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Biomedical subjects

P Jakobsen

Publications and source records attributed to P Jakobsen.

At least 19 recordsLinked to original sources
PubMed2006

Effect of the oral hypoglycaemic sulphonylurea glibenclamide, a blocker of ATP-sensitive potassium channels, on walking distance in patients with intermittent claudication.

AIMS: The oral hypoglycaemic sulphonylurea glibenclamide stimulates endogenous insulin secretion through blockade of ATP-sensitive potassium (KATP) channels on pancreatic beta cells, but also blocks cardiovascular KATP channels, leading to increased peripheral vascular resistance and reduced peripheral blood flow in non-diabetic subjects. Therefore, this study examined whether a single oral dose of glibenclamide adversely affected the pain-free or maximal walking distance in patients with intermittent claudication. METHODS: In a double-blind, randomized crossover study, 12 non-diabetic patients with intermittent claudication were given a single oral dose of glibenclamide (5.25 mg) or placebo separated by a washout period of 1 week. A treadmill test was carried out 180 min after glibenclamide/placebo intake for determination of pain-free and maximal walking distance. Plasma glucose concentrations were kept constant by an euglycemic clamp. Changes in ankle/brachial blood pressure index (ABI), serum insulin, and serum glibenclamide were also assessed. RESULTS: The pain-free walking distance was 62.8 +/- 9.8 metres (mean +/- sem) after glibenclamide and 52.6 +/- 5.9 metres after placebo (P = 0.52). The maximal walking distance was 142.7 +/- 18.7 metres after glibenclamide and 132.6 +/- 16.6 metres after placebo (P = 0.23). The ABI was not significantly changed by glibenclamide compared with placebo. Serum glibenclamide was 0.51 +/- 0.08 microm 180 min after administration of the drug. Glibenclamide produced an 8-fold increase in circulating insulin compared with placebo (P < 0.001). CONCLUSIONS: Glibenclamide given as a single oral dose commonly used in glucose-lowering drug therapy does not reduce pain-free or maximal walking distance in non-diabetic patients with intermittent claudication.

Adenosine Triphosphate↗
PubMed2002

Identification of two novel and potent competitive inhibitors of the glucose-6-phosphatase catalytic protein.

AIM: In this study, we show that inhibitors of the glucose-6-phosphatase (G-6-Pase) catalytic protein could be an alternative approach to the recent G-6-Pase T1-translocase inhibitors to target this enzyme for the treatment of type 2 diabetes. METHOD: The active enantiomers of 4-methoxyphenyl-[4-(4-methoxyphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl]methanone (Compound A-1) and 4-methoxyphenyl-[4-(4-trifluoromethoxyphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl]methanone (Compound B-1) were characterized as inhibitors of the G-6-Pase catalytic protein using pig and rat liver microsomes and cultured rat hepatocytes. RESULTS: Both compounds were found to be potent competitive inhibitors of the G-6-Pase catalytic protein obtained from pig and rat liver microsomes. The K(i) values (microM) were calculated to be 0.61 +/- 0.02 and 0.63 +/- 0.08 for compound A-1 and B-1 on intact pig microsomes, and 0.27 +/- 0.02 and 0.29 +/- 0.06 on disrupted pig microsomes. The corresponding values for rat liver microsomes were found to be 3.3 +/- 0.6 and 4.0 +/- 1.2 for compound A-1 and B-1 on intact microsomes, and 1.54 +/- 0.1 and 1.21 +/- 0.1 on disrupted microsomes. Compound A-1 was also able to inhibit pyrophosphatase activities from both intact and disrupted microsomes with equal potency (IC50; 0.43-0.55 microm). Using cultured rat hepatocytes and glycerol as the substrate, these compounds were able to prevent glucose production up to 60% with a concomitant increase in the G-6-P content (2.3-fold) using compound A-1. No increase in glycogen levels was seen. CONCLUSION: These data demonstrated that these compounds were more potent inhibitors on G-6-Pase obtained from pig microsomes and were able to penetrate the microsomal membrane. The hepatocyte data further support the kinetic data, and are also consistent with the evoked mechanism of action.

