Biomedical subjects

K Wolff

Publications and source records attributed to K Wolff.

At least 37 records · Page 2Linked to original sources

PubMed2001

Overcoming turf battles: developing a pragmatic, collaborative model to improve glycemic control in patients with diabetes.

BACKGROUND: Collaboration between primary care physicians (PCPs) and endocrinologists should be the first step in improving care of patients with diabetes. However, the coordination of care between specialists and PCPs often does not work well. At Vanderbilt University Medical Center, a collaborative model between PCPs and endocrinology was used in an effort to improve glycemic control for patients with diabetes. METHODS: In 1998 a project team was formed; the team members attempted to find ways to improve the care of patients with diabetes, specifically patients with poor glycemic control. The team proceeded through ten iterations of the model before reaching one accepted by all-one with clear responsibilities and referral criteria. RESULTS: Survey results indicated a high level of satisfaction with the collaborative model among patients and PCPs. Appropriate referrals to the diabetes improvement program--a 12-week outpatient program consisting of instruction and support in diabetes self-management coupled with adjustment of insulin and oral hypoglycemic medications-increased during the team effort, and a control chart indicated a change in the process that was significant and sustained. The patients enrolled in the program experienced a reduction of mean glycated hemoglobin levels from 9.2% at entry to 7.5% after 3 months (p < 0.05). DISCUSSION: An initial first step to improving care is to create an environment of trust and collaboration between the PCPs and specialists who assist in that care. After this collaboration has been established, many of the improvements identified in other studies can more easily be implemented.

Adult↗

PubMed2001

Perilesional injection of r-GM-CSF in patients with cutaneous melanoma metastases.

Based on evidence that granulocyte-macrophage colony stimulating factor (GM-CSF) induces a potent systemic antitumor immunity, we tested recombinant GM-CSF in advanced melanoma. Seven patients with histologically confirmed cutaneous melanoma metastases were treated with perilesional intracutaneous injections of recombinant GM-CSF and observed for a follow-up time of 5 y. All but two patients had a decrease in the total number of metastases. At the end of the 5 y follow-up three of the seven patients are still alive with only one patient receiving other than surgical therapy, and one patient died tumor free at the age of 93. The remaining three patients died from progressive melanoma. Perilesional intradermal GM-CSF therapy resulted in a mean survival time of 33 mo. The treatment was well tolerated and no side-effects other than local erythema at the injection sites and mild drowsiness were seen. Immunohistochemical analysis with staining for CD14 and GM-CSF receptor demonstrated an increased infiltration of monocytes into both injected and noninjected cutaneous melanoma metastases compared with lesions excised prior to the initiation of therapy. The same was true for CD4- and CD8-positive lymphocytes. This phenomenon, together with GM-CSF-induced leukocyte counts of more than 20,000 during therapy, support the possible impact of a systemic over a locally induced reaction by GM-CSF. To our knowledge this is the first report that intracutaneously injected GM-CSF results in long-lasting reduction of melanoma metastases.

Aged↗

PubMed2001

Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner.

Fumaric acid esters are thought to improve psoriasis by altering leukocyte, keratinocyte, and/or endothelial functions. To determine specificity, kinetics, and molecular mechanisms of different fumaric acid esters in their ability to inhibit endothelial cell activation, we analyzed CD62E and CD54 expression in endothelial cells in vivo and in vitro. In lesional skin of psoriatic patients, oral fumaric acid ester treatment resulted in a marked reduction of CD62E but not CD54 expression on dermal microvessels. Using human umbilical vein endothelial cells, dimethylfumarate almost completely inhibited tumor-necrosis-factor-induced CD62E, but not CD54 expression at concentrations < or = 70 microM, mimicking the situation in vivo. A 60 min dimethylfumarate preincubation was sufficient to block tumor-necrosis-factor-induced CD62E expression for up to 24 h. In contrast, equimolar concentrations of methylhydrogenfumarate, the hydrolysis product of dimethylfumarate, did not suppress tumor-necrosis-factor-induced CD62E expression. Likewise, all fumaric acid esters other than dimethylfumarate were ineffective. Using CD62E, NF-kappa B, or AP-1-responsive promoter constructs, dimethylfumarate inhibited tumor-necrosis-factor-induced activation of the CD62E and the NF-kappa B but not the AP-1 promoter construct. In summary, at a dose range < or = 70 microM, dimethylfumarate appeared to be a specific inhibitor of CD62E expression in an NF-kappa B-dependent manner.

