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Biomedical subjects

S Harder

Publications and source records attributed to S Harder.

At least 55 records · Page 3Linked to original sources
PubMed2000

Cytotoxic hepatosplenic gammadelta T-cell lymphoma following acute myeloid leukemia bearing two distinct gamma chains of the T-cell receptor. Biologic and clinical features.

BACKGROUND AND OBJECTIVES: Hepatosplenic gd T-cell lymphoma is a rare entity of peripheral T-cell lymphomas. We characterized in detail the first case of hepatosplenic gd -T-cell lymphoma following acute myeloid leukemia. DESIGN AND METHODS: Hepatosplenic gd -T-cell lymphoma was diagnosed in a woman who had been in complete remission (CR) of acute myeloid leukemia (AML) for two years. Improvement but no objective response of the disease was observed after various types of chemotherapy. CR was achieved after related donor stem cell transplantation. Thirteen months later relapse of hepatosplenic gd T-cell lymphoma was diagnosed. While being prepared for a second transplantation the patient developed meningeal lymphoma and died. The patient's lymphoma cells were studied by immunologic, functional and molecular techniques. RESULTS: Lymphoma cells expressed the gd T-cell receptor (TCR), CD2, CD3, CD5, CD7, CD38, CD45, CD161 (NKR-P1), TIA and Ki67. Further analysis revealed expression of Vd1 and two distinct TCRg chains, Vg3 and Vg9, by the malignant cell clone. The clonality of the T-cells was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) followed by sequencing of TCR Vg3, Vg9 and Vd1 junctional regions. Clone-specific PCR was negative at diagnosis of AML and was positive at all times during follow-up of the hepatosplenic gd T-cell lymphoma. The lymphoma cells mediated strong natural killer cell-like cytotoxic activity, possibly explained by expression of CD161 and a lack of killer inhibitory receptor. INTERPRETATION AND CONCLUSIONS: Several so far undescribed features were observed in this case of hepatosplenic gd T-cell lymphoma, such as T-cell lymphoma following AML, expression of two distinct T-cell receptor g-chains, and an unexpected cytotoxic phenotype.

Acute Disease↗
PubMed1999

Pharmacokinetics and pharmacodynamic effects of a new antibody glycoprotein IIb/IIIa inhibitor (YM337) in healthy subjects.

BACKGROUND: This study describes the first administration of YM337, the Fab fragment of a humanized monoclonal antibody against the fibrinogen GP IIb/IIIa receptor, in healthy male humans. METHODS AND RESULTS: Platelet aggregation (20 micromol/L ADP), platelet adhesion, fibrinogen binding, bleeding time, and YM337 concentrations in plasma were studied in substudy 1 after single boluses of 0.025, 0. 05, 0.1, 0.2, and 0.4 mg/kg YM337 and in substudy 2 after a bolus (0. 35 mg/kg) plus 6 hours of infusion at different dose levels of YM337 (0.5, 0.75, 1.0, 1.5 microg. kg(-1) x min(-1)), with abciximab as reference drug (n=5 or 6 subjects per group). After the 0.2-mg/kg and 0.4-mg/kg boluses, fibrinogen binding was reduced by >80% and bleeding time was prolonged to approximately 60 minutes. Bolus followed by infusion of 1.0 and 1.5 microg x kg(-1) x min(-1) YM337 maintained inhibition of platelet aggregation >80%. Aggregation and bleeding time returned to normal within 24 hours. A bolus of 0.25 mg/kg of abciximab followed by an infusion of 0.125 microg x kg(-1) x min(-1) showed effects similar to those observed with the 0.5- and 0. 75-microg x kg(-1) x min(-1) infusion of YM337. In 53 subjects exposed to YM337, 1 case of transient thrombocytopenia and 3 minor bleeding events occurred. No human anti-chimeric antibodies were detected 2 weeks and 2 months after administration. CONCLUSIONS: YM337 effectively inhibits IIb/IIIa-mediated platelet aggregation and adhesion in humans. The results of this phase 1 study will give rise to further clinical evaluation of YM337.

Abciximab↗
PubMed1999

Pharmacokinetics of oxypolygelatine in healthy volunteers.

