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R Larsson

Publications and source records attributed to R Larsson.

At least 91 records · Page 5Linked to original sources
PubMed1998

Microphysiometry: new technology for evaluation of anticancer drug activity in human tumor cells in vitro.

Microphysiometry is a non-invasive, physiological method where measurement of metabolic activity can be made on living human tumor cells. Indirect measurement of the extracellular acidification is measured over a pH-sensitive silicon membrane. In this study microphysiometry was employed for the study of cytotoxic agents used in therapy of cancer. Standard cytotoxic drugs with different postulated mechanisms of action were investigated using cell lines as well as primary cultures of patient tumor cells. Each investigated cytotoxic drug induced a characteristic pattern of metabolic activity. From these patterns, key features, like stimulation and inhibition of acidification, the time point when the response curves of the drugs fall below the control curve, and the maximum inhibition of acidification at 20 h, could be quantified. Most of the investigated drugs showed some initial stimulation of acidification rate during the experiments. For drugs producing a reduced metabolic rate at 20 h a concentration-response relationship was observed. The drug effects measured at 20 h were irreversible and correlated reasonably well with parallel measurements of membrane integrity using a standard cytotoxicity test. The results demonstrate the feasibility of 'on-line' measurements of metabolic activity using this approach and also revealed an unexpected variety of drug response profiles.

Antineoplastic Agents↗
PubMed1997

Renal elimination of islet amyloid polypeptide.

Six healthy volunteers showed significantly higher plasma islet amyloid polypeptide levels following an oral glucose tolerance test compared to fasting levels. The urine IAPP concentration before and after the OGTT was comparable to that in plasma. Reverse phase HPLC and radioimmunoassay analysis of urine samples revealed a single IAPP-immunoreactive peak. Before hemodialysis, the plasma levels of IAPP and C-peptide, but not of insulin, were significantly elevated in eight fasting patients with chronic renal failure, compared to eight healthy matched control subjects. After hemodialysis, there was a tendency for decreased IAPP levels compared to before dialysis. In summary, elevated levels of plasma IAPP were found in patients with chronic renal failure and the peptide is eliminated by hemodialysis. Furthermore, immunoreactive IAPP is normally present in the urine. These results suggest that IAPP is, at least in part, renally eliminated from the plasma by excretion (glomerular filtration and/or tubular secretion.

Adult↗
PubMed1997

In vitro determination of cytotoxic drug response in ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA).

The fluorometric microculture cytotoxicity assay (FMCA), a short-term in vitro assay based on the concept of total tumor cell kill, was used for testing the cytotoxic drug sensitivity of tumor cells from patients with ovarian carcinoma. A total of 125 fresh specimens was obtained, 98 (78%) of which were analyzed successfully. Data from 45 patients were available for clinical correlations. The FMCA appeared to yield clinically relevant cytotoxic drug sensitivity data for ovarian carcinoma as indicated by a comparison with tumor samples obtained from patients with non-Hodgkin's lymphoma or kidney carcinoma. Considering the most active single agent in vitro actually given in vivo, and using the median drug activity among all ovarian carcinoma samples as a cut-off, the sensitivity of the assay and its specificity were 75 and 52%, respectively. Cross-resistance in vitro was frequently observed between standard drugs but not between standard drugs and Taxol. Ten percent of the specimens showed an extreme resistance for at least 4 of 6 of the drugs investigated.

Antineoplastic Agents↗
PubMed1997

Differential activity of Cremophor EL and paclitaxel in patients' tumor cells and human carcinoma cell lines in vitro.

