[Extended guaranteed care. What are we going to do?].
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Health Services Accessibility↗
Biomedical subjects
R Larsson
Publications and source records attributed to R Larsson.
Single-fibre laser Doppler flowmetry and electromyography for evaluating microcirculation in forearm muscle during static and continuous handgrip contractions.
A technique is described for intramuscular measurement of muscle blood flow in the forearm, by using a 0.5-mm thin optical single-fibre for laser Doppler flowmetry (LDF) inserted percutaneously. Continuous recordings were performed of the brachioradial muscle during an 11-min series of alternating 1-min periods of increased static contraction and rest determined by an electronic handgrip forcemeter and surface electromyography (EMG) of the muscle. Stepwise increased handgrip contractions were performed at 10%, 20%, 30%, 40% and 50% maximal voluntary contraction (MVC). This was followed by a similar series of continuous contractions. Finally, an endurance test was performed with a handgrip force of 50% MVC maintained for as long as possible. A group of ten healthy men of different ages was studied. Signal processing was done on line by computer. Successive increases in rootmean square (rms)-EMG and a fall in the mean power frequency (MPF) of the EMG spectrum occurred during the series of static contractions, which evoked perceived local fatigue in the forearm. Muscle blood flow recorded simultaneously showed no change from resting level during contractions at 10%, 20% and 30% MVC, while at 40% and 50% MVC mean increases of 150% and 200% were recorded. Blood flows measured during the rest periods showed large variability with no significant changes. This was also found after continuous contractions of the same intensities. The endurance time was 1.2-3.5 min (mean 2.4 min). Muscle blood flow showed mean increases of 214%, 256% and 229% of resting level each minute of the maintained contraction. Nevertheless, EMG signs of local fatigue developed, such as a rise in rms-EMG and a fall in MPF, and the subject experienced local fatigue. To conclude, this technique of percutaneous, continuous LDF recorded, at high sensitivity, the microcirculation at different fluxes and EMG-defined muscle activity.
Adult↗
Correlation between sensitivity in vitro of patient chronic lymphocytic leukemia cells and clinical systemic exposure at the maximum tolerated dose for cell cycle phase-specific (type 2) anticancer drugs.
Previously in Anti-cancer Drugs we have reported a high correlation between clinical plasma concentration-time products (C x T) and the concentration of cytotoxic drugs giving 50% cell survival (IC50) in primary cultures of human lymphatic cells. In the present study we investigated the relationship separately for cell cycle-specific (type 1) and cell cycle non-specific (type 2) drugs in chronic lymphatic leukemia cells. A high correlation (R = 0.92) was observed between C x T and IC50 for cell cycle non-specific drugs, while for cell cycle-specific, or C x T-dependent, drugs, the relationship was much weaker (R = 0.58). Since the opposite pattern has been observed for the relationship between clinical C x T and LD10 in mice, these results further imply that drug sensitivity assays may be a useful complement to animal data in the selection of starting dose and dose escalation procedure in phase I clinical trials of new cytotoxic drugs.
Animals↗
Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients.
PURPOSE: The aim of this study was to investigate the covariance between the pharmacokinetics of the three components of the FEC regimen, epirubicin (EPI), fluorouracil (5-FU), and the cyclophosphamide (CP) metabolite 4-hydroxycyclophosphamide (4-OHCP), in breast cancer patients. PATIENTS AND METHODS: Data from 21 women were collected over a total of 35 cycles. 5-FU (300 to 600 mg/m2) and CP (300 to 600 mg/m2) were administered as bolus injections, whereas EPI (15 to 60 mg/m2) was administered either as a bolus injection or as an infusion. The pharmacokinetics of the component drugs were monitored using a limited sampling scheme. Population pharmacokinetic models for each of the three drugs were developed using the program NONMEM. RESULTS: The data for 5-FU were best described by a one-compartment model with nonlinear elimination, where the maximal rate of elimination (Vmax) and the concentration at which the elimination was half-maximal (Km) were 105 mg/L.h and 27 mg/L, respectively. EPI concentration-time profiles showed a triexponential decline, with a mean terminal half-life of 24 hours and a clearance (CL) of 59 L/h. The elimination of 4-OHCP was monoexponential, with a mean half-life of 7 hours. The interindividual coefficients of variation (CVs) in CL were 30%, 22%, and 41% for 5-FU, EPI, and 4-OHCP, respectively. The corresponding values for intrapatient course-to-course variability in CL were 11%, 8%, and 27%. No significant correlation in any of the pharmacokinetic parameters between the drugs was found. CONCLUSION: Individualization of dosing of the FEC regimen using therapeutic drug monitoring and attempts to find concentration-response relationships may be successful, but requires that the exposure of all three drugs is considered simultaneously.