Animals↗
PubMed2001

Novel anionic annelation tactics for construction of fused heteroaromatic frameworks. 1. Synthesis of 4-substituted pyrazolo[3,4-c]quinolines, 9-substituted pyrazolo[3,4-c]quinolines, and 1,4-dihydrochromeno[4,3-c]pyrazoles.

4-Substituted pyrazolo[4,3-c]quinolines 4a-i and 6a-b were prepared from pyrazole 3 whereas 9-substituted pyrazolo[3,4-c]quinolines 9a-d and 17 were prepared from pyrazole 13 utilizing anionic annelation techniques. 1,4-dihydrochromeno[4,3-c]pyrazoles 7a-c were accessed from pyrazole 3, extending the method for the synthesis of 4a-i.

Journal Article↗
PubMed2001

Pharmacokinetics of Erwinia asparaginase after intravenous and intramuscular administration.

PURPOSE: To describe the pharmacokinetics of Erwinia asparaginase (ASNase) after intravenous (i.v.) and intramuscular (i.m.) administration. METHODS: A group of 29 children with newly diagnosed acute lymphoblastic leukemia (ALL) received Erwinia ASNase 30,000 IU/m2 every day for 10 days during multiagent induction therapy. Of these patients. 13 received i.v. therapy and 16 received i.m. therapy. During the reinduction phase the patients received Erwinia ASNase 30,000 IU/m2 twice a week for 2 weeks (Mondays and Thursdays) (8 patients in the i.v.-treated group and 11 patients in the i.m.-treated group). ASNase activity (spectrophotometric assay) was measured in plasma samples obtained from the patients at various times during therapy. RESULTS: The estimated half-life was 6.4 +/- 0.5 h (n = 13), the absorption rate after i.m. administration was found to limit elimination. The apparent volume of distribution corresponded well with the volume of plasma. The estimated clearance suggested that Erwinia ASNase is a low-clearance drug. Bioavailability after i.m. administration was (mean +/- SEM) 27.0 +/- 4.5% (range 11-61%; n = 12). CONCLUSIONS: In this study the pharmacokinetic parameters after i.v. and i.m. administration of Erwinia ASNase were determined based on a substantial number of patients. The present findings emphasize the importance of conducting proper pharmacokinetic studies before a new drug or a new preparation of a drug is introduced in a different schedule.

Adolescent↗
PubMed2001

Iminosugars: potential inhibitors of liver glycogen phosphorylase.

The first synthesis of the single isomers (3R,4R,5R); (3S,4S,5S): (3R,4R,5S) and (3S,4S,5R) of 5-hydroxymethyl-piperidine-3,4-diol from Arecolin is reported, including the synthesis of a series of N-substituted derivatives of the (3R,4R,5R)-isomer (Isofagomine). The inhibitory effect of these isomers as well as of a series of N-substituted derivatives of the (3R,4R,5R)-isomer and selected hydroxypiperidine analogues on liver glycogen phosphorylase (GP) showed that the (3R,4R,5R) configuration was essential for obtaining an inhibitory effect at submicromolar concentration. The results also showed that all three hydroxy groups should be present and could not be substituted, nor were extra OH groups allowed if sub-micromolar inhibition should be obtained. Some inhibitory effect was retained for N-substituted derivatives of Isofagomine; however, N-substitution always resulted in a loss of activity compared to the parent compound, IC50 values ranging from 1 to 100 microM were obtained for simple alkyl, arylalkyl and benzoylmethyl substituents. Furthermore, we found that it was not enough to assure inhibitory effect to have the (R,R,R) configuration. Fagomine, the (2R,3R,4R)-2-hydroxymethylpiperidine-3,4-diol analogue, showed an IC50 value of 200 microM compared to 0.7 microM for Isofagomine. In addition, Isofagomine was able to prevent basal and glucagon stimulated glycogen degradation in cultured hepatocytes with IC50 values of 2-3 microM.

Animals↗
PubMed2001

Application of enzymatically stable dipeptides for enhancement of intestinal permeability. Synthesis and in vitro evaluation of dipeptide-coupled compounds.