OBJECTIVE/METHODS: The pharmacokinetics of the plasma substitute oxypolygelatine (OPG) were studied in 12 healthy volunteers after single-dose administration of 27 ml x kg(-1) body weight, with a maximum of 2000 ml. OPG was determined in plasma and urine over 48 h after the infusion. Peak plasma OPG concentrations at the end of the infusion were determined to 4.600 (623) microg x ml(-1), the area under the plasma concentration/time curve (AUC(0-infinity)) was calculated to 70.135 (15.861) microg x h x ml(-1). RESULTS: The model-independently calculated volume of distribution came to 23.1 (4.8) 1 with a clearance total is (Cl(tot)) of 24.6 (6.8) ml x min(-1). The initial half-life according to a three-compartment model came to 0.3 (0.2) h, followed by a distribution half-life of 3.1 (2.6) h and a terminal elimination half-life of 13.4 (2.2) h. Cumulative urinary excretion of OPG was 64% after 48 h. CONCLUSION: This low recovery rate may be explained by the distribution of OPG into the extravascular space and subsequent degradation in tissue sites.

Contrast Media↗
PubMed1999

Chromosome aberrations are restricted to the CD56+, CD3- tumour cell population in natural killer cell lymphomas: a combined immunophenotyping and FISH study.

Natural killer (NK) cell lymphomas are a newly recognized entity of non-Hodgkin's lymphoma with a highly aggressive clinical course and strong association with Epstein-Barr virus (EBV) infection. Although no recurrent chromosome aberrations have been identified in NK-cell lymphoma, deletions of 6q and trisomy 7 have been described repeatedly in this type of lymphoma. In this study we attempted to determine the immunophenotypes of tumour cells with certain chromosome aberrations, i.e. deletions of 6q and trisomy 7, in three cases of NK cell lymphomas by means of combined immunophenotyping and fluorescence in situ hybridization (FISH). In all three cases clonal chromosome aberrations were detected only in CD56+ cells but not in CD3+ or CD5+ cells. However, not all CD56+ cells were shown to contain these chromosome aberrations. Double immunophenotyping combined with FISH confirmed that the chromosome aberrations occurred only in CD56+CD3- cells. This study indicates that chromosome aberrations in NK-cell lymphomas are restricted to the CD56+, CD3- and CD5- cell population and that NK-cell lymphomas are indeed derived from mature true NK cells and not from T lymphocytes.

Adult↗
PubMed1999

Clinical pharmacokinetics of sevoflurane.

Sevoflurane is a comparatively recent addition to the range of inhalational anaesthetics which has been recently released for clinical use. In comparison to older inhalational agents such as isoflurane or halothane, the most important property of sevoflurane is its low solubility in the blood. This results in a more rapid uptake and induction than the 'older' inhalational agents, improved control of depth of anaesthesia and faster elimination and recovery. The more rapid pharmacokinetics are a result of the low blood/gas partition coefficient of 0.69. With an oil/gas partition coefficient of 47.2, the minimum alveolar concentration (MAC) of sevoflurane is 2.05%. Two to 5% of the drug taken up is metabolised by the liver. The pharmacokinetics of sevoflurane do not change in children, obese patients or patients with renal insufficiency. The pharmacokinetics and pleasant odour of sevoflurane make mask induction feasible, which is an obvious advantage in paediatric anaesthesia. The hepatic metabolism of sevoflurane results in the formation of inorganic fluoride. Upon contact with alkaline CO2 absorbent, a small amount of sevoflurane is degraded and a metabolite (compound A) is formed and inhaled in trace amounts. Whether inorganic fluoride or compound A are nephrotoxic is presently a matter of controversy.

Age Factors↗
PubMed1998

[Dose-response relation: relevance for clinical practice].

Dose-finding studies are performed routinely in patients and--if appropriate surrogate models exist--also in healthy volunteers. Such studies aim at establishing the optimal dose range for further clinical studies on the efficacy and the risk-benefit ratio of a new drug. The dose-response relationship of a drug is most often described by a sigmoidal curve. Its parameters include the mean effective dose, the maximal effect and the steepness. Interpretation of such curves should be done in the context of the intended clinical indications of the drug. The risk-benefit ratio of a drug can be assessed by overlapping the dose-response curve of wanted and unwanted clinical effects, again, any overlapping (which can be described e.g. by the therapeutic index) should be seen in the context of the indication and available therapeutic alternatives.

Chemistry, Pharmaceutical↗
PubMed1998

Influence of the angiotensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension.

