Biomedical subjects

S Eksborg

Publications and source records attributed to S Eksborg.

At least 37 records · Page 2Linked to original sources

PubMed2000

Stage-specific inhibition of deoxyribonucleic acid synthesis and induction of apoptosis by antracyclines in cultured rat spermatogenic cells.

A rapid in vitro method has been developed to detect early effects of cytostatic drugs on rat spermatogenesis. The induction of programmed cell death (apoptosis) and changes in DNA synthesis induced by doxorubicin and idarubicin were measured in specific stages of the cycle of seminiferous epithelium including mitotic (stage V) and meiotic (stage VIII-IX) S-phase cells. The model was used to investigate the protective effect of an organic thiophosphate, amifostine, against the toxicity of antracyclines. Premitotic DNA synthesis was found to be more sensitive than premeiotic DNA synthesis to antracyclines. Idarubicin was more toxic than doxorubicin to germ cells in inducing apoptosis and suppressing DNA synthesis. Amifostine had no protective effect against doxorubicin- or idarubicin-induced inhibition of DNA synthesis. In contrast, a significant stimulation of DNA synthesis in premitotic cells by amifostine was found, suggesting that this compound may have a stimulative effect on spermatogenic stem cells. These data show that stage-specific dissection of the seminiferous tubules and their in vitro exposure to predetermined doses of drugs may give us a unique possibility to detect drug action and protection against the cytotoxicity of antineoplastic agents at the cellular level of the spermatogenic cycle.

Animals↗

PubMed2000

A comparative pharmacokinetic study of doxorubicin and 4'-epi-doxorubicin in children with acute lymphocytic leukemia using a limited sampling procedure.

Antraquinone glycosides are an important class of antineoplastic drugs, frequently used for treatment of a variety of malignancies in children. Doxorubicin (Dox) is the most frequently used drug within this class of antineoplastics. 4'-epi-doxorubicin (Epi), a Dox isomer, was developed with the aim of reducing risks for fatal heart toxicity observed with Dox. The aim of the present study was to investigate the pharmacokinetics of Dox and Epi in children with acute lymphocytic leukemia. In total 31 patients (13 females and 18 males; median age 5.4 years; range 0.73-15.3 years) were studied using a simplified sampling procedure. The pharmacokinetic differences of the two drugs were established by their simultaneous administration. The plasma pharmacokinetics of neither Dox nor Epi correlated with the age of the patients. There were no gender differences in dose-normalized maximum concentrations of neither Dox nor of Epi. The inter-patient variation of the dose-normalized maximum concentrations of Dox and Epi is larger among females than among males. The Cmax ratio Dox/Epi was 1.39+/-0.19 (mean +/- SD). The pharmacokinetic differences of Dox and Epi in children, although less pronounced than in adults, are still of a magnitude that might be of clinical importance.

Adolescent↗

PubMed2000

Plasma pharmacokinetics of etoposide (VP-16) after i.v. administration to children.

The pharmacokinetics of etoposide (VP-16), a semi-synthetic derivative of podophyllotoxin, were studied in 16 pediatric patients (median age 8.3 years; range 4 months to 22 years) including two girls with Down's syndrome (DS). The drug was administered as infusions (1-3 h) in a wide range of doses (9-322 mg, corresponding to 32-210 mg/m2). The area under the plasma concentration versus time curve (AUC), dose normalized by the body surface area, was independent of age, while AUC normalized by the dose in mg/kg increased with increasing age of the patients. The interpatient variability of AUC, normalized for the dose in mg/m2, was 23% (CV) compared to 32% (CV) normalized for the dose in mg/kg. The terminal half-life time was 4.1 h (median value; range 2.0-7.8 h). The pharmacokinetics of etoposide in children with DS and chromosomally normal children were very similar with regard to systemic drug exposure and plasma half-life time. From the pharmacokinetic point of view it was therefore not necessary to make any dose modifications in the two girls with DS. The two DS patients did not experience any enhanced degree of toxicity from their etoposide treatments. The results support that dosing of etoposide to children should be based on body surface area.

Adolescent↗

PubMed2000

Bioavailability of aciclovir after oral administration of aciclovir and its prodrug valaciclovir to patients with leukopenia after chemotherapy.

