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R Larsson

Publications and source records attributed to R Larsson.

At least 73 records · Page 4Linked to original sources
PubMed1999

Relationship between diagnosis-specific activity of cytotoxic drugs in fresh human tumour cells ex vivo and in the clinic.

The aim of this investigation was to evaluate the relationship between the disease-specific activity of cytotoxic drugs in the clinic and in fresh human tumour cells from patients, as detected by a non-clonogenic cytotoxicity assay. The activity of 18 different cytotoxic drugs in fresh human tumour cells ex vivo was analysed in up to 15 samples from each of 13 different diagnoses using the fluorometric microculture cytotoxicity assay (FMCA). For each drug and diagnosis, relative activity indices (RAIs) were calculated, defined as the fraction of samples within the diagnosis having a survival index (SI) less than the median SI for the drug in all tested samples. Clinical response rates for the drug in the same diagnoses were collected from published phase II trials and were compared with the RAIs using Spearman's rank correlation (Rho) and Pearson's correlation coefficient (R). Correlation coefficients could be calculated for 12 drugs. The coefficients varied between 0.02 and 0.92 (Rho) and between 0.07 and 0.91 (R), but for most drugs the correlation between RAI and clinical response rates was good, with Rho > 0.6 and R > 0.7. Weak correlations were observed for cyclophosphamide and vincristine (Rho = 0.32 and 0.16, respectively), which might be due to old clinical data, and for paclitaxel (Rho = 0.02), which perhaps could be explained by in vitro activity of the solvent, Cremophor EL. The 18 drugs were also categorised according to their suggested clinical use in solid or haematological tumours, and were then compared regarding the activity in solid compared with haematological tumours ex vivo, expressed as the ratio between the number of responders among solid and haematological tumours (S/H ratio). The mean ex vivo S/H ratios in the group of drugs registered for use in haematological tumours was only 0.09 and was significantly different (P = 0.05) from the mean S/H ratios for the drugs used in both haematological and solid tumours (0.31) and in solid tumours only (0.47). Furthermore, the FMCA could identify the 50% most and least sensitive diagnoses with respect to clinical phase II activity with 74% (78/106) correct classifications. The results indicate that the relative activity of cytotoxic drugs in different diagnoses may be detected by the FMCA. Thus, 'phase II trials ex vivo' using non-clonogenic cytotoxicity assays might be used to make clinical trials more effective by targeting trials to diagnoses in which a new agent is most likely to be active.

Antineoplastic Agents↗
PubMed1999

Evaluation of purine and pyrimidine analogues in human tumor cells from patients with low-grade lymphoproliferative disorders using the FMCA.

The purine analogues fludarabine and cladribine (CdA) have recently become established to be effective treatment for low-grade non-Hodgkin's lymphoma (NHL). The pyrimidine nucleoside analogue cytarabine (AraC) has an important place in the treatment of acute leukemia, and gemcitabine is a new pyrimidin antimetabolite which has shown clinical activity against solid tumors. We have used the semiautomated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA), to study these drugs. Eighty samples from 60 patients with low-grade NHL were studied. Fifty samples from patients with acute lymphoid leukemia (ALL) and 118 samples from patients with acute myeloid leukemia (AML) were included for comparison. The results indicate that the purine- and pyrimidine nucleoside analogues tested may be as active against low-grade NHL as against acute leukemia. In low-grade NHL, AraC seems to be even more active in comparison to CdA (p=<0.0001) and fludarabine (p=0.001). Untreated patients were more drug sensitive than previously treated patients. Gemcitabine showed the highest correlation with AraC (0.90) whereas CdA showed the highest correlation with fludarabine (0.84). Based on these results we propose that AraC and gemcitabine may have a role in the treatment of low-grade NHL.

Acute Disease↗
PubMed1999

The plasma levels of homocysteine are elevated in moderate renal insufficiency but do not predict the rate of progression.