Capillaries↗

PubMed2001

Ecstasy pill testing: harm minimization gone too far?

Harm reduction has become the focus of public health initiatives and therapeutic intervention in the management of dependent drug use over the last 20 years. The last decade has seen such approaches being extended to recreational drug use. Most harm reduction initiatives have aimed to inform users about risks and ways of minimizing risk. The concept of providing illicit drug users with quality assessment of their chosen drug is one possible harm reduction intervention that until recently has received little attention. In response to well-publicized 'ecstasy'-related deaths organizations in some European countries and the United States have chosen to provide a 'pill testing service' for users. There are two broad categories of pill testing offered. Simple colour reagent test kits (Marquis Reagent and colour charts) form the most widely used on-site pill testing method. Less frequently, but more accurately, laboratory personnel with access to sophisticated chromatographic equipment (high performance liquid chromatography (HPLC) or gas chromatography-mass spectrometry (GC-MS)) may provide analysis of a pill. Pill testing kits have been advocated as a 'tool to protect yourself against the polluted XTC market'. We refute this line of reasoning. Of the different tests only techniques such as GC-MS can identify satisfactorily the psychoactive constituents present in ecstasy pills. Colour tests based on an interpretation of a colour response in the presence of a drug are, at best, subjective. Pill testing of any description does not guarantee safety, or protect the consumer against individual responses to pills. At best it gives an artificial 'shine of safety' to a group of diverse drugs that remain both illicit and potentially harmful. Other simpler harm reduction mechanisms are likely to be more effective.

Chromatography, Gas↗

PubMed2001

Platelet endothelial cell adhesion molecule-1 and vascular endothelial cadherin cooperatively regulate fibroblast growth factor-induced modulations of adherens junction functions.

Cellular adherens junctions are formed by cadherins linked to proteins of the catenin family. In endothelial cells, not only vascular endothelial cadherin but also platelet endothelial cell adhesion molecule-1 localizes into junctions and associates with beta-catenin. To explore a putative cooperation of platelet endothelial cell adhesion molecule-1 and vascular endothelial cadherin, we analyzed transfectants expressing either platelet endothelial cell adhesion (CD31 cells) or vascular endothelial cadherin (CD144 cells) or both molecules (CD31/CD144 cells), and, for comparison, human umbilical vein endothelial cells. Basic fibroblast growth factor completely dissociated vascular endothelial cadherin/beta-catenin complexes and robustly moved beta-catenin into the nucleus in CD144 cells, whereas in CD31/CD144 cells as well as in human umbilical vein endothelial cells, fibroblast growth factor only partially dissociated the junctional complex followed by a significantly reduced nuclear translocation of beta-catenin. In contrast, in CD31 cells, the subcellular distribution of beta-catenin remained unaffected by fibroblast growth factor. As a functional consequence, fibroblast growth factor induced a complete collapse of the F-actin network in CD144 cells, a limited rearrangement of F-actin fibers in CD31/CD144 cells and no F-actin rearrangement in CD31 cells. We also analyzed the effect of fibroblast growth factor-induced rearrangement of junctions on junction permeability for leukocytes: in line with our observation that vascular endothelial cadherin was required for cells to respond to fibroblast growth factor, only in CD31/CD144 cells, but not in CD31 cells, leukocyte transmigration was significantly enhanced by fibroblast growth factor. In conclusion platelet endothelial cell adhesion molecule-1 cooperates with vascular endothelial cadherin in a mutual fashion; platelet endothelial cell adhesion molecule-1 reduces and temporarily limits fibroblast growth factor-induced dissociation of vascular endothelial cadherin/beta-catenin complexes, but requires vascular endothelial cadherin to control leukocyte transmigration in dependence of fibroblast growth factor.

Adherens Junctions↗

PubMed2001

Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L).