Transport across the intestinal barrier of compounds with low permeability may be facilitated by targeting the human oligopeptide transporter, hPepT1. A flexible synthetic pathway for attaching compounds to dipeptides through ester or amide bonds was developed. Furthermore, a synthetic approach to functionalize model drugs from one key intermediate was generated and applied to a glucose-6-phosphatase active model drug. The model drug was coupled to D-Glu-Ala through various linkers, and the G-6-Pase activity as well as the aqueous solubility and transport properties of these prodrugs, as compared to those of the parent drugs, were examined. None of the peptide-coupled compounds seemed to be transported by hPepT1, though one of the peptide-coupled compounds had affinity for hPepT1. Interestingly, in one case the parent drug was actively effluxed, while the corresponding peptide-coupled prodrug was not. The low aqueous solubility of the parent compounds was not increased after attachment to a dipeptide. This suggests that only compounds with a certain intrinsic aqueous solubility should be targeted to hPepT1 by attachment to a dipeptide. Important information about the design of peptide-coupled drugs targeted for hPepT1 is presented.

Benzyl Alcohols↗
PubMed2001

Monitoring of Erwinia asparaginase therapy in childhood ALL in the Nordic countries.

AIMS: Evaluation of L-asparaginase therapy in the NOPHO-92 ALL-protocol (treatment protocol of acute lymphoblastic leukaemia of the Nordic Society of Paediatric Haematology and Oncology, initiated in 1992) after intravenous and intramuscular administration of Erwinia asparaginase during induction and re-induction therapy. METHODS: Forty children with newly diagnosed acute lymphoblastic leukaemia received Erwinia asparaginase (30 000 IU/m2 i.v. or i.m.) during induction therapy (every day for 10 days), and 19 children received Erwinia asparaginase (30 000 IU/m2 i.v. or i.m.) during re-induction therapy (twice a week for 2 weeks). Within the treatment periods asparaginase trough activity (using a spectrophotometric assay) was determined on specific days. The goal of therapy is complete L-asparagine depletion, which asparaginase activities above 100 IU l(-1) have been shown to ensure. Therefore determination of L-asparagine (using a h.p.l.c. method) was performed only in plasma samples with asparaginase activities below 100 IU l(-1). RESULTS: During induction therapy 92.2% of the trough enzyme activities were above 500 IU l(-1) for the i.v.-treated patients, and 92.4% of the trough enzyme activities were above 500 IU l(-1) for the i.m.-treated patients. During re-induction therapy 64.7% of the trough enzyme activities were below 100 IU l(-1) in the i.v.-treated group, and 73.3% of the trough enzyme activities were below 100 IU l(-1) in the i.m.-treated group. For trough enzyme activities below 100 IU l(-1) L-asparagine depletion was complete in two thirds of the samples. CONCLUSIONS: In the NOPHO-92 ALL-protocol L-asparaginase treatment during induction therapy was unnecessarily intense, but during the re-induction phase it appeared inadequate.

Adolescent↗
PubMed2001

Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system.

Asparaginase comes from different biological sources and the various preparations have different pharmacokinetic properties, and their tendency to induce side-effects is different. Erwinia asparaginase (ASNase) has a shorter half-life than the Escherichia coli preparations, and it has been reported to be less immunogenic than the E. coli preparations and to induce fewer coagulation disorders. Children with newly diagnosed acute lymphoblastic leukaemia (ALL) were included in this study. Twenty-seven patients were treated with Erwinia ASNase (induction therapy 30.000 IU/m2/d i.m. for 10 d, and re-induction therapy 30.000 IU/m2 twice a week for 2 weeks) and 15 were treated with ASNase Medac (induction therapy 1.000 IU/m2/d i.m. for 10 d, and re-induction therapy 5.000 IU/m2 i.m. twice a week for 2 weeks). Blood samples were drawn to determine enzyme activity, l-asparagine, anti-asparaginase antibodies, and coagulation parameters. After i.m. administration, Erwinia ASNase displayed a protracted absorption phase compared to ASNase Medac. The mean bioavailability after i.m. administration was 27% for Erwinia ASNase and 45% for ASNase Medac respectively. Mean trough enzyme activities during induction therapy were Erwinia ASNase 1748 IU/l and ASNase Medac 272 IU/l, and during re-induction therapy Erwinia ASNase 83 IU/l and ASNase Medac 147 IU/l. We conclude that in this setting, therapy with ASNase Medac resulted in sufficient treatment during both phases of therapy, whereas treatment with Erwinia ASNase resulted in unnecessarily intense therapy during the induction phase and insufficient treatment during the re-induction phase. There was no significant difference in the incidence of antibody formation, and therapy with Erwinia ASNase resulted in a more pronounced influence on the coagulation parameters than therapy with ASNase Medac.