Adult↗
Does prophylactic treatment with felodipine, a calcium antagonist, prevent low-osmolar contrast-induced renal dysfunction in hydrated diabetic and nondiabetic patients with normal or moderately reduced renal function?
Twenty-seven patients (15 diabetics and 12 non-diabetics) with normal to moderately reduced renal function underwent femoral angiography with a low-osmolar contrast agent, iohexol (Omnipaque), under perexaminatory hydration. Fourteen patients were randomised to pretreatment with oral felodipine extended release (Plendil) 10 mg and 13 patients to placebo 3-4 h before angiography. GFR measured with [51Cr] EDTA-clearance decreased 24 hours after the angiography in the felodipine group from GFR 52.5 +/- 18.6 (mean +/- SD) to 46.2 +/- 16.5 ml/min (p < 0.01) and in the placebo group from 70.6 +/- 18.6 to 62.6 +/- 26.4 ml/min (p < 0.01). Serum creatinine increased significantly in the felodipine group from 128 +/- 61 to 139 +/- 67 mumol/l (p < 0.05) but not in the placebo group (122 +/- 54 to 125 +/- 51 mumol/l (ns)). The values of serum creatinine returned to baseline levels 7 days after angiography. During hydration there was only a slight reduction of GFR after angiography with iohexol. Thus, felodipine had no major effect on GFR after iohexol but, as baseline GFR tended to be lower in the felodipine pre-treated patients, it might have had some renoprotective effect in patients with more advanced renal failure.
Aged↗
Effects of interferons and tumour necrosis factor-alpha on human lung cancer cell lines and the development of an interferon-resistant lung cancer cell line.
Thirteen human lung cancer cell lines, 7 representing small cell lung cancer (SCLC) and 6 different types of non-SCLC, were tested for sensitivity to tumour necrosis factor alpha (TNF-alpha) and interferon alpha and gamma (IFN-alpha and gamma) using an automated fluorometric microculture cytotoxicity assay (FMCA). One SCLC line (H-82) was found to be sensitive to IFN-alpha in short-term (72 h) culture, whereas after prolonged (5 days) culture two additional SCLC cell lines responded to IFN-gamma. TNF-alpha inhibited the growth of one large cell carcinoma cell line (H-157), whereas all SCLC lines were found to be insensitive. The combination of IFN-gamma and TNF-alpha produced no further response compared with the single agents used alone. By continuous cultivation of the IFN-alpha-sensitive cell line H-82 in the presence of increasing concentrations of IFN-alpha, an IFN-alpha-resistant subline (H-82) was established. This line displayed a high degree of resistance ( > 100 fold) to IFN-alpha and cross-resistance to IFN-gamma. There was no alteration in the number of IFN binding sites, in the growth rate, the expression of selected surface markers for SCLC or the expression of multidrug resistance markers in the H-82R subline compared with the parental H-82 cell line. The results demonstrate a heterogeneous response of SCLC cell lines to IFN-alpha and gamma and TNF-alpha with only a minority of the cell lines responding to these agents by growth inhibition. The IFN-alpha and gamma H-82R subline may serve as a valuable tool in future studies on the mechanisms of IFN antitumour activity.
Antigens, Neoplasm↗
Plasma cyanate concentrations in chronic renal failure.
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Cyanates↗
Selective sensitivity of solid tumors to suramin in primary cultures of tumor cells from patients.
