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Biomedical subjects

H Ehrsson

Publications and source records attributed to H Ehrsson.

At least 19 recordsLinked to original sources
PubMed2005

Short-time infusion of oxaliplatin in combination with capecitabine (XELOX30) as second-line therapy in patients with advanced colorectal cancer after failure to irinotecan and 5-fluorouracil.

BACKGROUND: The efficacy of oxaliplatin combined with capecitabine (XELOX) as second-line therapy in patients with advanced colorectal cancer (ACRC) resistant to irinotecan is not well established. Oxaliplatin induces acute, cold-induced neuropathy in most patients. The incidence is claimed to be infusion rate-dependent and therefore a 2-h infusion is recommended. PATIENTS AND METHODS: For practical and economic reasons, but also for patient's convenience, we performed a phase II study to examine XELOX30 (capecitabine 1000 mg/m2 orally twice daily on days 1-14 and oxaliplatin 130 mg/m2 as a 30 min infusion on day 1) in patients with ACRC resistant to irinotecan. In addition the pharmacokinetics of oxaliplatin was studied. RESULTS: From November 2002 to September 2003, 70 patients with ACRC were treated with XELOX30. Median age was 62 (range 33-74 years) years and median performance status was 1 (range 0-2). The median number of courses was four (range 1-12) and median cumulative dose of oxaliplatin was 530 (range 125-1560) mg/m2. The response rate was 17% (95% CI 10-23), median time to progression (TTP) was 5.4 months (95% CI 4.6-6.4) and median survival 9.5 months (95% CI 8.5-11.2). White blood cell count (WBC) and performance status were significantly correlated to TTP. Neurotoxicity was moderate: grade 1 56%, grade 2 17% and grade 3 6%. Other grade 3 toxicities were nausea/vomiting 9%, diarrhoea 14% and PPE 8%. The maximum blood concentration and total body clearance of oxaliplatin was higher than previously reported in studies examining 2-h infusions, but the volume of distribution and terminal half-life was in close agreement with previous results. CONCLUSION: XELOX30 is a very convenient second-line regimen in ACRC with an activity and safety profile similar to other oxaliplatin schedules.

Adenocarcinoma↗
PubMed2004

Transdermal delivery from a lipid sponge phase--iontophoretic and passive transport in vitro of 5-aminolevulinic acid and its methyl ester.

The hydrochloride salts of 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA), respectively, were dissolved in a lipid sponge phase comprising monoolein, propylene glycol and aqueous buffer at concentrations of approximately 0.25% and 16% w/w m-ALA. The iontophoretic and passive delivery of ALA and m-ALA from this formulation through porcine skin in vitro were measured and compared to formulations used in clinical practice, 20% w/w ALA in Unguentum M and Metvix (a cream containing 16% w/w m-ALA). A sponge phase with 16% w/w m-ALA showed a higher passive flux (approximately 140 nmol cm(-2) h(-1) at 5 h) but a lower iontophoretic flux (approximately 800 nmol cm(-2) h(-1) at 5 h) compared to the clinically used products but the differences are hardly significant due to large standard deviations. ALA and m-ALA in sponge phase formulation showed iontophoretic fluxes in the range 80-100 nmol cm(-2) h(-1) at 3 h, i.e. values comparable to the passive fluxes from the more concentrated vehicles. The results demonstrate that the lipid sponge phase, a thermodynamically stable liquid with amphiphilic character, may have potential as a transdermal drug delivery vehicle.

Administration, Cutaneous↗
PubMed2003

Intracochlear administration of thiourea protects against cisplatin-induced outer hair cell loss in the guinea pig.

Amelioration of cisplatin-induced side-effects is of great clinical importance. Local administration of a cytoprotective agent to the inner ear offers a possibility to prevent cisplatin-induced ototoxicity without risk of interference with the antitumour effect. The ideal substance for local administration has yet to be identified. Thiourea (TU) has unique properties that make it an interesting candidate. This study was initiated to test the hypothesis that TU given by local administration protects against cisplatin ototoxicity in the guinea pig. After baseline auditory brainstem response (ABR) assessment, the left cochlea was implanted with a microtip catheter connected to an osmotic pump filled with either 27 mg/ml TU in artificial perilymph (AP), or AP administered for the full duration of the study. Three days post-implant, animals with normal ABRs received an intravenous injection of 8 mg/kg body-weight cisplatin. Five days after the cisplatin treatment ABRs were reassessed, animals decapitated and bilateral cytocochleograms prepared. TU-treated ears demonstrated significantly lower outer hair cell (OHC) loss as compared to contralateral untreated ears, and significantly lower OHC loss compared to AP-treated ears. ABR threshold shift did not differ significantly between the two groups. It can be postulated that TU demonstrates partial protection against cisplatin-induced ototoxicity.