Absorption↗
PubMed2000

Synthesis of 1-hydroxy-substituted pyrazolo[3,4-c]- and pyrazolo[4, 3-c]quinolines and -isoquinolines from 4- and 5-aryl-substituted 1-benzyloxypyrazoles.

1-Hydroxypyrazolo[3,4-c]quinoline (22), 1-hydroxypyrazolo[4, 3-c]quinoline (21), 1-hydroxypyrazolo[3,4-c]isoquinoline (20), and 1-hydroxypyrazolo[4,3-c]isoquinoline (19) were prepared from 1-benzyloxypyrazole (6), establishing the pyridine B-ring in the terminal step. The pyridine ring of pyrazoloquinolines 14 and 18 was formed via cyclization of a formyl group at C-4 or C-5 and an amino group of a 2-aminophenyl substituent at C-5 or C-4 in 1-benzyloxypyrazole. The pyridine ring of pyrazoloisoquinolines 5 and 9 was created via cyclization of a formyl group in a 2-formylphenyl substituent at C-4 or C-5 with an iminophosphorane group installed at C-5 or C-4 of 1-benzyloxypyrazole by lithiation followed by reaction with tosyl azide and then with tributylphoshine utilizing the Staudinger/aza-Wittig protocol. The 2-aminophenyl and the 2-formylphenyl substituent were introduced at C-5 or C-4 by regioselective metalation followed by transmetalation to the pyrazolylzinc halide and subsequent palladium-catalyzed cross-coupling with 2-iodoaniline or 2-bromobenzaldehyde. The order of reactions and use of protecting groups in the individual sequences have been optimized. The 1-benzyloxy-substituted pyrazoloquinolines and isoquinolines thus obtained were debenzylated by strong acid to the corresponding 1-hydroxy-substituted pyrazoloquinolines and isoquinolines 19-22.

Indicators and Reagents↗
PubMed2000

Studies on concentration-time profiles of nimodipine enantiomers following intravenous and oral administration of nimodipine in patients with subarachnoid hemorrhage.

After i.v. and oral administration of nimodipine the concentration-time profiles of the drug and its enantiomers were studied in seven patients with subarachnoid hemorrhage. Concentrations of nimodipine, (+)-(R)-, and (-)-(S)-nimodipine were analyzed using a new stereoselective high-performance liquid chromatographic method. During the first 3 h after oral administration the concentrations of (+)-(R)- and (-)-(S)-nimodipine were significantly different, the (-)-(S)-enantiomer being found in much lesser concentrations compared to the (+)-(R)-enantiomer. The results indicate that if uptake from the gastrointestinal system is equal for the two enantiomers, then (-)-(S)-nimodipine is metabolized at a much faster rate compared to (+)-(R)-nimodipine after oral administration of the drug in patients with subarachnoid bleeding. After i.v. administration; no significant differences between the concentrations of the (-)-(S) and the (+)-(R) isomers were demonstrated.

Administration, Oral↗
PubMed2000

Inhibitors of the tissue factor/factor VIIa-induced coagulation: synthesis and in vitro evaluation of novel specific 2-aryl substituted 4H-3,1-benzoxazin-4-ones.

