Pentoxyfylline in and prevention and treatment of chronic lung disease.

The anti-inflammatory effects of pentoxfylline are associated with a number of clinical benefits. These include reduction in mortality in patients who have undergone bone marrow transplants or suffer peritonitis. In infants with sepsis, a reduction in mortality has also been associated with pentoxyfylline administration. The anti-inflammatory effects of pentoxyfylline, as well as its bronchodilator, diuretic and respiratory muscle stimulant effects suggest it may have a useful role in BPD. Interim analysis of a prophylactic trial suggests pentoxyfylline may reduce treatment requirements after the neonatal period and that, in established BPD, pentoxyfylline and dexamethasone may be of similar efficacy.

Pharmacokinetic interaction between imipramine and carbamazepine in patients with major depression.

RATIONALE: Despite the fact that carbamazepine (CBZ) is frequently added to the existing tricyclic antidepressant (TCA) therapy, to date little is known about serum levels of pharmacologically active hydroxy metabolites of TCAs, as well as about possible changes in free (non-protein-bound) concentrations of these drugs and their metabolites during such combination treatment of depression. OBJECTIVE: The aim of this study was to evaluate the effect of CBZ on steady-state total and free serum concentrations of imipramine (IMI) and its metabolites, desipramine (DMI), 2-hydroxyimipramine and 2-hydroxydesipramnine, in depressed patients. In addition, the free and total serum concentrations of CBZ and 10,11-epoxycarbamazepine were measured. METHOD: Thirteen patients with DSM-III-R diagnosis of major depression were enrolled in the study. All patients hospitalised at the Department of Psychiatry, Collegium Medicum, Jagiellonian University were treated with IMI at a dose of 2 mg/kg per day for 3 weeks, after which CBZ at a dose of 400 mg/day was added. Steady-state serum concentrations of IMI, CBZ and their metabolites were assayed by HPLC. Free drug concentrations were measured by ultrafiltration. RESULTS: After 2 weeks of combination therapy a significant decrease in mean steady-state total serum concentrations of IMI (from 168.84 +/- 102.18 to 98.12 +/- 43.79 ng/ml) and DMI (from 293.89 +/- 171.93 to 221.85 +/- 153.21 ng/ml) was observed. Simultaneously, steady-state serum concentrations of total hydroxy metabolites and free IMI and its metabolites, measured just before and 2 weeks after CBZ were started, did not differ significantly. In consequence, a significant increase in free fraction of the parent drug was observed (3.36 +/- 3.24% vs 5.75 +/- 3.60%). Also free fraction of DMI tended to be higher after CBZ addition. CONCLUSION: CBZ affects not only the metabolism of IMI and its metabolites, but also their protein binding. Therefore, despite considerable reductions in total serum levels of IMI and DMI, but when the unchanged free fraction concentration of these compounds is maintained, a dosage elevation of IMI does not seem to be necessary after CBZ addition to TCA therapy.

[Clinically significant interactions of psychotropic drugs used in psychiatry]. / Znaczenie kliniczne niepozadanych interakcji leków psychotropowych w psychiatrii.

The effect of psychotropic drugs on the several neurotransmitter systems as well as the fact that main CYP isozymes are involved in the metabolism of these drugs, lead to unwanted pharmacodynamic and pharmacokinetic interactions. The present paper is focused on the interactions of psychotropic drugs with other drugs used in the treatment of coexisting somatic diseases.

The impact of chirality of the fluorinated volatile inhalation anaesthetics on their clinical applications.

This review discusses the various chromatographic enantioseparation methods on an analytical and preparative scale for fluorinated inhalation anaesthetics used clinically, namely halothane, enflurane, desflurane and isoflurane. The differences in the pharmacodynamics and pharmacokinetics between the enantiomers of those anaesthetics are presented. It can be concluded that using a single enantiomer for these fluorinated anaesthetics is advantageous over using the racemic mixture. The racemic switch to a single enantiomer for these fluorinated volatile anaesthetics offers a more effective and safe general anaesthetic.

The kinetics of pentoxifylline release from drug-loaded hydroxyapatite implants.

Hydroxyapatite (HAP) was synthesized by the aqueous precipitation method from CaO and H3 PO4 as the reagents. The HAP powders, either subjected or not subjected to preliminary calcination, were mixed with a pore-creating medium and isostatically shaped at a pressure of 350 MPa to form cylindrical samples. A natural product such as flour served as a pore-creating medium. Sintering was performed in the air, at 1200 or 1250 degrees C. The employed procedure allowed for achieving microporous materials of pore sizes ranging from 0.1 to 15 microm and with open porosity values of 23-44%. It was demonstrated that the porosity of the obtained materials depended mainly on the amount of the added pore-creating medium and the temperature of sintering. The implants, shaped as hollow cylinders, were filled with 50 mg of pentoxifylline (PTX) as a model drug. Internal wells for drug placement were drilled in the samples using a high precision drill. The drug release study was performed in pH = 7.35 phosphate buffer, at 37 degrees C. The results showed that the amount and time of PTX release, as well as the lag time were mainly controlled by the open porosity of the carriers.

Enantioselective high performance liquid chromatographic assay of acebutolol and its active metabolite diacetolol in human serum.

