Stability and fitness costs associated with etoxazole resistance in Tetranychus urticae (Acari: Tetranychidae).

The two-spotted spider mite, Tetranychus urticae Koch, is one of the most important pests on a wide range of crops worldwide. Studies on stability of resistance and possible fitness costs associated with etoxazole resistance were carried out in T. urticae to provide basic information necessary to define effective acaricide resistance management strategies for this pest. Selection for resistance to etoxazole was performed in a population of T. urticae collected from a commercial rose field, in Holambra County, in the State of São Paulo, Brazil. After five rounds of selection for resistance, the resistance ratio (R/S) at the LC50 reached 8739 fold value in comparison with a susceptible strain (Brazabrantes S Strain). The stability of etoxazole resistance was studied under laboratory conditions, using a population with initial frequency of 75 % of resistant mites. The frequencies of etoxazole resistance were evaluated monthly for a period of 13 months. The frequency of etoxazole resistance decreased from 75 to 37 % in this period. Comparison of biological traits between resistant and susceptible strains indicated the presence of fitness costs associated with etoxazole resistance. The resistant strain showed lower fecundity and a higher proportion of males in the population. The figures for net reproductive rate (R 0), intrinsic rate of natural increase (r m) and finite rate of increase (λ) were higher in the susceptible strain. The instability of etoxazole resistance is a favorable aspect for the acaricide resistance management in the spider mite.

[Drug resistant epilepsy. Clinical and neurobiological concepts]. / Farmacorresistencia en epilepsia. Conceptos clínicos y neurobiológicos.

Drug-resistant epilepsy, is a condition defined by the International League Against Epilepsy as persistent seizures despite having used at least two appropriate and adequate antiepileptic drug treatments. Approximately 20-30% of patients with epilepsy are going to be resistant to antiepileptic drugs, with different patterns of clinical presentation, which are related to the biological basis of this disease (de novo resistance, relapsing-remitting and progressive). Drug resistant epilepsy, impacts negatively the quality of life and significantly increases the risk of premature death. From the neurobiological point of view, this medical condition is the result of the interaction of multiple variables related to the underlying disease, drug interactions and proper genetic aspects of each patient. Thanks to advances in pharmacogenetics and molecular biology research, currently some hypotheses may explain the cause of this condition and promote the study of new therapeutic options. Currently, overexpression of membrane transporters such as P-glycoprotein, appears to be one of the most important mechanisms in the development of drug resistant epilepsy. The objective of this review is to deepen the general aspects of this clinical condition, addressing the definition, epidemiology, differential diagnosis and the pathophysiological bases.

TITLE: Farmacorresistencia en epilepsia. Conceptos clinicos y neurobiologicos.La epilepsia farmacorresistente es una condicion definida por la Liga Internacional contra la Epilepsia como la persistencia de crisis epilepticas a pesar de haber utilizado al menos dos tratamientos con farmacos antiepilepticos apropiados y adecuados. Cerca de un 20-30% de los pacientes con epilepsia van a ser resistentes a los farmacos antiepilepticos, con diferentes patrones de presentacion clinica, los cuales estan en relacion con las bases biologicas de esta enfermedad (resistencia de novo, recaida-remision y progresiva). La farmacorresistencia en epilepsia impacta negativamente en la calidad de vida y aumenta significativamente el riesgo de muerte prematura. Desde el punto de vista neurobiologico, esta condicion clinica es el resultado de la interaccion de multiples variables relacionadas con la enfermedad de base, las interacciones medicamentosas y los aspectos geneticos propios de cada paciente. Gracias a los avances en la investigacion farmacogenetica y de biologia molecular, actualmente se plantean algunas hipotesis que podrian explicar la causa de esta condicion y que promueven el estudio de nuevas opciones terapeuticas. En la actualidad, la sobreexpresion de transportadores de membrana, como la glucoproteina P, parece ser uno de los mecanismos mas importantes en el desarrollo de la farmacorresistencia en epilepsia. El objetivo de esta revision es profundizar en los aspectos generales de esta condicion clinica, abordando la definicion, los aspectos epidemiologicos, los diagnosticos diferenciales y las bases fisiopatologicas.

Fitness cost of resistance for lumefantrine and piperaquine-resistant Plasmodium berghei in a mouse model.