BACKGROUND: Chronic renal failure is characterized by specific alterations of the lipoprotein metabolism. It is also characterized by elevated plasma levels of total homocysteine (tHcy). Hyperhomocysteinemia has been shown to be a risk factor for atherosclerosis in both the general population and in patients with end-stage renal disease. AIM: To analyze whether elevated tHcy levels also may contribute to a higher rate of progression of renal insufficiency in patients with moderately advanced renal failure. METHODS: To investigate whether tHcy concentrations are associated with an accelerated rate of progression of renal insufficiency, we have correlated baseline plasma concentrations of tHcy with the progressive decline of renal function in an observational study of human chronic renal disease. RESULTS: Sixty-three nondiabetic patients (49 men, 14 women) were studied as part of an observational study of patients with moderately advanced renal insufficiency. The average follow-up time of the patient population was 3.0 years, and the mean rate of decline in glomerular filtration rate ((51)Cr- EDTA clearance) was -3.2 +/- (SD) 3.9 ml/min x 1.73 m(2) body surface area. The mean plasma concentration of tHcy at the beginning of the study was 28.3 +/- 12.0 micromol/l. Plasma tHcy concentrations correlated significantly with the glomerular filtration rate (r = -0. 32, p < 0.01). However, there was no association between the initial plasma level of tHcy and the rate of progression as assessed by linear regression analysis (r = 0.02; NS). In contrast, increased levels of apolipoprotein B, low-density lipoprotein cholesterol, and proteinuria were all significantly associated with a more rapid decline in renal function. CONCLUSIONS: Patients with moderately advanced chronic renal insufficiency have elevated plasma levels of homocysteine. The tHcy plasma levels increase in parallel with the degree of reduction in renal function. However, the hyperhomocysteinemia is not prospectively associated with a higher rate of progression of the renal functional impairment. Hence, there is no indication that elevated homocysteine levels play a contributing role for an accelerated glomerulosclerotic process.

Adult↗
PubMed1999

Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation?

The remarkable difference in success rates between clinical pancreas transplantation and islet transplantation is poorly understood. Despite the same histocompatibility barrier and similar immunosuppressive treatments in both transplantation procedures, human intraportal islet transplantation has a much inferior success rate than does vascularized pancreas transplantation. Thus far, little attention has been directed to the possibility that islets transplanted into the blood stream may elicit an injurious incompatibility reaction. We have tested this hypothesis in vitro with human islets and in vivo with porcine islets. Human islets were exposed to nonanticoagulated human ABO-compatible blood in surface-heparinized polyvinyl chloride tubing loops. Heparin and/or the soluble complement receptor 1 (sCR1) TP10 were tested as additives. Adult porcine islets were transplanted intraportally into pigs, and the liver was recovered after 60 min for immunohistochemical staining. Human islets induced a rapid consumption and activation of platelets. Neutrophils and monocytes were also consumed, and the coagulation and complement systems were activated. Upon histological examination, islets were found to be embedded in clots and infiltrated with CD11+ leukocytes. Furthermore, the cellular morphology was disrupted. When heparin and sCR1 were added to the blood, these events were avoided. Porcine islets retrieved in liver biopsies after intraportal islet allotransplantation showed a morphology similar to that of human islets perifused in vitro. Thus, exposure of isolated islets of Langerhans to allogenic blood resulted in significant damage to the islets, a finding that could explain the unsatisfactory clinical results obtained with intraportal islet transplantation. Because administration of heparin in combination with a soluble complement receptor abrogated these events, such treatment would presumably improve the outcome of clinical islet transplantation by reducing both initial islet loss and subsequent specific immune responses.

Adult↗
PubMed1999

Titanium is a highly thrombogenic biomaterial: possible implications for osteogenesis.

Titanium has superior osteointegrating properties compared to other biomaterials. The mechanism for this is unknown. During the initial phase of bone implantation the biomaterial comes into direct contact with whole blood. In this study we use a newly developed in vitro chamber model to compare different commonly used biomaterials in contact with whole blood. These materials were selected with respect to their different osteointegrating properties in order to correlate these properties with the response to whole blood. In the presence of 3 IU/ml of heparin only titanium induced macroscopic clotting. This was reflected by the generation of thrombin-antithrombin which was much increased in blood in contact with titanium compared with steel and PVC. The coagulation activation caused by titanium was triggered by the intrinsic pathway because the generation of FXIIa-AT/C1 esterase inhibitor paralleled that of thrombin-antithrombin, and both thrombin-antithrombin complex and FXIIa-AT/C1 esterase inhibitor generation were abrogated by corn trypsin inhibitor, which is a specific inhibitor of FXIIa. The binding of platelets was increased on the titanium surface compared to the other biomaterial surfaces and the state of platelet activation was much more pronounced as reflected by the levels of beta-thromboglobulin and PDGF. This study indicates that titanium is unsuitable as a biomaterial in devices which are in direct contact with blood for a prolonged period. Furthermore, PDGF and other alpha-granule proteins e.g. TGF-beta, are known to be potent promotors of osteogenesis which suggests that the pronounced thrombogenic properties of titanium might contribute to the good osteointegrating properties.

