[Effect of Relative Dose Intensity(RDI)-Guided Dose Adjustments of Palbociclib on Duration of Treatment in Patients with Severe Neutropenia].

The study subjects consisted of 54 patients with inoperable or recurrent breast cancer who were administered a combination of palbociclib plus endocrine therapy. We examined the onset of neutropenia during the first course of treatment and evaluated the influence that various risk factors had on treatment continuity. Patients with neutropenia Grade≥3 had significantly lower relative dose intensity(RDI) values during the first course of treatment than did patients with neutropenia Grade ≤2. Patients with neutropenia Grade≥3 showed significantly longer treatment to failure than did patients with neutropenia Grade≤2. These results suggest that the degree of neutropenia during the first course of treatment might contribute to treatment continuity and that it is important to improve the curative effect by maintaining appropriate RDI and by continuously administering palbociclib in patients with neutropenia Grade≥3.

The Effect of Ethanol on the Hydrolysis of Ester-Type Drugs by Human Serum Albumin.

Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and hydrolyzes compounds at both sites. Although the hydrolytic interaction of ester-type drugs with other drugs by HSA has been reported, there are only a few studies concerning the effect of pharmaceutical excipients on the hydrolysis of ester-type drugs by HSA. In the present study, we investigated the effect of ethanol (2 vol%; 345 mM) on the hydrolysis of aspirin, p-nitrophenyl acetate, and olmesartan medoxomil, which are ester-type drugs, with 4 different lots of HSA preparations. The hydrolysis activities of HSA toward aspirin, p-nitrophenyl acetate, and olmesartan medoxomil were measured from the pseudo-first-order degradation rate constant (kobs) of salicylic acid, p-nitrophenol, and olmesartan, respectively, which are the HSA-hydrolyzed products. Ethanol inhibited hydrolysis of aspirin by HSA containing low levels of fatty acids, but not by fatty acid-free HSA. Ethanol inhibited hydrolysis of p-nitrophenyl acetate by both fatty acid-free HSA and HSA containing low levels of fatty acids. In contrast, the hydrolysis of olmesartan medoxomil by HSA was insignificantly inhibited by ethanol, but inhibited not only by warfarin and indomethacin but also by naproxen, which are site I binding drugs and a site II binding drug, respectively. These results suggest that the inhibitory action of ethanol on the hydrolysis of ester-type drugs by HSA differs between site I binding drugs and site II binding drugs.

Differences in Esterase Activity to Aspirin and p-Nitrophenyl Acetate among Human Serum Albumin Preparations.

Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and also hydrolyzes some compounds at both sites. In the present study, we investigated differences in esterase activity among HSA preparations, and also the effects of warfarin, indomethacin, and naproxen on the hydrolytic activities of HSA to aspirin and p-nitrophenyl acetate. The esterase activities of HSA to aspirin or p-nitrophenyl acetate were measured from the pseudo-first-order formation rate constant (kobs) of salicylic acid or p-nitrophenol by HSA. Inter-lot variations were observed in the esterase activities of HSA to aspirin and p-nitrophenyl acetate; however, the esterase activity of HSA to aspirin did not correlate with that to p-nitrophenyl acetate. The inhibitory effects of warfarin and indomethacin on the esterase activity of HSA to aspirin were stronger than that of naproxen. In contrast, the inhibitory effect of naproxen on the esterase activity of HSA to p-nitrophenyl acetate was stronger than those of warfarin and indomethacin. These results suggest that the administration of different commercial HSA preparations and the co-administration with site I or II high-affinity binding drugs may change the pharmacokinetic profiles of drugs that are hydrolyzed by HSA.

Efficacy and safety of mycophenolate mofetil in treating immune-related hepatitis induced by immune checkpoint inhibitor use: A retrospective study.

Background and Aim: To investigate the outcomes in eight Japanese patients with cancer treated with mycophenolate mofetil (MMF) and corticosteroids for immune checkpoint inhibitor treatment-induced severe immune-related hepatitis (ir-hepatitis) and the efficacy and safety of MMF. Methods: We retrospectively examined patient background, treatment course, as well as examination and imaging data using electronic medical records. Results: The ratio of male to female patients was 7:1, and the median age was 60 years (27-72 years). There were five and two cases of kidney cancer and malignant melanoma, respectively, and one case of lung cancer. The median number of days until MMF administration in addition to systemic corticosteroid therapy after the onset of ir-hepatitis was 14.5 (2-42). The patients were categorized as four "good responders" who showed an improvement in the liver function tests following MMF treatment and four "poor responders" who did not. Furthermore, the time from the onset of ir-hepatitis to initial MMF administration was significantly shorter in good responders (median 3 days, range 2-15 days) than in poor responders (median 25.5 days, range 14-42 days) (P = 0.042). No significant intergroup difference was observed in other clinical factors. No serious adverse events caused by MMF were observed in any case. Conclusions: According to these findings, early recognition of corticosteroid refractoriness and the use of MMF may be beneficial in patients with ir-hepatitis.

