Biomedical subjects

F Nielsen-Kudsk

Publications and source records attributed to F Nielsen-Kudsk.

At least 19 recordsLinked to original sources

PubMed1992

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)

Animals↗

PubMed1992

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.

Adult↗

PubMed1992

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.

Administration, Oral↗

PubMed1992

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.

Adult↗

PubMed1992

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.

Drug Interactions↗

PubMed1991

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.

Acitretin↗

PubMed1991

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.

Animals↗

PubMed1990

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 less than .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.

Drug Interactions↗

PubMed1990

Myocardial accumulation kinetics and pharmacodynamics in the isolated rabbit heart of a new inhibitor of dopamine reuptake, GBR 12909.

Myocardial accumulation of GBR 12909 showed monophasic exponential kinetics with a half-life of 93 min. The disposition followed a three-phasic exponential time-course with half-lives of 1.1, 17 and 98 min., respectively, which was interpreted as three-compartment kinetics. The drug accumulated 430 times in the myocardium at steady-state with 8, 30 and 61% of the drug amount referable to a central, superficial and two deeper myocardial drug pools. GBR 12909 produced concentration dependent (range 0.01 to 12400 nM) biphasic negative inotropic and chronotropic effects. The inhibitory Em-values with regard to contraction velocity were 42 and 105% with corresponding EC50-values of 29 and 688 nM and the related Hill-exponents were 0.6 and 1.1, respectively. Frequency and contraction amplitude related inhibitory Em-values were of similar size. Apparent dynamic steady states developed within about 17 min. Very marked monophasic negative dromotropic effects were observed with computer-derived inhibitory Em-values related to the electrocardiographic PQ- and QRS-intervals exceeding 100%. The frequency-corrected QTc-interval showed an initial increase of 10% but decreased to about 20% below control level at the highest two drug concentrations. Coronary flow-rate increased about 30% and then gradually decreased to near the control value. Oxygen consumption only decreased at the three highest concentrations. Our findings seem compatible with the view that GBR 12909 may possibly act in the myocardium as a membrane-stabilizer which causes inhibition of Na(+)- and Ca+(+)-influx over sarcolemma. Intracellular inhibition of Ca+(+)-liberation from organelles and other calcium depots also seems possible.

Animals↗

PubMed1990

Myocardial effects of adrenaline, isoprenaline and dobutamine at hypothermic conditions.

The pharmacodynamic myocardial effects of adrenaline, isoprenaline and dobutamine were studied in isolated, perfused and spontaneously beating rabbit hearts at hypothermic conditions. Cardiac contraction amplitude increased from the control value at 37 degrees set equal to 100% to about 165% at 22 degrees, whereas contraction velocity decreased to 52%, frequency to 30% and oxygen consumption to about 19%. At 22 degrees all drugs produced pronounced positive inotropic and chronotropic effects. Em-values related to contraction velocity, frequency and oxygen consumption were for isoprenaline 152, 98 and 136%, respectively, for adrenaline 127, 100 and 198% and for dobutamine 120, 86 and 165%, respectively. The corresponding EC50-values decreased and a marked left-shift of the log-concentration response curves was observed as an expression of increased myocardial sensitivity to the drugs. Em for contraction velocity for dobutamine was distinctly reduced at 32 and 27 degrees and for adrenaline at 27 degrees in comparison to the increase seen at 22 and 37 degrees. Em for oxygen consumption showed for all drugs an increase at decreasing temperatures. The frequency-corrected QTc-interval decreased slightly to moderately during exposure to the drugs at hypothermic conditions. None of the drugs caused arrhythmias during the experiments. Coronary flow rate decreased only moderately at the higher drug concentrations at decreased temperatures. Dobutamine and adrenaline at 37 degrees and isoprenaline at 37 and 22 degrees caused an increase of Em for oxygen consumption that was slightly less than proportional to the increase of Em for contraction velocity.

Animals↗

PubMed1989

Pinacidil uptake and effects in the isolated rabbit heart.

The myocardial accumulation of pinacidil showed one-compartment characteristics with a half-time of 1.11 min., whereas the disposition followed three-compartment kinetics with half-times for the relevant two redistributory and the terminal phases of 0.39, 1.51 and 5.44 min., respectively. At a steady-state drug concentration in the perfusate of 6.12 nmol ml-1, the average concentration of pinacidil in the myocardium was 20.6 nmol g-1. The accumulated amount could predictically be referred with 57% to a central and 31 and 12% to two peripheral (deeper) drug pools. The pharmacodynamic effects of pinacidil in the isolated perfused rabbit heart were studied at stepwise increasing concentrations from 0.15 to 100 microM. Coronary flowrate increased initially up to 24.5% at 1.5 microM pinacidil and then gradually decreased. Amplitude and velocity of contraction were both inhibited in a biphasic way up to 92.7 and 94.1%, respectively. Apparent dynamic steady states developed within 13-15 min. The computer-derived inhibitory Em-values related to the first phase were 49.2 and 52.4% and those related to the second phase were 111.7 and 108.3%, respectively. Heart frequency decreased monophasically and exhibited an inhibitory Em-value of 19.6%. Oxygen consumption decreased at pinacidil concentrations higher than 15 microM and the Em-value was 69.7%. The frequency-corrected QT-interval decreased biphasically and the related inhibitory Em-values were 8.6 and 58.7%. The QRS-interval did not change and the PQ-interval only showed a minor increase at the highest pinacidil concentration. Our findings are compatible with the concept of pinacidil being a potassium channel opener.

