The metabolism and pharmacokinetics of isotretinoin in patients with acne and rosacea are not influenced by ethanol.

BACKGROUND: Isotretinoin is effective in the treatment of severe acne and rosacea. Both parent drug and its main metabolite 4-oxo-isotretinoin are potentially teratogenic compounds and contain a carboxylic acid moiety. In the presence of ethanol, naturally occurring as well as synthetic retinoids also containing a carboxylic acid moiety are capable of undergoing an ethyl esterification with the metabolic formation of more lipophilic compounds with a much longer terminal half-life. OBJECTIVES: To determine if isotretinoin (13-cis-RA), its main metabolite 4-oxo-isotretinoin (4-oxo-13-cis-RA), and other possible metabolites in the presence or absence of ethanol are converted to their corresponding ethyl derivatives in patients with severe acne or rosacea after multiple isotretinoin dosing. In addition, pharmacokinetic parameters of the parent drug and its 4-oxo metabolite were determined. PATIENTS/METHODS: Eleven patients with severe acne or rosacea were treated with isotretinoin daily for 3 months and investigated pharmacokinetically during 24 h after 1 month of treatment and for up to 28 days after discontinuation of therapy. A possible influence of ethanol was evaluated using a simple self-administered questionnaire and by measuring serum ethanol levels during treatment. The concentrations of isotretinoin, 4-oxo-isotretinoin and possible ethylated and nonethylated metabolites were measured by reverse-phase high-performance liquid chromatography. RESULTS: Although seven of 11 patients had a considerable weekly alcohol intake, no endogenous synthesis of ethyl derivatives of isotretinoin, the main 4-oxo metabolite or the all-trans compounds was chromatographically detectable in any of the patients' plasma samples during the treatment period. Multiple dose pharmacokinetic data for the parent drug and its main metabolite were comparable to previous studies. CONCLUSIONS: The metabolism and pharmacokinetics of isotretinoin and its main metabolites are not influenced by ethanol during long-term isotretinoin treatment. After ceasing long-term isotretinoin therapy the recommended period of 1 month for using anticonceptive measures in fertile women seems adequate.

Ocular fluorescein kinetics before and after vitrectomy on swine.

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.

Acitretin is converted to etretinate only during concomitant alcohol intake.

BACKGROUND: Acitretin has replaced etretinate in the treatment of various disorders of keratinization due to a considerably shorter terminal half-life. Possible esterification of acitretin to etretinate in the presence of ethanol has been reported. OBJECTIVES: To determine the plasma concentrations of etretinate as a metabolite in patients with various disorders of keratinization after multiple acitretin dosing, and to assess the influence of alcohol consumption using a questionnaire. In addition, to study the influence of alcohol consumption on the risk of metabolic formation of etretinate. PATIENTS/METHODS: Eighty-six acitretin (Neotigason(R), Roche)-treated outpatients from three centres provided pre-dose (trough) samples for determining plasma concentrations of acitretin and its metabolites 13-cis-acitretin and etretinate. Patients received acitretin doses of between 0.1 and 1.3 mg kg-1 daily. The concentrations of etretinate, acitretin and 13-cis-acitretin were determined by reverse-phase high-performance liquid chromatography. RESULTS: Of the 86 patients, 30 had detectable plasma etretinate levels. No etretinate was found in 20 patients who reported that they never drank alcohol, while etretinate was found in all 16 patients with an average weekly alcohol consumption of > 200 g ethanol, corresponding to about 15 U (1 U equals half a pint of standard beer or a wine glass of non-fortified wine). Etretinate was detected in 14 of 50 patients with a moderate weekly alcohol intake of up to 200 g ethanol. A trend linking higher alcohol intake with both higher risk of etretinate formation and higher etretinate levels was observed. The study also revealed that the ethylesterification only relates to acitretin (13-trans-) and not to the main metabolite 13-cis-acitretin, although the latter compound showed higher plasma trough concentration levels at steady state. CONCLUSIONS: Owing to the teratogenic potential and possible side-effects of oral retinoids, fertile women especially should be informed about the importance of strict alcohol abstinence during treatment and for at least 2 months after stopping therapy. In case of non-compliance with alcohol abstinence a post-therapy contraceptive period of 2-3 years should be recommended.

Can vitreous fluorophotometry predict the necessity for photocoagulation? A 5-year follow-up study.