A stereoselective direct liquid chromatographic method for assay of the enantiomers of the beta-adrenergic blocker acebutolol (AC) and its active metabolite, diacetolol (DC), in human serum was developed. The assay is based on extraction with ethyl acetate and separation of enantiomers on an amylose tris-(3,5-dimethylphenylcarbamate) chiral stationary phase (Chiralpak AD) column. The method was validated and proved useful for the determination of the enantiomers in serum samples of patients suffering from hypertension and chronically treated with racemic AC. The results were compared and found similar with an indirect assay based on derivatization of the enantiomers with (+)-(S)-1-(1-naphthyl)ethyl isocyanate (NEIC).

[Clinical pharmacokinetics of tricyclic antidepressants Part II. Drug therapy monitoring]. / Farmakokinetyka kliniczna trójpierscieniowych leków przeciwdepresyjnych Czesc II. Terapia monitorowana.

Large interindividual variation in steady-state TCA plasma concentrations, the presence of active metabolites, narrow therapeutic range and life-threatening results of TCA overdosage constitute indications for therapeutic drug monitoring. Conditions which must be fulfilled in order that serum concentration measurements may be taken into consideration in routine practice were discussed. The most important ones are: relationship between TCA concentration and antidepressant effect, the knowledge of therapeutic TCA range and availability of rapid and sensitive analytical method. Pharmacokinetic methods of TCA dosage individualization were also described. TCA serum concentration monitoring and dosage individualization of these drugs allows the clinician to optimize treatment of depression.

[Clinical pharmacokinetics of tricyclic antidepressants. Part I. Pharmacokinetic properties]. / Farmakokinetyka kliniczna trójpierscieniowych leków przeciwdepresyjnych. Czesc I. Wlasciwosci farmakokinetyczne.

Pharmacokinetic properties of tricyclic antidepressants (TCA) and factors changing pharmacokinetics of these drugs were presented. The following factors were discussed: age, genetically determined rate of metabolism and TCA interaction with co-administered drugs. As a consequence of these factors alterations mainly in elimination of TCA are observed. It leads to large interindividual variation in TCA plasma concentrations and lack of correlation between TCA concentration and dosage.

[Clinical usefulness of monitoring serum levels of imipramine and desipramine in patients treated for endogenous depression]. / Uzytecznosc kliniczna monitorowania poziomu imipraminy i dezipraminy w surowicy chorych leczonych z powodu depresji endogennej.

Fifteen patients with endogenous unipolar and bipolar depression were treated with imipramine and, if necessary, one of benzodiazepine or neuroleptic. Total serum concentrations of imipramine (IMI) and its active metabolite desipramine (DMI) were measured in steady-state by FPIA method . Severity of depression was assessed using the Hamilton Depression Rating Scale. IMI + DMI serum concentration monitoring appeared to be useful in every case. It helped to arrive more quickly at the optimal dosage, confirmed the suspicion of overdosage or noncompliance. In nonresponders group, it helped with the earlier decision of changing brands of tricyclic antidepressant or it contributed to intensify the diagnostic process which detected the additional pathology.

[Physiological principles of imipramine pharmacokinetics]. / Fizjologiczne podstawy farmakokinetyki imipraminy.

Part I. Assessment of hepatic elimination of IMI based on the in vivo, in vitro an isolated rat liver perfusion experimental data. The isolated rat liver perfusion was carried out acc. to Miller at two different hepatic blood flow 6 and 11 ml/min respectively. The postmitochondrial liver fraction (9000 g) as a source of enzymes metabolized of IMI was incubated acc. to Nakazawa to estimate Vm, Km and Clintr values. Based on these enzymatic parameters and using ("well stirred") model of hepatic elimination, the hepatic clearance (ClH) and hepatic extraction ratio (E) of IMI were predicted and compared with the values derived from perfusion experiments as well as from in vivo studies. A good agreement was obtained between predicted and observed ClH and E values. It was found that systemic clearance of IMI is similar to hepatic clearance and is affected by change in hepatic blood flow. The hepatic elimination of IMI is unaffected by protein binding of this drug and both free and bound fraction were available for metabolism. Part II. Studies on the rat brain transport of IMI. Using Oldendorf's method (BUI method) the rat brain uptake of 3H-IMI in the presence of unlabeled IMI (0.25-250 microM) as well as after multiple dosing of IMI was studied. It was found, that the transport of 3H-IMI through blood brain barrier was nonsaturable up to 250 microM, what can reflect the transport via passive diffusion. Only very high brain concentration of IMI can inhibited the brain uptake of 3H-IMI. The uptake of 3H-IMI is not restrictive by plasma protein binding of this compound.

The distribution of imipramine and desipramine in rat brain regions after single and chronic administration of imipramine.

The regional distribution of imipramine (IMI) and desipramine (DMI) in rat brain after single and chronic oral administration of IMI was studied. The distribution of IMI and DMI in all examined brain regions was similar, except for hippocampus + septum. After chronic administration of IMI the disappearance of the parent drug and its metabolite was slowing down in all investigated brain regions as well as in the plasma. The accumulation of IMI and DMI after chronic treatment of IMI was significantly higher in plasma than in all examined brain regions.

Pharmacokinetics of imipramine after single and multiple intravenous administration in rats.

Plasma and brain levels of imipramine (IMI) and desmethylimipramine (DMI) in rats after single and multiple iv administration were estimated. IMI accumulated only in plasma, while DMI accumulated in plasma and brain of rats. The brain level of IMI and DMI was higher than plasma level. After multiple administration plasma DMI concentration was significantly greater than IMI concentration. It seems that IMI was obtained steady-state plasma concentration already at fifth day of multiple administration. High dose of IMI (10 mg/kg) caused that the relationship between steady-state concentration and dose of IMI cannot be expressed as a linear function.