The antineoplastic activity of suramin is currently the subject of clinical trials. We therefore used the semi-automated fluorometric microculture cytotoxicity assay (FMCA) to evaluate the cytotoxicity of suramin in vitro in primary cultures of cells from patients with hematological or solid tumors. The activity patterns of some standard cytotoxic agents were included for comparison. A total of 159 samples were tested using continuous drug exposure. Suramin showed relatively high activity against solid tumors, with colorectal, adrenal and kidney carcinomas being the most sensitive, whereas hematological malignancies were more resistant. Suramin and standard drugs showed very low cross-resistance. The results indicate that suramin is differentially active against some solid tumors with comparatively little activity against hematological tumors. The study provides an experimental motive for evaluation of suramin therapy in patients with solid tumors and exploration of less toxic suramin analogues.
Antineoplastic Agents↗
Pharmacokinetics of HI-6 and atropine in anaesthetized pigs after administration by a new autoinjector.
A newly developed autoinjector (Astra Tech, Sweden) containing 500 mg HI-6 and 2 mg atropine sulphate was tested in anaesthetized normal pigs. The pharmacokinetics and pharmacodynamics of the drugs after administration by the autoinjector were compared with those after conventional needle and syringe delivery intramuscularly and intravenously. Cardiopulmonary parameters were monitored and serum concentrations of oxime, atropine, and acetylcholinesterase were determined in blood samples taken at intervals over a 6 h period postinjection. After injection in anaesthetized pigs, both HI-6 and atropine were absorbed rapidly and completely from the injection site. Therapeutic serum concentrations of HI-6, arbitrarily taken as 4 micrograms mL-1, were reached within 1 min of intravenous and autoinjector administration, and within 5 min of intramuscular injection. The concentrations remained above this level for 3-4 h. There were no significant changes in acetylcholinesterase activity, mean arterial blood pressure, or respiration frequency after injection of HI-6 and atropine sulphate. The heart rates increased significantly after administration of the two drugs (cardioacceleration defined as > or = 5% increase in heart rate), regardless of the technique employed. Our results show that HI-6 and atropine sulphate can be given intramuscularly by the new autoinjector with the same effectiveness and speed as when given intravenously. Irrespective of the injection technique, no overt signs of toxicity were observed at the drug concentrations used.
Acetylcholinesterase↗
Microcirculation in the upper trapezius muscle during sustained shoulder load in healthy women--an endurance study using percutaneous laser-Doppler flowmetry and surface electromyography.
Microcirculation in the upper portion of the trapezius muscle was measured percutaneously in a group of 16 healthy women of different ages by continuous laser-Doppler flowmetry (LDF) in relation to electromyography (EMG) during an endurance test. During the measurements the subject kept her arms straight and elevated at 45 degrees in the scapular plane and held a 1-kg load in each hand as long as possible. This was followed by rest with the arms hanging and carrying no load. The 10-min recording period comprised 1-min initial rest followed by the endurance test and then recovery. Signal processing was done by computer on line. The LDF and root-mean-square (rms) EMG signals were normalized. Spectrum analyses of EMG mean power frequency (MPF) were performed. The amount of load produced was on average 2,267 (SD 939) N.m.s, i.e. shoulder torque x time expressed as Newton meter seconds, and the endurance time was 4.3 (SD 1.20) min. The rms-EMG as well as the LDF increased significantly during endurance, both when related to endurance time and to amount of load. The MPF showed no significant changes. The mean total increase in muscle blood flow was 175% of that recorded in the initial rest period. The average increase per each 10 s of contraction was 2.9%. Maximum was reached during the 1st min of recovery followed by a fall to the base level that was reached within 77 s on average. The amount of load produced and the blood flow increase was smaller than that found in a separate study of men, indicating a lower functional capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Measurement by laser-Doppler flowmetry of microcirculation in lower leg muscle at different blood fluxes in relation to electromyographically determined contraction and accumulated fatigue.