In an attempt to identify novel diagnostic markers for mast cell (MC)-proliferative disorders, serial bone marrow (bm) sections of 22 patients with mastocytosis (systemic indolent mastocytosis, n = 19; mast cell leukemia [MCL], n = 1; isolated bm mastocytosis, n = 2) were analyzed by immunohistochemistry using antibodies against CD2, CD15, CD29, CD30, CD31, CD34, CD45, CD51, CD56, CD68R, CD117, HLA-DR, bcl-2, bcl-x(L), myeloperoxidase (MPO), and tryptase. Staining results revealed expression of bcl-x(L), CD68R, and tryptase in neoplastic MCs (focal dense infiltrates) in all patients. Mastocytosis infiltrates were also immunoreactive for CD45, CD117 (Kit), and HLA-DR. In most cases, the CD2 antibody produced reactivity with bm MCs in mastocytosis, whereas in control cases (reactive bm, immunocytoma, myelodysplastic syndrome), MCs were consistently CD2 negative. Expression of bcl-2 was detectable in a subset of MCs in the patient with MCL, whereas no reactivity was seen in patients with SIM or bm mastocytosis. Mastocytosis infiltrates did not react with antibodies against CD15, CD30, CD31, CD34, or MPO. In summary, our data confirm the diagnostic value of staining for tryptase, Kit, and CD68R in mastocytosis. Apart from these, CD2 may be a novel useful marker because MCs in mastocytosis frequently express this antigen, whereas MCs in other pathologic conditions are CD2 negative.

Adolescent↗

PubMed2001

Differential expression levels of Par-4 in melanoma.

The pro-apoptotic prostate apoptosis response-4 gene product Par-4 sensitizes prostate cells to the induction of programmed cell death. In this study we examined Par-4 expression in human melanoma cell lines and melanoma metastases. The heterogeneous expression detected prompted us to investigate the biological relevance of Par-4 in a human melanoma xenotransplantation model. Overexpression of Par-4 by transfection decreased tumour development in xenotransplanted A375-C6 melanoma cells in SCID mice and correlated to an increase in tumour cell apoptosis. These data suggest that high expression of the pro-apoptotic protein Par-4 could qualify as a prognostic marker in human melanoma.

Animals↗

PubMed2001

Elevated procaspase levels in human melanoma.

In this study procaspase expression levels were investigated by Western blotting in a panel of established melanoma cell lines, transformed melanocytic cell lines and normal primary melanocytes. Upstream caspases such as procaspase-8 that contain a death effector domain were found to be overexpressed in transformed melanocytes and melanoma cell lines compared with melanocytes. Heterogeneous levels of procaspase-8 were seen in melanoma cells, including one cell line that completely lacked procaspase-8 expression. Procaspase-10 is generally overexpressed in transformed melanocytes and melanoma cell lines. Expression of the downstream procaspases-3 and -7 was increased in melanoma cells compared with normal melanocytes. Procaspases containing caspase recruitment domains such as procaspase-2 were expressed at similar levels in nearly all the cell lines investigated. Reduced levels of procaspase-1 compared with normal melanocytes were detected in transformed melanocytes and melanoma cell lines. These data indicate that procaspase levels in general increase during the malignant transformation of melanocytic cells.

Blotting, Western↗

PubMed2001

Cisplatin and carboplatin combination as second-line chemotherapy in dacarbazine-resistant melanoma patients.

High-dose cisplatin regimens have been shown to be highly active in advanced melanoma patients but are associated with unacceptable side effects. In order to increase the platinum dose but avoid severe side effects, we treated 15 dacarbazine (DTIC)-resistant metastatic melanoma patients with a combination regimen of cisplatin (100 mg/m2) and carboplatin (200 mg/m2), two platinum analogues with a similar mode of action but a different toxicity pattern. After a mean follow-up period of 10.7 months (range 4-18 months), two patients (13.3%) achieved complete remission and two patients (13.3%) showed partial remission, giving an overall response rate of 26.4% (95% confidence interval [CI] 4.2-49%). Furthermore, three patients (20%; 95% CI 0-40.2%) experienced stable disease. The median duration of response was 7.1 months (95% CI 4.2-10.0 months), and the median overall survival was 12.5 months (95% CI 5.8-19.2 months), with eight patients still alive. The main side effects were haematological (leukopenia/thrombocytopenia World Health Organization [WHO] grade I-IV; anaemia WHO grade I-III), gastrointestinal (WHO grade I-III), neurological (WHO grade I-II) and renal (WHO grade I) toxicity. Nevertheless, except in one patient, side effects did not result in discontinuation of therapy. Despite the small number of patients treated in this preliminary study, we believe that combining cisplatin and carboplatin represents a novel, active and well-tolerated therapeutic option as second-line chemotherapy in DTIC-resistant advanced melanoma patients.

