Effect of partial ornithine carbamoyltransferase deficiency on urea synthesis and related biochemical events

1987 ◽  
Vol 72 (2) ◽  
pp. 187-193 ◽  
Author(s):  
J. D. S. Kay ◽  
V. G. Oberholzer ◽  
J. W. T. Seakins ◽  
M. Hjelm
Keyword(s):  
Maximum Rate ◽  
Load Level ◽  
Ammonium Concentration ◽  
Maximum Plasma ◽  
Urea Synthesis ◽  
Ornithine Carbamoyltransferase ◽  
Group A ◽  
Adequate Stimulus ◽  
Partial Deficiency ◽  
Protein Load

1. The biochemical response to an intravenous alanine load of 0.25 g/kg was studied in nine adult female relatives of children with ornithine carbamoyltransferase deficiency. Six were classified as affected by partial deficiency and three as unaffected. 2. The plasma ammonium concentration showed no change after the alanine load in the unaffected group, but marked increases occurred in all but one of the affected group. The maximum rate of urea synthesis after the alanine load was decreased by 37% (P = 0.02) and delayed by 43% (P = 0.02) in the affected group. 3. In the affected group a low rate of urea synthesis was associated with high urinary orotate excretion, high maximum plasma ammonium concentration and delay in the time taken to reach the maximum rate of urea synthesis (Kendall concordance W = 0.55, P < 0.05). 4. The effects of a higher dose of alanine and of oral protein were compared. The alanine load of 0.25 g of alanine/kg body weight was shown to provide an adequate stimulus to urea synthesis with a more rapid return of ammonium concentration to the pre-load level than with the protein load. 5. The implication of these results in determining the distribution of flux control of urea synthesis, the discrepancy between them and predicted results and the necessary modifications to quantitative simulations are discussed.

RELATIONS BETWEEN APROTININ CONCENTRATIONS AND HEMODYNAMICS IN EXPERIMENTAL ACUTE PANCREATITIS

1987 ◽  
Author(s):  
T E Ruud ◽  
W Müller-Esterl ◽  
H Fritz ◽  
J O Stadaas ◽  
A O Aasen
Keyword(s):  
Acute Pancreatitis ◽  
Peritoneal Exudate ◽  
West Germany ◽  
Maximum Plasma ◽  
Plasma Kallikrein ◽  
Peptide Substrate ◽  
Experimental Acute Pancreatitis ◽  
Group A ◽  
Group B ◽  
Observation Period

Acute pancreatitis (AP) was induced in juvenil pigs by injection of Na-taurocholate into the pancreatic duct. Eight animals remained untreated (group A), while 7 pigs (group B) received 60000 KIU/kg aprotinin (Tras-ylol, Bayer AG Leverkusen, West Germany) intravenously during 30 min before the induction of AP, thereafter 10000 KIU/kg/h during a 6 h observation period. Seven pigs (group C) received 60000 KIU/kg aprotinin during 30 min starting 3 h after the induction of AP, thereafter 10000 KIU/kg/h. The total infusion volume was the same in all 3 groups (5 ml/kg/h). Using an enzym-linked immunosorbent assay for aprotinin, maximum plasma concentration of aprotinin in group B was found 30 min after start of the infusion (2.8(1.9-5.4)umol/l). The aprotinin concentration thereafter remained elevated for the rest of the observation period (1.4(0.4-1.9) umol/1 after 6 h). The aprotinin concentration gradually increased in the peritoneal exudate during ongoing aprotinin infusion. After 1 h the aprotinin conc. in plasma and the exudate were within the same range. Similar results were observed in group C experiments, where the aprotinin conc. in plasma and peritoneal exudate both were approximately 2 umol/1 1 h after start of the infusion. Assayed by the chromogenic peptide substrate S-2302 (Kabi Vitrum AB, Stockholm, Sweden), markedly elevated values of plasma kallikrein inhibition were detected both in plasma and peritoneal exudate after start of aprotinin infusion in group B and C.In group A, 5 out of 8 animals died in a circulatory collapse, while the animals in group B and C remained hemodynamic stable and all survived the observation.Aprotinin concentrations of 1-3 umol/1 in plasma and peritoneal exudate improves the outcome during experimental acute pancreatitis in pigs.