BACKGROUND: Previous studies indicate that Cremophor EL (CEL), the excipient for Taxol, a clinical preparation of paclitaxel, has biologic properties per se. METHODS: The cytotoxic activity of Taxol and its solvents CEL/ethanol, paclitaxel in ethanol, and 14 other cytotoxic drugs was investigated in vitro in 10 human carcinoma cell lines and 183 tumor samples from patients with tumors of various types. Cytotoxicity was determined by the fluorometric microculture cytotoxicity assay. RESULTS: In the cell lines, Taxol was generally more active than paclitaxel; this may have been due to an additive effect of the diluent. This activity was pronounced in sublines expressing tubulin-associated and P-glycoprotein-mediated drug resistance, indicating involvement of these mechanisms in paclitaxel resistance and their modulation by CEL. Taxol and paclitaxel were highly cross-resistant to other tubulin-active agents, whereas the low cytotoxic effect of CEL seemed unrelated to other drugs. In the samples from patients, Taxol was less active than in the cell lines but showed a differential activity that corresponded reasonably well with that in the clinic. CEL and Taxol were similarly active, indicating that paclitaxel did not add substantially to the activity of Taxol. CONCLUSIONS: Whereas the cell line data clearly confirmed the well-known properties of paclitaxel, a more valid model using tumor cells from patients demonstrated that CEL significantly contributes to the efficacy of Taxol in vitro. The clinical relevance of this finding remains to be elucidated.

Antineoplastic Agents↗
PubMed1997

Pharmacokinetics and effect of ticlopidine on platelet aggregation in subjects with normal and impaired renal function.

The pharmacokinetics and the effect of ticlopidine on platelet aggregation were determined in patients with chronic renal failure (n = 6), who were not on dialysis and had glomerular filtration of 16.9 +/- 4.4 mL/min, and were matched with the pharmacokinetics and effects in healthy volunteers (n = 7). Participants were studied after acute oral administration of ticlopidine at the beginning of the study and after 36 days of treatment with 250 mg twice daily. For unchanged ticlopidine there were no significant differences between the concentration profiles for the two study groups. By day 36 the minimum concentrations in plasma were identical (0.35 +/- 0.22 mg/L and 0.36 +/- 0.21 mg/L, respectively). Using 14C-labeled ticlopidine, the concentration profiles of radioactivity on day 1 were similar to those on day 36 for both groups. However, maximum concentrations and area under the concentration-time curve at 72 hours were both higher in patients with renal failure than in healthy volunteers. Treatment with ticlopidine progressively decreased sensitivity to adenosine diphosphate-induced platelet aggregation. At day 36, the concentration of adenosine diphosphate required to achieve 50% platelet aggregation was approximately 2.5 times greater than before treatment. Both patients and healthy volunteers exhibited closely comparable changes. The response to collagen-induced platelet aggregation was not changed in patients by treatment with ticlopidine. In contrast, volunteers required a three- to fourfold increase in collagen concentration to achieve 50% platelet aggregation after 36 days of therapy. Although some differences in both pharmacokinetics and pharmacodynamics of ticlopidine have been demonstrated between patients and and healthy volunteers, results in this study demonstrated that a change of dosage is not required in renal failure.

Adult↗
PubMed1997

A new fluorometric assay for determination of osteoblastic proliferation: effects of glucocorticoids and insulin-like growth factor-I.

A novel fluorometric proliferation assay, AlamarBlue (AB), was used to study the proliferative capacity of isolated human osteoblasts (hOBs). AB is an oxidation-reduction indicator that yields a fluorescent signal in response to metabolic activity. The assay was performed by replacing the experiment media in a microtiter plate with a 10% AB solution and measuring fluorescence after a 3-8-hour incubation. The assay was optimized with respect to incubation time, cell density, and AB concentration. When the results of the AB assay were compared with cell counting in a Bürker chamber there were consistently good correlations (r > 0.9), regardless of the agonist with which the cells were treated. The mean intraassay coefficient of variance (CV) values were 9.9-11.8% in experiments where osteoblasts were treated for 12 days with insulin-like growth factor-I (IGF-I; 100 nM), or dexamethasone (1 micro;M). IGF-I dose dependently, at and above 1 nM, stimulated proliferation of hOBs. This effect was detectable after 3 days and reached 130-140% of untreated controls after 12 days in culture. The effects of dexamethasone (DEX) on the proliferation rate of hOBs were more complex. In short-term cultures, 3 days, DEX dose dependently stimulated proliferation. However, at and above 6 days, DEX exerted a biphasic effect, with stimulation seen at 1-10 nM and a marked inhibition of cell proliferation at and above 100 nM. dexamethasone, hydrocortisone, prednisolone, and deflazacort had almost identical biphasic effects on osteoblastic proliferation in 12 day cultures with a stimulation seen at 1-10 nM, and a marked inhibition down to 50-60% of untreated controls at and above 100 nM. When IGF-I (0. 1-100 nM; 12 day culture) was combined with different doses of DEX, IGF-I still dose dependently stimulated the proliferation rate in hOBs regardless of the amount of DEX added. The stimulatory effect of DEX (10 nM, 12 days culture) was additive to the effect of 100 nM IGF-I. We conclude that AB is an easy and reliable assay for osteoblastic cell proliferation, well suited for large scale studies of cell growth using small amounts of cells, and that IGF-I partly reverses the glucocorticoid-induced inhibition of osteoblastic proliferation.