Animals↗
PubMed2002

Pharmacokinetics of oxaliplatin in humans.

Oxaliplatin is a novel platinum complex used for the treatment of metastatic colorectal carcinoma. The pharmacokinetics of the free fraction of oxaliplatin in blood were evaluated in 10 patients given 85 mg/m2 of oxaliplatin using an infusion time of 2 h. Blood samples were collected during and after the infusion and immediately placed on ice. The samples were ultrafiltrated centripetally and the concentration of oxaliplatin in the ultrafiltrate was determined by liquid chromatography in combination with postcolumn derivatization. The in vitro degradation rate was determined in blood from the patients taken immediately before drug administration. The maximal blood concentration (C(max)) and terminal half-life (t1/2) were 1.44 +/- 0.20 (SD) microg/mL and 14.1 min (range: 10.2-24.5), respectively. The area under the blood concentration time curve (AUC), clearance (CL), and distribution volume (V(ss)) were (means +/- SD) 161 +/- 22 microg min/mL, 32.1 +/- 4.2 L/h/m2, and 0.26 +/- 0.06 L/kg, respectively. There was a significant correlation between the clearance of oxaliplatin in the patients and the degradation rate in whole blood (r = 0.746; p = 0.017). Oxaliplatin has a short elimination half-life, which is in a sharp contrast to previously reported elimination half-lives obtained by analysis of the platinum content in plasma and ultrafiltrate. The correlation between in vivo and in vitro data suggests that the degradation in whole blood plays a role for the elimination of the drug.

Aged↗
PubMed2000

Cisplatin-induced hearing loss: influence of the mode of drug administration in the guinea pig.

Cisplatin (8 mg/kg) was given intravenously to guinea pigs either as a 15 s bolus injection (25 animals) or as a 1 h infusion (28 animals). To determine the influence of the mode of cisplatin administration and pharmacokinetics on the ototoxic side-effect, the concentrations of cisplatin and the biotransformation product monoaquated cisplatin were determined in blood ultrafiltrate using liquid chromatography with post-column derivatization. Ototoxic effect was evaluated as difference in pre- and 96 h post-exposure auditory brainstem response (ABR) threshold. The cisplatin peak concentration was considerably higher, 19.2+/-2.4 microg/ml, in the bolus injection group than in the infusion group, 6.7+/-0.5 microg/ml (mean+/-S.E.M.). The area under the blood ultrafiltrate concentration time curve (AUC) for cisplatin was slightly greater in the infusion group, 442+/-26 microg/ml/min, than in the bolus injection group, 340+/-5 microg/ml/min. For monoaqua cisplatin, the AUC was not different between the groups (bolus injection: 30.8+/-1. 5 microg/ml/min, infusion: 34.1+/-3.3 microg/ml/min). A significant ototoxic effect was observed in both groups at 20 and 12.5 kHz, but there was no difference between the groups in the extent of threshold shift. The interindividual variability in susceptibility to ABR threshold shift was far greater than the variability in pharmacokinetics, suggesting that other factors are more important in determining the degree of hearing loss.

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↗
PubMed1998

The kinetics and cytotoxicity of cisplatin and its monohydrated complex.

This paper examines the monohydrated complex of cisplatin (MHC) with respect to kinetics and cytotoxicity. Equilibrium mixtures of cisplatin and hydrated species have been used in previous studies of a similar nature. To our knowledge, this is the first paper examining MHC after isolation and quantification. This was accomplished using liquid chromatography with porous graphitic carbon. MHC and cisplatin were quantified over time in a suspension of the small-cell lung cancer cell line U-1285. Cytotoxicity was evaluated using the fluorescent microculture cytotoxicity assay. MHC was significantly more cytotoxic than cisplatin at the high end of the drug concentrations tested. In culture media with low chloride ion concentrations, the stability of MHC was related to changes in pH. At a pH of between 6.0 and 7.2, MHC was rapidly converted to cisplatin. In culture media with a pH above 7.2, MHC was considerably more stable. These findings might have clinical significance given that MHC circulates in the blood stream of patients receiving cisplatin infusions and that solid tumours often have environments that are extremely acidotic.