Kinetics of hepatic alanine uptake and urea synthesis in pigs

1988 ◽  
Vol 254 (4) ◽  
pp. G602-G609
Author(s):  
H. Vilstrup ◽  
L. T. Skovgaard
Keyword(s):  
Maximum Rate ◽  
Maximum Likelihood Method ◽  
Blood Flow Rate ◽  
Likelihood Method ◽  
Synthesis Rate ◽  
Urea Synthesis ◽  
Half Maximum ◽  
Concentration Gradients ◽  
Saturation Kinetics ◽  
Kinetics Of

The kinetics of hepatic alanine uptake and urea synthesis in relation to sinusoid alanine concentration was investigated in seven anesthetized pigs weighing 63 kg, using liver vein catheterizations. Each experiment consists of four steady-state periods of 40 min with alanine concentrations in the range of 0.4-27 mmol/l. The process rates were measured as the products of transhepatic concentration gradients and hepatic blood flow rate, determined by indocyanine green. The data suggest that both processes follow saturation kinetics, that there exists a sinusoidal concentration of alanine below which net removal is limited, and that urea synthesis consists of two components: one alanine independent and one depending on alanine concentration according to Michaelis-Menten kinetics. The kinetic parameters were estimated iteratively by the maximum likelihood method. The maximum rate of alanine uptake was 1.13 +/- 0.74 mmol.min-1.kg liver wt-1 (mean +/- SD), the alanine concentration resulting in half-maximum alanine uptake rate was 1.69 +/- 0.99 mmol/l, and the removal-limiting alanine concentration was 0.27 +/- 0.09 mmol/l. The maximum rate of urea-N synthesis was 1.49 +/- 0.87 mmol.min-1.kg liver wt-1, the alanine concentration resulting in half-maximum urea-N synthesis rate was 2.32 +/- 1.11 mmol/l, and the alanine concentration-independent urea-N synthesis rate was 0.13 +/- 0.10 mmol.min-1.kg liver wt-1.

Regulation of urea synthesis by acid-base balance in vivo: role of NH3 concentration

1987 ◽  
Vol 252 (2) ◽  
pp. F221-F225 ◽  
Author(s):  
S. Cheema-Dhadli ◽  
R. L. Jungas ◽  
M. L. Halperin
Keyword(s):  
Ammonium Concentration ◽  
Urea Synthesis ◽  
Carbamoyl Phosphate ◽  
Acid Base Balance ◽  
Acid Base ◽  
Fixed Rate ◽  
Rate Limiting Step ◽  
Base Balance

The purpose of this study was to clarify how changes in acid-base balance influence the rate of urea synthesis in vivo. Since ureagenesis was increased by an ammonium infusion into rats, regulation seemed to be a function of the blood ammonium concentration. The rate of urea synthesis was constant at a fixed rate of ammonium infusion and independent of the conjugate base infused, chloride or bicarbonate. The steady-state blood ammonium concentration was higher in the rats that developed metabolic acidosis. Thus it appeared that regulation was not directly mediated by this ammonium concentration per se. The rate of urea synthesis was also independent of the blood pH. Accordingly, the rate of urea synthesis was examined as a function of the plasma NH3 concentration. The rate of ureagenesis was found to be directly proportional to the plasma NH3 concentration. Assuming that plasma NH3 levels reflect those in mitochondria, the NH3 concentration yielding half-maximal rates of urea synthesis (close to 2 microM) was in the same range as Km for the rate-limiting step in ureagenesis, carbamoyl phosphate synthetase (EC 6.3.4.16). These results suggest that, at a constant ammonium concentration, the decreased rate of ureagenesis caused by a pH fall in vitro could reflect an acidosis-induced decline in the concentration of true substrate (NH3) for this pathway.

Prevention of 5-FU-induced health-threatening toxicity by pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3601-3601
Author(s):  
Michele Boisdron-Celle ◽  
Olivier Capitain ◽  
Jean-Philippe Metges ◽  
Roger Faroux ◽  
Christophe Borg ◽  
...  
Keyword(s):  
Economic Assessment ◽  
Economic Benefits ◽  
Severe Toxicity ◽  
Safe Treatment ◽  
Dose Adaptation ◽  
Screening Cost ◽  
Group A ◽  
Group B ◽  
Partial Deficiency ◽  
Deficiency Screening

3601 Background: While 5-FU is the foundation of many in GI oncology treatments, pts with DPD deficiency can experience early-onset severe (5%) even fatal (0.3%) toxicities. This study aimed to confirm the pharmaco-economic benefits of pre-therapeutic screening for DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (NCT01547923). Methods: Two parallel cohorts of pts treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD deficiency screening; Group B: no evaluation. Enrollment was based on 5-FU administration guidelines of each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) (1,2,3). The 2 groups were to be compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed in the case of proven 5-FU-related toxic death. Results: 1,130 pts were included from 06/01/2008 to 07/31/2012. Group A: no severe toxicity despite 1 pt with complete deficiency (pt not treated with 5-FU), 20 pts with partial deficiency had safe PK-monitored 5-FU (ODPM Protocol) with only one hospitalization due to toxicity. Group B: One death due to complete DPD deficiency, confirmed retrospectively. Enrollment prematurely closed after experts’ unanimous decision citing ethical concerns. 21 pts with partial DPD deficiency. 5 reported toxicity-related hospitalizations. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A pt had safe treatment whereas Group B pt died due to 5-FU toxicity. Pre-therapeutic DPD deficiency screening using this multi-parametric approach should be performed before 5-FU-based treatment and PK-guided dose adaptation allows for safe treatment of even partially DPD deficient patients. Clinical trial information: NCT01547923. [Table: see text]

