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Biomedical subjects

G Achtert

Publications and source records attributed to G Achtert.

At least 19 recordsLinked to original sources
PubMed1998

The NA"null" phenotype of a young man is caused by an Fc gammaRIIIB gene deficiency while the products of the neighboring Fc gammaRIIA and Fc gammaRIIIA genes are present.

A 27-year-old man with an allergy to house dust mites was found to lack the Fc gammaRIIIb on his neutrophils. Cell surface marker and PCR techniques were used to investigate possible reasons for this deficiency. Agglutination and immunofluorescence assays using the man's neutrophils together with NA1- and NA2-specific antibodies were negative, and there was no reaction with the Fc gammaRIII-specific mAb 3G8. Indirect immunofluorescence demonstrated the presence of the CD24 molecule, which, like the Fc gammaRIIIb, is anchored to the cell membrane by glycosylphosphatidylinositol. Thus a lack of the Fc gammaRIIIb cell membrane anchor was excluded. PCR analysis confirmed the absence of the NA1 and NA2 alleles. The individual was therefore typed as NA"null". The products of those genes located together with the Fc gammaRIIIB gene within a complex on chromosome 1 (q23-24) were examined. Fc gammaRII was demonstrated on monocytes and B cells with the use of Fc gammaRII-specific monoclonal antibodies. About 5% of the individual's peripheral blood monocytes were positive with the 3G8 antibody, indicating the presence of Fc gammaRIIIa. From these data we concluded that the Fc gammaRIIIb deficiency on the neutrophil cell surface of this individual is due to a lack of the Fc gammaRIIIB gene while excluding a lack of the Fc gammaRIIA and the Fc gammaRIIIA genes.

Adult↗
PubMed1997

Inhibition of monocyte and polymorphonuclear granulocyte immune phagocytosis by monoclonal antibodies specific for Fc gamma RI, II and III.

We tested two Fc gamma receptor I (Fc gamma RI); six Fc gamma RII; and six Fc gamma RIII-specific monoclonal antibodies (mAb) for their capacity to inhibit monocyte and polymorphonuclear granulocyte (PMN) immune phagocytosis which is mediated by Fc gamma R. We used human red blood cells (rbc) coated with hIgG1 or mIgG1 as Fc gamma RI- and Fc gamma RII-specific target cells, respectively. The Fc gamma RI-specific mAbs 22.2 and 32.2 did not inhibit Fc gamma RI- or Fc gamma RII-specific monocyte immune phagocytosis. The Fc gamma RII-specific mAbs IV.3, CIKM5, FLI8.2, FLI 8.26, 2E1, and 41H16 inhibited Fc gamma RII-specific monocyte immune phagocytosis in all Fc gamma RIIa high-responder (HR) individuals but did not inhibit Fc gamma RI-specific phagocytosis. Using PMN, FL18.2 and 2E1 only partially inhibited phagocytosis in HR individuals, but the Fc gamma RIII-specific mAbs 3G8, DJ130c. MFM-154. B88-9 and MG38 completely inhibited Fc gamma RII-specific phagocytosis if the corresponding antigen was available on the cell surface. In these cases phagocytosis inhibition may be explained by cross-linking of Fc gamma RII and Fc gamma RIII via one antibody molecule, with the Fab portion binding to Fc gamma RIII and the Fc portion binding to Fc gamma RII.

Animals↗
PubMed1994

[Absolute bioavailability of folic acid after oral administration of a folic acid tablet formulation in healthy volunteers].

5 mg folic acid were administered in two sessions to 9 female and 8 male healthy subjects within a balanced 2-way crossover trial either as one Folsan tablet (CAS 59-30-3, test preparation A) or as 2.5 ml of an injection solution (Folsan 2, reference preparation B). Folic acid was determined in serum and urine collected in fractions over 12 h after administration by means of a radioassay. Before each session a saturation period of 9 days duration was performed by administering 1 tablet per day containing 5 mg folic acid followed by a 4-day wash-out period. The mean predose serum level of folic acid amounted to 17.9 +/- 5.62 ng/ml before the oral and 18.2 +/- 5.73 ng/ml before the intravenous administration. The post dose serum levels were corrected with the individual predose levels. After oral administration of test preparation. A a mean peak serum concentration of 243 +/- 33.0 ng/ml (Cmax) was obtained after 2.24 +/- 0.85 h (tmax). The mean area under the corrected serum level time curve was determined with 1160 +/- 177 ng x h/ml (AUC(0-12)). 6 min after intravenous administration serum levels ranged from 559 to 1490 ng/ml. Following correction with the individual predose levels the mean area under the curve amounted to 1550 +/- 249 ng x h/ml. The individual bioavailability ratios of AUC(0-12) (A versus B) varied between 49.3% and 96.7%. The mean absolute bioavailability of folic acid was 76.2% +/- 13.8% (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Minimal biliary excretion and enterohepatic recirculation of metoclopramide in patients with extrahepatic cholestasis.