Cell Division↗
PubMed1997

Cytotoxic activity of cyclosporin A and [3-keto-Bmt1]-[Val2]-cyclosporin (SDZ PSC 833) on tumour cells from patients with haematological malignancies.

OBJECTIVE AND METHOD: The fluorometric microculture cytotoxic assay was employed for characterisation of the cytotoxic effect of cyclosporin A (CsA) and its non-immunosuppressive analogue SDZ PSC 833, [3-keto-Bmt1]-[Val2]-cyclosporin (PSC) in tumour cells from patients with haematological or solid tumours. RESULTS: Tumour cells from patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin's lymphoma (NHL) were found to be more sensitive to both drugs than those of tumour cells from patients with acute lymphocytic leukemia (ALL), acute myoblastic leukaemia (AML) and various solid tumours. There was a close correlation between the effects of the two drugs (correlation coefficient 0.71), but CsA was slightly more active than PSC in most diagnoses. No tumour cells sample showed sensitivity to PSC without also being sensitive to CsA. There was a moderate level of correlation between the activity pattern of CsA and doxorubicin (correlation coefficient 0.66), whereas the correlations with other cytostatics, such as vincristine, cytarabine and melphalan, were low (correlation coefficient -0.11 to 0.33). CONCLUSION: The results indicate that PSC shares the direct cytotoxic properties of CsA, but is slightly less potent. Clinical testing of the cytotoxic effect of these agents in haematological malignancies seems warranted and the apparent non-cross-resistance with standard agents makes cyclosporins a potentially useful adjunct to chemotherapy in those diagnoses.

Antineoplastic Agents↗
PubMed1997

Inhibition of complement activation by soluble recombinant CR1 under conditions resembling those in a cardiopulmonary circuit: reduced up-regulation of CD11b and complete abrogation of binding of PMNs to the biomaterial surface.

The influence of soluble recombinant CR1 (sCR1) on complement activation, and its indirect effects on the coagulation system and cellular responses were assessed in two models for the study of blood/surface and blood/air interactions, as are encountered in e.g. cardiopulmonary bypass circuits. The concentrations of C3a and sC5b-9 and the amount of bound C3/C3 fragments were analyzed as indicators of complement activation. Thrombin-antithrombin complexes, the platelet count, surface-ATP, beta-thromboglobulin, and the expression of CD11b on leukocytes were the parameters analyzed to reflect coagulation and cellular responses. In addition, immunochemical analyses of the phenotypes of surface-bound leukocytes and platelets were performed. Recombinant sCR1, at doses ranging between 0.1-0.25 mg/ml, was found to completely inhibit the generation of sC5b-9, and of C3a by two thirds; the binding of C3 and/or C3 fragments to the surface was almost entirely abolished. As a result of the inhibition of complement activation, the expression of CD11b on PMNs, and the binding of these cells to the biomaterial surface was almost completely lost. In contrast, the thrombin-antithrombin complexes, the platelet count, and the adherence of platelets to the surface, as reflected by the ATP binding and the release of beta-thromboglobulin, were not affected. These data show that complement activation, in association with extra-corporeal treatment, causes activation and binding of PMNs to the biomaterial and that these effects can be completely abolished by the addition of soluble recombinant sCR1.