The median bioavailabilities of aciclovir after administration of aciclovir and its prodrug valaciclovir were 21.5 and 70.1%, respectively, in 12 patients with malignant hematological diseases with leukopenia after chemotherapy. The interindividual variations of the bioavailability were 48.5 and 21.0% after administration of aciclovir and valaciclovir, respectively. Neither the bioavailability nor the interindividual variation of area under the concentration-time curve of oral aciclovir or valaciclovir differed from that reported in healthy volunteers.

Acyclovir↗

PubMed1999

Anthraquinone-induced cell injury: acute toxicity of carminomycin, epirubicin, idarubicin and mitoxantrone in isolated cardiomyocytes.

Acute toxic effects of the antineoplastic anthraquinones carminomycin, epirubicin, idarubicin and mitoxantrone were studied in primary cultures of cardiomyocytes, which were isolated from adult rats. Both time- and concentration-dependent changes of cell structure and viability (trypan blue exclusion) following incubation of myocytes with subclinical, clinical and toxic concentrations of the anthraquinones were examined by light microscopy. The area under the decay curve of viable and rod-shaped myocytes was used to express cytotoxicity of the drugs. Mitoxantrone was found to reduce cell viability and number of rod-shaped cells to the greatest extent, followed by carminomycin, idarubicin and epirubicin. A significantly lower accumulation in cardiomyocytes was obtained with epirubicin and idarubicin compared with carminomycin. An inhibitory effect on oxygen consumption by the cells occurred already at 0.1 microM with epirubicin, whereas inhibition caused by other anthraquinones was less pronounced. Our data indicate a weak association of net accumulation and the toxicity parameter IC50 for carminomycin and idarubicin. In contrast to these results, a more significant correlation of cytotoxicity and anthraquinone lipophilicity was found, which suggests that the lipophilic character of a particular anthraquinone may be an important factor in drug-induced acute cardiotoxicity.

Animals↗

PubMed1999

In vivo evaluation of the biodistribution of 11C-labeled PD153035 in rats without and with neuroblastoma implants.

The biodistribution of 11C-labeled 4-(3-bromoanilino)-6,7-dimethoxyquinazoline, an inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase, has been evaluated in vivo in rats using positron emission tomography (PET). Time-activity data obtained after i.v. administration in one rat revealed that the radiotracer rapidly cleared from plasma with subsequent uptake in major organs of the body (brain, heart, liver, gastrointestinal tract and bladder). Uptake in proliferating tissue in rats with human neuroblastoma xenografts indicate that [O-11C-methyl]PD153035 shows promise as a new agent for in vivo imaging of tumors with PET.

Animals↗

PubMed1999

Stability of 5-aminolevulinic acid in aqueous solution.

The chemical stability of 5-aminolevulinic acid (ALA) was studied in aqueous solution as a function of concentration, pH, temperature and in the presence of ethylenediaminetetraacetic acid (EDTA). The degradation of ALA was followed by reversed-phase liquid chromatography using a pH where ALA is protonated (pKa1=3.90; pKa2=8. 05, as determined potentiometrically). ALA was degraded by a reaction following second order kinetics. Stock solutions of 1% (60 mM) ALA were incubated at 50 degrees C. At pH 2.35, ALA was stable during the whole incubation period (37 days). The half-lives for the second-order decomposition of 1% ALA at pH 4.81 and 7.42 were 257 and 3.0 h, respectively. The degradation rate increased about 1.5 times with each 10 degrees C rise in temperature at pH 7.53 within the range studied (37-85 degrees C). The energy of activation, Ea, for the second-order decomposition of ALA was 43.7 kJmol-1. EDTA did not influence the degradation of ALA when a mixture of 1% ALA and 1% EDTA was incubated at pH 7.42.

Aminolevulinic Acid↗

PubMed1999

Neuropeptide Y response to tracheal intubation in anaesthetized children: effects of clonidine vs midazolam as premedication.