Prevention of 5-FU-induced toxicities using pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 351-351 ◽  
Author(s):  
Michele Boisdron-Celle ◽  
Olivier Capitain ◽  
Roger Faroux ◽  
Christophe Borg ◽  
Jean-Philippe Metges ◽  
...  
Keyword(s):  
Economic Assessment ◽  
Patient Characteristics ◽  
Severe Toxicity ◽  
Screening Cost ◽  
Grade 5 ◽  
Group A ◽  
Multicenter Prospective Cohort Study ◽  
Group B ◽  
Partial Deficiency ◽  
Deficiency Screening

351 Background: 5-FU is the backbone of most chemotherapy regimens in GI oncology. Patients with DPD deficiency can experience early onset severe (5%) even fatal (0.3%) toxic side-effects. We decided to confirm the medical and economic interest of pre-therapeutic screening of DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (Eudract n°2008-000026-39). Methods: Two parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD activity evaluation; Group B: no evaluation. Enrollment in either group was based on 5-FU administration guidelines at each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) as well as other patient characteristics (1,2,3). The 2 groups were compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed if 5-FU-induced toxic death occurred. Results: 1,130 patients were included from to 16/06/2008 to 07/31/2012. Group A: no severe toxicity despite 1 patient with complete deficiency (5-FU replaced by another TS inhibitor), 17 patients with partial deficiency safely received PK-monitored 5-FU (ODPM Protocol). Group B: 1 death: 65 y.o. patient, adjuvant FOLFOX 4, 5-FU-induced SAE at day 6: grade 4 febrile neutropenia, septicemia, diarrhoea, mucositis and secondary dehydration, renal failure, then death. 5-FU imputable Grade 5 SAE declared by investigator. Complete DPD deficiency retrospectively confirmed. The enrollment was prematurely closed after unanimous experts’ decision for ethical reasons. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A patient had safe treatment whereas Group B patient died due to 5-FU grade 5 toxicity. DPD deficiency screening by a multiparametric approach (ODPM Tox) should be performed before 5-FU treatments. Clinical trial information: 2008-000026-39. [Table: see text]

scholarly journals Pharmacokinetics and Safety of a New Parenteral Carbapenem Antibiotic, Biapenem (L-627), in Elderly Subjects

1998 ◽  
Vol 42 (6) ◽  
pp. 1433-1436 ◽  
Author(s):  
Osamu Kozawa ◽  
Toshihiko Uematsu ◽  
Hiroyuki Matsuno ◽  
Masayuki Niwa ◽  
Yoshiharu Takiguchi ◽  
...  
Keyword(s):  
Renal Function ◽  
Plasma Concentration ◽  
Elderly Subjects ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Healthy Elderly ◽  
Age Related ◽  
Group A ◽  
Group B ◽  
Carbapenem Antibiotic

ABSTRACT The pharmacokinetics and tolerability of a new parenteral carbapenem antibiotic, biapenem (L-627), were studied in healthy elderly volunteers aged 65 to 74 years (71.6 ± 2.7 years [mean ± standard deviation], n = 5; group B) and ≥75 years (77.8 ± 1.9 years, n = 5; group C), following single intravenous doses (300 and 600 mg), and compared with those of healthy young male volunteers aged 20 to 29 years (23.0 ± 3.5 years, n = 5; group A). The agent was well tolerated in all three age groups. Serial blood and urine samples were analyzed for biapenem to obtain key pharmacokinetic parameters by both two-compartment model-dependent and -independent methods. The maximum plasma concentration and area under plasma concentration-versus-time curve (AUC) increased in proportion to the dose in all three groups. Statistically significant age-related effects for AUC, total body clearance, and renal clearance (CLR) were found, while elimination half-life (t 1/2β) and percent cumulative recovery from urine of unchanged drug (% UR) remained unaltered (t 1/2β, 1.51 ± 0.42 [300 mg] and 2.19 ± 0.64 [600 mg] h [group A], 1.82 ± 1.14 and 1.45 ± 0.36 h [group B], and 1.75 ± 0.23 and 1.59 ± 0.18 h [group C]; %UR, 52.6% ± 3.0% [300 mg] and 53.1% ± 5.1% [600 mg] [group A], 46.7% ± 7.4% and 53.0% ± 4.8% [group B], and 50.1% ± 5.2% and 47.1% ± 7.6% [group C]). A significant linear correlation was observed between the CLR of biapenem and creatinine clearance at the dose of 300 mg but not at 600 mg. The steady-state volume of distribution tended to be decreased with age, although not significantly. Therefore, the age-related changes in parameters of biapenem described above were attributable to the combination of decreased lean body mass and lowered renal function of the elderly subjects. However, the magnitude of those changes does not necessitate dosage adjustment in elderly patients with normal renal function for their age.

