several inorganic saturable absorbers, Cr/sup 4+/:YAG, Cr/sup 4+/:GGG, and Cr/sup 4+/:YSGG, is presented. We provide the theoretical background of absorption characteristics in saturable absorbers that exhibit ESA, with some new results: approximate analytical solutions are proposed for the optical transmission in the case of a slow absorber, and for various light intensity conditions of spatially or temporally Gaussian beams in fast and slow absorbers. Experimentally, partial bleaching of the first excited state itself could be observed in Cr/sup 4+/:YAG at /spl lambda/=1064 nm, yielding the higher excited-state lifetime as /spl tau/*=(0.55/spl plusmn/0.1) ns. The regular transmission bleaching curve was measured in Cr/sup 4+/:GGG, for the first time in this material, yielding /spl sigma//sub ga/=(58/spl plusmn/5)/spl times/10/sup -1/ cm/sup 2/, and /spl sigma/e/sub s/=(13/spl plusmn/2)/spl times/10/sup -19/ cm/sup 2/ at /spl lambda/=1064 nm, ESA spectra were measured for the three materials between /spl sim/700 and 900 nm. All three exhibit crossing between saturable absorption at longer wavelengths and inverse saturable absorption at shorter wavelengths.

Theory of mode-locked semiconductor lasers

We present a theoretical study of semiconductor mode-locked lasers at a phenomenological level. We use the slow absorber model of New and Haus, but extend the analysis by taking into account the shift in the gain maximum due to the changing number of carriers. In our analysis of the resulting equation, we show that due to stability requirements the shortest attainable pulse duration is limited. The use of self-phase modulation due to a slow medium can at most lead to a shortening of the pulse by a factor of 2. We show that the shifting of the gain maximum due to the changing number of carriers in the laser is a crucial aspect in the operation of mode-locked semiconductor lasers. We further find that the end mirrors must be reflecting more than about half of the light intensity to prevent a self-pulsation type instability similar to the relaxation oscillation.

Pulse-shaping mechanism in colliding-pulse mode-locked laser diodes

The large signal dynamics of passively colliding pulse mode-locked laser diodes is studied. We derive a model which explains modelocking via the interplay of gain and loss dynamics; no bandwidth limiting element is necessary for pulse formation. It is found necessary to have both fast and slow absorber dynamics to achieve mode-locking. Significant chirp is predicted for pulses emitted from long lasers, in agreement with experiment. The pulse width shows a strong dependence on both cavity and saturable absorber length.

Single-beam time-resolved Z-scan measurements of slow absorbers

A single-beam time-resolved Z-scan method is introduced to characterize the nonlinear refraction of slow (millisecond) response absorbers with cw radiation. Owing to the elimination of parasitic linear effects, the technique is able to measure induced phase distortions as small as λ/104. We demonstrate this method on several materials using low power Ar+ and He-Ne lasers.

Stability of lasers mode locked by two saturable absorbers

An analytic model that takes into account dispersion, chirp, self-phase modulation, bandwidth limitation, frequency walkoff, and cavity length detuning is applied to lasers passively mode locked by two saturable absorbers-one fast and one slow. This general model predicts that the balance between slow gain and slow absorber affects pulse timing shifts and frequency changes. Such shifts limit the range of permitted intracavity dispersion.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Passive mode locking in a cw dye laser with a rapidly relaxing absorber

Theoretical and experimental investigations were made of the characteristics of passive mode locking in a cw dye laser with a rapidly relaxing absorber. It was found that such a fast absorber was prone to fluctuations. This altered the limits and widened the mode-locking range in the direction of higher energy densities of the pulses, compared with a slow absorber of the DODCI type. This made it possible to generate pulses shorter than 100 fs with an average power of 30–50 mW.

Antroduodenal motility and gastric emptying. Gastroduodenal motility and pH following ingestion of paracetamol

The influence of paracetamol on antroduodenal motility and gastric pH was studied in 11 healthy subjects and the relationship between gastroduodenal motility and gastric emptying rate time, tmax, to peak concentration of serum paracetamol, Cmax, was evaluated. The incidence of antral phase III activity and the duration of phase III was diminished with paracetamol (P less than 0.05). The other motility parameters assessed were unchanged. Three patterns of motility and absorption were observed. One group (n = 5) were fast absorbers with a tmax of 1 h and a motility pattern characterized by antral activity, a high motility index and a short duration of phase II (33-60 min); the phase IIIs were complete except in one case. The second group (n = 4) had tmax at 1.5 h and their phase II motility was characterized by a longer duration (80-133 min) (P less than 0.05), by antral activity, and by a high motility index; their phase IIIs were all incomplete. The last group (n = 2) were slow absorbers: Cmax was not reached in the investigation period, no antral contractions were seen, and the motility index was low. The area under the serum-concentration curve of paracetamol differed between the groups at 90 and 180 min (P less than 0.01).