Efficacy and safety of Infliximab for steroid-resistant immune-related adverse events: A retrospective study.

The present study investigated outcomes of infliximab (IFX) treatment among 8 Japanese patients with various types of cancer (4 with malignant melanoma, 3 with lung cancer and 1 with renal cancer) who developed severe steroid-resistant immune-related adverse events (irAEs) in association with immune checkpoint inhibitors (ICIs) to determine its efficacy and safety. Information, including patient background, treatment progress, examination data and imaging data, was collected retrospectively from electronic medical records. Adverse reactions were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Specific ICIs used were anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibody preparations in 7, 2 and 5 patients, respectively. Specific irAEs included grade 3 diarrhea/colitis in 7 patients and disseminated intravascular coagulation and myocarditis attributed to autoimmune activation in 1 patient. The median duration between systemic steroid and IFX treatments was 9 (range, 2-39) days. A total of 3 patients responded to IFX, 1 of whom responded after one dose and 2 responded after two doses. Respective diseases improved to grade 0 after a median of 18 (range, 9-32) days. No AEs were attributable to IFX. Additionally, anti-cytomegalovirus (CMV) and antibacterial agents were administered in parallel given the presence of CMV and Clostridium difficile (CD) infections in all patients, except in 1 exhibiting a marked IFX response after one dose. The combination of highly immunosuppressive IFX and high-dose systemic steroid administration over a long period presumably predisposed the patients to opportunistic enteric infections. Accordingly, early initiation of IFX treatment in conjunction with systemic steroid therapy should be considered for severe diarrhea/colitis and other irAEs. However, the possibility for CMV and CD infections should be recognized, and for these the treatment strategy may need to be modified at an early stage.

[Controlled release of prednisolone from suppository prepared using powder of pulverized tablet].

Prednisolone suppositories have been used successfully for the treatment of ulcerative colitis in hospital settings. However, the raw material of prednisolone suppository, JP prednisolone powder (JP Powder), was recently removed from the market. Therefore we studied the effects of raw material and suppository base on the release of prednisolone suppository for the purpose of designing a new suppository with similar effects to those of suppository prepared using JP powder (old suppository). New suppositories consisting of the powder of pulverized tablet as raw material and Witepsol H-15 and Witepsol E-75 as suppository base were prepared according to the fusion method. Suppository release test was performed by reciprocating dialysis tube method with tapping (RDT method) and dialysis tubing method (DT method). Both RDT method and DT method were performed using a suppository dissolution apparatus (modified JP disintegration apparatus) and a JP15 paddle apparatus, respectively. The test fluid was 50 mM phosphate buffer solution (pH 7.4) maintained at 37+/-0.5 degrees C. The results of release test by RDT method were similar to those of DT method. Release rate of prednisolone from the new suppository was much faster than that of old suppository. The addition of Witepsol E-75 to new suppository base markedly delayed the release of prednisolone from the new suppository. Release rate of prednisolone from the new suppository, consisting of pulverized tablet and Witepsol H-15 and Witepsol E-75 (76:24), corresponded well with that of the old suppository. It was suggested that this suppository could be used as incoming preparation of suppository prepared using JP powder.

[Quality evaluation of magnesium oxide tablets using acid neutralization test and dissolution test].

For the purpose of quality evaluation of commercially available magnesium oxide (MgO) tablets, we studied their acid neutralization and dissolution behaviors. The dissolution test was carried out by the paddle method in 1st fluid (pH 1.2). The dissolution amount of MgO from tablets was determined by chelatometric titration. The medium pH was periodically measured. The neutralization reaction in 750 ml of 1st fluid was markedly different between two kinds of commercial tablets. The pH of medium including Magmit tablet reached 8.9 and the dissolution rate of MgO was 81.1% after 20 min. