[Problems of equivalency points during therapy with glucocorticoids. A comparison of the clinical pharmacokinetics and pharmacodynamics of prednisolone and methylprednisolone].
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Animals↗
Biomedical subjects
G Hochhaus
Publications and source records attributed to G Hochhaus.
Leucine enkephalin-tyrosinase reaction products--identification and biological activity.
Leucine enkephalin (1 mM) was reacted with mushroom tyrosinase under reductive conditions (ascorbic acid, 50 mM). Reaction products were isolated by high-performance liquid chromatography and identified using electrospray ionization mass spectrometry. The products of the reaction were found to be hydroxylated at the Tyr1 moiety of the peptide. The major product was a monohydroxylated derivative of leucine enkephalin ([HO-Tyr1]LE) and the minor product of the reaction was a dihydroxylated derivative ([(HO)2-Tyr1]LE). The affinity of [HO-Tyr1]LE to receptors in rat brain homogenate was compared to that of leucine enkephalin itself. Hydroxylation of LE was found to decrease receptor affinity to both mu and delta opioid receptor sites by a factor of about 20.
Amino Acid Sequence↗
Clinical pharmacology of pancreatic enzymes in patients with cystic fibrosis and in vitro performance of microencapsulated formulations.
Improving protein and fat absorption in patients with cystic fibrosis relates to the amount of biologically active enzyme reaching the duodenum. Microencapsulated formulations are more effective than conventional products but differ in content, ability to retard acid inactivation and the pH at which they release enzymes. Contaminants in these products contribute to hyperuricosuria.
Adolescent↗
Receptor-based pharmacokinetic-pharmacodynamic analysis of corticosteroids.
The pharmacodynamics of three corticosteroids were investigated after intravenous administration of the phosphate esters of methylprednisolone, dexamethasone, and triamcinolone acetonide to healthy subjects at 20, 50, and 80 mg as well as placebo. Twenty-two different pharmacodynamic parameters were followed as a function of time for 48 hours. Statistically significant effects of the glucocorticoids were an increase in blood glucose levels, a decrease in the number of lymphocytes, eosinophils, basophils, and monocytes, and an increase in the number of granulocytes and stab cells. For the most significant pharmacodynamic effects (lymphocytes, granulocytes, and glucose) a previously derived integrated pharmacokinetic/pharmacodynamic model using plasma concentrations, protein-binding data, and in vitro receptor-binding affinities was used to predict the pharmacodynamic effect-time profiles. Good agreement of predicted and measured effects was observed, confirming the validity of the model. The clinical significance of the model was demonstrated by comparison of model-predicted maintenance doses with empirically determined clinical equivalency doses.
Adolescent↗
Studies on the pharmacokinetics and metabolism of prednicarbate after cutaneous and oral administration.
Prednicarbate (PC) is a nonhalogenated derivative of prednisolone which is used for the local treatment of corticoid-sensitive skin diseases. In this study, the pharmacokinetics and the metabolism of PC in humans are investigated after cutaneous ointment application (75 mg PC) and after systemic oral administration (40 mg PC) in 8 healthy volunteers. In addition, the possible suppression of endogenous cortisol secretion by both application forms was monitored. After oral administration no intact PC, but significant levels of the first metabolite prednisolone-17-ethylcarbonate (PRED-17-EC) were determined. PRED-17-EC was further metabolized with a half life of 1.6 h to prednisolone. After percutaneous administration neither PC nor other known metabolites could be detected systemically. The low systemic bioavailability after dermal application was also reflected in an unchanged cortisol secretion pattern. According to animal studies our metabolic studies in humans suggest that the prednisolone-17-ester PRED-17-EC, which has a receptor binding affinity comparable to that of dexamethasone is the pharmacologically active compound. As PRED-17-EC subsequently undergoes an inactivation step to the low active prednisolone this may be the reason for the dissociation of good local efficacy and low systemic side effects.
Administration, Oral↗
Prednicarbate after different forms of administration. Plasma levels of drug and metabolites and effects on endogenous cortisol levels in humans.
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Administration, Cutaneous↗
Generic and alternative brand-name pharmaceutical equivalents: select with caution.
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Drug Approval↗
Pharmacokinetic characterization and tissue distribution of the new glucocorticoid soft drug loteprednol etabonate in rats and dogs.