BACKGROUND: The evolution of drug-resistant parasites is a major hindrance to malaria control, and thus understanding the behaviour of drug-resistant mutants is of clinical relevance. The study aimed to investigate how resistance against lumefantrine (LU) and piperaquine (PQ), anti-malarials used as partner drugs in artemisinin-based combination therapy (ACT), impacts parasite fitness. This is important since resistance to ACT, the first-line anti-malarial regimen is increasingly being reported. METHODS: The stability of Plasmodium berghei ANKA strain that was previously selected for LU and PQ resistance was evaluated using the 4-day assay and established infection test in mice. Fitness cost of resistance was determined by comparing parasites proliferation rates in absence of drug pressure for the drug-exposed parasites between day 4 and 7 post-infection (pi), relative to the wild-type. Statistical analysis of data to compare mean parasitaemia and growth rates of respective parasite lines was carried out using student's t-test and one-way analysis of variance, with significance level set at p<0.05. RESULTS: During serial passaging in the absence of the drug, the PQ-resistant parasite maintained low growth rates at day 7 pi (mean parasitaemia, 5.6% ± 2.3) relative to the wild-type (28.4% ± 6.6), translating into a fitness cost of resistance of 80.3%. Whilst resistance phenotype for PQ was stable, that of LU was transient since after several serial passages in the absence of drug, the LU-exposed line assumed the growth patterns of the wild-type. CONCLUSIONS: The contrasting behaviour of PQ- and LU-resistance phenotypes support similar findings which indicate that even for drugs within the same chemical class, resistance-conferred traits may vary on how they influence parasite fitness and virulence. Resistance-mediating polymorphisms have been associated with less fit malaria parasites. In the absence of drug pressure in the field, it is therefore likely that the wild-type parasite will out-compete the mutant form. This implies the possibility of reintroducing a drug previously lost to resistance, after a period of suspended use. Considering the recent reports of high failure rates associated with ACT, high fitness cost of resistance to PQ is therefore of clinical relevance as the drug is a partner in ACT.

Fitness costs of resistance to Bti toxins in the dengue vector Aedes aegypti.

Sustainable insect vector disease control strategies involve delaying the evolution of resistance to insecticides in natural populations. The evolutionary dynamics of resistance in the field is highly dependent on the fitness cost of resistance alleles. To successfully manage resistance evolution in target species, it is not only important to find evidence of fitness cost in resistant insects, but also to determine at which stage of the insect's life it is expressed. Here, we show that resistance costs to the bacterio-insecticide Bacillus thuringiensis subsp. israelensis (Bti) are expressed at all the life-stages of the dengue vector Aedes aegypti, including egg survival, larval development time, and female fecundity. We show that the storage of eggs for 4 months is long enough to counter-select resistance alleles. This suggests that Bti resistance is not likely to evolve in temperate climates where most mosquito species overwinter as eggs. In tropical regions with a rapid turn-over of generations, resistance alleles are likely to be counter-selected in only few generations without treatment through fitness costs expressed in terms of larval development time and female fecundity. We discuss the implications of our findings in terms of sustainable management strategies in light of the challenge of preserving the long-term efficiency of this environmentally safe anti-mosquito bio-insecticide.

Assessment of follicular development in cryopreserved primate ovarian tissue by xenografting: prepubertal tissues are less sensitive to the choice of cryoprotectant.

Improvements in cancer survival rates have renewed interest in the cryopreservation of ovarian tissue for fertility preservation. We used the marmoset as a non-human primate model to assess the effect of different cryoprotectives on follicular viability of prepubertal compared to adult ovarian tissue following xenografting. Cryopreservation was performed with dimethylsulfoxide (DMSO), 1,2-propanediol (PrOH), or ethylene glycol (EG) using a slow freezing protocol. Subsequently, nude mice received eight grafts per animal from the DMSO and the PrOH groups for a 4-week grafting period. Fresh, cryopreserved-thawed, and xenografted tissues were serially sectioned and evaluated for the number and morphology of follicles. In adult tissue, the percentage of morphologically normal primordial follicles significantly decreased from 41.2 ± 4.5% (fresh) to 13.6 ± 1.8 (DMSO), 9.5 ± 1.7 (PrOH), or 6.8 ± 1.0 (EG) following cryopreservation. After xenografting, the percentage of morphologically normal primordial (26.2 ± 2.5%) and primary follicles (28.1 ± 5.4%) in the DMSO group was significantly higher than that in the PrOH group (12.2 ± 3 and 5.4 ± 2.1% respectively). Proliferating cell nuclear antigen (PCNA) staining suggests the resumption of proliferative activity in all cellular compartments. In prepubertal tissues, primordial but not primary follicles display a similar sensitivity to cryopreservation, and no significant differences between DMSO and PrOH following xenografting were observed. In conclusion, DMSO shows a superior protective effect on follicular morphology compared with PrOH and EG in cryopreserved tissues. Xenografting has confirmed better efficacy of DMSO versus PrOH in adult but not in prepubertal tissues, probably owing to a greater capacity of younger animals to compensate for cryoinjury.