Adult↗

PubMed2001

MART-1/Melan-A and tyrosinase transcripts in peripheral blood of melanoma patients: PCR analyses and follow-up testing in relation to clinical stage and disease progression.

The use of tyrosinase-based polymerase chain reaction (PCR) tests for the detection of circulating tumour cells in the blood of melanoma patients has led to highly controversial results. We here report on the analysis of 120 blood samples from 76 stage I to IV melanoma patients using a new MART-1/Melan-A PCR system in conjunction with the tyrosinase-specific assay reported in the literature. While there were no positive results in localized disease (stages I and II), identification of specific PCR products in stage III melanoma patients was restricted to the MART-1/Melan-A tests, with positive results in 11% (two out of 19) of the blood specimens analysed. Stage IV melanoma patients presented with the highest incidence of detectable mRNA levels, with positive results for tyrosinase in 38% (12 out of 32) and for MART-1/Melan-A in 22% (seven out of 32). By delineating 64 follow-up specimens covering sampling periods of up to 33 weeks, stable mRNA expression profiles were identified in nearly 95%. Four patients, however, showed PCR changes towards positive MART-1/Melan-A expression that were linked to metastatic melanoma progression. Taken together, PCR tests for tyrosinase and MART-1/Melan-A seem to lack sufficient detection frequencies for the routine monitoring of melanoma disease. Regarding the link between MART-1/Melan-A seroconversion and the development of metastatic disease, further studies are needed to clarify the clinical value of this observation.

Adult↗

PubMed2000

Chemosensitisation of malignant melanoma by BCL2 antisense therapy.

BACKGROUND: Chemoresistance of malignant melanoma has been linked to expression of the proto-oncogene BCL2. Antisense oligonucleotides (ASO) targeted against BCL2 mRNA decreased BCL2 protein concentrations, increased tumour-cell apoptosis, and led to tumour responses in a mouse xenotransplantation model when combined with systemic dacarbazine. This phase I-II clinical study investigated the combination of BCL2 ASO (augmerosen, Genasense, G3139) and dacarbazine in patients with advanced malignant melanoma expressing BCL2. METHODS: In a within-patient dose-escalation protocol, 14 patients with advanced malignant melanoma were given augmerosen intravenously or subcutaneously in daily doses of 0.6-6.5 mg/kg plus standard dacarbazine treatment (total doses up to 1000 mg/m2 per cycle). Toxicity was scored by common toxicity criteria. Plasma augmerosen concentrations were assayed by high-performance liquid chromatography. In serial tumour biopsy samples, BCL2 protein concentrations were measured by western blotting and tumour-cell apoptosis was assessed. FINDINGS: The combination regimen was well tolerated, with no dose-limiting toxicity. Haematological abnormalities were mild to moderate. Lymphopenia was common, but no febrile neutropenia occurred. Higher doses of augmerosen were associated with transient fever. Four patients had liver-function abnormalities that resolved within 1 week. Steady-state plasma concentrations of augmerosen were attained within 24 h, and increased with administered dose. By day 5, daily doses of 1.7 mg/kg and higher led to a median 40% decrease in BCL2 protein in melanoma samples compared with baseline, concomitantly with increased tumour-cell apoptosis, which was greatly increased after dacarbazine treatment. Six patients have shown antitumour responses (one complete, two partial, three minor). The estimated median survival of all patients now exceeds 12 months. INTERPRETATION: Systemic administration of augmerosen downregulated the target BCL2 protein in metastatic cancer. Such downregulation of BCL2, combined with standard anticancer therapy, offers a new approach to the treatment of patients with resistant neoplasms.

Adult↗

PubMed2000

Dermal microvascular endothelial cells express the 180-kDa macrophage mannose receptor in situ and in vitro.

Expression of the 180-kDa mannose receptor (MR) is mainly found on cells of the macrophage lineage. MR mediates the uptake of micro-organisms and host-derived glycoproteins. We demonstrate that endothelium of the human skin in situ and dermal microvascular endothelial cells (DMEC) in vitro expressed MR at both the protein and mRNA levels. In contrast, HUVEC were consistently negative for MR expression. DMEC internalized dextran as well as Escherichia coli by the way of MR into acidic phagosomes, only a few of which fused with CD63- and lysosomal-associated membrane glycoprotein-2-positive lysosomes. This contrasts with the situation in monocyte-derived dendritic cells, where almost all of the MR-Ag complexes reached CD63- and lysosomal-associated membrane glycoprotein-2-positive compartments, indicating differences in the phagolysosomal fusion rate between DMEC and dendritic cells. In conclusion, DMEC express functional MR, a finding that corroborates a role of skin endothelium in Ag capture/clearing.