Single-fibre percutaneous laser-Doppler flowmetry (LDF) of the tibialis anterior muscle was performed continuously for measurement of the microcirculation during different blood fluxes, as well as in relation to different muscle activities and fatigue determined electromyographically (EMG). The laser-Doppler power spectrum density function was studied in a frequency range of 0-8.2 Hz as representing the blood flow most selectively. Reduced blood flow from tourniquet inflation caused a decrease in signal power density, compared to that of intact blood flow at rest. During postocclusion reactive hyperaemia an increased signal power was recorded. This reached its maximum within 4.4 (SD 1.88) s after deflation of the tourniquet. The different fluxes were recorded at high sensitivity and disturbances were small. Periods of 1-min static dorsi-flexion of the foot at 10, 20, 30, 40, and 50% MVC (maximal voluntary contraction) with 1-min rest between were associated with a significant increase in LDF, the recordings obtained during the rest periods showing a tendency towards an increase. A decrease in the EMG mean power frequency (MPF) indicated accumulated fatigue. The LDF for the rest periods that followed upon continuous contractions up to the same MVC levels showed a tendency towards an increase but variability was large. With further development, these techniques may be useful in the evaluation of insufficiency of the peripheral circulation.
Adult↗
Treatment of organophosphate poisoning in pigs: antidote administration by a new binary autoinjector.
The therapeutic effectiveness of a new binary autoinjector containing 500 mg HI-6 and 2 mg atropine sulphate was tested in anesthetized pigs poisoned by a lethal dose of soman i.v. (9 micrograms/kg per 20 min). Pharmacokinetics and pharmacodynamics of HI-6 were studied concomitantly on administration of HI-6 alone, together with atropine sulphate, or together with atropine sulphate during soman intoxication. Cardiopulmonary parameters were monitored and serum concentrations of oxime and acetylcholinesterase (AChE) were measured in blood samples taken at intervals over a 6-h period postinjection. Five minutes after the start of soman infusion, mean AChE activity was decreased to 27 +/- 4.3% of baseline and signs of poisoning appeared. The antidotes, HI-6 and atropine sulphate, were then administered i.m. One minute after this injection there was a transient significant increase in AChE activity of 76 +/- 8.2% of baseline (p < 0.01). It then again decreased and remained suppressed throughout the experiment. Mean respiratory rate was significantly decreased (p < 0.01) to 20 +/- 3.2% of baseline after 20 min of soman infusion and remained low during the rest of the experiment. The poisoning signs were counteracted 15-20 min after antidote therapy and all pigs survived soman intoxication without ventilatory assistance. Administration of either atropine or atropine and soman had no significant effect on the pharmacokinetics of HI-6 in anesthetized pigs.
Animals↗
Expression of the 85-kd membrane protein in primary human breast cancer: relationship to hormone receptor levels, DNA ploidy, and tumor grade.
Using the monoclonal antibody (MAb) MRK20 the immunohistochemical expression of the 85-kd membrane protein (MP)/cell adhesion molecule (CAM) CD36 was investigated in tumors from 41 patients with untreated breast adenocarcinoma. DNA ploidy as measured by flow cytometry and estrogen (ER) and progesterone receptor (PgR) tumor contents also were determined. Immunohistochemistry on frozen tissue showed expression of 85-kd MP localized to the carcinoma cells in tumors from 16 patients (39%). These samples also displayed variable staining of the capillary endothelium. Twenty-one samples (51%) showed 85-kd MP expression in small blood vessels. Thus, a total of 37 of 41 tumors (90%) were MAb MRK20 positive in carcinoma and/or mesenchymal cells. Expression of 85-kd MP in carcinoma cells was negatively associated with expression of ER (P < .05) and PgR (P < .01) receptors and positively associated with nondiploid tumors (P < 0.05) and tumor grade (P < .05). Axillary lymph node status, tumor size, and (patient) age were not associated with expression of 85-kd MP. In cytological smears obtained by fine-needle aspiration (FNA) cytology from 19 of the samples, expression of 85-kd MP in carcinoma cells showed a good correlation with tumor cell positivity in the corresponding histological section. Expression of 85-kd MP in breast carcinoma cells thus was associated with some recognized adverse prognostic factors. Future studies of its pathophysiological and prognostic roles in breast cancer seem warranted.
Adenocarcinoma↗
Relationship between pharmacokinetic parameters in patients and cytotoxicity in vitro of standard and investigational anticancer drugs.