We have determined if tracheal intubation causes an increase in neuropeptide Y (NPY), a marker of major adrenergic activation, and investigated if rectal premedication with clonidine 2.5 micrograms kg-1 might be capable of attenuating the stress response to tracheal intubation compared with midazolam 300 micrograms kg-1, in 20 paediatric patients (1-9 yr). Prospective randomization was performed in a double-blind manner. After induction of anaesthesia with 1% isoflurane, tracheal intubation was performed, and norepinephrine, NPY concentrations and haemodynamic variables were recorded. Tracheal intubation did not increase NPY plasma concentrations, despite transient increases in norepinephrine concentrations, heart rate and arterial pressure. There was no significant difference between the two groups. We conclude that the adrenergic stress reaction in response to tracheal intubation in children was short-lived and of limited magnitude, as indicated by the lack of NPY release.

Adrenergic alpha-Agonists↗

PubMed1999

In vitro cellular accumulation and cytotoxicity of liposomal and conventional formulations of daunorubicin and doxorubicin in resistant K562 cells.

Previous investigations have indicated the possibility to circumvent multidrug resistance (MDR) by incorporation of an anthracycline into liposomes. We examined the in vitro cytotoxicity and cellular drug accumulation of the anthracyclines daunorubicin and doxorubicin compared with the commercially available liposomal formulations DaunoXome and Caelyx in human myelogenous leukemia K562 cells. The drug-sensitive parental K562/K line was compared with the P-glykoprotein (P-gp)-expressing cell lines K562/Dnr and K562/Vcr. Two cell lines with reduced levels of topoisomerase II (K562/Nov and K562/Ida) were also included. The cytotoxicity was determined by fluorometric microculture cytotoxicity assay and the cellular drug levels were determined by high performance liquid chromatograghy. There was a strong inverse correlation between P-gp levels and cellular drug accumulation (rho = -0.83, p = 0.04) and cytotoxicity (rho = -0.95, p = 0.01) of daunorubicin. Also the cytotoxicity of DaunoXome and doxorubicin was related to P-gp levels (rho = -0.96, p = 0.01 and rho = -0.90, p = 0.07, respectively). Caelyx did not show any cytotoxic effect due to impaired cellular uptake of the pegylated liposome. Regardless of the P-gp levels of the treated cells, DaunoXome showed the same cytotoxic effect despite lower intracellular accumulation (range 22-47%), compared with conventional daunorubicin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

A randomized trial on effects of hormone therapy on ambulatory blood pressure and lipoprotein levels in women with coronary artery disease.

OBJECTIVE: To investigate 1-year effects of hormone replacement therapy (HRT) on ambulatory blood pressure (ABP) and lipoprotein levels in postmenopausal women with coronary artery disease (CAD). METHODS: Sixty patients at a mean age (+/- SD) of 59 +/- 7 years were randomized into three groups: conjugated equine oestrogens (CEE) 0.625 mg daily (n = 20), 50 microg 17beta-oestradiol transdermally (TTSE) per 24 h (n = 20) or placebo (n = 20) for 18 days, then combined with medroxyprogesterone acetate 5 mg for 10 days. Each cycle of 28 days was repeated for one year. RESULTS: Night-time systolic ABP had decreased by 9.6% (P= 0.0075) in 15 of 18 women in the CEE group and by 22% in 12 of 13 women (P = 0.0034) in the placebo group after 1 year. In the CEE group, a 4.6% rise in daytime systolic ABP (P< 0.05) and a 4.2% rise in night-time systolic ABP (P< 0.05) appeared from baseline to 6 months in 13 of 18 women. In the CEE group (14 women analysed), high-density lipoprotein levels showed a 15.8% increase (P= 0.0018) in 13 women, low-density lipoprotein levels a 15.2% decrease (P= 0.0129) in 12 women and total cholesterol levels a 7.5% decrease (P = 0.057) in 11 women after 1 year. Triglyceride levels showed no changes. In the TTSE group and in the placebo group, with 12 and 13 women analysed respectively, no significant changes appeared. CONCLUSIONS: One year of HRT in patients with CAD does not influence ABP. Oral HRT induces beneficial effects on lipoprotein levels.

Adult↗

PubMed1998

Pharmacokinetics and effects of intravesical oxybutynin on the paediatric neurogenic bladder.