BACKGROUND: Left ventricular hypertrophy (LVH) represents an independent risk factor in patients with essential hypertension. Because reversal of LVH may be associated with an improvement of prognosis, the influence of new antihypertensive compounds, such as angiotensin II AT1 receptor antagonists, on LVH should be determined. METHODS AND RESULTS: In a randomized, double-blind trial, 69 predominantly previously untreated hypertensive patients with echocardiographically proven LVH, ie, left ventricular mass index (LVMI) >134 g/m2 in men and >110 g/m2 in women and/or end-diastolic septal thickness >12 mm, received either the angiotensin II antagonist valsartan or atenolol for 8 months. Echocardiographic data of 58 patients were available. After 8 months of valsartan treatment (n=29), LVMI decreased from 127+/-23 to 106+/-25 g/m2 (ratio [R]=0.83; 95% CI, 0.79 to 0.87; P<0.0001 versus baseline). Under atenolol (n=29), LVMI decreased to a smaller extent, from 127+/-25 to 117+/-27 g/m2 (R=0.92; 95% CI, 0.86 to 0.98; P=0.0082 versus baseline). The mean reduction of LVMI came to 21 g/m2 under valsartan and only to 10 g/m2 under atenolol (R=0.91; 90% CI, 0.85 to 0.97 versus atenolol). Baseline mean blood pressure values were determined to be 163+/-12/101+/-6 mm Hg before treatment with valsartan and 160+/-14/103+/-6 mm Hg before atenolol treatment. After 8 months of treatment, mean blood pressure decreased to 146+/-13/90+/-7 mm Hg with valsartan and to 147+/-18/90+/-7 mm Hg with atenolol. Nine patients in the valsartan group and 8 patients in the atenolol group required additional medication with hydrochlorothiazide. CONCLUSIONS: Antihypertensive treatment with the angiotensin II antagonist valsartan for 8 months produced a significant regression of LVH in predominantly previously untreated patients with essential hypertension. The drug may be safely administered in this subset of hypertensive patients; however, the long-term benefit in terms of risk reduction has still to be evaluated in further trials.

Angiotensin II↗
PubMed1998

[Structure and activities of drug committees in Germany. Results of a survey of 143 hospitals. Pharmaco-economic Study Group and Rational Drug Therapy of the German Society of Clinical Pharmacology and Therapy].

BACKGROUND: To obtain information on the structure, present activities and decision making process of hospital drug committees in Germany in 1995 a questionnaire with 36 items was designed and sent to 450 hospitals in Germany with more than 400 beds. 143 returned questionnaires could be evaluated. RESULTS: According to hospital size the median value of the annual drug budget 1993 ranged between DM 2.4 Mio for hospitals with less than 500 beds and DM 30.0 Mio for university hospitals with more than 1,000 beds (including blood and blood derived products). In 53% of drug committees a pharmacist held the position of the chairman, followed by medical specialists (32%), (clinical) pharmacologists held this position only in 8% of the hospitals, but in almost 50% of the university hospitals. In most cases all clinical specialties are represented in the drug committee, the number of members ranging between 5 and 40 (median 12). The number of drugs included in the internal drug list ranging between 400 in hospitals with < 500 beds and about 700 in university hospitals was strongly correlated with the number of beds and, interestingly, with the number of drug committee members. Treatment guidelines were implemented mainly for antiinfectives (87%), infusion solutions (30%), antiemetic drugs (5-HT3-receptor antagonists, 27%) and blood and blood-derived products such as intravenous immunoglobulins (23%). However, effective control of these guidelines was only performed in about 50% of the hospitals. A drug information service was provided in most hospitals, where 95% of queries were answered by pharmacists. CONCLUSION: The results of our survey showed, that German hospital drug committees vary considerably with regard to their function and control mechanisms on drug use. Most of the responders would appreciate a more intensive exchange of current problems and treatment guidelines.

Drug Costs↗
PubMed1998

Application of interphase fluorescence in situ Hybridization for the detection of the Burkitt translocation t(8;14)(q24;q32) in B-cell lymphomas.