Cell Membrane↗

PubMed2000

Molecular analysis of plant migration and refugia in the Arctic.

The arctic flora is thought to have originated during the late Tertiary, approximately 3 million years ago. Plant migration routes during colonization of the Arctic are currently unknown, and uncertainty remains over where arctic plants survived Pleistocene glaciations. A phylogenetic analysis of chloroplast DNA variation in the purple saxifrage (Saxifraga oppositifolia) indicates that this plant first occurred in the Arctic in western Beringia before it migrated east and west to achieve a circumpolar distribution. The geographical distribution of chloroplast DNA variation in the species supports the hypothesis that, during Pleistocene glaciations, some plant refugia were located in the Arctic as well as at more southern latitudes.

Arctic Regions↗

PubMed2000

Frequency and characteristics of enlarging common melanocytic nevi.

OBJECTIVE: To analyze the frequency and characteristics of enlarging common melanocytic nevi. DESIGN: Cohort study using digital epiluminescence microscopy (ELM) for documentation and follow-up, with a median follow-up interval of 11.4 months. SETTING: A dermatology department at a university hospital in Vienna, Austria. PATIENTS: One thousand six hundred twelve melanocytic nevi appearing clinically as common nevi, obtained from 385 patients (mean [+/-SD] age, 34.2 +/- 14.8 y; 55.6% female). INTERVENTIONS: Follow-up examination and documentation by digital ELM. MAIN OUTCOME MEASURES: Frequency of enlarging nevi according to age and comparison of ELM features observed in enlarging and nonenlarging nevi. RESULTS: Enlargement was found in 5.3% (n = 86) of nevi. The frequency of enlarging nevi was inversely related to age (P<.001), in that enlarging nevi were common in patients younger than 20 years and relatively rare in older age groups. Epiluminescence microscopy revealed a peripheral rim of brown globules in 48.8% (n = 42) of enlarging nevi. In contrast, a peripheral rim of brown globules was found in only 0.7% (n = 11) of nevi without enlargement (P<.001). Enlarging nevi that were excised in children and adolescents showed no histological signs of atypia. In older age groups, 48.1% of excised enlarging nevi that were clinically diagnosed as common nevi showed some histological signs of atypia. None of the excised enlarging lesions was histologically diagnosed as melanoma. CONCLUSIONS: The frequency of enlarging common nevi is inversely related to age. In the absence of clinical signs of atypia, enlargement alone does not indicate malignancy. A peripheral rim of brown globules is a characteristic ELM feature of symmetrically enlarging melanocytic nevi.

Adult↗

PubMed2000

P45, an extracellular 45 kDa protein of Listeria monocytogenes with similarity to protein p60 and exhibiting peptidoglycan lytic activity.

A monoclonal antibody obtained by immunization of mice with heat-killed cells of Listeria monocytogenes serotype 4d showed reactivity towards a protein (P45) from L. monocytogenes with an apparent molecular mass of 45 kDa. This protein was detected in the culture supernatant and at the cell surface of L. monocytogenes. Proteins cross-reacting with the monoclonal antibody were present in all Listeria strains investigated, except L. grayi. The structural gene was cloned in Escherichia coli and sequenced. Translation of the gene starts at a TTG initiation codon. The gene was found to code for a protein of 402 amino acid residues with a predicted molecular mass of 42.7 kDa. It has a signal peptide of 27 amino acid residues, resulting in a molecular mass for the mature polypeptide of 39.9 kDa. Protein database searches showed that this protein has 55% similarity and 38% identity to protein p60 of L. monocytogenes and exhibits significant sequence similarities to p54 from Enterococcus faecium and Usp45 from Lactococcus lactis. P45 was shown to have peptidoglycan lytic activity and the encoding gene was named spl (secreted protein with lytic property).

Amino Acid Sequence↗

PubMed2000

Effects of interferon-alpha2b treatment on ex vivo differentiation of mast cells from circulating progenitor cells in a patient with systemic mastocytosis.