The synthesis of a series of novel 2-aryl substituted 4H-3,1-benzoxazin-4-ones and their evaluation as specific inhibitors of the Tissue Factor (TF)/Factor VIIa (FVIIa)-induced pathway of coagulation is reported. Inhibitory activities (IC50 values) in the range 0.17 to > 40 microM on the activation of Factor X (FX) by the TF/FVIIa complex were found for compounds having one or two electronegative substituents such as F, Cl and NO2 in the 2-aryl substituent. Different substitutions both electron-attracting and donating groups were allowed in the 5, 6, 7 and 8 positions. Several of the compounds showed a selectivity ratio towards FX and thrombin of > 50, thus being the first small molecules described as potential drugs for oral antithrombotic treatment without side effects such as bleeding which is observed especially with thrombin inhibitors. The best substituent pattern being the 2-aryl group substituted with: 2-F; 2,6-F2; or 2-FX; 6-Cl; together with electronegative substitution in the 5, 6, 7, or 8 positions. 2-Heteroaryl substituents like thienyl and furanyl were of low activity while some 2-(2-chloro-3-pyridyl) derivatives had inhibitory activity < 10 microM and a good selectivity.

Animals↗
PubMed2000

Glucose-6-phosphatase catalytic enzyme inhibitors: synthesis and in vitro evaluation of novel 4,5,6,7-tetrahydrothieno[3,2-c]- and -[2,3-c]pyridines.

The discovery of the first class of potent glucose-6-phosphatase catalytic site inhibitors, substituted 4,5,6,7-tetrahydrothieno[3,2-c]- and -[2,3-c]pyridines, is described. Optimisation of this series involved solution phase combinatorial synthesis and very potent compounds were prepared with IC50 values down to 140 nM. The structure activity relationship (SAR) of these compounds indicates that: a tetrahydrothieno[3,2-c]pyridine core ring system and the isomeric [2,3-c] system are equipotent and much better than the corresponding benzo analogue, 1,2,3,4-tetrahydro-isoquinoline. The 4-substituent of the tetrahydrothieno[3,2-c]pyridine ring has to be a phenyl group, optionally substituted with a lipophilic 4-substituent, such as trifluoromethoxy or chloro. The 5-substituent of the tetrahydrothieno[3,2-c]pyridine ring has to be a substituted benzoyl; anisoyl and (E)-3-furan-3-ylacryloyl are the best of the investigated groups. Substitution in the benzoyl ortho position seems to be forbidden, whereas substitution in the meta position is tolerated only if a methoxy para substituent is present. These SAR findings were parallel to those obtained in the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine system. Enantioselectivity in enzyme recognition was observed and the activity resided in all cases only in one of the enantiomers.

Animals↗
PubMed2000

Inhibitors of the tissue factor/factor VIIa-induced coagulation: synthesis and in vitro evaluation of novel 2-aryl substituted pyrid.

The synthesis of a series of 2-aryl substituted hetero annulated 1,3-oxazin-4-ones and their evaluation as specific inhibitors of the tissue factor (TF)/factor VIIa (FVIIa)-induced pathway of coagulation is reported. Inhibitory activities (IC50 values) in the range 0.64 to > 40 microM on the activation of factor X (FX) by the TF/FVIIa complex were found for compounds having one or two electronegative substituents such as F and NO2 in the 2-aryl substituent. Some of the compounds showed a selectivity ratio towards FX and thrombin of > 50, thus being similar in specificity to 2-aryl substituted 4H-3,1-benzoxazin-4-ones described as potential drugs for oral antithrombotic treatment without side effects, such as bleeding, which is observed especially with thrombin inhibitors.

Anticoagulants↗
PubMed2000

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.

Acitretin↗
PubMed1997

The pharmacokinetics of octreotide in cirrhosis and in healthy man.