PURPOSE: To examine the long-term outcome of vitreous fluorophotometry including the predictability of retinopathic proliferative development in diabetic subjects. METHODS: 21 diabetic subjects were examined by long-term kinetic vitreous fluorophotometry and their barrier properties, as revealed by a permeability-index, were compared to a group of normal subjects. 13 diabetics were classified as having a high permeability-index, while 8 diabetics were classified as having a low permeability-index. The two groups were followed for 5 years with regard to development of proliferative retinopathy. RESULTS: 6 of 13 diabetics with a high permeability-index developed proliferative retinopathy within the 5-year follow-up period. This was in contrast to the low permeability-index group where none of 8 diabetics developed proliferative retinopathy. CONCLUSION: An increased permeability-index points towards an increased risk of development of proliferative retinopathy.

Anterior chamber fluorescein kinetics compared with vitreous kinetics in normal subjects.

PURPOSE: Describe and compare barrier properties in various parts of the eye. METHODS: Fluorophotometric measurements of the anterior chamber, vitreous and plasma fluorescein concentrations were performed and subjected to a kinetic two-compartment analysis. RESULTS: The overall barrier properties as revealed by a permeability-index was found to be 12.2% (anterior chamber) and 3.5% (vitreous). The apparent rate constant of permeation into the anterior chamber (Kin=1,59 h(-1)) was found to be significantly higher than into the vitreous (Kin=0,66 h(-1)) and into the apparent peripheral body compartment (Kin=0,23 h(-1)). The terminal rate constant of fluorescein disposition from the anterior chamber (Kout=0,21 h(-1)) was in agreement with the terminal disposition rate constant for plasma fluorescein (P=0,23 h(-1)), whereas elimination from the vitreous (Kout=0,072 h(-1)) was significantly slower. CONCLUSION: Compartment analysis of ocular fluorescein kinetics is suitable for the study of anterior and posterior barrier properties in the eye. In this study fluorescein elimination from the anterior chamber was restricted by terminal plasma fluorescein decay rather than by ocular tissue.

Anterior chamber and vitreous fluorescein kinetics in normal and diabetic subjects.

PURPOSE: Describe and compare drug exchange between various parts of the eye. METHODS: Fluorophotometric measurements of the anterior chamber, vitreous and plasma fluorescein concentrations were performed and subjected to a kinetic two-compartment analysis. RESULTS: The overall barrier properties as revealed by a permeability-index were found to be 12.2% and 3.5% for the anterior chamber and the vitreous, respectively. The apparent rate constant of permeation into the anterior chamber was found to be significantly higher than into the vitreous and the apparent peripheral body compartment. The terminal rate constant of fluorescein disposition from the anterior chamber was in agreement with the terminal disposition rate constant for plasma fluorescein, whereas elimination from the vitreous was significantly slower. CONCLUSION: Compartment analysis of ocular fluorescein kinetics is suitable for the study of anterior and posterior barrier properties in the eye. In this study fluorescein elimination from the anterior chamber was restricted by terminal plasma fluorescein decay rather than by ocular tissue.

Amlodipine dynamic effects and myocardial pharmacokinetics in the isolated and perfused guinea-pig heart.

Myocardial dynamic effects and pharmacokinetics of amlodipine were studied in the isolated retrogradely perfused and spontaneously beating guinea-pig heart. Pharmacokinetic analysis of drug accumulation showed one-compartment characteristics with an half-life of 76 min. Whereas disposition exhibited two-compartment characteristics with phasic half-lives of 25 and 174 min., respectively. Myocardial drug accumulation was increased by 600 times at steady-state compared to the perfusion liquid. Dynamic effect parameters were studied during increasing amlodipine concentrations from 0.16 to 220 nM. Dynamic steady-states developed within 20 min. Coronary flow-rate increased with an Emax of 119% and an EC50 of 1.2 x 10(-8) M. Amlodipine produced inhibitory effects on contraction amplitude and velocities of contraction and relaxation. Observed Emax-values and curve-fitted EC50-values were: 97, 97 and 94% and 1.10(-8), 7.7 x 10(-9) and 2.1 x 10(-8) M, respectively. Heart frequency was not changed. Oxygen consumption increased markedly to a maximum of 44% at 3 x 10(-8) M amlodipine and then decreased to nearly initial values. The frequency-corrected QT-interval decreased to a maximal extent of 20% at the three highest concentrations. Myocardial efficiency expressed as the ratio of contraction velocity times frequency to oxygen consumption exhibited a progressive decline to about 2% of initial values. The PQ-interval was not changed and the QRS-interval showed only a small but significant decrease at the highest amlodipine concentration. No arrythmogenic effects were observed. The study demonstrated a very slow accumulation and disposition of amlodipine in the guinea-pig heart with a steady-state myocardial drug concentrating accumulation of 600 times. Marked increase in coronary flow-rate and oxygen consumption accompanied by a progressive negative inotropic effect were observed.