OBJECTIVE: To evaluate the pharmacokinetics of both oxybutynin and its active metabolite, N-desethyl oxybutynin (NDO), when the drug is instilled directly into the bladder in children with myelodysplasia and neurogenic bladder disturbance, in whom it may improve continence and decrease the risk of upper urinary tract deterioration. PATIENTS AND METHODS: The study comprised 13 children (five girls and eight boys, mean age 9.3 years, range 1-15) with neurogenic bladders who were treated using clean intermittent catheterization and intravesical instillation of a sterile, pharmacy-produced solution of oxybutynin. Steady-state minimum plasma levels of oxybutynin and NDO, together with their effect on urodynamic variables and incontinence, were evaluated. The dose (0.04-0.17 mg/kg, mean 0.1 mg/kg) was instilled twice daily. RESULTS: The effects of the drug on incontinence and urodynamic variables were pronounced, improving both in most cases. Minimum plasma levels were < 0.3-7.2 ng/mL for oxybutynin and 0.8-14 ng/mL for NDO. The ratio of oxybutynin to NDO was 0.29-0.83 (mean 0.47). CONCLUSION: There was no clear relationship between minimum plasma levels of the drug or NDO and their clinical effects; however, the combination of oxybutynin and NDO seemed to be more strongly correlated with the clinical effects.

Administration, Intravesical↗

PubMed1998

Does sublingual 17 beta-oestradiol have any effects on exercise capacity and myocardial ischaemia in post-menopausal women with stable coronary artery disease?

BACKGROUND: A variety of vascular effects have been ascribed to 17 beta-oestradiol. These effects may partially explain the reduced incidence of cardiovascular disease found in post-menopausal women on oestrogen replacement therapy. OBJECTIVES: To evaluate the effects of 2 mg sublingual 17 beta-oestradiol on exercise capacity, exercise-induced myocardial ischaemia and circulating levels of endothelin-1 in post-menopausal women with stable coronary artery disease. METHODS: Twelve post-menopausal women, mean age 61 (range 52-72) years, with angiographically verified significant coronary artery disease, were randomly assigned to 2 mg of sublingual 17 beta-oestradiol, 2.5 mg of buccal nitroglycerine and to placebo in a double-blind cross-over study design with at least 2 days between each of the study arms. Antianginal medications, with the exception of beta-blockers, were discontinued before investigation. All study patients underwent a maximal bicycle exercise test 30 min after drug intake. Blood was withdrawn immediately before and up to 8 h after medication for analyses of circulating levels of oestradiol and endothelin-1. RESULTS: The mean serum levels of oestradiol increased from a control level of 72 +/- 28 pmol.l-1 to 3557 +/- 1731 pmol.l-1 after 30 min and to 5028 +/- 3971 pmol.l-1 after 60 min with a gradual decline thereafter. Sublingual 17 beta-oestradiol did not induce any improvement in exercise duration when compared with nitroglycerin and placebo (500 +/- 112 s, 505 +/- 107 s, 498 +/- 157 s), and did not influence time to onset of ST-segment depression (358 +/- 89 s, 436 +/- 93 s, 384 +/- 116 s). The plasma levels of endothelin-1 did not change after administration of 17 beta-oestradiol, nitroglycerin or placebo. CONCLUSIONS: No effects of exercise capacity, exercise-induced acute ischaemia, or plasma levels of endothelin-1 were found after a single dose of 2 mg 17 beta-oestradiol in post-menopausal women with documented coronary artery disease.

Administration, Sublingual↗

PubMed1998

Plasma levels of clonidine following epidural bolus injection in children.