Loteprednol etabonate, a new glucocorticoid soft drug with a characteristic chloromethyl ester function in the 17 beta-position, is currently in the early phases of clinical development. As the basis for human trials, this study describes a new reversed-phase high-performance liquid chromatographic method for the determination of levels of drug in plasma and urine samples and assesses the pharmacokinetic properties of loteprednol etabonate in dogs and rats. Intravenous administration of loteprednol etabonate (5 mg/kg) to dogs revealed a terminal half-life of 2.8 h, a volume of distribution of 3.7 L/kg, and a total body clearance of 0.9 L/h/kg. Intact loteprednol etabonate was not detectable in the urine. After oral administration of the drug (5 mg/kg) to dogs, only metabolites, but no intact drug, were found in the plasma, an indication for a high first-pass effect. A pronounced binding of the drug to plasma protein (> 90%) and a high erythrocyte-buffer partition coefficient of 7.8 were determined in vitro. Preliminary information about tissue distribution and possible metabolic pathways were obtained in rats after oral administration of a 14C-labeled loteprednol etabonate suspension (5 mg/kg). pH-selective extraction into ethyl acetate revealed three distinguishable fractions: (1) a neutral lipophilic fraction, presumably intact drug, (2) an acidic, lipophilic fraction, and (3) a hydrophilic nonextractable fraction. Levels of intact drug and metabolites were highest in liver and kidney, whereas significantly lower levels were found in other investigated organs (lung, brain, heart).(ABSTRACT TRUNCATED AT 250 WORDS)
Androstadienes↗
Pharmacokinetic/dynamic correlation of pulmonary and cardiac effects of fenoterol in asthmatic patients after different routes of administration.
Pulmonary and cardiac effects of the beta 2-adrenergic drug fenoterol were studied in 27 asthmatic patients using an integrated pharmacokinetic/dynamic (PK/PD) approach. Airway resistance (Rf), intrathoracic gas volume (IGV), heart rate, and plasma levels were monitored after placebo, injection (12.5 and 25 micrograms), nasal instillation (400 micrograms), inhalation (200 and 400 micrograms), and infusion (200 micrograms/180 min with or without loading dose). The pharmacokinetics were best described by an open three-compartment model with a terminal half-life of 200 min (gamma = 0.23 +/- 0.08 L/hr), a volume of distribution at steady state of 1.9 +/- 0.8 L/kg, and a clearance of 0.86 +/- 0.32 L/hr/kg, with 14 and 9% absorbed after nasal and pulmonary administration, respectively. For the noninhalation regimens, a PK/PD correlation linked the concentration in the shallow pharmacokinetic compartment to the investigated effects via an Emax relationship, resulting in three to five times higher EC50 values (concentration necessary to achieve half-maximal effect) for the heart rate than for the beta 2-mediated effects on IGV and Rf. In contrast, pulmonary effects after inhalation could not be incorporated into the correlation, indicating that these effects are induced locally after inhalation. Intrapatient variability for EC50 and Emax was approximately 90%.
Administration, Intranasal↗
Pharmacokinetic/pharmacodynamic characteristics of the beta-2-agonists terbutaline, salbutamol and fenoterol.
The clinical pharmacokinetics and pharmacokinetic/dynamic properties of the beta-adrenergic drugs fenoterol, salbutamol and terbutaline are reviewed. Sulfate conjugates are the main metabolites in man. The protein binding of these derivatives is rather weak with most pronounced binding observed e.g. fenoterol (40%). Disposition after parenteral administration shows a multi-exponential behavior for all the substances with linear but also stereo-selective pharmacokinetics. After parenteral administration, the drugs are mainly eliminated by renal processes while after oral administration a pronounced metabolic clearance (high first pass effect) is responsible for a low bioavailability, especially for fenoterol (2%). The total clearance for fenoterol is about twice that of salbutamol and terbutaline. Seven to 15% of the delivered aerosol reach typically the systemic circulation. In patients with respiratory disorders, pulmonary absorption is however highly dependent on the disease state. Pharmacokinetics in children do not significantly differ from adults when expressed per kg body weight. Patients with renal failure but not asthmatics show changed pharmacokinetic profiles. Only insignificant interactions with other drugs have been found. Pharmacokinetic/dynamic modeling approaches indicated that fenoterol is 25 times more active at the site of action than salbutamol and terbutaline, but all three drugs show similar bronchopulmonary selectivities. When the overall clinical activity, determined by pharmacokinetic and dynamic properties is compared, the activity gap is reduced: fenoterol (8) greater than salbutamol (2) greater than terbutaline (1). Differences in the first pass effect even inverse the pattern after oral administration. PK/PD modeling quantified the pulmonary effect after inhalation and suggested that the higher incidence of side effects for fenoterol might be linked to an overdosing problem. The application of PK/PD principles may improve the clinical usage and therapy of beta-2-adrenergic drugs.