Antineoplastic Agents↗
PubMed1998

Comparison of the cytotoxic activity of melphalan with L-prolyl-m-L-sarcolysyl-L-p-fluorophenylalanine in human tumour cell lines and primary cultures of tumour cells from patients.

m-L-sarcolysin (m-L-SL) is an isomer of melphalan (Mel) with the di(2-chloroethyl) amino group being substituted in the meta position of phenylalanine. By covalent conjugation of amino acids to m-L-SL, a peptide complex consisting of six m-L-SL-based oligopeptides known as peptichemio (PTC) was developed previously. In the present study, the cytotoxic activity pattern of the different oligopeptides of PTC was investigated in ten human tumour cell lines representing different mechanisms of cytotoxic drug resistance using the fluorometric microculture cytotoxicity assay (FMCA). In the cell line panel, L-prolyl-m-L-sarcolysyl-L-p-fluorophenylalanine (P2) was the most active oligopeptide, showing slightly lower mean IC50 values (2.6 vs 3.9 and 4.1 microg ml(-1)) than Mel and m-L-SL. The other five oligopeptides were less active than Mel. All active oligopeptides showed mechanistic similarity to Mel as judged by the correlation analysis of the cell line panel log IC50 values (R > or = 0.90), although P2 appeared to be less sensitive to GSH-mediated drug resistance. The relative activity of Mel and P2 was found to be related to degree of proliferation, P2 being more active towards low-proliferating cell lines. P2 and Mel were then further characterized in 49 fresh human tumour samples. In these samples P2 was considerably more active than Mel and showed a higher relative solid tumour activity (2.7 to 4.5-fold). However, the correlation of log IC50s between P2 and Mel in patient cells was high (R = 0.79), indicating a similar mechanism of action in this tumour model too. Cross-resistance with other standard drugs was lower for P2 than Mel. The results show that P2 is the most potent component of PTC and demonstrates a favourable activity profile compared with Mel. These data suggest that further investigation of P2 as a potential anti-tumour agent is warranted.

Cell Line↗
PubMed1996

Pharmacokinetics of cisplatin and its monohydrated complex in humans.

The pharmacokinetics of cisplatin and its cytotoxic hydrolysis product cis-diammineaquachloroplatinum(II) ion (monohydrated complex) were investigated in seven patients after they received a 1-h infusion of cisplatin in normal saline at 100 mg/m2. The concentrations of intact cisplatin and the monohydrated complex were determined in blood by liquid chromatography with post-column derivatization, using diethyldithiocarbamate as the reagent. A pharmacokinetic model was developed assuming that a fraction of the dose (2.3%) is present as the monohydrated complex in the infusion solution and that reversible reactions between cisplatin and its monohydrated complex prevail. The clearances of cisplatin and the monohydrated complex were 0.32 +/- 0.05 and 0.27 +/- 0.11 L/min/m2, respectively. The apparent volume of distribution was considerably smaller for the monohydrated complex (4 +/- 2 L/m2) than for cisplatin (11 +/- 2 L/m2). The elimination rate constants were 0.030 +/- 0.002 and 0.07 +/- 0.02 min-1 for cisplatin and the monohydrated complex, respectively. The area under the time-concentration curve for the monohydrated complex was approximately 15% of that for cisplatin. It is concluded that the significant amounts of the monohydrated complex present in blood are due to the fraction already present in the administered dose and to the fraction formed in blood.

Antineoplastic Agents↗
PubMed1996

An expanded CAG repeat sequence in spinocerebellar ataxia type 7.

Expanded CAG repeat sequences have been identified in the coding region of genes mutated in several neurodegenerative disorders, including spinocerebellar ataxia type 1 and Machado-Joseph disease. In all disorders described to date the CAG expansion codes for an elongated polyglutamine chain. An increased polyglutamine chain size leads to a more severe disease, thus correlating with the genetic anticipation seen in repeat expansion disorders. Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant spinocerebellar ataxia with anticipation and a progressive degeneration of the cerebellar cortex. Using repeat expansion detection (RED), a method in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA, we have analyzed 8 SCA7 families for the presence of CAG repeat expansions. RED products of 150-240 bp were found in all affected individuals and found to cosegregate with the disease (P < 0.000001, n = 66), indicating strongly that a CAG expansion is the cause of SCA7. On the basis of a previously established correlation between RED product sizes and actual repeat sizes in Machado-Joseph disease, we were able to estimate the average expansion size in SCA7 to be 64 CAG copies.