Animals↗

PubMed1989

Pharmacokinetics of etretinate in psoriatic patients with liver fibrosis.

A study of the pharmacokinetics of etretinate in 7 psoriatic patients with liver fibrosis or liver cirrhosis is reported. Maximum plasma concentrations occurred within 1.5-4.0 hr. Absorption lag-times ranged from 0.3-2.5 hr, whereas the apparent absorption first order half-times (t1/2ka) were within the range of 0.3-1.2 hr. As judged from the AUC-values corrected for dose and body weight a six-fold interindividual variation existed with regard to the systemic availability of etretinate. Absorption and disposition rates of etretinate in subjects with hepatic fibrosis increasing to cirrhosis were not significantly altered compared with previous results in psoriatic patients with normal liver function.

Acitretin↗

PubMed1988

Bepridil, myocardial accumulation kinetics and dynamic effects in the isolated rabbit heart.

Both myocardial uptake and disposition of bepridil in the isolated rabbit heart showed two-compartment characteristics which possibly reflects the existence of superficial and deep binding sites. Terminal accumulation and disposition half-lives were 218 and 196 min., respectively. The half-times of the initial distributory processes were about 33 min. At a drug concentration in the perfusion liquid of 0.54 micrograms ml-1 (1.27 microM) the average concentration of bepridil in the myocardium at steady state was about 489 micrograms g-1 (1161 microM) with 43% referable to the deepest, presumably intracellular compartment. Increasing bepridil concentrations from 3 to 2333 ng ml-1 (7-5542 nM) in the perfusion liquid caused a terminal decrease in coronary flowrate to 58% of the mean control flowrate. Amplitude and velocity of myocardial contraction both decreased in a biphasic way to about 28.6 and 13.6%, respectively. Apparent dynamic steady states developed within about 20 min. Inhibitory Em-values related to the first phase were 39.8 and 53.2%, and to the second phase 97.7 and 98.5%, respectively. Heart beating frequency also decreased biphasically to 53.9% and showed inhibitory Em-values of 17.2 and 47.5% related to the two phases. Myocardial oxygen consumption decreased to 55.6%. The electrocardiographic PQ- and QRS-intervals increased to 147 and 133%, respectively. The frequency-corrected QT-interval also increased significantly from 100 to 123%. Our findings demonstrate a slow and very pronounced accumulation of bepridil in the rabbit heart. Biphasic and very marked negative inotropic and chronotropic effects and a less than proportional decrease in oxygen consumption developed much faster.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Pharmacokinetics of etretin and etretinate during long-term treatment of psoriasis patients.

The aromatic retinoic acid derivative etretin has recently been introduced in the treatment of severe psoriasis and other dyskeratoses. 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. Seven patients of either sex from whom we recently reported single-dose pharmacokinetics have been studied after 1 and 3 months multiple dose administration of the drugs. Four were given etretin and three etretinate. Etretin, both as drug and as metabolite, was absorbed faster than etretinate as judged from t-lag, tm and t 1/2 ka. Etretin as drug was eliminated faster than the metabolite etretin, t 1/2 beta 2.39 +/- 1.16 days compared to 6.51 +/- 2.06 days. In patients receiving etretinate the terminal disposition or elimination half-lives for cisetretin (t 1/2 lambda 3 15.9 +/- 9.9 days) were longer than for the metabolite etretin and exhibit a pronounced interindividual variation from 4.25 to 22.8 days. Similarly, cis-etretin accumulated very marked in comparison to the metabolite etretin of the drug etretinate. Assuming 40% systemic availability for both drugs, the central compartment of distribution constituted about 12-32% in case of etretin and about 0.8-3.6% in case of etretinate of the calculated apparent total volume of distribution at steady state, which showed mean values of 3.5 and 39.6 1.kg.-1, respectively, presumably reflecting the higher lipophilic nature of the latter compound.

Acitretin↗

PubMed1988

Pharmacokinetics and dynamic effects of diltiazem in the isolated guinea-pig heart.