The translocation t(8;14)(q24;q32) is the characteristic chromosomal aberration of Burkitt's-type lymphomas and leukemias (BLs). On the molecular level, the t(8;14) juxtaposes the c-myc gene in 8q24 next to the IgH locus in 14q32, resulting in overexpression of the transcription factor c-Myc. The detection of a t(8;14) is a major aim in the diagnostic process of all patients with high-grade B-cell lymphomas because treatment strategies differ between BL and other high-grade lymphomas. As chromosome analyses are sometimes hampered by the low yield or poor quality of metaphase spreads and as the application of molecular genetic techniques is limited by the distribution of the 8q24 breakpoints over a region of about some hundred kilobases, we set out to establish an interphase fluorescence in situ hybridization (FISH) assay for the detection of the t(8;14). A cosmid probe hybridizing to the IgH constant region in 14q32 was combined with a differently labeled probe of pooled cosmid clones spanning the c-myc locus in 8q24. Interphase nuclei lacking a t(8;14) show two separated signals corresponding to each probe, whereas interphase nuclei carrying a t(8;14) display a split of the c-myc probe and a colocalization of at least one of the splitted signals with the IgH probe. Based on the results of extensive control studies, the cutoff level for this stringent (type I) criteria was set at 2%. Additionally, colocalization of at least one c-myc signal with one IgH signal alone (without signal split for the c-myc probe) was used as a less stringent (type II) criteria with a cutoff limit of 11%. Nine BLs and one Burkitt-like lymphoma were investigated by this approach. Cytogenetically, all tumors contained a translocation t(8;14)(q24;q32) except for one BL, in which cytogenetic analysis had failed. In interphase FISH, all lymphomas and leukemias met the less stringent criteria for the diagnosis of the t(8;14). Additionally, in all tumors but the Burkitt-like lymphoma, a t(8;14) could be diagnosed according to the stringent criteria. The percentage of cells found to harbor the t(8;14) by FISH ranged from 4.3% to 100%. Comparison of cytogenetic and FISH results revealed a significantly lower percentage of t(8;14)+ interphase nuclei than metaphase cells (P = .004). In conclusion, the described FISH assay provides a feasible and sensitive tool for the routine detection of the translocation t(8;14) in interphase cells which might also offer new insights into the biology of high-grade B-cell lymphomas.

Adult↗
PubMed1998

When are bioavailability studies required? A German proposal.

The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German drug regulation authority, issued guidelines for determining whether bioavailability/bioequivalence studies are required for certain drugs. This decision tree is based on pharmacodynamic, pharmacokinetic, and physicochemical criteria. Details of this decision tree were worked out by an expert panel, the Bioavailability Commission at the BfArM. The decision tree has been in use by German regulatory authorities for more than 10 years. In the meantime, its essentials were adopted by the European Committee for Proprietary Medicinal Products (CPMP) and by the World Health Organization (WHO) for their "Guidelines on interchangeability of multisource pharmaceutical products." This article reviews the original decision tree of the BfArM and provides examples of drugs that have been assessed according to its rules. The current procedure of the German regulatory authorities for judging the necessity of bioavailability trials, which reflects the status quo of regulatory practice in Germany, is also discussed.

Biological Availability↗
PubMed1998

Detection of 6q deletions in breast carcinoma cell lines by fluorescence in situ hybridization.

Dual-color fluorescence in situ hybridization was performed to detect the frequency and extent of 6q deletions in ten breast carcinoma cell lines. In five cell lines, the 6q deletions involved large regions extending from 6q12-q16 to 6q27, and in one the deletion extended from the region distal to YAC 751G10 at 6q25.1 to 6q27. In two cell lines, 6q deletions occurred only in cells with polysomy 6, indicating that such deletions might be secondary chromosomal aberrations and reflect late genetic changes in breast carcinomas. In addition, an overrepresentation of 6q21-q22.2 was detected in one cell line.

Aneuploidy↗
PubMed1998

Concentration-response relationship of levodopa in patients at different stages of Parkinson's disease.