Adrenergic beta-Agonists↗
Pharmacokinetics and pharmacodynamics of prednisolone after intravenous and oral administration.
The pharmacokinetics and pharmacodynamics of prednisolone were investigated according to four different routes of administration: 20 and 40 mg prednisolone orally in the morning, 20 mg prednisolone orally in the evening and 40 mg prednisolone intravenously in form of prednisolone phosphate in the morning. The plasma levels of prednisolone were followed using HPLC. To study the pharmacodynamics of prednisolone, glucose levels and various blood cell parameters such as erythrocytes, leukocytes, segmented neutrophilic granulocytes, eosinophils, basophils, monocytes and lymphocytes were followed. To summarize the data, the area under the effect-time-curve (AUCE) was calculated by the trapezoidal rule. The results show that the pharmacokinetics of prednisolone is dose-dependent (non-linear) and time-dependent. Prednisolone concentrations in plasma after a 20 mg and 40 mg dose are very similar, indicating that the pharmacokinetics of prednisolone are non-linear and dose-dependent with a higher clearance for higher concentrations. The comparison of 20 mg administered in the morning with the same dose given in the evening shows that the pharmacokinetics of prednisolone after oral administration of equal doses changes during the day with higher concentrations in the morning than in the evening. Furthermore, the results of the present study confirm the presence of pharmacodynamic corticosteroid effects on blood cell count and blood glucose. No statistically significant differences were observed for the four different treatments. In summary, it can be concluded that due to the complex pharmacokinetics of prednisolone, it is difficult to make accurate predictions of the expected effect-time relationships.
Administration, Oral↗
cAMP accumulation in opioid-sensitive SH-SY5Y neuroblastoma cells is modified by estradiol and progesterone.
We have recently demonstrated that acute and chronic treatments with estradiol and progesterone induce changes in the responsiveness of endogenous opioid systems to painful stimulation. In the present study the neuroblastoma SH-SY5Y subclone known to contain predominantly mu opioid receptors was used as a model to characterize the gonadal steroid effect on this opioid receptor system. The function of opioid receptors was assessed by measuring prostaglandin E1 (PGE1)-induced cyclic AMP accumulation after various treatments with estradiol and progesterone. Differentiated SH-SY5Y cells respond to PGE1 with a dramatic increase in cAMP level. Morphine (MOR) inhibits by about 75% the stimulatory effect of PGE1 on cAMP. Pretreatment with 5 nM of estradiol for 6 days resulted in a significant increase of PGE1-stimulated cAMP accumulation. Exposure of cells for 48 h to estradiol in doses of 5 nM or 50 nM did not affect cell sensitivity to the PGE1 effect on cAMP. Moreover, neither dose of estradiol changed the inhibitory effect of morphine on PGE1-induced cAMP response. There was a significant increase in PGE1-stimulated cAMP accumulation after treatment with 100 nM progesterone for 1 h or 15 min and a marked elevation of cAMP levels was also measured after 15 min treatment with 10 nM progesterone. Exposure to either dose of progesterone for 8 h, 48 h or 6 days did not affect basal or PGE1-induced cAMP in neuroblastoma cells. Progesterone-treated groups responded to MOR with 56-67% inhibition of PGE1-stimulated cAMP accumulation. The potency of MOR-induced inhibition was comparable to the MOR effect in cells not treated with the steroid.(ABSTRACT TRUNCATED AT 250 WORDS)
Alprostadil↗
A new fluorogenic assay for tyrosine-containing peptides.