The biliary excretion and apparent oral clearance of metoclopramide (MCL) were determined after oral administration of 1 mg MCL/kg body weight to 10 patients suffering from extrahepatic cholestasis with nasobiliary tube for drainage of the common bile duct. A bilioduodenal endoprosthesis was subsequently fitted in 6 of these patients, i.e. the enterohepatic circulation was restored, and the apparent oral clearance was re-determined. Biliary excretion, comprising free MCL and the products of conjugation, accounted for less than 1% of the administered dose. In accordance with this, the median areas under the plasma concentration-time-curves AUC(0-15 h) in patients with intact and interrupted enterohepatic recirculation were of similar size. The pharmacokinetic values in patients with cholestasis (median apparent oral clearance 0.5 l.kg-1.h-1; median t1/2 4.5 h) were similar to those previously reported in patients with healthy liver function. We conclude that it is not necessary to adjust single doses of MCL in patients recovering from obstructive jaundice.

Administration, Oral↗
PubMed1992

Pharmacokinetics of colchicine: a review of experimental and clinical data.

Thanks to the development of a sensitive and specific radioimmunoassay for colchicine, the pharmacokinetics of colchicine is now well-established after single oral doses. Absorption is characterized by a zero-order rate constant while disposition appears biexponential with a rapid distribution phase (t1/2 = 1.8 h) and a long elimination phase (t1/2 = 20 h). All studies confirm the large total body clearance (35 l/h) predominantly by the extrarenal route and the large distribution volume (700 l). Further studies need to be performed to investigate colchicine absorption and to describe the metabolic pathway of the drug. To date, relationships between colchicine plasma levels and pharmacological effects have not been defined. Monitoring of plasma levels in patients with familial Mediterranean fever should improve treatment with colchicine. However, the therapeutic range has not been precisely determined. The use of colchicine in the treatment of liver cirrhosis and primary biliary cirrhosis is a recent development; so, assuming that a large part of total body clearance depends on hepatic function, the influence of hepatic diseases on colchicine disposition needs to be investigated in order to define the most appropriate therapeutic dosing.

Administration, Oral↗
PubMed1991

Alloantiserum recognizing a DQw2 split which is associated with DR3.

A typing serum MUE 38539 II, was found to recognize a DR3-associated split of DQw2. In cytotoxicity tests, MUE 38539 II yielded positive test results with B lymphocytes but not with monocytes of DR3-positive cell donors. This was in contrast to other typing reagents for DR3 that react with B lymphocytes as well as monocytes. Lymphocytotoxicity tests using MUE 38539 II were negative with DR7- and DQw2-positive cells. The assumption that the serum recognizes a DR3-associated split of DQw2, and not DR3 itself, was confirmed by the lack of reactivity with a DQw4- and DR3-positive lymphoblastoid cell line (RSH). The assumption was also corroborated using reagents from a family in which DR3 and DQw2 were not found in the usually described linkage. In two lines, DR3 was associated with DQw- (2707 and 2710), and in the cell line 2704, DQw2 was associated with DRw-. The serum MUE 38539 II was exclusively cytotoxic with lymphoblastoid cell lines from those family members who were positive for DQw2, independently of the DR3 antigens of the cells.

Cytotoxicity Tests, Immunologic↗
PubMed1989

Some properties of an inhibitory cytochrome P-450 metabolic-intermediate complex existing in a spin-state equilibrium.

Incubation, in the presence of NADPH/O2, of the type II compound revenast with a partially solubilized, phenobarbital-induced rat liver microsomal cytochrome P-450 system results in the formation of a difference spectrum exhibiting a Soret band at 407 nm and a trough at 423 nm. Experiments with N2 and metyrapone suggest this spectral perturbation to originate from binding to the hemoprotein of a metabolic intermediate derived from the amine substrate. The percentage of pigment complexed can be assessed to be about 7%, with half-maximal complexation occurring at a revenast concentration of 125 microM. Adduct formation is inhibitory to the N-hydroxylation of 4-chloroaniline and N-demethylation of N,N-dimethylaniline; kinetic analysis suggests a competitive interaction at the catalytic site of the reactive revenast derivative with the tertiary arylamine. Inhibition of the two monooxygenation reactions is reversible, indicating weak heme bonding of the active intermediate. This behaviour differs from that of most other product adducts so far examined. The aberrant functional properties of the metabolic adduct appear to reflect complex molecular organization of this compound, as is also evidenced by the unique position of the Soret region absorption maximum at 407 nm; this spectral data hints at the presence of a mixture of high- and low-spin forms. Indeed, chemical reduction or oxidation of the product complex reveals the existence of a low-spin component hidden in the metabolic spectrum. Model studies suggest that the product adduct possibly arises from N-oxidation of the revenast molecule.

Aniline Compounds↗
PubMed1989

Transfer of metaclazepam and its metabolites into breast milk.

Ten young women took part in this study a few days after delivery (day 3 and day 5 post partum). Lactation had developed normally but the newborn infants were not breast-fed. The study was intended to investigate whether metaclazepam (Talis), a new 1,4-benzodiazepine, and some of its metabolites were present in breast milk. Levels were measured in the plasma and milk. The levels in the milk showed that metaclazepam, N-desmethylmetaclazepam and two of its metabolites with a lactam structure could be found in small amounts. Differences in metaclazepam and N-desmethylmetaclazepam concentrations in the breast milk on days 3 and 5 post partum are discussed.

Administration, Oral↗
PubMed1987

[Biotransformation and bioequivalence of a new nifedipine preparation].

Following a single dose of two 5 mg soft gelatine capsules with nifedipine (Pidilat as a test preparation and a commercially available reference preparation) to 12 healthy volunteers in a randomized, 2-fold cross-over trial (latin square), blood samples were drawn up to 16 h post application (p.a.). The nifedipine plasma levels were quantitatively determined by a capillary gas chromatographic assay. Some important pharmacokinetic parameters as well as the bioavailability/bioequivalence were evaluated and subsequently compared for possible statistically significant differences between the preparations. Approximately 0.5 h p.a. mean peak plasma concentrations of about 110-120 ng/ml were reached; the mean terminal half-live was 1.5 h. The plasma level-time curves were-except for the negligible different peak concentrations-virtually identical; thus both preparations are considered to be bioequivalent.

Adult↗
PubMed1987

Absolute bioavailability of metoclopramide given orally or by enema in patients with normal liver function or with cirrhosis of the liver.

Single dose studies were performed with three different dosage forms of metoclopramide (0.25 mg/kg body weight) in patients with normal liver function (i.v. (Paspertin): n = 4, oral liquid preparation: n = 4, rectal micro-enema n = 4) and patients with histologically confirmed cirrhosis of the liver (i.v.: n = 6, oral liquid preparation n = 4, rectal micro-enema: n = 8). Drug plasma-concentrations were measured over 8 h by a specific gas chromatographic method. The median areas under the plasma concentration-time curves (AUC0-8) after i.v. and rectal administration were similar in both groups. In contrast, the median oral bioavailability was considerably higher in patients with cirrhosis of the liver (82%) than in patients with normal liver function (60%). It can be concluded from this study, that dosage adjustments may be necessary in oral treatment of patients with cirrhosis of the liver, especially if prolonged therapy is required.

Administration, Oral↗
PubMed1986

[Dose-effect relation of N-prajmalium bitartrate with control of plasma levels].

15 patients with ventricular ectopic beats classified to at least Lown class III with more than 100 ventricular ectopic beats in one hour were treated with N-prajmalium bitartrate (NPAB) in increasing dosages. The first dosage of 4 X 5 mg/d has been increased by 5 mg in three steps of three days to a level of 4 X 20 mg/d. A resting ECG, the systolic time intervals and a 24 h ECG were registered before treatment and after every dose. The median PQ time increased from 170 msec to 200 msec, the increase becoming significant (p less than 0.05) with a dose of 4 X 5 mg/d NPAB and above. Frequency, QRS and the frequency-corrected QT time did not change significantly. At a dose of 4 X 10 mg/d NPAB the increase of the quotient pre-ejection period to ejection time PEP/LVET became significant, increasing continuously from 0.35 to 0.48. Six of the 15 patients showed a significant reduction of ventricular ectopic beats, couplets and salvoes. In two patients the antiarrhythmic effect was significant at 4 X 5 mg/d. With an increasing dose from 4 X 10 mg/d each responder showed a significant reduction of ventricular ectopy. The lowest effective plasma concentrations ranged from 15 to 213 ng/ml with a median value of 58 ng/ml and an upper quartile of 94 ng/ml. There was no significant difference in plasma concentrations between responders and non-responders.

Aged↗
PubMed1985

Pharmacokinetics of N-propylajmaline in relation to polymorphic sparteine oxidation.

In order to determine whether the metabolism of the antiarrhythmic drug N-propylajmaline is under the same genetic control as sparteine metabolism, the pharmacokinetics of this antiarrhythmic drug were studied in a groups of six extensive and four poor metabolizers of sparteine. Pronounced differences in terminal half-life, total plasma clearance, metabolic clearance and urinary excretion of N-propylajmaline were observed between extensive and poor metabolizers. A close relationship between the total clearance and metabolic clearance of N-propylajmaline and sparteine could be demonstrated. Clinically available N-propylajmaline is a 55% to 45% mixture of the i- and n-diastereomers. The extensive metabolizers exhibited stereoselective metabolism; the i-diastereomer was preferentially metabolized. Poor metabolizers were characterized by a loss of this stereoselective metabolism. Five subjects were treated for 7 days with a daily N-propylajmaline dosage of either 60 mg or 20 mg. Since a close relationship between the clearance of N-propylajmaline and the metabolic ratio of sparteine had been observed after single dosing the metabolic ratio of sparteine was used to predict N-propylajmaline steady-state plasma concentrations during multiple dosing. Only in two extensive metabolizers with a metabolic ratio less than 0.4 predicted and observed, steady-state plasma concentrations were in good agreement. In the other three subjects observed steady-state plasma concentrations were appreciably higher than predicted. In these three subjects metabolic N-propylajmaline clearance decreased indicating saturation N-propylajmaline metabolism during multiple dosing. The data indicate that N-propylajmaline metabolism is subject to a genetic polymorphism controlled by the sparteine/debrisoquine gene locus.

Adult↗
PubMed1985

Metoclopramide kinetics at high-dose infusion rates for prevention of cisplatin-induced emesis.

Eleven male subjects aged 24 to 58 yr received cisplatin, 90 to 120 mg/m2 iv, in combination with other cytostatic drugs such as doxorubicin HCl and bleomycin. To prevent emesis, two high-dose metoclopramide regimens were started 2 hr before cytostatic therapy. Regimen A (n = 7) consisted of a loading dose infusion of 1 mg/kg/hr over 2 hr, followed by a maintenance infusion of 0.5 mg/kg/hr over 24 hr (total dose was 14 mg/kg in each cytostatic cycle). Regimen B (n = 6) consisted of half the metoclopramide dose. The following kinetics were derived from the metoclopramide steady-state plasma levels and the t1/2 of the elimination phase 26 to 38 hr after dosing (median value and range are listed): Steady-state plasma concentration in group A and group B was 750 (480 to 1520) and 360 (300 to 480) ng/ml plasma. Drug clearance in group A and group B was 0.67 (0.3 to 1.0) and 0.70 (0.5 to 0.8) l/hr/kg. Volumes of drug distribution in group A and group B were 4.4 (1.9 to 6.5) and 4.3 (3.2 to 5.9) l/kg. Values for the t1/2 in the elimination phase in group A and group B were 4.7 (3.0 to 5.4) and 4.3 (3.7 to 5.1) hr. It appears that metoclopramide kinetics at high doses were dose linear, i.e., without evidence of cumulation. There were few side effects; vomiting was effectively suppressed by both regimens.

Adult↗