Chromosome Mapping↗
PubMed1996

Aspects concerning busulfan pharmacokinetics and bioavailability.

Busulfan as a high-dose therapy is an important component of many of the myeloablative regimens for both allogeneic and autologous bone marrow transplantation (BMT) in adults and children. During the last decade, several studies have shown a wide inter- and intra-patient variability of busulfan disposition in adults and children. Some of the factors affecting the interpatient-variability were identified as circadian rhythmicity, age, disease, drug interaction, alteration in hepatic function and recently busulfan bioavailability. In adults, pharmacodynamic studies have shown a positive correlation between high-systemic exposure of the drug and venocclusive disease (VOD). However, pharmacodynamic studies in children did not establish any correlation between the systemic exposure and VOD. Drug-monitoring and dose adjustment in adults were used successfully to decrease the occurrence of VOD and mortality. It was observed that about 20% of the busulfan dose crosses the blood brain barrier. The high amount of the drug which enters the brain can probably be involved in the CNS toxicities reported. In children, a low rate of toxicity combined with a high rate of engraftment failure were observed. Several investigators have expressed their concern about the dosage in children and many suggested higher doses based on the body surface area for young children. However, recently it was shown that busulfan bioavailability varied by 2-fold in adults (0.5-1.03) while in children a 6-fold variation was observed (0.22-1.20). The access to an intravenous form of busulfan and a deeper understanding of pharmacodynamics of the drug might be essential to optimize the treatment, reach a successful engraftment and lower the therapy related toxicities.

Adolescent↗
PubMed1995

Distribution of cisplatin in perilymph and cerebrospinal fluid after intravenous administration in the guinea pig.

The concentration of free cisplatin was followed in plasma, scala tympani perilymph and cerebrospinal fluid (CSF) after an intravenous injection (12.5 mg/kg) in guinea pigs. Liquid chromatography with postcolumn derivatization was used for quantitative determination of the drug. The distribution of cisplatin to CSF was fast; at 10 min after drug administration the concentration was 7 micrograms/ml and the CSF:plasma ratio was 0.37. Cisplatin seems to distribute more slowly to the perilymphatic compartment. The highest concentration measured was 4 micrograms/ml at 20 min after the injection, and the perilymph:plasma ratio was 0.40 at that time. The concentration-time curves generated for cisplatin in perilymph and CSF were similar. No accumulation in the perilymphatic compartment or CSF was observed.

Animals↗
PubMed1995

Stability of cisplatin and its monohydrated complex in blood, plasma and ultrafiltrate--implications for quantitative analysis.

The stability of cisplatin and its monohydrated complex has been studied in blood, plasma and plasma ultrafiltrate at 37 degrees C (pH 7.4). Intact cisplatin and the monohydrated complex were determined by liquid chromatography with post-column derivatization. The half lives for cisplatin and the monohydrated complex were 1.43 +/- 0.03 h (SEM) and 0.36 +/- 0.03 h (SEM), respectively, in blood and 0.88 +/- 0.05 h (SEM) and 0.26 +/- 0.02 h (SEM), respectively, in plasma. The compounds were unstable at -25 degrees C (t1/2 for cisplatin was 52 +/- 5 h (SEM) and for the monohydrated compound 26 +/- 2 h (SEM)), but at -70 degrees C both compounds were stable for at least 3 weeks. The monohydrated complex was found to be formed to a small extent when cisplatin was added to plasma (37 degrees C, pH 7.4). A sampling procedure using centripetal ultrafiltration of whole blood was evaluated and found applicable if the samples were stored at 0 degree C and ultracentrifuged within 1 h.

Cisplatin↗
PubMed1995

Initiation of locomotion by lateral line photoreceptors in lamprey: behavioural and neurophysiological studies