Biocompatible Materials↗
PubMed1997

Cytotoxic activity of topotecan in human tumour cell lines and primary cultures of human tumour cells from patients.

The cytotoxic activity and cross-resistance pattern of the novel topoisomerase I inhibitor topotecan (Topo) were investigated in ten cell lines, representing different mechanisms of cytotoxic drug resistance, and in 218 fresh human tumour samples using the fluorometric microculture cytotoxicity assay (FMCA). Resistance to Topo in the cell lines was associated with expression of the multidrug resistance-associated protein (MRP), whereas the cell lines with P-glycoprotein (P-gp), topoisomerase II and glutathione-associated resistance did not show decreased sensitivity to the drug. Topo was more active in haematological than in solid tumour samples, but substantial activity was observed in carcinomas of the ovary and breast, sarcoma and childhood solid tumours. Cross-resistance to standard drugs representing different mechanisms of action was generally low in patient cells. The effect of Topo was better after longer exposure, but this time-dependent effect was largely abolished when adjustment for in vitro exposure was made. Topo showed activity both in proliferative and non-proliferative cell systems. The results indicate that Topo is insensitive to major mechanisms of resistance except for MRP. Proliferation does not seem to be necessary for the effect of Topo, and no superiority for protracted dosing schedules was observed. The results also suggest that, for example, leukaemias, lymphomas, sarcomas and childhood solid tumours may be suitable targets for future phase II trials.

Camptothecin↗
PubMed1997

Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency.

BACKGROUND: Chronic renal insufficiency is accompanied by specific alterations of the lipoprotein metabolism. It has been suggested that the renal dyslipoproteinaemia of renal insufficiency contributes to the progression of glomerular and tubular lesions, with subsequent deterioration of renal function. The objective of this prospective study was to investigate whether the specific lipoprotein abnormalities of renal insufficiency are associated with the rate of decline of renal function in patients with moderately advanced chronic renal failure. METHODS: A patient population of 73 adult non-diabetic patients with primary chronic renal disease were followed with repeated measurements of the glomerular filtration rate (GFR) for an average of 3.2 (SD 0.7) years. Forty-three of these patients had chronic glomerulonephritis as the underlying renal disease. Patient characteristics including plasma levels of lipids and apolipoproteins were determined at entry and were prospectively related, using linear regression, to the rate of progression. RESULTS: The mean GFR at entry was 41.3 (SD 15.3) ml/min x 1.73 m2 BSA. The average rate of progression was a decline in GFR of -2.8 (SD 3.7) ml/min x 1.73 m2 BSA per year. In the whole patient study group total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) were all significantly associated with a more rapid decline in renal function, whereas triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoprotein A (apoA) were not. In the more homogeneous subgroup of patients with chronic glomerulonephritis the association between dyslipidaemia and the rate of progression was even more pronounced. In this subgroup of patients also serum triglycerides and apoE were significantly associated with a higher rate of progression. Both the initial blood pressure and proteinuria were also significantly associated with a more rapid decline in renal function in the whole study group as well as in patients with chronic glomerulonephritis. The associations between these variables with the rate of progression were all independent of the entry GFR values. CONCLUSIONS: These results indicate that the lipoprotein abnormalities of renal insufficiency contribute to the progression of renal failure in human chronic renal disease.

Adult↗
PubMed1997

Effect of gemfibrozil on lipoprotein abnormalities in chronic renal insufficiency: a controlled study in human chronic renal disease.