Blood Coagulation↗
PubMed1999

Pharmacokinetic models for the saturable distribution of paclitaxel.

Paclitaxel pharmacokinetics are nonlinear with saturable metabolism and saturable distribution to the tissues. The saturable distribution has in previous pharmacokinetic modeling been described as a saturable transport process, whereas the present study was undertaken to investigate alternative explanations. Using a sparse sampling scheme (on average 3.3 samples per profile), 101 plasma concentration-time profiles in 22 female patients with metastatic cancer of the breast or ovary were monitored. It was found that the observed data could be equally well described by saturable tissue binding as well as by capacity-limited tissue transport. The data were better described by a model where equilibrium was achieved with drug in the central rather than in the peripheral compartment. Models where the binding was assumed to be an instantaneous or a noninstantaneous process were tried, but the data did not allow resolution between these two possibilities. The value at which the saturable transport was half-maximal was 0.55 microM. The K(d) values of the binding models were 0.06 to 0.12 microM. These are close to the values reported as a threshold for drug toxicity of paclitaxel, suggesting a possible connection between the binding sites involved in the pharmacokinetics and the mechanism responsible for the toxicity. For all models, a saturable elimination of paclitaxel was included using the Michaelis-Menten model. K(m) for the elimination ranged in the different models from 2.5 to 5.6 microM.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Heparin-Coated Coronary Stents.

The development of the heparin-coated (HC)-stent should be viewed against the backdrop of the early unfavorable results with noncoated stents in the pre-intravascular ultrasound and pre-ticlopidine era. Notwithstanding, results of pilot and randomized trials show a surprisingly low incidence of (sub)acute stent thrombosis under challenging circumstances, such as acute coronary syndromes. Considering the quite low incidence of early complications with noncoated second-generation stents, it may require large trials to prove the clinical efficacy of the heparin- coating against noncoated devices. However, even if the "added value" of the heparin-coating will never be clinically proven, it has helped to enhance the penetration of stent therapy in interventional cardiology. Unlike the situation in 1992, very few cardiologists will now disagree with the statement that stents contribute to the state-of-the-art treatment of patients with angina pectoris or acute myocardial infarction. A preliminary comparison of available trials also suggests that the heparin-coated Palmaz-Schatz stent (Cordis Corp., Waterloo, Belgium) is as effective as the noncoated stent plus abciximab treatment.

Journal Article↗
PubMed1998

Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation.

Recently, a C3-binding cyclic synthetic peptide (Compstatin) has been identified that binds to complement component C3 and inhibits complement activation. Here we have examined the influence of Compstatin on complement activation and its indirect effects on cellular responses in whole blood in two models for extracorporeal circulation. Compstatin effectively inhibited the generation of C3a and sC5b-9 and the binding of C3/ C3 fragments to the polymer surface. As a result of the inhibition of complement activation, the activation of polymorphonuclear leukocytes (PMNs; as assessed by the expression of CD11b) and the binding of these cells (CD16(+)) to the polymer surface were almost completely lost. In contrast, blood cell counts were not affected. Using surface plasmon resonance technology, we have confirmed that Compstatin exerts its inhibitory effect on complement activation by binding to native C3. These data show that complement activation, leading to activation and binding of PMNs to the biomaterial surface, can be abolished by the addition of Compstatin. The properties of Compstatin make Compstatin a promising drug for use in extracorporeal circuits to avoid bioincompatibility reactions, eg, during cardiopulmonary bypass, but also a favorable precursor peptide for the development of an anticomplement drug for oral use.

Amino Acid Sequence↗
PubMed1998

Relationship between cytotoxic drug response patterns and activity of drug efflux transporters mediating multidrug resistance.

Drug activity patterns in 10 human tumor cell lines representing defined mechanisms of drug resistance, including cell lines with high expression of P-glycoprotein and multidrug resistance associated protein (MRP), have previously been used for prediction of mechanism of drug action. In the present study, this cell line panel was analyzed for cellular accumulation of the fluorescent probe calcein/AM [4'5'-bis(N,N-bis (carboxymethyl) aminomethyl) fluorescein acetoxymethyl ester] and compared with drug response patterns of 20 standard chemotherapeutic drugs. According to degree of correlation with the ability to exclude calcein/AM, topoisomerase II inhibitors and tubulin actives were at the top of the list although the correlations were of lower magnitude than those obtained from the drug response patterns of mechanistically similar drugs. There was a significant relationship between the rank-order of drugs based on correlation with calcein/AM accumulation and Pgp/MRP mediated drug resistance suggesting that compounds being substrates for these pumps were identified. In simulated drug response profiles, the impact of Pgp and MRP expressing cell lines on the mechanistic prediction was found to be marginal. The results indicate that the differential molecular function/expression in the cell line panel may identify drugs interacting with specific biochemical pathways. Furthermore, the presence of cell lines overexpressing drug efflux mechanisms in the panel do not significantly influence the mechanistic predictions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Synergistic interactions of combinations of topotecan with standard drugs in primary cultures of human tumor cells from patients.

