Folmer Nielsen-Kudsk

Pharmacokinetics and therapeutic efficacy of retinoids in skin diseases.

SummaryThe retinoids are a class of compounds that includes the natural forms and synthetic analogues of vitamin A. Isotretinoin, often referred to as a first generation retinoid, may be of considerable benefit to patients with severe, recalcitrant acne. Etretinate and acitretin, 2 aromatic compounds representing the second generation, have found their major success in the treatment of psoriasis, particularly in combination with more traditional therapies. Retinoid therapy is associated with a distinctive adverse effect profile typical of hypervitaminosis A; thus, it is especially important that fertile women undergoing retinoid therapy adhere to a contraceptive regimen. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. The terminal elimination half-lives of isotretinoin, etretinate and acitretin after long term treatment are up to 20h, 120 days and 48h, respectively. Because of lack of definite correlation between plasma concentration and desired pharmacological effects, in conjunction with the very pronounced inter- and intraindividual variation in systemic availability (15 to 90%) after oral administration of these drugs, initial dosages in individual patients can only be roughly judged on the basis of the general pharmacokinetics of the agents. Later dosage adjustments should be made on the basis of monitoring of both plasma drug (and possible metabolite) concentrations, and the efficacy and tolerability of the drugs.

In vitro studies on the interactions of β2-adrenoceptor agonists, methylxanthines, Ca2+-channel blockers, K+-channel openers and other airway smooth muscle relaxants in isolated guinea-pig trachea

Pharmacodynamic interactions in vitro between different types of airway smooth muscle relaxants were systematically and quantitatively evaluated by using a new methodological technique. Relaxant concentration-effect curves for terbutaline, theophylline, cromakalim, sodium nitroprusside and isradipine were obtained in isolated guinea-pig trachea contracted by histamine (1 microM). The effects of three different fixed concentrations of each airway smooth muscle relaxant were initially attained and concentration-effect curves for combinations with increasing concentrations of either one of the other relaxants were produced. Based on pharmacodynamic parameters obtained by non-linear regression analysis of experimental data for the relaxants alone theoretical concentration-effect curves for predicted additive interaction were constructed by using the isobolic method. Synergistic (over-additive) interaction was defined as existing when data points and derived pharmacodynamic parameters obtained with combinations of the relaxants showed statistically significant deviation from the predicted additive interaction curve and its functional parameters. Significant synergistic interaction with terbutaline was found for both theophylline (70 or 200 microM), cromakalim (0.1, 0.3 or 1 microM), sodium nitroprusside (30 or 100 nM) and isradipine (1, 3 or 10 nM). Theophylline showed synergistic interaction with cromakalim (0.1, 0.3 or 1 microM), sodium nitroprusside (10 nM) and isradipine (1, 3 or 10 nM). Interactions between cromakalim and sodium nitroprusside (10, 30 or 100 nM) were also synergistic, whereas cromakalim and isradipine (1, 3 or 10 nM) produced only additive interaction. Possible mechanisms underlying the interactions are discussed on basis of existing knowledge with special regards to phosphodiesterase isoenzymes, K+ and Ca2+ channels.

Interaction of Etretinate with Methotrexate Pharmacokinetics in Psoriatic Patients

Combined treatment of psoriasis with methotrexate and etretinate may be associated with hepatoxicity. This study investigated the potential effects of steady state etretinate administration on methotrexate pharmacokinetics in six psoriatic patients. When compared with a matched group a significantly higher mean value for the maximum plasma concentration Cmax (992 nmol/L ± 94 SE vs 721 nmol/L ± 35 SE) for methotrexate was found (P < .05) after intramuscular administration of 0.2 mg/kg body weight of the drug. In accordance with this finding mean values of the time (tmax) to reach Cmax, half‐life of the absorption (t1/2ka) and the apparent volume of distribution at steady state Vss were also lower than in the control groups but did not deviate significantly. Total clearance differed very little and insignificantly between the two groups. Absorption and disposition rates of etretinate during combined treatment with methotrexate were not significantly altered compared with previous results in psoriatic patients only receiving etretinate. Overall, these results indicate that the apparently increased risk for developing hepatotoxic reactions during coadministration of methotrexate and etretinate cannot be explained by drug accumulation due to pharmacokinetic interaction. A possible influence on potential hepatotoxicity of an increase of Cmax for methotrexate cannot be excluded.