Effects of five different airway smooth muscle relaxants on inhibitory neurotransmission in isolated guinea-pig trachea in vitro.

Pharmacodynamic effects produced by terbutaline (10 nM), theophylline (10 microM), sodium nitroprusside (30 nM), levcromakalim (0.3 microM) or isradipine (1 nM) on frequency-dependent relaxations induced by electric field stimulation of either proximal or distal parts of isolated guinea-pig trachea were studied in vitro. Preparations were depleted for tachykinins by capsaicin, pretreated with atropine (0.1 microM) and contracted by histamine (2 microM). Drug effects were studied in preparations with combined adrenergic and inhibitory non-adrenergic non-cholinergic (NANC) innervation and in preparations with inhibitory NANC innervation either with or without additional treatment with N(G)-nitro-L-arginine methyl ester (L-NAME) (100 microM). In preparations with combined adrenergic and inhibitory NANC innervation terbutaline, sodium nitroprusside, levcromakalim and isradipine significantly reduced relaxant responses to electric field stimulation in proximal preparations, whereas distal preparations were only affected by terbutaline. In preparations with inhibitory NANC innervation without L-NAME pretreatment, terbutaline significantly enhanced relaxant responses to electric field stimulation only in distal preparations, whereas theophylline, sodium nitroprusside and levcromakalim significantly augmented responses to electric field stimulation in both proximal and distal preparations. In preparations with inhibitory NANC innervation pretreated with L-NAME, theophylline significantly inhibited relaxant responses in distal preparations, whereas sodium nitroprusside, levcromakalim and isradipine significantly augmented relaxant responses to electric field stimulation in proximal preparations. It was concluded that drugs used in the present study can modulate the effects of inhibitory autonomic and NANC neurotransmission in isolated guinea-pig trachea. Furthermore, it was shown that some variation in drug effects exists in relation to proximal and distal parts of guinea-pig trachea.

Interaction between prostaglandins and selective phosphodiesterase inhibitors in isolated guinea-pig trachea in vitro.

The possible interaction between spontaneously synthesized relaxant prostaglandins and the relaxation produced by three different isoenzyme-selective phosphodiesterase inhibitors was investigated in the isolated guinea-pig trachea in vitro. The relaxant action of siguazodan (phosphodiesterase III inhibitor), rolipram (phosphodiesterase IV inhibitor) and zaprinast (phosphodiesterase V inhibitor) was investigated in preparations with either spontaneously tone alone or in preparations with spontaneous tone and additionally stimulated with histamine (1 microM). In addition, relaxant effects were assessed in preparations without spontaneous tone (inhibited by indomethacin 2 microM) and precontracted with histamine (1 microM) or prostaglandin F2 alpha (10 microM), either alone or in the presence of a non-relaxant concentration (20 nM) of prostaglandin E2. All three phosphodiesterase inhibitors preferentially relaxed preparations with spontaneous tone and showed increased relaxant effects in preparations with spontaneous tone and additionally stimulated with histamine compared to preparations contracted by histamine alone. This enhanced relaxing effect observed in the presence of initial spontaneous tone was mimicked by exogenous application of prostaglandin E2 to indomethacin treated preparations either precontracted by histamine or prostaglandin F2 alpha. Furthermore, the study revealed marked differences in the relaxant profiles of siguazodan, rolipram and zaprinast, differences which most likely are related to the functional importance of the phosphodiesterase isoenzymes inhibited by these drugs. It is concluded that endogenously synthesized relaxant prostaglandins and exogenously applied prostaglandin E2 are capable of enhancing the relaxant action of the phosphodiesterase inhibitors siguazodan, rolipram and zaprinast and that cyclooxygenase inhibition is an important way to avoid this interaction in experimental studies of airway smooth muscle relaxants in isolated guinea-pig trachea in vitro.

Fluorometric evaluation of panretinal photocoagulation in diabetic subjects.