The lateral line system of lampreys includes photoreceptors distributed in the skin of the tail region. These are innervated by the trunk lateral line nerves, and the afferents terminate bilaterally in the medial octavolateral nucleus, crossing the midline through the cerebellar commissure. Stimulation of the dermal photoreceptors by tail illumination initiates locomotion. The present study was performed to characterize the response to illumination in larval and adult lampreys in detail and to elucidate the neuronal pathways responsible for the activation of locomotion. In both larval and adult quiescent lampreys, the response to unilateral illumination of the tail was found to consist of an initial turn followed by rectilinear swimming. The sign and magnitude of the turning angle were not correlated with the laterality of the optic stimulus. In mechanically restrained lampreys, spinalized at the level of segments 15&shy;20, tail illumination evoked a complex motor response in the rostral part of the body, with switches between different patterns of coordination (turns in different directions, locomotion, and turns combined with locomotion). Thus, the response to tail illumination is not a simple reflex, but includes a behavioural choice. Reticulospinal neurones play a crucial role in the initiation of locomotion in lampreys. The response to unilateral tail illumination in rhombencephalic reticular cells was studied with extracellular single-unit recordings. It was found that neurones in the middle and posterior rhombencephalic reticular nuclei were activated bilaterally. Tonic activity or slow bursts (<0.5 Hz) were evoked, in some cases lasting up to 60 s after the stimulation. The response remained bilateral after transection of one lateral line nerve and the cerebellar commissure. Afferents from one side can thus activate reticulospinal cells on both sides through a pathway outside the cerebellar commissure. This bilateral activation of reticulospinal neurones is presumably responsible for the activation of spinal locomotor networks, without any directional bias to the left or the right side, and for the rectilinear swimming observed in behavioural experiments. In the caudal part of the termination area of the lateral line nerve afferents, neurones with contralateral projections were retrogradely stained with horseradish peroxidase. These neurones appear to be likely candidates for mediating the contralateral effects of the lateral line fibres.

Journal Article↗
PubMed1994

Determination of cisplatin and cis-diammineaquachloroplatinum(II) ion by liquid chromatography using post-column derivatization with diethyldithiocarbamate.

A post-column derivatization method has been developed for the determination of cisplatin and its monohydrated form. Cisplatin was isolated on a strong anion-exchange column, while a strong cation-exchange column was used for the monohydrated complex. Diethyldithiocarbamate was used as reagent and the influence of temperature, pH and methanol content on the yield of derivative was investigated. The reaction was quantitative using a packed-bed reactor with a surrounding temperature of 115 degrees C and a mobile phase consisting of 0.125 M succinic acid-sodium hydroxide buffer pH 5.2 and methanol (2:3, v/v). The resulting complex, Pt(DDTC)2, was monitored photometrically at 344 nm. The precision of the determination was 11.5% (C.V.) at an injected amount of 20 ng (n = 12) for monoaqua and 8.0% (C.V.) at 9 ng (n = 10) for cisplatin. The method was used to evaluate the plasma concentration of cisplatin and its monohydrated form in a patient.

Anions↗
PubMed1994

Determination of the acid dissociation constant for cis-diammineaquachloroplatinum(II) ion. A hydrolysis product of cisplatin.

The biological activity of the anticancer drug cisplatin is supposed to be mediated by its reactive hydrolysis product cis-diammineaquachloroplatinum(II) ion (monoaqua). The monohydrated complex (monoaqua and its deprotonated form monohydroxy) was isolated from an equilibrium mixture of cisplatin in distilled water using a strong cationic exchanger. The structure of the monoaqua complex was established by 252Cf time-of-flight mass spectrometry. The acid dissociation constant was determined at 37 degrees C by studying the influence of pH on the reaction between the monoaqua complex and chloride ion (0.1 M). The concentration of monohydrated compound was determined by liquid chromatography with post-column derivatization using sodium diethyldithiocarbamate as a reagent. The pKa was determined to 6.56 +/- 0.01 (SEM). Thus, at physiological pH, the monoaqua complex is present mostly in its less reactive monohydroxy form.

Antineoplastic Agents↗
PubMed1994

Food-induced increase in bioavailability of 5-methoxypsoralen.

5-Methoxypsoralen (5-MOP) in combination with ultraviolet light exposure is used for the treatment of psoriasis. The effect of food on the pharmacokinetics of 5-MOP was evaluated in a randomized, crossover study in nine healthy subjects. Each subject received the tablets with a standardized breakfast or under fasting conditions. The food had a dramatic effect on the bioavailability of 5-MOP. Five of the subjects showed no measurable quantities (detection limit of the analytical technique 1 ng.ml-1) of 5-MOP when the drug was given under fasting conditions. However, plasma peak concentration within the range 37-144 ng.ml-1 (median 102 ng.ml-1) was measured when the drug was taken with food. The time for the plasma peak concentration was within the range 2.0-5.1 h (median 3.0 h) under non-fasting conditions. The elimination half-life was within the range 1.4-2.7 h (median 1.9 h). We conclude that it is imperative that 5-MOP tablets are administered together with food.

5-Methoxypsoralen↗