Interferon (IFN)-alpha, a known inhibitor of myelopoiesis, is increasingly used to treat patients with systemic mastocytosis (SM). However, the mechanisms of IFN-alpha effects on mast cell (MC) growth remain unknown, and the treatment responses may be variable. In the present study, factor-dependent ex-vivo differentiation of MCs from peripheral blood mononuclear cells (PBMNCs) was analyzed in a patient with SM treated with IFN-alpha2b (3 million U/day). The patient exhibited an extensive MC infiltration in his bone marrow (BM) and increasing serum total tryptase levels (spiking to > 1,400 ng/ml). PBMNCs were collected before and during IFN-alpha2b treatment and cultured in the presence or absence of stem cell factor (SCF, 100 ng/ml) for 42 days. In the absence of SCF, no MC growth was detectable. However, in the presence of SCF, MC containing tryptase appeared in the cultures. Treatment with IFN-alpha2b resulted in a time-dependent decrease in SCF-inducible formation of MCs from PB progenitor cells in vitro. Also, during IFN-alpha2b treatment, blood histamine concentrations decreased. Serum total tryptase levels initially increased despite IFN-alpha2b treatment. However, after a latency period of a few months, tryptase concentrations declined and then reached a plateau. In healthy individuals, the SCF-induced in vitro growth of MCs from their progenitor cells was also inhibitable by the addition of IFN-alpha2b. In summary, our data show that IFN-alpha2b can exhibit inhibitory effects on factor-dependent growth of MC progenitor cells. However, it still remains open which of the patients with mastocytosis can benefit from long-term IFN-alpha treatment.

Adult↗

PubMed2000

Dihydrocodeine: a useful tool in the detoxification of methadone-maintained patients.

We investigated the merit of dihydrocodeine tartrate for withdrawal in detoxifying 20 methadone-maintained patients presenting for treatment at the Leeds Addiction Unit (LAU). Thirteen patients (65%) successfully completed methadone detoxification and were abstinent from both methadone and opiate-type drugs at the end of the 2-week program. On completion, three patients began treatment with Naltrexone and another was abstinent at a follow-up appointment, 1 week later. A further patient relapsed back to heroin use but remained in contact with the LAU. The remaining six patients dropped out of the 2-week detoxification program between days 3 and 11 of the dihydrocodeine cross-over period. We believe dihydrocodeine may have advantages in detoxifying methadone-maintained patients.

Adolescent↗

PubMed2000

Population-based pharmacokinetic approach for methadone monitoring of opiate addicts: potential clinical utility.

AIMS: There is evidence that plasma methadone measurements may be of benefit in dosage adjustment during methadone maintenance treatment for opiate dependence. However, to date the kinetics of oral rac-methadone have been poorly characterized. We describe plasma methadone concentration-time data collected from 35 opiate addicts. SUBJECTS: Oral doses of rac-methadone were given to 24 male and 11 female addicts attending a community-based drug treatment centre. MEASUREMENTS: Plasma methadone concentrations were measured by liquid chromatography (HPLC). PROCEDURES: Plasma concentration-time data were collected from patients prescribed oral rac-methadone in order to describe the complex kinetics of the drug incorporating its long elimination half-life. FINDINGS: Auto-induction of methadone metabolism was demonstrated and it was observed that clearance of methadone was significantly lower (p < 0.05) in opiate addicts at the start of treatment (median elimination half-life, 128-hours) than in those who had reached steady-state (median elimination half-life, 48 hours). Our data has provided the basis for a population-based pharmacokinetic (POP-PK) model which is intended for use as a clinical tool in association with plasma measurements in methadone maintenance patients. CONCLUSIONS: Using plasma monitoring in combination with the application of Bayesian forecasting it should be possible to predict trough levels of methadone during daily dosing. The model is able to utilize sparse sampling, and two blood samples are expected to be sufficient to define patient compliance. Random samples during treatment could be used to assess methadone dosing by comparing predicted with observed measurements for each individual. The clinical tool could therefore help to detect incomplete (failure to consume the whole daily dose as prescribed) and poor (due to ingestion of extra illicit methadone) compliance as well as therapeutic failure due to drug-drug interactions. Targeting resources in this way could be a cost-effective tool for supervision of methadone dosing.

Administration, Oral↗