Ibuprofen: plasma concentrations in man.

The plasma levels of ibuprofen were measured in five healthy subjects who took 600 mg tablets of ibuprofen twice daily, three times daily and four times daily in a crossover study. Peak plasma levels were obtained 1 hour after the first dose in all but one subject (slow absorber), the mean peak value being 51.3 micrograms X ml-1 (range 39.4-63.7 micrograms X ml-1). After the repeated dose regimens of two, three or four times daily of ibuprofen, the peak levels achieved were in a similar range to those seen after the first dose: Twice daily 39.4-66.4 micrograms X ml-1; Three times daily 43.6-63.3 micrograms X ml-1; Four times daily 44.1-58.4 micrograms X ml-1. There was no evidence of accumulation of the drug and no side-effects occurred during the trial.

Bioavailability of hydrocortisone retention enemas in relation to absorption kinetics.

The rate and extent of absorption of hydrocortisone from two commercial formulations of rectal enemas were determined in 12 normal subjects. The bioavailability of the enema was related to its absorption rate constant. Four subjects absorbed hydrocortisone slowly from both enemas at a mean rate of 0.361 hr-1 and five subjects absorbed hydrocortisone rapidly from both preparations at a mean rate of 1.05 hr-1 (p < 0.001). The bioavailability of hydrocortisone retention enemas ws 0.810 and 0.502 in slow and rapid absorbers (p < 0.01).

Generic inequivalence--clinical observations.

Abstract: Different preparations of a drug containing the same amount of active chemical in stable form are “chemically equivalent”. Unless they have identical biological activity under clinical conditions, however, they cannot be considered generic equivalents. Differences in drug formulation affecting availability for absorption are a frequent cause of generic inequivalence. The truth of the matter is that although drug formulation has been studied extensively in vitro, the clinical significance and extent of generic inequivalence is unknown. Minor changes in the formulation of prednisone, diphenylhydantoin and dicoumarol produced alarming variation in clinical effect, although each preparation conformed to official standards. In experimental studies, generic inequivalence has been demonstrated in preparations of tolbutamide, phenacetin, nitrofurantoin, chloramphenicol, tetracycline and a combination of triamterene and hydro‐chlorothiazide. In some cases, inequivalence could be explained by differences in tablet disintegration, dissolution rate and particle size. Preliminary studies with different dosage forms of paracetamol suggest that significant generic inequivalence might occur with some drugs only in certain individuals (“slow absorbers”). The risk of generic inequivalence is increased with enteric coated and delayed release preparations since absorption may be poor and erratic. Apart from active drug, modern tablets and capsules usually contain many other substances. Some of these may occasionally contribute to generic inequivalence in the form of unsuspected toxicity.

Absorption of methotrexate and hepatotoxicity.

To the Editor:— Recently interest has been aroused in hepatotoxicity in psoriasis patients with methotrexate. 1,2 One factor which may be of importance in the development of hepatotoxicity is the rate of intestinal absorption of the drug. Freeman-Narrod 3 showed that there were at least two distinct patterns of intestinal absorption of methotreaxate. The first pattern showed quite slow absorption, with low peak blood levels and slow clearing from the blood. The second pattern showed rapid absorption with high peak blood levels and rapid clearing. In addition, after several weeks of treatment, in many of the patients with the second (rapid) absorption pattern, the absorption curve altered in such a way that they became slow absorbers. The same author 3 also showed that the patient who retained a rapid methotrexate absorption pattern throughout the course of therapy did not develop signs of toxic effects. Those who were slow absorbers, or

Inter- and Intrasubject Variations in Drug Absorption Kinetics

Inter- and intrasubject variations in drug absorption kinetics were studied in 15 subjects who ingested 975 mg. of aspirin in compressed tablets on two separate occasions. The group included unusually rapid and unusually slow eliminators of salicylate. Average as well as individual absorption data could be described as firstorder processes preceded by a short induction period. The magnitude of variations in rate constants and induction times between subjects and between tests in any one subject has been determined, and the possible existence of consistently slow and rapid drug absorbers has been examined. In vitro dissolution of drug from the dosage form was describable as a first-order process, and a quantitative correlation between in vitro dissolution and in vivo absorption data has been obtained. Acceptance of a given mathematical model, based on average data, as a description of drug absorption and elimination processes is justified only if the model fits the majority of the individual data. It also must be appreciated that considerable inter- and intrasubject variations in rate constants may exist.