Chronic gout: epidemiology, disease progression, treatment and disease burden.

BACKGROUND: Gout is a painful and disabling inflammatory arthritis of increasing prevalence associated with hyperuricemia and the deposition of monosodium urate crystals in soft tissues and joints. Diagnosed gout cases have been estimated at 2.13% of the 2009 US population. The highest incidence occurs in the 65+ year age group, with males more than twice as likely to be afflicted as females. OBJECTIVE: To present the epidemiology of chronic gout and to discuss its disease burden. METHODS: This commentary is based on expert opinion and supplemented with published/presented information identified through PubMed and rheumatology associations. RESULTS: The steady rise of diagnosed gout cases can generally be linked to an aging population with multiple comorbidities, the use of certain prescription medications, and changes in diet and lifestyle. Progression to chronic gout has numerous causes such as poor compliance with, ineffectiveness of, or inability to tolerate prescribed regimens. Despite the availability of urate-lowering therapies (ULT), patients may either have contraindications to them or may not adequately respond. Patients with high flare frequency, tophi, and the inability to maintain serum urate levels below 6 mg/dL with ULT can be categorized as having chronic gout that is refractory, with a substantial disease burden. Based on lack of therapeutic options for urate-lowering for patients with chronic gout refractory to conventional therapy, the economic burden of this small but substantial population contributes disproportionately to the overall economic burden of chronic gout. Recent availability of gout-specific ICD-9-CM codes capturing the cost intense and impactful aspects of the disease - flares and tophi - is likely contribute to understanding the full health economic burden in gout. CONCLUSION: The impact of chronic gout, especially if refractory to treatment, on functionality, productivity, quality of life and health care costs can be substantial and is deserving of future research.

Cost-effectiveness of treating resistant hypertension with an implantable carotid body stimulator.

The purposes of this study are to investigate the cost-effectiveness of an implantable carotid body stimulator (Rheos; CVRx, Inc, Minneapolis, MN) for treating resistant hypertension and determine the range of starting systolic blood pressure (SBP) values where the device remains cost-effective. A Markov model compared a 20-mm Hg drop in SBP from an initial level of 180 mm Hg with Rheos to failed medical management in a hypothetical 50-year-old cohort. Direct costs (2007$), utilities, and event rates for future myocardial infarction, stroke, heart failure, and end-stage renal disease were modeled. Sensitivity analyses tested the assumptions in the model. The incremental cost-effectiveness ratio (ICER) for Rheos was $64,400 per quality-adjusted life-years (QALYs) using Framingham-derived event probabilities. The ICER was <$100,000 per QALYs for SBPs > or =142 mm Hg. A probability of device removal of <1% per year or SBP reductions of > or =24 mm Hg were variables that decreased the ICER below $50,000 per QALY. For cohort characteristics similar to Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm (ASCOT-BPLA) participants, the ICER became $26,700 per QALY. Two-way sensitivity analyses demonstrated that lowering SBP 12 mm Hg from 220 mm Hg or 21 mm Hg from 140 mm Hg were required. Rheos may be cost-effective, with an ICER between $50,000 and $100,000 per QALYs. Cohort characteristics and efficacy are key to the cost-effectiveness of new therapies for resistant hypertension .

The metabolic and fitness costs associated with metal resistance in Nereis diversicolor.

The population of Nereis diversicolor inhabiting the upper reaches of Restronguet Creek, Cornwall, UK is highly resistant to acute zinc and copper toxicity. Here we employ bioenergetic accounting and fecundity counts to demonstrate the energetic costs associated with this phenomenon in terms of the worms' allocation of metabolic resources and reproductive output [P(r)]. Metal-resistant animals exhibited a scope for growth that was 46-62% less than that of animals from two non-resistant reference populations, corresponding to a mean metabolic cost of 1.31 mJ h(-1)mg DW(-1). The resistant population also contained 13% less lipid than animals from the reference populations and 73-81% less carbohydrates. Consequently, mass-specific fecundity was reduced in resistant animals by 39-45%, although material investment in individual gametes did not appear to vary. This demonstrates fitness costs associated with metal resistance in this ecologically important polychaete and adds to our understanding of phenotypic trade-offs associated with resistance.