BACKGROUND: The use of clonidine as an adjunct to epidural administration of local anesthetics in children has been reported to substantially improve the duration and quality of postoperative analgesia. The aims of the present study were to determine the pharmacokinetic profile and to investigate the interaction between postoperative sedation and analgesia after epidurally administered clonidine in children. METHODS: Plasma levels of clonidine (0-10 h postop) and assessment of postoperative analgesia and sedation (0-24 h postop) were performed at predetermined intervals following lumbar epidural administration of bupivacaine 2.0 mg/kg and clonidine 2 mg/kg in 8 children undergoing ureteral re-implantation surgery using general anesthesia (age range: 1-9 yr, weight range: 9-41 kg). Plasma levels of clonidine were analyzed by radioimmunoassay, and sedation and analgesia were assessed by previously described scoring systems. RESULTS: The venous plasma pharmacokinetics of clonidine following epidural administration showed a considerable interindividual variation. Cmax and Tmax values of clonidine were found to be within the 0.45-0.77 ng/mL and 48-193 min range, respectively. The time to absorb 95% of the clonidine dose from the epidural space into plasma varied between 36 min and 7.6 h. In 6 of the 8 patients postoperative analgesia substantially outlasted the duration of sedation (> or = 2 h). Sedation could not be detected in any patients at plasma concentrations below 0.3 ng/mL. CONCLUSIONS: The pharmacokinetic profile associated with epidural clonidine administration in children (1-9 y) was similar to that previously reported in adults. The postoperative analgesia seen after administration of epidural bupivacaine-clonidine during general anesthesia in children cannot only be explained by residual postoperative sedation.

Adrenergic alpha-Agonists↗

PubMed1998

Follow-up of long-time treatment with intravesical oxybutynin for neurogenic bladder in children.

OBJECTIVE: Anticholinergic treatment for the hyperreflexic neurogenic bladder in childhood is an established method, together with clean intermittent catheterization (CIC), to promote continence and protect the upper urinary tract from deterioration. Recently, the use of oxybutynin, a compound with anticholinergic, smooth muscle relaxant and local anesthetic effects, has become widely used with both oral and intravesical administration. METHOD: In this study we report 39 children with myelodysplasia, neurogenic bladder disturbance with detrusor hyperreflexia and/or high bladder pressure treated with CIC to which intravesical oxybutynin 0.1 mg/kg twice daily was added and administered as a sterile pharmacy-produced solution. The follow-up period was 0.66-5 years (mean 2.25). RESULTS: Continence was clearly promoted and urodynamic parameters improved whereas an increased occurrence of asymptomatic bacteriuria and lower urinary tract infections was noted. Compliance was good, adverse reactions rare, and in some cases vesicoureteral reflux (VUR) resolved. Also infants and very young children were treated without complications. CONCLUSIONS: Intravesical oxybutynin is effective to diminish bladder pathophysiology and promote continence in this patient group and is also well tolerated. Attention should be paid to the occurrence of urinary tract infections and VUR may resolve.

Administration, Intravesical↗

PubMed1997

Pharmacokinetics of doxorubicin and epirubicin in mice during chlorpromazine-induced hypothermia.

Blood concentrations of doxo- and epirubicin were studied in mice after i.v. or i.p. administration under normal and hypothermic conditions. The animals either were pretreated i.p. with chlorpromazine at 15 mg/kg and allowed to cool to a rectal temperature of 28 degrees C or were given saline i.p. with their rectal temperature remaining at 37 degrees C. The anthracyclines were 14-14C-labeled and were given at a dose of 0.85 mg/kg. Blood samples were taken at 5, 15, and 25 min and 2, 6, 24, and 48 hours after injection and were analyzed by liquid scintillation counting. The blood concentration related to time was similar for the two anthracyclines. The peak concentration was highest for i.v. administration and was higher for the hypothermic groups. The peak concentration and the area under the curve were highest under hypothermic conditions. The terminal half-life was longer after i.p. administration. The ratio calculated for the blood concentration under hypothermic/normothermic conditions over time was substantially increased after i.p. administration, the increase being most pronounced for epirubicin. The pharmacokinetic characteristics found might be related to the anthracycline toxicity encountered in tumor-inoculated mice treated at different body temperatures.

Animals↗

PubMed1997

Plasma pharmacokinetics of idarubicin and its 13-dihydro metabolite--a comparison of bolus versus 2 h infusion during a 3 day course.