The selection of the starting dose for initial clinical trials of anticancer agents is mostly determined by toxicological endpoints in mice (LD10). So far, very few attempts have been made to evaluate the potential value of cytotoxicity assays for this purpose. The present study was undertaken as a first attempt to investigate the relationship between cytotoxicity of anticancer drugs in vitro and pharmacokinetic parameters in vivo in patients, at suggested maximum tolerated doses. Using the fluorometric microculture cytotoxicity assay (FMCA), we determined the concentration giving 50% cell survival (IC50) in vitro, for 25 cytotoxic drugs in fresh preparations of normal peripheral blood mononuclear cells (PBMC) and of tumor cells from patients with acute or chronic lymphocytic leukemia (ALL or CLL). Using linear regression, we investigated the relationship between the IC50s and clinically achievable peak plasma concentrations (Cmax) or concentration-time products (C x T) in humans. The clinical data was obtained from the literature. Based on all drugs tested, good correlations were obtained between IC50s for CLL cells, and both Cmax and C x T (R approximately 0.7, p < 0.0002), and for ALL cells and normal PBMC between IC50 and Cmax, while the two latter cell types showed somewhat weaker relationships to C x T. Using the IC50 data of CLL cells, predictions of Cmax and C x T exceeded 1 log for only four drugs. No tendencies to under- or overprediction within different classes of drugs were noted. The results demonstrate a significant relationship between toxicity in vitro and achievable systemic exposure of anticancer drugs in humans, which suggests that non-clonogenic in vitro assays for drug sensitivity testing may provide pharmacokinetic information useful in the development of investigational cytotoxic drugs.
Administration, Oral↗
Cytotoxic effect of calcein acetoxymethyl ester on human tumor cell lines: drug delivery by intracellular trapping.
Calcein acetoxymethyl ester (calcein/AM) and some related cellular dyes with a cytoplasmic distribution were investigated with respect to cellular hydrolysis, accumulation, efflux and cytotoxicity in a panel of established human cell lines, including multidrug resistant (MDR) phenotypes. At 0.1-1 micrograms/ml, calcein/AM was highly cytotoxic against several cell lines, even after short-term exposure (30 min). Calcein/AM induced no immediate loss (3 h) of membrane integrity and the drug was more active against low compared with high density plated cells. In cell lines with the MDR phenotype and in the renal carcinoma cell line ACHN, the drug was considerably less active. Non-esterified calcein had no effect and calcein/AM was significantly more potent than other structurally related fluorescein analogs and AM esters tested. Although MDR cell lines showed a decreased cellular hydrolysis and accumulation of the dye, there was no strict relationship between cytoplasmic calcein exposure and cytotoxic activity. The rate of efflux was low in the two most sensitive cell lines, the human lymphoma U-937-GTB and its vincristine (vcr) resistant subline U-937/vcr10, while the remaining cell lines showed similar biphasic efflux patterns, including cell lines of the MDR phenotype. The results show that calcein/AM has cytotoxic activity against human tumor cell lines at low concentrations. The effect appears dependent on the intracellular trapping of the drug, although the specific cellular target remains unknown. Due to its cytotoxic efficacy and unique principle of cellular drug delivery, further investigation of calcein/AM and related compounds as potentially new anticancer agents seems warranted.
Antineoplastic Agents↗
Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors.
Gemcitabine (2'-deoxy-2',2'-difluorocytidine; dFdC) is a novel nucleoside analog that has shown clinical activity against solid tumors. The semiautomated fluorometric microculture cytotoxicity assay (FMCA) was used for evaluation of the cytotoxicity of gemcitabine in vitro in primary cultures of human cells from patients with hematologic or solid tumors. The activity pattern of cytarabine (ara-C), 2-chlorodeoxyadenosine (CdA), etoposide (VP-16), doxorubicin, and cisplatin were included for comparison. One hundred forty samples were tested using continuous drug exposure. Gemcitabine showed high activity against hematologic samples, whereas little or no activity was observed in the solid tumor groups. A similar pattern of activity also was observed for ara-C and CdA, whereas etoposide, cisplatin, and doxorubicin were relatively more active in solid tumors. Cross-resistance analysis between gemcitabine and the standard drugs revealed the following rank order of correlation coefficients: ara-C > doxorubicin > CdA > cisplatin > VP-16. The results indicate that gemcitabine is differentially active against hematologic tumors and that the activity pattern of gemcitabine resembles that of ara-C. However, these results also indicate that gemcitabine may be more active against some solid tumor groups in comparison to ara-C and CdA.