The effect of panretinal photocoagulation on the blood-retinal barrier was examined by long-term kinetic vitreous fluorophotometry in eight insulin treated diabetic subjects, before and one month after unilateral panretinal photocoagulation. The fluorophotometric investigations revealed an increased permeability-index following this treatment. A further analysis based upon a two-compartment fluorescein kinetic model revealed a decreased penetration rate constant together with increased zero-time concentration coefficients for fluorescein following panretinal photocoagulation. No alterations were observed in kinetic parameters in the group of untreated eyes. This points towards a delayed but increased fluorescein penetration to the vitreous following panretinal photocoagulation, probably indicating an increased net flux of fluorescein across the entire retina. In patients with unilateral proliferative retinopathy the permeability-index obtained from eyes with classified proliferative retinopathy was 18.1%, whereas the permeability-index from eyes without proliferative retinopathy was 15.4%. This relatively small difference seems to indicate that the main part of vitreous fluorescence comes from an increased penetration across the entire retina, whereas a direct leakage from the proliferations themselves is less in magnitude. This increased retinal penetration might possibly be caused by affected transport processes for fluorescein within the retina.

In vitro studies on the interactions of beta2-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.

Dynamic effects and pharmacokinetics of lemakalim in the isolated guinea-pig heart.

Myocardial effects of lemakalim were studied in the isolated retrogradely perfused and spontaneously beating guinea-pig heart. Pharmacokinetic analysis of drug accumulation and disposition showed two-compartment characteristics with phasic half-times of about 0.27 and 2.1 min., respectively. Myocardial clearance was 6.8 ml min.-1, and myocardial drug accumulation was 5-fold. Dynamic parameters were studied during increasing lemakalim concentrations from 1.4 nM up to 10 microM. Dynamic steady-states developed within 3-4 min. Increase of coronary flowrate showed an Emax of 185% with an EC50 of 60 nM. Lemakalim produced biphasic inhibitory actions on contraction velocity and amplitude. Emax and EC50 for the two phases were: 48% and 47% and 100 nM and 65 nM, respectively, for the first phase and 100% in both cases and 1.7 microM and 1.6 microM for the second phase. Heart frequency increased to a maximum of 15% above baseline at 0.3 microM. Oxygen consumption increased progressively at concentrations above 7 nM and reached a maximum of 175% at 0.3 microM. The frequency-corrected QT-interval was biphasically shortened to a maximal extent of 30% at the highest concentration. Myocardial efficiency expressed as the ratio of amplitude times frequency to oxygen consumption exhibited a progressive decline to about 20% of control values. PQ- and QRS-intervals showed only minor or no changes, respectively. No arrythmogenic effects were observed. The study demonstrated a rapid and very moderate accumulation of lemakalim in the guinea-pig heart accompanied by a marked increase in coronary flowrate and a progressive negative inotropic effect followed by reduced myocardial efficiency.

Conversion of acitretin to etretinate in psoriatic patients is influenced by ethanol.

Acitretin has recently been introduced to replace etretinate in the treatment of severe psoriasis due to a considerable shorter terminal half-life. The previously recommended 2-month anticonceptive period after acitretin treatment has been extended to 2 years after the detection of etretinate in certain acitretin recipients. In the present study, 10 patients with severe psoriasis were treated with 30 mg acitretin daily for 3 months. Seven patients had detectable mean steady-state plasma etretinate concentrations in the range of 2.5 to 56.7 ng/ml. Four of the patients showed teratogenic levels of plasma etretinate. Consumption of alcohol appeared to be an important contributing factor for the formation of etretinate. As judged from the dose- and body-weight-normalized AUC values (AUCcor) there was a great inter-individual variation (sixfold) in the systemic availability of acitretin. After discontinuation of therapy, the rate of elimination of both acitretin (t1/2 range 1.0 to 25.4 d) and 13-cis-acitretin (t1/2 range 1.5 to 25.7 d) was found to be related to the observed mean steady-state level of etretinate as evidenced by a longer terminal t1/2 of patients with high levels of etretinate in plasma. A mean terminal elimination half-life of etretinate was found to be 45.7 d +/- 10.6 (mean +/- SD; range 27.0 to 59.3 d). The risk of metabolic formation of etretinate in acitretin recipients makes it impossible to draw any definite conclusion with regard to recommendation of length of anticonceptive period following acitretin therapy in psoriatics. Monitoring of plasma etretinate levels in acitretin-treated fertile women is advisable.

Long-term kinetic vitreous fluorophotometry.