The plasma pharmacokinetics of a second generation anthracycline derivative, idarubicin (Ida), have been studied in 17 patients with acute myelocytic leukemia (AML) and high risk features. The drug (10 mg/m2) was given in a randomized cross-over design as 3 min and 2 h infusions for three consecutive days. Cytosine arabinoside (Ara-C, 1 g/m2) was given on days 1-4. The plasma concentration time course of Ida was most properly described by the three-compartment pharmacokinetic model, independent of administration time. The maximum plasma concentration (Cmax) of Ida was reduced by a factor of 3 by increasing the infusion time from 3 min to 2 h. The pharmacokinetic pattern of the active metabolite idarubicinol (IdaOH) was only to a minor extent affected by the longer infusion time. The time course of IdaOH following each dose of Ida was accurately described by the one-compartment model with a first-order formation phase. The are under the plasma concentration versus time curves (AUC) of Ida and IdaOH were not affected by the administration time. Following Ida in combination with Ara-C, the medial duration of leukopenia (< 1.0 x 10(9)/l) was 14 days (range 5-56) and of thrombocytopenia (< 50 x 10(9)/l) was 22 days (range 7-120). The large majority of patients developed infectious complications. Two patients with MDS-AML showed a good response. The results of the present study give no evidence of reduced hematologic toxicity by increasing the administration time of Ida from 3 min to 2 h. However, minimizing Cmax, by administration of Ida as prolonged infusion during a 3 day course, might be clinically important in order to reduce cardiotoxicity and hopefully to increase anti-tumor efficacy through an increased accumulation of Ida and IdaOH in leukemic cells.

Aged↗

PubMed1997

Low-dose intravenous clonidine in children: plasma concentrations and haemodynamic response.

The beneficial perioperative effects of the alpha-2 agonist clonidine have recently been verified in paediatric patients, and the pharmacokinetics have been found to be similar to what has been reported in adults. In a previous study we found that 2.5 micrograms/kg of clonidine causes a significant reduction in blood pressure. The aim of the present study was to evaluate if even lower doses of clonidine are associated with dose dependent or plasma-dependent haemodynamic changes. In a prospective, single, blind, controlled clinical trial, 24 paediatric patients (age range: 13-78 months) were randomised into three groups: control, intravenous clonidine 0.625 microgram/kg and intravenous clonidine 1.25 micrograms/kg respectively. Non-invasive blood pressure and heart rate were recorded at 3-min intervals for 30 min. Plasma concentrations of clonidine were analysed at 15 and 30 min post-injection. A decrease in MABP compared to baseline values was observed in all groups. A significantly greater reduction in blood pressure was seen in all groups receiving clonidine compared to control. In conclusion, low doses of clonidine (0.625 and 1.25 micrograms/kg) were found capable of causing a blood pressure reduction compared to control. We could not establish a plasma concentration dependent blood pressure effect. The observed blood pressure reductions caused by clonidine were of moderate magnitude. No effect on heart rate was observed, a finding which most likely is explained by the inclusion of atropine in the premedication.

Adrenergic alpha-Agonists↗

PubMed1996

Methotrexate plasma pharmacokinetics: importance of assay method.

Intravenous methotrexate (MTX) therapy is widely used for treatment of various neoplastic diseases in children. The optimization of the MTX dose and/or the subsequent leucovorin rescue is based on pharmacokinetic data calculated from plasma concentrations collected after cessation of the MTX administration. The influence of the MTX assay method on the subsequent pharmacokinetic evaluation was studied in 13 children with acute lymphoblastic leukemia. Plasma samples were collected after administration of MTX (5-8 g/m2) as 24 h infusions. All samples were analyzed by five different analytical procedures, viz. liquid chromatography (LC), enzyme inhibition assay (EIA), two fluorescence polarization immunoassays (FPIA1 and FPIA2) and enzyme multiplied immunoassay (EMIT). Using measurements from the four non-chromatographic procedures, only about 50% of determined pharmacokinetic parameters (area under the plasma concentration time curve, calculated by the trapezoidal rule and from pharmacokinetic modelling, and the terminal half life time) were within the range 75-125% of the values obtained from LC data. We conclude that the clinical outcome of MTX therapy using estimated MTX pharmacokinetics as guidelines for proper dosing of MTX and/or leucovorin rescue might be affected by the lack of accuracy of non-chromatographic procedures for MTX analysis. There is still a need for improving the accuracy of the procedures aimed at therapeutic drug monitoring of MTX.

Adolescent↗