Background
S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase ...exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided.
Methods
We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m
2
. A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis.
Results
The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9–108.8 mL/min as estimated by the Cockcroft–Gault equation. The S-1 dosage formula was derived as follows:
dose
=
target AUC
×
21.9
+
0.375
×
CLcr
×
BSA
,
where AUC is the area under the concentration–time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration–time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies.
Conclusions
We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.
Neonatal disseminated herpes simplex virus (HSV) infection with acute liver failure (ALF) and neonatal hemophagocytic lymphohistiocytosis (HLH) are severe diseases. We recently experienced a male ...infant with HLH and ALF induced by HSV type 1 (HSV-1). The infant, born at 39 weeks of gestation by normal delivery, developed a fever on day 4. On day 9, laboratory investigations showed progressive liver dysfunction and coagulopathy, and the serum ferritin was excessively elevated. Furthermore, the blood levels of interleukin (IL)-6, IL-10, and interferon-gamma were also elevated. HSV-1 DNA was detected in the serum and cerebrospinal fluid by the real-time PCR method. A diagnosis of HLH was established based upon the following criteria: fever, splenomegaly, cytopenia (two cell lines), serum ferritin (> 500 μg/l) and hypofibrinogenemia (< 150 mg/dl). High-dose acyclovir therapy, steroid pulse therapy using methylprednisolone, high-dose gamma globulin therapy and a blood transfusion were given. The patient recovered without neurological deficit. Neonatal disseminated HSV infections may be complicated by the development of HLH and hypercyokinemia. If HLH is suspected, not only high-dose acyclovir therapy but also anti-cytokine therapy should be considered.
Signal transduction mediated by heterotrimeric G proteins regulates a wide variety of physiological functions. We are interested in the manipulation of G‐protein‐mediating signal transduction using ...G‐protein‐coupled receptors, which are derived from evolutionarily distant organisms and recognize unique ligands. As a model, we tested the functionally coupling GOA‐1, Gαi/o ortholog in the nematode Caenorhabditis elegans, with the human muscarinic acetylcholine receptor M2 subtype (M2), which is one of the mammalian Gαi/o‐coupled receptors. GOA‐1 and M2 were prepared as a fusion protein using a baculovirus expression system. The affinity of the fusion protein for GDP was decreased by addition of a muscarinic agonist, carbamylcholine and the guanosine 5′‐3‐O‐thiotriphosphate (35SGTPγS) binding was increased with an increase in the carbamylcholine concentrations in a dose‐dependent manner. These effects evoked by carbamylcholine were completely abolished by a full antagonist, atropine. In addition, the affinity for carbamylcholine decreased under the presence of GTP as reported for M2–Gαi/o coupling. These results indicate that the M2 activates GOA‐1 as well as Gαi/o.
Signal transduction mediated by heterotrimeric G proteins regulates a wide variety of physiological functions. We are interested in the manipulation of G-protein-mediating signal transduction using ...G-protein-coupled receptors, which are derived from evolutionarily distant organisms and recognize unique ligands. As a model, we tested the functionally coupling GOA-1, G alpha(i/o) ortholog in the nematode Caenorhabditis elegans, with the human muscarinic acetylcholine receptor M2 subtype (M2), which is one of the mammalian G alpha(i/o)-coupled receptors. GOA-1 and M2 were prepared as a fusion protein using a baculovirus expression system. The affinity of the fusion protein for GDP was decreased by addition of a muscarinic agonist, carbamylcholine and the guanosine 5'-3-O-thiotriphosphate (35SGTPgammaS) binding was increased with an increase in the carbamylcholine concentrations in a dose-dependent manner. These effects evoked by carbamylcholine were completely abolished by a full antagonist, atropine. In addition, the affinity for carbamylcholine decreased under the presence of GTP as reported for M2-G alpha(i/o) coupling. These results indicate that the M2 activates GOA-1 as well as G alpha(i/o).
Signal transduction mediated by heterotrimeric G proteins regulates a wide variety of physiological functions. We are interested in the manipulation of G‐protein‐mediating signal transduction using ...G‐protein‐coupled receptors, which are derived from evolutionarily distant organisms and recognize unique ligands. As a model, we tested the functionally coupling GOA‐1, Gα
i/o
ortholog in the nematode
Caenorhabditis elegans
, with the human muscarinic acetylcholine receptor M
2
subtype (M
2
), which is one of the mammalian Gα
i/o
‐coupled receptors. GOA‐1 and M
2
were prepared as a fusion protein using a baculovirus expression system. The affinity of the fusion protein for GDP was decreased by addition of a muscarinic agonist, carbamylcholine and the guanosine 5′‐3‐
O
‐thiotriphosphate (
35
SGTPγS) binding was increased with an increase in the carbamylcholine concentrations in a dose‐dependent manner. These effects evoked by carbamylcholine were completely abolished by a full antagonist, atropine. In addition, the affinity for carbamylcholine decreased under the presence of GTP as reported for M
2
–Gα
i/o
coupling. These results indicate that the M
2
activates GOA‐1 as well as Gα
i/o
.
We evaluated the significance of immature granulocyte (IG) count during the clinical course after liver transplantation. We counted IG using the flow cytometric method with CD16, CD11b, and CD45 ...antibodies. Samples were obtained from 31 patients in the Department of Transplantation and Immunology, and we determined (i) the distribution of IG peak value, (ii) the distribution of IG peak time-points, (iii) the clinical background of patients with high IG, and (iv) the clinical course of high IG cases. We observed the appearance of IG (100/μl or higher) in the majority of the patients (23 out of 31 patients; 74.2%). The IG peak was detected on the 19th day after transplantation. We observed serious complications, such as melena, rejection, or severe infection, in high IG (500/μl or higher) cases. We observed instances of inflammation with low C-reactive protein (CRP) value in the presence of IG. We believe that IG is a useful marker to monitor inflammation.
Objective: We investigated the state of Helicobacter pylori (H. pylori) infection in patients with severe motor and intellectual disabilities (SMID) admitted to Tsudumigaura Medical Center for ...Children with Disabilities. Methods: The subjects were 77 patients with SMID (male: female = 52:25; median age = 27 years; range = 2-53 years) who were admitted to our center between September 2013 and March 2014. H. pylori antigens in the stool and serum H. pylori IgG antibodies were determined. Patients with positive results for either or both of the tests were defined as having H. pylori infection. Infected patients were treated with primary therapy of lansoprazole, amoxicillin and clarithromycin. Results: Of 77 patients, 18 (23.4%) were antigen-positive, 33 (42.9%) were antibody-positive, and 35 (45.5%) were determined to have H.pylori infection. The infection rates of patients with tube feeding had significantly higher infection rates than those with oral feeding (60.7% vs. 36.7%; p < 0.05). Among patients under 19 years of age, patients with tube feeding had significantly higher infection rates than those with oral feeding (60% vs. 8.3%; p < 0.01). The primary therapies were successful in 60.0% of the infected patients. Conclusions: The H. pylori infection rate of patients with SMID in our hospital was high. In particular, the infection rates of patients with tube feeding were very high. The efficacy of the primary therapy was not sufficient.
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