OBJECTIVE: Combination therapies are important in the treatment of many tumor types. This study was undertaken to find candidates for combination therapy with the novel topoisomerase I inhibitor topotecan. METHODS: The cytotoxic effect of topotecan alone and in combination with five standard cytotoxic drugs was studied in 27 primary cultures of human tumor cells from patients with various diagnoses using the fluorometric microculture cytotoxicity assay (FMCA). The combinations were analysed according to the multiplicative concept of drug interaction. RESULTS: The additive model was shown to be a better descriptor than the effect of the most effective agent (Dmax) for all drug combinations tested. Topotecan in combination with cisplatin (CisP) was the drug combination showing synergy in the highest percentage of samples (54%), followed by topotecan in combination with doxorubicin (Dox: 39%), etoposide (P16; 23%), paclitaxel in the formulation Taxol (22%) and cytarabine (AraC; 12%). The high percentage of synergistic interactions was especially pronounced in solid tumors. In 28% of the samples tested, drug sensitivity testing of only single drugs failed to predict response to the drugs in combination. CONCLUSION: Cisplatin and doxorubicin showed promising effects in combination with topotecan, and clinical trials with these combinations seem warranted. The results also indicate the value of testing drug combinations in in vitro drug sensitivity testing.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

A general model for time-dissociated pharmacokinetic-pharmacodynamic relationship exemplified by paclitaxel myelosuppression.

BACKGROUND: Hematologic toxicity after cancer chemotherapy and other drug effects that occur late compared to the exposure are usually modeled with use of some summary exposure variable such as the area under the concentration-time curve (AUC model) or the time of exposure above a threshold concentration (threshold model). An underlying assumption for both of these models is that the drug exerts a direct effect while present in the body and that it is the time integral of this direct effect that is related to the ultimate observed effect, either linearly (AUC model) or by a step function (threshold model). We propose a more general model that allows this relationship to be characterized by a nonlinear continuous function. METHODS: Data on survival fraction of neutrophiles and time course of leukopenia from 92 courses of paclitaxel therapy in 21 patients with breast or ovarian cancer was related to paclitaxel concentration-time profiles with the AUC, threshold, and general models. The properties of the general model were also investigated with use of simulations. RESULTS: For both pharmacodynamic end points, the general model described the data significantly better than the AUC or threshold models. CONCLUSION: The general model is an extension to the present way of relating concentration-time profiles to late-effect measures, and it may provide an improved description of the concentration-response relationship and more accurate predictions of the ultimate effect when doses and schedules are varied. It can explain complex relationships between concentration-time profiles and the observed effect, and predictions from it lack some of the counterintuitive properties that the AUC or threshold model have when extrapolations are made.

Antineoplastic Agents, Phytogenic↗
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↗
PubMed1998

Intestinal microsporidiosis in a HIV-seronegative patient.

Microsporidial infections have been increasingly reported in immunocompromised patients, particularly those infected with the human immunodeficiency virus (HIV), but only rarely in immunocompetent individuals. We report a case of intestinal microsporidiosis in a HIV-seronegative patient with acute self-limited diarrhoea. Examination of stool specimens revealed plenty of spores that correspond with Enterocytozoon bieneusi in size and shape as well as ultrastructural details.

Adult↗
PubMed1998

Effects of ticlopidine in AV-fistula surgery in uremia. Fistula Study Group.

Two hundred and fifty-eight patients with uremia who were offered surgery for placement of an arteriovenous fistula for hemodialysis were recruited in nine regional dialysis centers. The patients were randomized to receive the platelet aggregation inhibitory compound ticlopidine, 250 mg b.d., or matching placebo. Study medication was targeted at 7, minimum 3, days before scheduled surgery and continued for 28 days after surgery. The overall rate of occlusion was 41/260 evaluable operations (16%), 25/131 (19%) in the placebo group and 16/129 (12%) in the ticlopidine group. The risk of early occlusion was a non-significant 35% lower in the ticlopidine group. Limited risk factor analysis did not clearly identify any subgroup other than females at greater risk of early thrombosis nor any subgroup deriving particular benefit from ticlopidine treatment.