Neuronal and Extraneuronal Uptake of 3H-Norepinephrine in the Heart of the Active Bat: An Electron Microscopic Radioautographic Study

1973 ◽  
Vol 31 ◽  
pp. 522-523
Author(s):  
Martin Hagopian ◽  
Michael D. Gershon ◽  
Eladio A. Nunez
Keyword(s):  
Smooth Muscle ◽  
Monoamine Oxidase ◽  
Vascular Smooth Muscle ◽  
Cardiac Muscle ◽  
Maximum Rate ◽  
External Medium ◽  
Extraneuronal Uptake ◽  
Electron Microscopic ◽  
Cardiac Tissues ◽  
High Affinity

The ability of cardiac tissues to take up norepinephrine from an external medium is well known. Two mechanisms, called Uptake and Uptake respectively by Iversen have been differentiated. Uptake is a high affinity system associated with adrenergic neuronal elements. Uptake is a low affinity system, with a higher maximum rate than that of Uptake. Uptake has been associated with extraneuronal tissues such as cardiac muscle, fibroblasts or vascular smooth muscle. At low perfusion concentrations of norepinephrine most of the amine taken up by Uptake is metabolized. In order to study the localization of sites of norepinephrine storage following its uptake in the active bat heart, tritiated norepinephrine (2.5 mCi; 0.064 mg) was given intravenously to 2 bats. Monoamine oxidase had been inhibited with pheniprazine (10 mg/kg) one hour previously to decrease metabolism of norepinephrine.

Electron microscopic radioautographic studies on the incorporation of 3H proline in the glomerular basement membrane (GBM) in antistreptococcal-cell-membrane (SCM) injected mice

1984 ◽  
Vol 42 ◽  
pp. 188-189
Author(s):  
R.P. Nayyar ◽  
C.F. Lange ◽  
J. L. Borke
Keyword(s):  
Body Weight ◽  
Cell Membrane ◽  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Mesangial Matrix ◽  
Electron Microscopic ◽  
Group A ◽  
Injection Protocol

Streptococcal cell membrane (SCM) antiserum injected mice show a significant thickening of glomerular basement membrane (GBM) and an increase in mesangial matrix within 4 to 24 hours of antiserum administration (1,2,3). This study was undertaken to evaluate the incorporation of 3H proline into glomerular cells and GBM under normal and anti-SCM induced conditions. Mice were administered, intraperitoneally, 0.1 ml of normal or anti-SCM serum followed by a 10 µC/g body weight injection of 3H proline. Details of the preparation of anti-SCM (Group A type 12 streptococcal pyogenes) and other sera and injection protocol have been described elsewhere (2). After 15 minutes of isotope injection a chase of cold proline was given and animal sacrificed at 20 minutes, 1,2,4,8,24 and 48 hours. One of the removed kidneys was processed for immunofluorescence, light and electron microscopic radioautographic studies; second kidney was used for GBM isolation and aminoacid analysis.

An ultrastructural study of sertoli cells in two geographically isolated populations of Aphanius dispar

1992 ◽  
Vol 50 (1) ◽  
pp. 548-549
Author(s):  
Taber A. Ba-Omar ◽  
Philip F. Prentis
Keyword(s):  
Ultrastructural Level ◽  
Uranyl Acetate ◽  
Freshwater Teleost ◽  
Isolated Populations ◽  
En Bloc ◽  
The North ◽  
Group A ◽  
Ultrathin Sections ◽  
Group B ◽  
Geographically Isolated

We have recently carried out a study of spermiogenic differentiation in two geographically isolated populations of Aphanius dispar (freshwater teleost), with a view to ascertaining variation at the ultrastructural level. The sampling areas were the Jebel Al Akhdar in the north (Group A) and the Dhofar region (Group B) in the south. Specimens from each group were collected, the testes removed, fixed in Karnovsky solution, post fixed in OsO, en bloc stained with uranyl acetate and then routinely processed to Agar 100 resin, semi and ultrathin sections were prepared for study.

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