OBJECTIVE: To assess differences in the pharmacokinetic and pharmacodynamic relations of levodopa in clinically defined groups and to prove that pharmacokinetic and pharmacodynamic parameters are associated with duration of disease and length of treatment. METHODS: We studied the pharmacokinetic and pharmacodynamic relations of levodopa after a single dose (100 mg levodopa with 25 mg benserazide) among four groups of patients with Parkinson's disease. Group 1 was levodopa-naive patients (n = 8); group 2 was patients in stable condition taking levodopa (n = 10); group 3 was patients with on-and-off fluctuations (n = 11); and group 4 was patients with on-and-off fluctuations and peak-dose dyskinesia (n = 8). The Columbia University Rating Scale was used for clinical assessment. The pharmacokinetic-pharmacodynamic analysis was based on an estimate of the maximal response model with a semiparametric approach to effect-site equilibrium (equilibration half-life). RESULTS: The mean concentration at half-maximal effect estimated for the different groups was as follows (mean value +/- SD): group 1, 389 +/- 138 ng x ml(-1); group 2, 346 +/- 203 ng x ml(-1); group 3, 543 +/- 245 ng x ml(-1); group 4, 711 +/- 215 ng x ml(-1). Estimate of the maximal response was determined to be the following: group 1, 10 +/- 3; group 2, 12 +/- 5; group 3, 24 +/- 13; group 4, 18 +/- 7. A significant correlation was observed between duration of Parkinson's disease and mean concentration at half-maximal effect (p < 0.001), estimate of maximal response (p < 0.05), and, inversely, equilibration half-life (p < 0.05). CONCLUSIONS: The data suggested that levodopa-naive patients and patients in stable condition taking levodopa do not differ in pharmacokinetic-pharmacodynamic relations, whereas patients with fluctuations, especially patients with peak-dose dyskinesia, exhibit a larger threshold level (mean concentration at half-maximal effect). It was concluded that progression of the disease (loss of endogenous dopamine synthesis and reduced dopamine storage) is reflected by pharmacokinetic and pharmacodynamic parameters that characterize the demand for exogenous dopamine provided by levodopa.

Aged↗
PubMed1998

The effect of socio-demographic and crash-related factors on the prognosis of whiplash.

Whiplash injury, common after a motor vehicle crash, has a variable prognosis that is difficult to predict. To assess the role of various factors on this prognosis, we assembled a historical cohort of 3014 individuals who sustained a whiplash injury resulting from a motor vehicle crash in the Province of Quebec, Canada, in 1987 and were followed for 6 years. The data were obtained from the computerized databases created by the province's universal automobile insurance plan and police accident reports. The recovery time from whiplash, as measured by duration of compensation, was the primary outcome. Socio-demographic and crash-related factors measured at the time of the crash were investigated. The median recovery time for the cohort was 31 days, with 22% recovering within a week and 3% still not recovered after 1 year. For the 1551 subjects with a whiplash injury only, the socio-demographic factors that were found to be independently associated with a slower recovery from whiplash in this cohort are female gender, older age, having dependents, and not having full-time employment. The significant crash-related factors are occupancy in a truck or bus, being a passenger in the vehicle, colliding with a moving object, and being in a head-on or perpendicular collision. We classified the subjects according to a prediction score ranging from 0 to 11, devised from these factors. Subjects with a score of 0 to 2, that is those who had at most two risk factors present, had the fastest median recovery time of 19 days compared with 71 days for subjects who had a score of 6 or more. We conclude that several sociodemographic and crash-related factors are independently associated with a slow and costly recovery from whiplash injury. They are easily measurable at the time of the crash and combined so as to be simply incorporated in intervention programs aimed at early identification and management of whiplash patients with a poor prognosis.

Accidents, Traffic↗
PubMed1998

Inhibition of endothelial receptor expression and of T-cell ligand activity by mycophenolate mofetil.

The novel immunosuppressive drug mycophenolate mofetil (CellCept, MMF) blocks DNA-synthesis by the inhibition of the enzyme inosine monophosphate dehydrogenase (IMDH). IMDH is also involved in the synthesis of adhesion receptors which are known to play an important role in the regulation of cell-cell contacts. Therefore, application of MMF might lead to a reduction of cellular infiltrates in the course of transplant rejection. To evaluate the therapeutic value of MMF, we investigated to what extent MMF blocks T-lymphocyte infiltration in vitro with regard to (a) adhesion to endothelial cells, (b) horizontal migration along these cells and (c) penetration through the endothelial cells. The results demonstrated a strong inhibition of both CD4+ and CD8+ T-cell adhesion and penetration by MMF. The ID50 value for CD4+ T-cell adhesion was calculated to be 0.03 microM and the ID50 value for CD4+ T-cell penetration 1.21 microM. MMF did not significantly influence the horizontal migration of T-lymphocytes along the human vascular endothelial cell (HUVEC) borders. FACS-analysis revealed a diminished E-selectin and P-selectin expression on endothelial cell membranes in the presence of MMF. Although MMF did not interfere with the synthesis of T-cell adhesion ligands, the binding activity of lymphocytic leucocyte function associated antigen 1 (LFA-1), very late antigen 4 (VLA-4) and PSGL-1 (P-selectin glycoprotein ligand 1) to immobilized intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P-selectin was impaired. Moreover, MMF prevented VLA-4 and PSGL-1 receptor accumulation on the membranes of T-cell pseudopodia. It can be concluded that MMF possesses potent infiltration blocking properties. MMF evoked down-regulation of specific endothelial membrane molecules and the loss of protein localization in the lymphocyte protrusions might be predominantly responsible for the observed blockade of cell adhesion and penetration.