Flow cytometric assessment of platelet aspirin resistance using light scattering.

BACKGROUND: A simple and reliable assay is needed for the prediction of the clinical efficacy of antiplatelet aspirin therapy. We have devised another method for the evaluation of platelet function and aspirin resistance (AR), via conventional flow cytometry (FCM). METHODS: To devise an optimized protocol for the assessment of platelet AR, various analytic variables of FCM were investigated. Using this devised protocol, AR was assessed in healthy subjects as an example. RESULTS: The protocol utilized herein is as follows: citrate-anticoagulated platelet-rich plasma was mixed 1:1 with HEPES-buffered saline in two tubes, one of which is treated with aspirin. During the acquisition of FCM, arachidonate is added to the tube. The response of the aspirin-treated platelets is then compared with those of nontreated ones on a time/forward scatter plot. In the 61 total subjects, none was identified as aspirin resistant by this assay. CONCLUSIONS: Using light scattering, platelet aggregation and aspirin's antiplatelet effects can be readily and cost-effectively detected. According to this assay, biochemical AR appears to be rare. This new protocol may prove useful in a clinical setting or as a research tool.

Use of omalizumab in a severe asthma clinic.

There is an urgent need to define new treatment strategies for severe persistent asthma. Using a severe asthma clinic model, it is possible to systematically assess diagnosis, self-management skills, and treatment efficacy. The addition of single-patient trials of therapy is useful to detect individual responders to drugs where use is limited because of access, cost, or toxicity. Omalizumab is effective in severe asthma, however access is restricted by cost and availability. We conducted single patient efficacy trials of omalizumab in 12 subjects with severe refractory asthma. There were 2 definite and 6 partial responders. Patients with difficult/therapy resistant or refractory asthma can respond to omalizumab, and this response can be detected in individual patients using a single patient controlled trial conducted in the setting of a severe asthma clinic.

Assessment of biochemical aspirin resistance at rest and immediately after exercise testing.

Some aspirin-treated patients experience thromboembolic events, a phenomenon termed 'aspirin resistance', which may be clinical or biochemical by definition. Physical exercise is known to enhance platelet secretion and aggregability. To evaluate the presence of biochemical aspirin resistance at rest and immediately after exercise in individuals with stable coronary artery disease or coronary artery disease risk factors. We prospectively enrolled 101 patients who had received 100 or 300 mg/day enteric-coated aspirin for at least 7 days. Biochemical aspirin resistance (defined as normal collagen-epinephrine closure time < 165 s) was studied using the standardized platelet function analyzer. Of the 101 patients, 63 were aspirin sensitive both at rest and immediately after exercise, 18 exhibited biochemical aspirin resistance both at rest and after exercise, and 20 were aspirin sensitive at rest but exhibited biochemical aspirin resistance immediately after exercise. The results of exercise testing were similar in all three groups (each P > 0.05). Our results indicate that in almost 20% of the patients, aspirin did not seem to protect against exercise-induced platelet activation, despite the presence of aspirin sensitivity at rest. We did not, however, determine the extent to which the biochemical aspirin resistance noted in our study applied to clinical events.

Quinupristin-dalfopristin resistance in gram-positive bacteria: mechanism of resistance and epidemiology.

Antimicrobial resistance in gram-positive bacteria is a continuing problem resulting in significant morbidity, mortality, and cost. Because of this resistance, new antimicrobial agents have been needed. Quinupristin-dalfopristin is a recently approved agent for treatment of these infections. Shortly after its introduction into clinical medicine, resistance was reported. Resistance can occur by one or more of several mechanisms, including enzymatic modification, active transport of efflux mediated by an adenosine triphosphate-binding protein, and alteration of the target site. Resistance is rare in isolates of staphylococci and Enterococcus faecium from humans. Resistance is common in isolates recovered from food animals and is related to the use of virginiamicin as a feed additive. Considering the effect antimicrobial resistance has on human health, as well as its economic impact, measures to preserve the usefulness of these agents and delay the development of resistance are urgently needed.

Management of anemia in erythropoietin-resistant hemodialysis patients.