Myocardial pharmacokinetics of diltiazem showed two-compartment characteristics in the isolated, spontaneously beating guinea-pig heart. Half-times of initial and terminal drug accumulation phases were about 2.1 and 14.4 min., respectively. At 1 microgram ml-1 (2.4 microM) in the perfusion liquid the average concentration of diltiazem in the myocardium at steady state was about 16 micrograms g-1 (38.6 microM) with 17% referable to the deepest, possibly intracellular compartment. Increasing diltiazem concentrations from 13 to 889 ng ml-1 (31-2144 nM) produced a progressive increase in coronary flowrate from 100 to 174%. The computed Em- and EC50-values were 73.2% and 187 nM, respectively. Oxygen consumption decreased to 27.6% showing Em = 106% and IC50 = 1536 nM. Amplitude and velocity of myocardial contraction decreased to about 6% and 2%; Em = 101% and 104%, IC50 = 266 and 186 nM, respectively. Heart beating frequency decreased to 63% exhibiting Em = 58% and IC50 = 2015 nM. The PQ- and QRS-intervals increased to 133% and 112%, respectively. The frequency-corrected QT-interval decreased to 81.6%. Our findings demonstrate a relatively rapid and moderate accumulation of diltiazem in the guinea-pig heart accompanied by a marked increase in coronary flow, progressive and pronounced negative inotropic and chronotropic effects and a less than proportional decrease in oxygen consumption.

Animals↗

PubMed1987

Cefotaxime disposition pharmacokinetics during peritoneal dialysis.

The pharmacokinetics of cefotaxime and its main metabolite des-acetyl-cefotaxime were studied after a single 1000 mg intravenous dose in 8 patients with end stage renal disease during peritoneal dialysis. Pharmacokinetic parameters were determined by iterative non-linear least squares regression analysis of plasma and dialysis fluid drug concentration curves. Biological half-life of cefotaxime ranged from 2.3 to 8.2 hours and total plasma clearance from 11 to 103 ml/min. (0.11 to 1.7 ml/min/kg b.wt). Only 1.4% to 4.2% of the intravenous dose of cefotaxime was distributed to the dialysis fluid. We conclude that the dosage of cefotaxime to uraemic patients adjusted to the renal function needs no further adjustment during peritoneal dialysis.

Aged↗

PubMed1987

A comparative study of the pharmacodynamics and pharmacokinetics of nicardipine and nitrendipine in the isolated rabbit heart.

The myocardial pharmacodynamic effects of the two dihydropyridine calcium-antagonists nicardipine and nitrendipine were comparatively studied in the isolated, spontaneously beating and retrogradely perfused rabbit heart at stepwise increased drug concentrations within the range 0.5-260 ng X ml-1 (1.1-721 nM). Both drugs produced a progressive and very pronounced inhibition of myocardial contractility as measured by both contraction amplitude and contraction velocity. The corresponding Emax-values were about 100% and IC50-values about 10 and 65 nM, respectively. Myocardial oxygen consumption did not decrease at the lower concentrations of neither nicardipine nor nitrendipine but were at the higher levels inhibited significantly with Emax-values of about 68 and 78% and IC50-values about 21 and 136 nM, respectively. Coronary flow-rate increased at the lower concentrations of the drugs to about 125 and 118% and then decreased to 80 and 77%, respectively. Both drugs, but especially nitrendipine, showed a marked negative chronotropic effect (Emax 33 and 56% and IC50 6 and 81 nM, respectively). The frequency-corrected QT-intervals were progressively decreased by the drugs. Myocardial accumulation and disposition pharmacokinetics of nicardipine, nitrendipine and nimodipine were also studied. The terminal half-lives for the drugs were about 56, 16 and 29 min., respectively. Apparent relative volumes of drug distribution in the myocardium which equals the average concentration ratio for the drugs between this tissue and the perfusion liquid at kinetic steady-states were about 290, 61 and 177 ml X g-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Single dose pharmacokinetics of etretin and etretinate in psoriatic patients.

Etretin, an aromatic retinoic acid derivative, has recently been introduced as a possible substitute for etretinate in the treatment of severe psoriasis and other dyskeratoses. A total of nine patients with psoriasis of either sex in the age range 23-76 years was investigated after single dose oral drug administration, six were given 40 mg of etretin and three 40 mg of etretinate. A newly developed reversed-phase HPLC method was applied for simultaneous determination of etretin and etretinate in plasma. In patients receiving etretinate, the lag-time i.e. the time elapsing until appearance of first-order drug absorption was 1.24 +/- 0.27 for the parent drug and 0.69 hrs +/- 0.16 (mean value +/- S.D.) for its metabolite, etretin. Absorption half-times were 0.86 +/- 0.04 and 0.55 hrs +/- 0.09, respectively. The patients receiving etretin showed a lag-time of 0.42 hrs +/- 0.23 and an absorption half-time of 0.33 hrs +/- 0.28. This suggests that a fraction of etretinate is rapidly hydrolysed to etretin during the absorption process. The mean half-times of the distributory phases of disposition for etretinate and etretin were about 1 and 1.3 hrs and the apparent terminal half-lives were 6.57 +/- 2.09 and 5.52 hrs +/- 1.76, respectively. Assuming 40% systemic availability for both drugs the mean apparent volumes of distributions were calculated to be 1.50 +/- 0.46 and 1.31 l X kg-1 +/- 0.53 and mean plasma clearances were 177.8 +/- 105.8 and 175.9 ml X kg-1 X hr-1 +/- 81.4 for etretinate and etretin, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acitretin↗