Adult↗
PubMed1998

Visualization of chronic neck-shoulder pain: impaired microcirculation in the upper trapezius muscle in chronic cervico-brachial pain.

This study pertains to the 71 patients who had received a diagnosis of cervico-brachial pain syndrome after thorough clinical examination of a total series of 300 patients, who had been referred to the National Insurance Hospital in Tranås because of chronic neck pain that interfered with their ability to work. Changes in trapezius muscle blood flow and EMG were examined and related to the anamnesis and physical findings. The microcirculation in the upper part of the right and left trapezius muscles was examined simultaneously by using optical laser-Doppler single-fibres after insertion into the muscle directly via the skin. Continuous recordings were made during stepwise increased static contraction determined electro-myographically. Signal processing was performed on-line by computer. MRT of the cervical spine was performed in 12 patients. None showed nerve root affliction. Ten showed a bulging intervertebral disc and two, a narrowed nerve hole (lateral stenosis). The muscle blood flow (LDF) was significantly lower in the most painful side compared with the opposite side in the group of 41 patients with predominantly unilateral pain (21 women and 20 men). A lowered blood flow was also found when the 21 females in this group was compared with a normal control group of 20 healthy women. The patients had lower rms-EMG and EMG mean power frequency (MPF) in the painful side compared with the opposite side. A further lowering of the MPF was observed with induced fatigue. It was concluded that the chronic neck pain in cervico-brachial syndrome can become visualized by the finding of lowered blood flow of the trapezius muscle which seems to be an expression of the chronic neck pain.

Adult↗
PubMed1998

Bicarbonate and bicarbonate/lactate peritoneal dialysis solutions for the treatment of infusion pain.

A randomized, double-blind, cross-over study was undertaken to determine the effects of novel bicarbonate (38 mM) and bicarbonate (25 mM)/lactate (15 mM) containing peritoneal dialysis (PD) solutions on infusion pain in patients who experienced inflow pain with conventional lactate (40 mM) solution. Pain was assessed using a verbal rating scale and the validated McGill Pain Questionnaire (MPQ). Eighteen patients were recruited to the study. Both novel solutions resulted in highly statistically significant reductions in inflow pain compared to the control lactate solution, as assessed with both the verbal rating scale and the MPQ. For all pain variables assessed, the bicarbonate/lactate solution was more effective than the bicarbonate solution in alleviating pain. In conclusion, both solutions reduced the infusion pain experienced with control solution, but the bicarbonate/lactate solution appears to be the most effective. In contrast to the most widespread current treatment, which is the manual injection of sodium bicarbonate, the bicarbonate/lactate solution does not have the associated increased risk of peritonitis.

Bicarbonates↗
PubMed1998

Complex apolipoprotein B-containing lipoprotein particles are associated with a higher rate of progression of human chronic renal insufficiency.

Chronic renal failure is characterized by specific alterations of the lipoprotein metabolism. It has been suggested that renal dyslipoproteinemia contributes to the progression of renal dysfunction. The objective of this study was to investigate the impact of different apoB-containing lipoprotein families on the progressive decline of renal function in patients with moderately advanced chronic renal failure. As part of a larger prospective study, 44 adult nondiabetic patients with primary chronic renal disease were followed with repeated GFR measurements for an average of 2.4 (SD 1.0) yr. Patients' characteristic variables, including plasma levels of lipids, apolipoproteins (apo), and apoA- and apoB-containing lipoprotein families (LP), were determined at the beginning of the observation period. The baseline variables were prospectively related, using linear regression, to the rate of progression (deltaGFR). The patient study group had a mean GFR at baseline of 40.3 (SD 16.7) ml/min per 1.73 m2 body surface area. The average rate of progression was a yearly decline in GFR of -3.2 (SD 5.1) ml/min per 1.73 m2 body surface area. A strong association was observed between the plasma concentration of complex, triglyceride-rich apoB-containing lipoproteins (LP-Bc) and the rate of progression (r=0.43, P < 0.01), whereas there was no association between the cholesterol-rich apoB-containing lipoproteins (LP-B) and deltaGFR. The association between the levels of LP-Bc and the rate of progression was not dependent on the baseline values of GFR, BP, and the degree of proteinuria. The results of this study extend earlier observations regarding the importance of renal dyslipoproteinemia for progressive renal insufficiency. In particular, elevated levels of intact or partially metabolized triglyceride-rich apoB-containing lipoproteins of intermediate- and low-density ranges seem to promote the progression of human renal insufficiency.

Adult↗