BACKGROUND: Human recombinant erythropoietin (rHuEPO) is administered to patients with end-stage renal disease for treatment of anemia. OBJECTIVE: To assess the impact of a structured team approach to anemia management in rHuEPO-resistant hemodialysis patients. METHODS: This was an 8-month prospective, open-label, quality-improvement initiative. Nineteen patients in a 160-bed hemodialysis unit receiving rHuEPO doses >300 units/kg/wk were defined as rHuEPO-resistant. Hemoglobin (Hb), iron indices, parathyroid hormone, folate, B12, aluminum, and reticulocyte counts were determined at baseline. The former 3 parameters were followed every 6, 12, and 26 weeks, respectively. Vascular access flow was regularly assessed via ultrasonic dilution methodology. Target Hb was 12.0-13.5 g/dL. All factors potentially contributing to rHuEPO resistance were assessed and, if possible, treated every 6 weeks by a dedicated anemia team. Downward rHuEPO dosage adjustments of 12.5-25% to the closest 1000 units were considered if underlying causes of rHuEPO resistance could not be identified or reversed, or if the Hb rose beyond the target level. RESULTS: Dysfunctional vascular access and iron deficiency were the predominant treatable factors associated with rHuEPO resistance. At 8 months, mean rHuEPO dosage decreased significantly from 469 to 319 units/kg/wk (p < 0.001) and mean Hb increased significantly from 10.6 to 11.6 g/dL (p = 0.023). Eight-month cost savings approximated $45 000 (CDN$). CONCLUSIONS: A structured team approach to the management of rHuEPO-resistant patients was successful in significantly lowering rHuEPO dosage with improvement in serum Hb at a substantial cost savings.

Therapeutic strategies in the choice of antiepileptic drugs.

The choice of treatment of newly diagnosed epilepsy involves many factors such as age, sex, life style, general health and concomitant medication. The seizure type, syndrome, and the pharmacology, efficacy and safety of the antiepileptic drugs (AEDs) should also be considered. Some of the new AEDs appear to provide at least equivalent efficacy with better tolerability. Some of these drugs have the potential to become drugs of first choice in newly diagnosed epilepsy. At the present time, we also must consider the criteria of reimbursement of these drugs. In this paper, we try to describe common and practical strategies to start a treatment of newly diagnosed epilepsy.

Potential mechanisms of increased disease in humans from antimicrobial resistance in food animals.

There are at least 5 potential mechanisms by which antimicrobial resistance can have adverse effects on human health. The first, called the "attributable fraction," relates to individuals who become infected only because they are taking an antimicrobial agent (for unrelated reasons) to which the pathogen is resistant: the antimicrobial agent, by suppressing their normal microbiota, renders them more vulnerable to infection. A second mechanism involves the linkage of virulence traits to resistance traits so that resistant organisms may be more virulent than susceptible organisms. A third mechanism is that treatment may be rendered ineffective by the choice of a drug to which the pathogens are resistant or may be complicated by the need to use an agent with less desirable attributes than would otherwise be the case. A fourth mechanism is the animal equivalent of the attributable fraction: resistant pathogens acquired by this mechanism in food animals may then be transmitted through the food chain to humans. Last, resistance traits can be acquired by the commensal flora of animals; from this reservoir, resistance traits could find their way through the food chain to commensals and pathogens of humans.

Humans as the world's greatest evolutionary force.

In addition to altering global ecology, technology and human population growth also affect evolutionary trajectories, dramatically accelerating evolutionary change in other species, especially in commercially important, pest, and disease organisms. Such changes are apparent in antibiotic and human immunodeficiency virus (HIV) resistance to drugs, plant and insect resistance to pesticides, rapid changes in invasive species, life-history change in commercial fisheries, and pest adaptation to biological engineering products. This accelerated evolution costs at least $33 billion to $50 billion a year in the United States. Slowing and controlling arms races in disease and pest management have been successful in diverse ecological and economic systems, illustrating how applied evolutionary principles can help reduce the impact of humankind on evolution.

A cost-effectiveness analysis of treatment options for patients with methotrexate-resistant rheumatoid arthritis.