A new tyrosine-specific LC assay with pre-column fluorogenic derivatization is described for Tyr-Gly as model peptide. o-Hydroxylation of the tyrosine residue with tyrosinase in the presence of ascorbic acid, followed by oxidation to the corresponding quinone by potassium ferricyanide at room temperature and condensation with 1,2-diamino-1,2-diphenylethane in the presence of acetonitrile gave a highly fluorescent species. The resulting fluorescence signal was stable over the investigated period of 5 h and exhibited a linear response curve on a reversed-phase LC system. Under optimized reaction conditions, the lower limit of detection for Tyr-Gly was 200 fmol per injection. Examination of a series of dipeptides (L-Tyr-L-X; X = Gly, Ala, Val, Leu, Phe) showed no significant influence of neighbouring amino acids on the enzymatic hydroxylation by tyrosinase. This and the formation of a highly fluorescent signal for Leu-enkephalin suggests the general feasibility of the approach for the determination of tyrosine-containing peptides.
Chromatography, High Pressure Liquid↗
A selective LC/RIA for dexamethasone and its prodrug dexamethasone-21-isonicotinate in biological fluids.
A combined LC/RIA procedure is described for the selective determination of dexamethasone (DEX) and its prodrug dexamethasone-21-isonicotinate (DIN) in plasma. The low affinity of the employed dexamethasone antiserum for DIN (cross-reactivity less than 0.5%) allowed the direct determination of DEX in plasma extracts. For the determination of DIN, both substances of interest were separated by LC, the DIN containing fraction was collected, hydrolysed and the generated DEX was consequently assayed by radioimmunoassay. The assay detection limits were 0.1 ng ml-1 for DEX and 0.75 ng ml-1 for DIN. For both substances, inter- and intra-day variabilities (RSDs) were 6 and 12%, respectively.
Binding Sites↗
Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate.
An improved synthesis of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene 17 beta-carboxylate) was achieved. The design of the new type of glucocorticoid was based on the soft drug concept. The relative binding affinities of loteprednol and its putative metabolites (PJ90 and PJ91) to rat lung type II glucocorticoid receptor were determined in a competitive binding experiment with [3H]triamicinolone acetonide. The medium contained cortienic acid (10(-5) M) in order to block transcortin binding sites. Loteprednol etabonate exhibited a binding affinity which was 4.3 times that of dexamethasone, both compounds having a Hill factor close to 1 whereas PJ90 and PJ91 did not show any affinity to the receptor. Loteprednol etabonate was compared to betamethasone 17 alpha-valerate in a vasoconstriction test which was performed on the forearm skin of human volunteers. The results showed that loteprednol etabonate has good skin-permeation properties and strong glucocorticoid activity.
Androstadienes↗
Glucocorticoid activity and structure activity relationships in a series of some novel 17 alpha-ether-substituted steroids: influence of 17 alpha-substituents.
A series of non-fluorinated glucocorticoids, cortienic acid analogs with a 17 beta-chloromethyl ester and various 17 alpha-ether functions, were tested for their affinity to the rat-lung type-II glucocorticoid receptor. The relative binding affinity of a set of 9 compounds was determined in a competitive experiment with [1,2,4-3H]triamcinolone acetonide. The highest binding affinities were observed with the 17 alpha-propoxy and butoxy analogs which were 1.3 times more active than the standard dexamethasone. Quantitative analysis of the results suggested that steric factors and lipophilicity of the side-chain were the major parameters affecting receptor affinity. Representative members of the series were compared to betamethasone 17 alpha-valerate in a vasonstriction test. The results paralleled those of the receptor binding experiment, indicating that the new steroids have good skin-permeation properties and good glucocorticoid activity.
Animals↗
Binding affinities of rimexolone (ORG 6216), flunisolide and their putative metabolites for the glucocorticoid receptor of human synovial tissue.
The relative binding affinities (RBA) of two locally used glucocorticoids, rimexolone and flunisolide have been measured for the glucocorticoid receptor of human synovial tissue. The non-fluorinated derivative rimexolone exhibited a binding affinity (RBA of 130) somewhat higher than that of dexamethasone (RBA of 100) but lower than that of flunisolide (RBA 190). Potential metabolites of rimexolone hydroxolated at the C17 side-chain, showed decreased binding affinities, while the 6-hydroxy metabolite of rimexolone and flunisolide (its main metabolite) and the 4,5-dihydro metabolites of rimexolone hardly bound at all. These results support previous pharmacological findings that the high ratio of local to systemic effects of both compounds are due to a pronounced receptor affinity of the parent compounds and the fast systemic metabolism to derivatives with low pharmacodynamic activity.
Anti-Inflammatory Agents↗
An avidin-biotin based enzyme-linked immunosorbent assay for dynorphin A 1-13.
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Avidin↗