Myocardial pharmacodynamics of dopamine, dobutamine, amrinone and isoprenaline compared in the isolated rabbit heart

The isolated spontaneously beating rabbit heart was used for comparing the myocardial effects of isoprenaline, dobutamine, dopamine and amrinone. Both isoprenaline and dobutamine produced a progressive concentration-dependent increase in contractility from 100% to a maximum of about 200% (pD2 7.81 and 7.01, respectively) as measured by the increase in isotonic contraction rate. The simultaneous augmentations in contraction amplitude reached maxima of about 127 and 143% (pD2 7.83 and 7.05) for each of the drugs and the heart frequency rose to 202 and 162% (pD2 7.80 and 6.63), respectively. The accompanying oxygen consumption increased from 100 to 194% (pD2 7.70) for isoprenaline and to only 177% (pD2 6.36) for dobutamine. Coronary flow rate rose to 153 and 134%, respectively. Dopamine increased the contraction rate to 181% (pD2 6.26), contraction amplitude to about 122% (pD2 6.25) and heart rate to 162% (pD2, 5.85), while oxygen consumption rose to a maximum of 202% (pD2 5.69). Coronary flow rate rose to 156%. In contrast amrinone produced an unexpected slowly progressing decrease in contraction rate and contraction amplitude to about 66% (pD2 4.45 and 4.01, respectively). Oxygen consumption increased to 159% (pD2 4.10) and coronary flow rate to 210%. The positive inotropic effect of dobutamine thus equalled that of isoprenaline but with a distinct lower concomitant increase in heart frequency and oxygen consumption which may reflect a better myocardial efficiency during the action of dobutamine.

FLUORESCEIN AND FLUORESCEIN GLUCURONIDE IN PLASMA

Abstract The evaluation of the blood‐ocular barrier for fluorescein requires the measurement of free and unconjugated fluorescein in plasma. This study introduces a new and simple method for the determination of free fluorescein in plasma on the basis of determined total free plasma fluorescense and the free fraction of fluorescence. An excellent good correlation between differential spectrofluorophotometry and this new method is demonstrated. After intravenous administration of sodium fluorescein, the contribution of fluorescein glucuronide to total free plasma fluorescence was evaluated on basis of the areas under the plasma concentration/time curves for fluorescein and fluorescein glucuronide, respectively. After 1 h 8.2% of total free fluorescence in plasma was found to originate from fluorescein glucuronide and after 24 h 18.3% originated from this metabolite. It was concluded that although plasma fluorescein glucuronide measurements are important in the exact evaluation of the blood‐ocular barrier, the contribution of fluorescein glucuronide to vitreous fluorescence after intravenous fluorescein administration seems to be of minor magnitude.

Ocular fluorescein kinetics before and after vitrectomy on swine

Abstract. Purpose: To study the quantitative effects of vitrectomy on fluorescein transport kinetics across the ocular barriers. Methods: Thirty-six domestic swine were used in this study. Twenty anesthetized swine were given a standardized fluorescein intravenous injection immediately after unilateral vitrectomy. This was followed by one single central sample aspiration from the vitreous and the anterior chamber of both eyes in individual animals at increasing intervals up to 24 h after the injection. Fluorescein concentrations in the samples were determined by high-pressure liquid chromatography (HPLC). Eight swine underwent unilateral vitrectomy followed by anterior chamber and vitreous fluorophotometry on both eyes 1 month later. The fluorescein concentrations determined using this method were followed for 24 h. Similar examinations were performed in a control group of eight swine that did not undergo vitrectomy. Anterior chamber, vitreous, and plasma fluorescein concentration/time courses were analyzed kinetically by iterative nonlinear regression analysis. Results: The barrier surrounding the anterior chamber of the eye was immediately impaired after vitrectomy, as evidenced by an increased area under the fluorescein concentration versus time curve, but the transport kinetics were restored within 1 month after surgery. The blood-retinal barrier was, however, persistently altered following vitrectomy. Transport rate and extent of drug penetration into the vitreous were increased, while drug elimination from the vitreous remained unchanged. Conclusion: Vitrectomy led to persistent kinetic fluorescein transport changes in the blood-retinal barrier resulting in faster and increased drug penetration to the vitreous, whereas similar alterations in the anterior chamber barrier transport were only transitory.

