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.

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.

[Absolute bioavailability of folic acid after oral administration of a folic acid tablet formulation in healthy volunteers]. / Absolute Bioverfügbarkeit von Folsäure nach einmaliger oraler Gabe einer Folsäure-Tablettenzubereitung an gesunde Versuchspersonen.

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)

Steady state investigation of possible pharmacokinetic interactions of moxonidine and glibenclamide.

The aim of the study presented here was to determine possible pharmacokinetic interactions of moxonidine and glibenclamide at steady state in 18 healthy male volunteers. Multiple oral doses of 0.2 mg of moxonidine b.i.d. (q. 12 h) and of 2.5 mg of glibenclamide o.i.d. (q. 24 h) were administered alone and in combination in an open, non-randomized, three-treatment design. The preparations were given for 5 days in each of the 3 periods. The results of this multiple dose study did not indicate substantial pharmacokinetic interactions of the drugs. Regarding the influence of glibenclamide on the pharmacokinetics of moxonidine, no significant changes were seen at all. In the presence of moxonidine, a minor decrease of bioavailability of glibenclamide was detectable, as could be derived from the AUC and clearance data. The actual differences were small and not considered to be of clinical significance.

Oral medium-dosed metoclopramide versus placebo as highly effective antiemetic prophylaxis in in- and outpatients on noncisplatin chemotherapy.

The antiemetic effect of oral medium-dosed metoclopramide (MCL, 3.5 mg/kg b.w./cycle) and placebo for chemotherapy-induced emesis of a noncisplatin regimen was assessed for inpatients and outpatients in two double-blind placebo-controlled sequential analyses according to Bross (1952). MCL was given in 5 single doses of 0.7 mg/kg b.w. at 0 h (loading) and at 2 h (i.e. start of chemotherapy) and 6, 10 and 14 h (as maintenance doses). Both studies ended after 8 sequential pairs in favor of MCL (2 alpha = 2 beta = 0.05). Major antiemetic protection (< 2 emetic episodes per 26 h) was achieved for 8/8 of inpatients and 7/8 of outpatients (placebo 0/8 and 0/8). Side effects neither required discontinuation of the antiemetic regimen nor additional therapy. The median of MCL plasma levels ranged from 150 to 750 ng/ml and terminal half-lives from 3.9 to 8.9 h.

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.

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.

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.

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.

Pharmacokinetics and metabolism of 14C isobytylnaphtyl acetic acid in rat.

After oral administration to rats, absorption of INAA was slow but complete. Plasma level curves reached a plateau for INAA as well as for the two metabolites, which were rapidly formed (MI and MII). The plateau concentration led to an increase of the apparent elimination half-life, which was short after i.v. administration due to the small volume of distribution and to the high rate of metabolism. In any case the half-life was independent of the dose and the pharmacokinetics of INAA remained linear from 1.5 to 15 mg/kg. The two rapidly formed plasma metabolites were eliminated more slowly than INAA. INAA and its metabolites were distributed only sparsely in all tissues under investigation, probably due to the high protein binding. Both routes of administration resulted in elimination of the radioactivity mainly by the urine. Besides the two main metabolites with known structures (MI and MII) small amounts of INAA and two additional metabolites were detected.

Pharmacokinetics/bioavailability of colchicine in healthy male volunteers.

In a randomized 2-way cross-over study with twelve healthy male volunteers, two colchicine preparations (tablets, A vs. oral solution, B) were tested. The preparations were administered as single doses of 1 mg; prior to and up to 72 h after medication blood samples were collected and the plasma colchicine concentrations determined. Additionally urine samples were collected at 0-2, 2-4, 4-6, 6-8, 8-10, 10-24, 24-48, 48-72 and 72-96 h intervals. The colchicine plasma and urine concentrations were determined by a newly developed and validated RIA method. The mean area under the plasma concentration-time curve (AUC-1, AUC-3) was calculated as 23.95 +/- 12.10 (AUC-1) and 26.73 +/- 12.75 (AUC-3) h.ng/ml after application of A and 28.01 +/- 14.74 (AUC-1) and 31.57 +/- 16.58 (AUC-3) h.ng/ml after application of B, respectively. Mean peak plasma concentrations of 4.15 +/- 2.35 (A) and 4.88 +/- 3.90 (B) ng/ml were reached at 1.15 +/- 0.38 (A) and 1.13 +/- 0.42 (B) h after application. The mean terminal half-lives accounted for 9.31 +/- 3.98 (A) and 10.57 +/- 5.53 (B) h. The mean total clearance (Cl/F) and volume of distribution (V/F) were found to be 40.12 +/- 20.87 (A) and 46.58 +/- 24.65 (B) l/h and 472.59 +/- 196.46 (A) and 624.89 +/- 304.09 (B) l, respectively. The mean total amount excreted in urine (Ae) was 172.66 +/- 91.51 (A) and 174.85 +/- 63.53 (B) micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Metabolism of isobutylnaphthyl acetic acid in rats: determination of the chemical structures of metabolites.

After oral and intravenous administration of radiolabelled isobutylnaphthyl acetic acid (INAA) to rats two metabolites were isolated from urine and plasma by HPLC. Field desorption, high resolution electron impact mass spectrometry as well as GC-MS after derivatization were used for structure elucidation and identification of the metabolites. The main biotransformation product in rat urine was found to be 5-(2'-hydroxy-2'-methyl-propyl)-1-naphthyl acetic acid (M1). The main metabolite in plasma was derived and was found to be 5-(2'-carboxypropyl)-1-naphthyl acetic acid (M2).

[Biotransformation and bioequivalence of a new nifedipine preparation]. / Bioverfügbarkeit und Bioäquivalenz einer neuen Nifedipin-Zubereitung.

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.

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.

Pharmacokinetics of n-propyl-ajmaline-bitartrate in elderly patients with ventricular ectopic activity.

11 patients (9m, 2f, median age 59 years) with ventricular ectopic activity of at least Lown grade III received 20 mg N-Propyl-ajmaline-bitartrate (N-PAB) p.o. Plasma concentrations of N-PAB were determined with HPLC from blood samples within 26 hours after administration. An open two-compartment model was used. In 8 patients with normal function of the liver and the kidneys, the median clearance of N-PAB was 6.86 ml/min/kg and the median volume of distribution was 1.56 l/kg. Two patients had a clearly diminished clearance of 1.58 ml/min/kg without obvious impairment of liver or renal function. One patient with chronic glomerulonephritis (plasma creatinine 3.4 mg/dl) had a N-PAB clearance of 2.79 ml/min/kg. None of the Spearman rank correlation coefficients between the pharmacokinetic parameters of N-PAB with age, plasma albumin/globulin-quotient, plasma creatinine and cholin-esterase were significant. All calculated parameters were in the range determined in young subjects. It is concluded that physiological changes with age do not lead to significant changes of the pharmacokinetics of N-PAB. On the other hand in patients with increased levels of plasma creatinine a diminished clearance of N-PAB can be expected. It is also possible that patients without an obvious impairment of liver or renal function may have diminished N-PAB clearance.