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 vitreous compartment (K(in) and K(out)). In the central compartment (plasma) a mean terminal disposition rate constant (beta) 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 (K(in)) was found to be 0.66 h-1, while the rate constant of elimination of fluorescein from the vitreous was 0.072 h-1 (K(out)). Kin was found to be significantly higher than K12, presumably indicating an active transport mechanism for fluorescein located at the blood-ocular barrier. K(out) 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 vitreous. Kinetic long-term fluorophotometry appears to be a promising new tool in the study of the blood-ocular barrier.

Long-term kinetic vitreous fluorophotometry in normal and diabetic subjects.

Nine normal and 24 diabetic subjects were examined by long-term vitreous and plasma fluorescein fluorophotometry and the observed concentration profiles were described by biexponential time courses. The rate constant of elimination of fluorescein from the body (K10) was significantly decreased in diabetics with background and proliferative retinopathy, presumably caused by affection of the liver and possibly representing alterations in membranes of liver cells. Increased kidney albumin excretion was observed with increasing degree of retinopathy. The apparent rate constant of fluorescein penetration into the eye (Kin) was found significantly decreased in background as well as in proliferative retinopathy; while the permeability index, calculated as areas under vitreous and plasma fluorescein curves, was significantly increased. In the normal subjects Kin was significantly higher than the rate constant of fluorescein transfer (K12) from the apparent central to the peripheral tissue compartment, whereas in the diabetics this difference was only found in the group with background retinopathy. The findings seem compatible with the concept that the breakdown of the blood-ocular barrier could be caused at least partly by affection of an active transport system for fluorescein, but thickening and compositional changes of the basement membranes in the eye might also be of importance.

Fluorescein and fluorescein glucuronide in plasma.

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 fluorescence 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.

Pharmacokinetics and therapeutic efficacy of retinoids in skin diseases.

The 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.

Isradipine dynamics and pharmacokinetics in the isolated rabbit heart.

The cardiac effects of increasing concentrations of isradipine (racemic) from 1.64 pM to 232 nM were studied in isolated spontaneously beating rabbit hearts. Inhibitory responses with regard to contraction amplitude, contraction velocity and oxygen consumption exhibited a biphasic progressive course at increasing drug exposure. Computer derived inhibitory Emax-values of the second phase were 104, 103 and 87% (IC50: 7.1, 6.3 and 28.7 nM), respectively, whereas those of the initial phase were 24.7, 25.9 and 19.5% (IC50: 0.012, 0.038 and 0.026 nM). A progressive inhibition of frequency reached a maximum of only 21%. The ECG-derived PQ-interval showed a rapid increase (maximum 46%) at drug concentrations above 1 nM. Complete AV-block and ventricular asystolia occurred in half of the hearts at the second highest (99 nM) and in all except one at the highest concentration. SA-node activity was retained in 9 of 10 hearts at the second highest and in 3 at the highest drug exposure. The QRS-and the frequency-corrected QT-interval did not increase significantly. Coronary flow-rate showed no initial increase, but a decrease to 70% of control at the highest concentration. Supplementary in vitro studies on rabbit coronary artery ring-preparations contracted with 124 mM K+ showed, however, an relaxant Emax-value for isradipine of about 100% and an inhibitory EC50-value of 0.63 nM with a 'Hill' coefficient of 1.1. At toxic concentrations isradipine showed a kinetic monophasic accumulation in the rabbit heart of about 44-fold with a half-time of 10.6 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac uptake kinetics and possible dynamic effects of a new cerebral antiischaemic compound FG 9202 (NBQX) studied in the isolated rabbit heart.

Accumulation of the putative drug FG 9202 in isolated rabbit hearts showed monophasic exponential kinetics with a half-life of only 0.59 min. The disposition showed a three-phasic exponential time course with half-lives of 0.34, 1.51 and 15.8 min, respectively, which was interpreted as three-compartment kinetics. FG 9202 accumulated only about 3 times in the myocardium at steady-state with 51, 32 and 17% referable to a superficial and two deeper myocardial drug pools. The drug did not significantly affect contraction amplitude or velocity of contraction at increasing concentrations up to 40.6 micrograms.ml-1 (119 microM). Heart beating frequency decreased slightly but only significantly at some of the higher concentrations. Neither dromotropic, bathmotropic nor ischaemic ECG-effects were observed. Coronary flow-rate and myocardial oxygen consumption decreased at the highest drug concentrations. Myocardial efficiency expressed as the ratio of contractile parameters to oxygen consumption showed a minor but insignificant increase at the highest drug-exposure levels. Our findings indicate that FG 9202 is not potentially toxic to the isolated, spontaneously beating rabbit heart in vitro.

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.