CD4-Positive T-Lymphocytes↗
PubMed1998

Application of interphase cytogenetics for the detection of t(11;14)(q13;q32) in mantle cell lymphomas.

BACKGROUND: The chromosomal translocation t(11;14)(q13;q32) is the hallmark of mantle cell lymphoma (MCL) in which it can be detected cytogenetically in about 75% of cases. The t(11;14) translocation juxtaposes the bcl-1 locus in chromosome band 11q13 next to the IgH locus in chromosome band 14q32 and, thus, leads to deregulation of the cell cycle regulatory protein cyclin D1, which is encoded by the CCND1 gene localized at the telomeric border of the bcl-1-locus. MCL has the worst prognosis of all low-grade non-Hodgkin's lymphomas (NHL). In some instances, however, histopathologic differentiation between MCL and other low-grade B-cell NHL is difficult. Therefore, detection of the t(11;14) translocation is of essential diagnostic value for the risk-adjusted management of patients with MCL. Unfortunately, chromosome analyses are frequently hampered by the low yield and quality of tumor metaphases. As the 11q13 breakpoints are scattered over a region of more than 120 kb the application of molecular genetic techniques is also limited. PATIENTS AND METHODS: We established an interphase fluorescence in situ hybridization (FISH) approach for the detection of the t(11;14) translocation by use of a cosmid probe hybridizing to the IgH constant region and a YAC spanning the bcl-1 region. Cells containing a t(11;14) translocation show a colocalisation of the signals for IgH and bcl-1. Eight control samples and 15 MCL specimens were investigated. RESULTS: According to our control studies, samples containing more than 10% of cells with this signal constellation can be diagnosed as carrying a clonal t(11;14) translocation. All eleven MCL found to carry the t(11;14) translocation by chromosome analysis were positive in our FISH assay. Additionally, two of four MCL lacking a clonal t(11;14) translocation by chromosome analysis were shown to carry this aberration in 14% and 37% of interphase nuclei. Southern blot data indicate that our FISH assay reliably detects the t(11;14) translocation irrespective of the location of the breakpoints within the bcl-1 region. CONCLUSIONS: The described interphase FISH assay provides a reliable and routinely applicable tool for diagnosis of the t(11;14) translocation.

Aged↗
PubMed1998

Single dose and steady state pharmacokinetics and pharmacodynamics of the ACE-inhibitor imidapril in hypertensive patients.

AIMS: To investigate the pharmacokinetic profile of the ACE-inhibitor imidapril in 10 hypertensive patients after a first single dose (10 mg) and after 28 days therapy with imidapril 10 mg once daily. METHODS: Cmax, tmax, t1/2 and AUC of imidapril and imidaprilat were obtained. ACE-activity and arterial blood pressure during imidapril were corrected by a preceding placebo-investigation. RESULTS: The AUC of imidapril was 140 (43 s.d.) ng ml(-1) h after the first dose and 123 (34 s.d.) ng ml(-1) h at steady state. AUC of the active moiety imidaprilat averaged 211 (101 s.d.) ng ml(-1) h after the first dose and 240 (55 s.d.) ng ml(-1) h at the steady state investigation. Maximal ACE-inhibition was 75% after the single dose as well as at steady state. ACE inhibition before drug intake at day 28 (i.e. trough) was 50%. The (placebo-corrected) maximal drop in diastolic blood pressure after imidapril was 22 mm Hg after the first dose and 25 mmHg at steady state. Exploratory analysis of imidaprilat plasma concentration vs effect profiles suggests a hyperbolic concentration effect relationship where data of the single dose contribute to the ascending part of an Emax-curve, whereas the plateau around Emax is maintained at steady state. CONCLUSIONS: In this group of hypertensive patients, the pharmacokinetic profile and the drop in ACE-activity as well as in blood pressure seen after a single dose of imidapril and at steady state were similar. The initial response to a test dose might therefore predict the response during chronic dosing.

Adult↗