The Pharmacokinetics of Acitretin and its 13-cis-metabolite in Psoriatic Patients

The synthetic retinoic acid derivative acitretin has recently been introduced for the treatment of severe psoriasis. Hitherto, the use of the carboxylic acid ester analogue, etretinate, has been hampered by an extremely long elimination half‐life of up to 120 days for this drug. In the presented study, 12 patients with severe psoriasis were treated with 30 mg acitretin daily for a period of 6 months. The maximum plasma concentration of the drug occurred within about 0.9 to 4.6 hours with an apparent absorption half‐life ranging from 0.2 to 1.7 hours and with half‐lives of the distribution phase within the range of 1.2 to 3.5 hours. After stopping therapy, the terminal elimination half‐life of acitretin varied between 16.5 and 111.1 hours (mean: 47.1 hr ± 29.8 SD), whereas that for the 13‐cis‐metabolite varied between 36.5 and 249.4 hours (mean: 119.4 hr ± 73.4 SD). Suction blister fluid concentrations of both the parent drug and metabolite were lower than plasma concentrations. The mean concentration of serum triglycerides was significantly elevated during the course of therapy, but still remained within the normal range. Saliva concentrations of drug and metabolite at steady‐state were below 1 ng/mL. It is not possible from the observed half‐lives of acitretin and its 13‐cis‐metabolite to draw any definite conclusion with regard to the anticonceptional period after acitretin therapy in psoriatic patients.

Pharmacokinetic curve fitting and parameter determination by non-linear, iterative least squares regression analysis using a programmed minicalculator

Abstract A pharmacokinetic non-linear, iterative least-squares program for the minicalculator TI-59 with adapted printer is described. The program utilizes the Gauss-Newton gradient method in an iterative, non-linear regression analysis of up to 18 data pairs. Single-dose plasma concentration data of 5-hydroxytryptophan, theophylline and prednisolone were comparatively analysed using both the described program (called NONTI-59 ) and Metzlers well-established digital computer program NONLIN .

Myocardial Pharmacokinetics and Pharmacodynamics of Dipyridamole in the Isolated Rabbit Heart

The myocardial accumulation and disposition pharmacokinetics of the antithrombotic drug dipyridamole were investigated in isolated perfused and spontaneously beating rabbit hearts. The rabbit myocardium behaved pharmacokinetically as a two-compartment system with regard to the drug. The half-lives of the alpha-phase of distribution and of the beta-phase of disposition were about 1.4 and 6.3 min., respectively. Perfusion with a modified Krebs-Henseleit solution containing 5.1 microgram ml-1 of dipyridamole caused an accumulation of about 140 micrograms g-1 of myocardial tissue at steady state. The initial measured pharmacokinetic parameters were unchanged after perfusion with the drug for 60 min. The accumulating dipyridamole in the rabbit heart caused a progressive decrease in myocardial contractility to about 65%. This was accompanied by a decrease in the ratio of contraction rate to oxygen consumption to about 0.7 as an expression of reduced myocardial efficiency. The coronary flow rate was not significantly increased. The heart beating frequency decreased only slightly and no dromotropic effects were observed.

Long‐term kinetic vitreous fluorophotometry

Abstract Fluorophotometric measurements of vitreous and plasma fluorescence were performed in 14 normal subjects up to 24 h after injection of a single intravenous dose of sodium fluorescein. The data were subjected to a kinetic two‐compartmental analysis, including the determination of the transfer rate constants between the central and the peripheral compartment (K12 and K21) as well as between the central and the vitreous compartment (Kin and Kout). In the central compartment (plasma) a mean terminal disposition rate constant (β) of free fluorescein of 0.23 h‐1 was found, corresponding to a half‐life of 3.01 h. The vitreous fluorescence reached a maximum 2–5 h after the injection and then declined monoexponentially and very slowly (t1/2 = 9.6 h). The rate constant of permeation into the eye (Kin) was found to be 0.66 h‐1, while the rate constant of elimination of fluorescein from the vitreous was 0.072 h‐1 (Kout). Kin was found to be significantly higher than K12, presumably indicating an active transport mechanism for fluorescein located at the blood‐ocular barrier. Kout was significantly lower than K21, reflecting a slow vitreous elimination of fluorescein. A permeability index defined as the percentage ratio between the areas under the vitreous and the plasma concentration curves was found to be 3.5%, illustrating the poor penetration of fluorescein into the vitrous. Kinetic long‐term fluorophotometry appears to be a promising new tool in the study of the blood‐ocular barrier.