OBJECTIVE: Recently, new treatment options for rheumatoid arthritis (RA) patients with an inadequate response to methotrexate (MTX) have become available. Given the wide variability in efficacy and costs among these different treatment options, we sought to determine their cost-effectiveness (CE) in order to guide policy in different cost-constrained settings. METHODS: We performed a CE analysis comparing 6 treatment options for patients with MTX-resistant RA: 1) etanercept + MTX, 2) etanercept monotherapy, 3) cyclosporine + MTX, 4) triple therapy (hydroxychloroquine, sulfasalazine, and MTX), 5) continuation of MTX monotherapy, and 6) no second-line agent. A decision model was used with a time horizon of 6 months. We used 2 measures of effectiveness based on published clinical trial data: the American College of Rheumatology 20% response criteria (ACR 20); and a weighted average of proportions of patients achieving responses of ACR 70, ACR 50, and ACR 20 (ACR 70 weighted response [ACR 70WR]). Incremental CE ratios were calculated as the additional cost per patient achieving either outcome, compared with the next least expensive option. To help interpret CE relative to these RA-specific outcomes, we conducted a separate, "reference" CE analysis of MTX use in MTX-naive RA patients, using the same outcomes. RESULTS: In our reference analysis, MTX therapy for MTX-naive RA cost $1,100 per ACR 20 outcome and $1,500 per ACR 70WR, compared with no second-line agent. In our base-case analysis with either outcome, MTX continuation, cyclosporine + MTX, and etanercept monotherapy cost more, but either were not more efficacious or had a higher incremental CE ratio than the next most expensive option (i.e., they were dominated). Therefore, these options were not cost-effective. The least expensive option, triple therapy, cost 1.3 times more per patient with ACR 20 outcome ($1,500/ACR 20) and 2.1 times more per ACR 70WR ($3,100/ACR 70WR) than MTX therapy for MTX-naive RA. The most efficacious option, the combination of etanercept and MTX, cost 38 times more per patient with ACR 20 outcome ($4,600/ACR 20) and 23 times more per ACR 70WR ($34,800/ACR 70WR) than MTX therapy for MTX-naive RA. Overall, the results of extensive sensitivity analyses did not substantially affect these results. CONCLUSION: Our analysis indicates that if 15 mg/week MTX is cost-effective for achieving ACR 20 or ACR 70WR in MTX-naive RA over a 6-month period, then most likely so is triple therapy in MTX-resistant RA. Whether etanercept + MTX is cost-effective depends on whether $34,800/ACR 70WR (or $42,600/ACR 20) over a 6-month period is considered acceptable.

Assessment of activated protein C resistance using a new and rapid venom-based test: STA Staclot APC-R.

Activated protein C (APC) resistance is related to a single point mutation in the factor V gene (FV:Q506) and appears to be the most common inherited risk factor for venous thromboembolism. A reliable screening test is therefore useful. We aimed to evaluate a new APC resistance test, on the basis of the procoagulant activity present in one snake venom of a crotalidae family: STA Staclot APC-R. We studied 36 consecutive patients with an acute deep venous thrombosis (DVT) confirmed by compression ultrasonography and carrying the FV:Q506 allele, assessed by DNA analysis, 103 of their family members and 35 consecutive patients with a proven DVT but who did not carry the FV:Q506 allele. Blood samples were collected within 24 h of admission for the DVT cases and on the day of medical registration for the family members. Tests were performed blind. The STA Staclot APC-R test, using a cut-off value of 0.80, had an overall sensitivity of 100% (95% CI, 95-100) and a specificity of 98.8% (95% CI, 92.0-99.6). An acute thrombosis process did not influence the performance of the test. We conclude that this test is easy and rapid to perform in every day practice and fulfills the criteria for a screening test.

Cytostatic drug resistance: parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA-alkyltransferase and P-glycoprotein in adult patients with leukaemia.

The levels of several potential indicators of resistance to cytostatic drugs were measured in leukaemic cells of a total of 64 adult patients with acute or chronic leukaemias before and during treatment and at relapse or recurrence of disease and compared with those of mononuclear cells from the bone marrow of healthy donors. The resistance factors included glutathione (GSH) and its associated enzymes glutathione-S-transferase (GST) and glutathione peroxidase (GPx) as well as O6-alkyguanine-DNA-alkyltransferase (ATase) and P-glycoprotein. Median values for most parameters were significantly higher in leukaemic cells than in those of normal donors although wide interindividual variation in the values of the various parameters, particularly GST, were seen. P-glycoprotein was measurable in 12.5% of untreated leukaemias but in none of the normal donors. The values of the parameters in untreated leukaemic patients were not statistically different from those at relapse or during disease progression. However, the median values for GSH, GST and GPx but not ATase in samples from untreated patients were significantly higher than those in samples taken during drug treatment. Patient response, disease-free survival or duration of remission did not correlate with the values of any of the parameters studied.