BACKGROUND: Renal dyslipoproteinemia is characterized by the accumulation of intact and partially metabolized triglyceride-rich lipoproteins. Reduced lipolytic enzyme activities may be one of the major pathophysiological mechanisms contributing to a retarded catabolism of these lipoproteins in patients with renal insufficiency. OBJECTIVE: To evaluate the effect of gemfibrozil treatment on renal dyslipoproteinemia. STUDY DESIGN: A randomized, controlled open study with 2 parallel groups. OUTCOME VARIABLES: Plasma concentrations of lipids, apolipoproteins and lipoprotein particles. PATIENTS AND METHODS: Fifty-seven non-nephrotic, non-diabetic patients with moderately advanced renal insufficiency were randomized to either treatment with gemfibrozil at dosages from 300 to 900 mg/day (n = 28) or dietary counseling (n = 29). The intervention period was 12 months. Plasma concentrations of lipids, apolipoproteins and apoA- and apoB-containing lipoprotein particles were determined at the entry and after 6 and 12 months of treatment. RESULTS: No serious adverse effects occurred during the study. Six patients experienced mild gastrointestinal symptoms and prematurely withdrew from the drug treatment. In the group treated with gemfibrozil the plasma concentrations of triglycerides, total cholesterol, very low density lipoprotein (VLDL) and low density (LDL) cholesterol decreased significantly by 47, 13, 43 and 14%, respectively, in comparison to baseline. High density lipoprotein (HDL) cholesterol increased significantly by 18%. ApoB, apoC-III, apoC-III in heparin-manganese precipitate (reflecting apoC-III in VLDL and LDL) and apoE decreased significantly by 21, 18, 26 and 49%, respectively. Furthermore, gemfibrozil treatment resulted in the reduction of plasma concentrations of complex (LP-Bc) and simple (LP-B) apoB-containing lipoprotein particles by 22 and 7%, respectively. However, these changes were not statistically significant. There was a slight, insignificant increase in the levels of LP-A-I:A-II particles and no change in the levels of LP-A-I particles. In contrast to the effect of the pharmacological intervention, the dietary counseling only resulted in minor changes in the plasma lipid and apolipoprotein profiles. The only significant changes were a 10% increase in HDL cholesterol and a 35% decrease in apoE. CONCLUSIONS: Gemfibrozil treatment significantly reduces both plasma lipids and apoB, apoC-III and apoE concentrations in patients with moderately advanced renal insufficiency. The results of this study indicate that gemfibrozil enhances the clearance of apoB-containing triglyceride-rich lipoproteins.

Apolipoproteins↗
PubMed1996

Tubing loops as a model for cardiopulmonary bypass circuits: both the biomaterial and the blood-gas phase interfaces induce complement activation in an in vitro model.

We describe here a model for the study of blood/surface and blood/air interaction as encountered in cardiopulmonary bypass (CPB) circuits. Polyethylene tubing was filled with serum or blood and closed end to end into loops whereby the volume of the remaining air bubble was inversely varied with respect to that of the fluid. The loops were rotated vertically in a water bath at 37 degrees C. The profiles of C3a, iC3, and TCC generation were similar to those observed at surgery, involving CPB. Soluble heparin and heparan sulfate inhibited both C3a and TCC formation, but surface-conjugated heparin had only a minor effect. Binding of C3 and/or C3 fragments to the heparin surface was much reduced compared to the amine matrix to which heparin was linked, but compared with the polyethylene surface the effect was less pronounced. These data suggest that, in addition to the biomaterial surface, the blood-gas interface seems to play an important role in the activation of complement and that this activation is inhibitable by high concentrations of soluble glucose aminoglycans.

Biocompatible Materials↗
PubMed1996

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↗
PubMed1996

Cytotoxic activity of calcein acetoxymethyl ester (Calcein/AM) on primary cultures of human haematological and solid tumours.