Antibiotics, Antineoplastic↗
Subcutaneous epoetin beta in renal anemia: an open multicenter dose titration study of patients on continuous peritoneal dialysis.
OBJECTIVE: To establish dose requirements (target hemoglobin > 100 g/L) and safety of subcutaneously administered epoetin beta. DESIGN: Open multicenter study. PATIENTS: Forty-five anemic patients (21 female, 24 male; mean age 55 years; range 20-79 years) who had been on continuous peritoneal dialysis for 1-157 months (mean 24 months). Thirty patients required blood transfusions during the year prior to the study. Mean hemoglobin concentration pretreatment was 75 g/L (range 57-89 g/L). INTERVENTION: After a pretreatment period of two weeks, 60 IU kg-1 week-1 divided into three weekly doses of epoetin beta was administered subcutaneously. The dose was increased by 60 IU kg-1 week-1 after ten weeks, and when necessary, every fourth week in patients with hemoglobin levels below 100 g/L. MAIN OUTCOME MEASURES: Hemoglobin concentration. Analysis of factors affecting the response to epoetin beta. Safety of epoetin beta. RESULTS: Thirty-eight of the 45 patients completed six months and 21 patients completed one year in the study. Twenty-six patients reached hemoglobin 100 g/L within six months and 8 patients did later on. The mean hemoglobin concentration after three months was 93 g/L (range 64-144 g/L) and after six months was 99 g/L (range 59-130 g/L; mean epoetin beta dose 122 IU kg-1 week-1). During the second six-month period of the study, hemoglobin levels were stable in most patients. After one year, the mean hemoglobin was 110 g/L (range 84-153 g/L) and the mean epoetin beta dose was 107 IU kg-1 week-1. Prolonged correction time and impaired response to epoetin were observed in patients with infections or hemorrhages and in patients with low hemoglobin concentration before starting epoetin treatment. Iron deficiency was controlled by iron supplementation, either orally or, in 10 patients, intravenously. Increased blood pressure, requiring intensified antihypertensive treatment, was observed in 13 patients. CONCLUSIONS: Continuous peritoneal dialysis patients with moderate anemia (Hb 75-90 g/L) and without complicating disorders can be managed with subcutaneous doses of epoetin < 120 IU kg-1 week-1. The epoetin beta dose should be adjusted after the first month of treatment since most patients required higher doses than the initial 60 IU kg-1 week-1.
Anemia↗
Cytotoxic activity of topoisomerase II inhibitors in primary cultures of tumor cells from patients with human hematologic and solid tumors.
BACKGROUND: Little is known about the in vitro activity and cross-resistance patterns of topoisomerase II (topo II) inhibitors in primary cultures of tumor cells from patients with different diagnoses. METHODS: The in vitro activity of the topo II inhibitors daunorubicin, doxorubicin, idarubicin, epirubicin, amsacrine, mitoxantrone, and etoposide was determined using the fluorometric microculture cytotoxicity assay. Four hundred seventy-six samples from patients with various diagnoses were tested with continuous drug exposure. RESULTS: Hematologic samples were more sensitive than solid tumors to all tested drugs. Etoposide was the most active drug in solid tumors followed by epirubicin, with amsacrine the least active. The anthracyclines doxorubicin, daunorubicin, and epirubicin showed similar in vitro activity. Conversely, idarubicin showed low to moderate cross-resistance with all tested topo II inhibitors. Mitoxantrone and amsacrine showed high in vitro activity and displayed cross-resistance to the anthracyclines in the hematologic neoplasms. In the solid tumor group, mitoxantrone and amsacrine had lower activity and weak correlations with the anthracyclines. Etoposide had intermediate to weak correlations with the other drugs. CONCLUSIONS: There is a marked difference in tumor-type specificity and cross resistance patterns among the different topo II inhibitors tested. This may indicate that minor differences in topo II interaction and/or other mechanisms of drug action may substantially determine the cytotoxic activity of topo II-targeted drugs.
Antineoplastic Agents↗