BACKGROUND/AIM: The aim of the study was to evaluate the pharmacokinetics of octreotide in patients with cirrhosis compared to healthy volunteers. METHODS: Seventeen patients with cirrhosis and nine normals received an intravenous bolus of octreotide (0.75 microgram/kg), followed by a continuous infusion of 0.75 microgram.kg-1.h-1 for 12 h. Eight patients were decompensated with ascites, while nine were without signs of decompensation. Serum octreotide levels were followed by blood sampling during the infusion period and for 24 h afterwards. RESULTS: The average clearance (+/-SEM) was 151 +/- 15 ml/min in normals compared to 102 +/- 9 (p < 0.05) and 105 +/- 9 (p < 0.05) in patients with compensated and decompensated cirrhosis, respectively. The average area under the serum octreotide curve was significantly increased by 53% (p < 0.05) in decompensated and 46% (p < 0.05) in compensated cirrhosis compared to healthy volunteers, while no difference was observed between the groups with cirrhosis. This difference was also reflected by an increased maximum serum concentration during the infusion period of 9797 +/- 580 ng/l in the patients with cirrhosis compared to 7081 +/- 547 ng/l (p = 0.006) in normals. The serum half-life for the beta-phase (T1/2 beta) was 165 +/- 26 min in normals, 200 +/- 21 min in the compensated and 216 +/- 26 min in the decompensated group (NS). The volume of distribution (Vd beta) showed no difference between the three groups. Because of the slow equilibration between plasma and ascitic fluid in decompensated cirrhosis, the calculated clearance may have been overestimated and T1/2 beta and Vd beta underestimated in these patients. CONCLUSIONS: The present study demonstrates that the pharmacokinetics of octreotide in cirrhosis is substantially different from that found in normals.

Adult↗
PubMed1997

Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study.

PURPOSE: To elucidate the effect of a doubled carboplatin dose-intensity in epithelial ovarian cancer in combination with a fixed dose of cyclophosphamide. PATIENTS AND METHODS: A total of 222 patients with epithelial ovarian cancer stages II to IV were included in the study. Following surgery, patients were randomly assigned to receive carboplatin at an area under the concentration-versus-time curve (AUC) of 4 (AUC4) or carboplatin at an AUC of 8 (AUC8) and cyclophosphamide 500 mg/m2 given every 4 weeks for six courses. The AUC was calculated according to Calvert's formula. In 123 patients, the carboplatin AUC was also measured based on a single-sample method and the results were compared with the calculated AUC. The end points of the trial were complete pathologic remission (CPR) and crude survival. RESULTS: Approximately 50% of patients in both arms underwent second-look surgery. The frequency of CPR was 32% and 30%, respectively. The survival curves showed no significant difference (P = .84). The dose-intensity of cyclophosphamide was almost identical in the two arms, whereas that of carboplatin was different. In the AUC8 arm, the dose-intensity was 1.86 times that of the AUC4 arm. The results also demonstrated good agreement between the calculated and the measured AUC in most patients. Bone marrow toxicity was significantly higher in the AUC8 arm. CONCLUSION: A doubling of the carboplatin dose-intensity did not result in any significant improvement of pathologic remission or survival. Calvert's formula can be used to give a fairly accurate estimate of the carboplatin AUC. Bone marrow toxicity increased with higher dose-intensity, and a further increase of dose is only feasible with growth-factor or stem-cell support.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group.

PURPOSE: To test for possible correlations between dose of single-drug epirubicin and efficacy/toxicity in postmenopausal women with metastatic breast cancer. The study also included analysis of a correlation between pharmacokinetic and pharmacodynamic parameters. PATIENTS AND METHODS: Two hundred eighty-seven women were randomized to receive either 40, 60, 90, or 135 mg/m2 of epirubicin intravenously (IV) every 3 weeks. Treatment consisted of first-line cytotoxic therapy for metastatic disease. In patients with early progressive disease after either 40 or 60 mg/m2, dose escalation to 135 mg/m2 was performed. A full pharmacokinetic analysis was performed in 78 patients. RESULTS: Among 263 eligible patients, an increase in response rate and time to progression was found with an increase in dose from 40 to 90 mg/m2, while no increase in efficacy was found from 90 to 135 mg/m2. Multivariate analysis, using the Cox proportional hazards model with time to progression as the end point, confirmed that epirubicin dose more than 60 mg/m2 was an independent prognostic covariate. Furthermore, a significant association was established between randomized dose and both hematologic and nonhematologic toxicity. No association between pharmacokinetic parameters and efficacy parameters was demonstrated. On the other hand, a significant correlation between pharmacokinetic parameters and both hematologic and nonhematologic toxicity was found. CONCLUSION: An increase in dose of epirubicin from 40 to 90 mg/m2 is accompanied by increased efficacy. Further increases in dose do not yield increased efficacy. A positive correlation between epirubicin dose and toxicity, as well as a correlation between pharmacokinetic parameters and toxicity, was also established.

Adult↗