The aim of this study was to determine the in vitro cytotoxicity of calcein acetoxymethyl ester (Calcein/AM) on primary cultures derived from solid and haematological human tumours. Calcein/AM is a fluorescent dye that localises intracellularly after esterase-dependent cellular trapping and which has shown cytotoxic activity against various established human tumour cell lines at relatively low concentrations. The semi-automated fluorometric microculture cytotoxicity assay, based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate to fluorescein, in microtitre plates was used for the evaluation of Calcein/AM activity in tumour cell suspensions from patients. The cytotoxicity was measured as a survival index (SI), defined as the fluorescence as a percentage of control cultures. A total of 163 evaluable samples from various tumours were tested with continuous drug exposure. The activity of Calcein/AM was compared with representatives of six major classes of standard chemotherapeutic drugs. Calcein/AM was found to induce concentration-dependent decreases in the SI of both haematological and solid tumour cells. The ratio of solid over haematological tumour activity increased at a rate that was concentration dependent. Although it was relatively less active than cisplatin against solid tumours, Calcein/AM showed higher solid tumour activity compared to leukaemic specific agents (cytarabine and amsacrine), vincristine and doxorubicin (Dox). Among the solid tumours tested, childhood tumours, non-small cell lung cancer and sarcomas were the most sensitive to Calcein/AM. The best correlation between SI values was seen between Calcein/AM and Dox, with weaker correlations to representatives of antimetabolites, platinum compounds, topoisomerase II inhibitors, tubulin interactive agents and alkylators. Non-cytotoxic concentrations of cyclosporin A significantly potentiated calcein-induced cytotoxicity. The results show that Calcein/AM is differentially active against haematological tumours, but with substantial activity against solid tumours. The drug may represent a new class of anticancer compound with a unique means of drug delivery.

Antineoplastic Agents↗
PubMed1996

Anti-cancer drug characterisation using a human cell line panel representing defined types of drug resistance.

Differential drug response in a human cell line panel representing defined types of cytotoxic drug resistance was measured using the non-clonogenic fluorometric microculture cytotoxicity assay (FMCA). In total 37 drugs were analysed; eight topoisomerase II inhibitors, eight anti-metabolites, eight alkylating agents, eight tubulin-active agents and five compounds with other or unknown mechanisms of action, including one topoisomerase I inhibitor. Correlation analysis of log IC50 values obtained from the panel showed a high degree of similarity among the drugs with a similar mechanism of action. The mean percentage of mechanistically similar drugs included among the ten highest correlations, when each drug was compared with the remaining data set, was 100%, 92%, 88% and 52% for the topoisomerase II inhibitors, alkylators, tubulinactive agents and anti-metabolites respectively. Classification of drugs into the four categories representing different mechanisms of action using a probabilistic neural network (PNN) analysis resulted in 29 (91%) correct predictions. The results indicate the feasibility of using a limited number of cell lines for prediction of mechanism of action of anti-cancer drugs. The present approach may be well suited for initial classification and evaluation of novel anti-cancer drugs and as a potential tool to guide lead compound optimisation.

Antineoplastic Agents↗
PubMed1996

Plasma levels of lipoprotein (a) do not predict progression of human chronic renal failure.

Chronic renal failure is frequently accompanied by elevated plasma levels of lipoprotein (a) [Lp(a)]. Elevated Lp(a) levels have been proposed to contribute not only to increased risk of atherosclerotic and thrombotic complications but also to the progression of renal insufficiency. To investigate whether higher Lp(a) plasma concentrations are associated with an accelerated rate of progression of renal insufficiency, we have correlated baseline plasma concentrations of Lp(a) with the progressive decline of renal function in an observational study of human chronic renal disease. Forty-nine non-diabetic patients (40 men, nine 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 3.1 years, and the mean rate of decline in glomerular filtration rate (51Cr-EDTA clearance) was -2.8 (SD 4.1) ml/min/1.73 m2. The mean plasma concentration of Lp(a) at the beginning of the study was 19.2 (SD 18.6) mg/100 ml with a median value of 12.2 mg/100 ml. There was no association between the initial plasma concentration of Lp(a) and the rate of progression as assessed by linear regression analysis. Furthermore, the progression rate in patients within the highest quartile of the Lp(a) distribution (> or = 30 mg/100 ml) did not differ from that in patients with lower levels of Lp(a). In contrast, increased levels of apolipoprotein (apo) B, low-density lipoprotein (LDL)-cholesterol, and proteinuria were all significantly associated with a more rapid decline in renal function. Based on these results, it was concluded that elevated plasma levels of Lp(a) are not associated with an increased rate of progression of renal insufficiency in human chronic renal disease. However, the results of this study suggest that other apoB-containing lipoproteins may play a significant role in this process.

Adult↗
PubMed1996

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↗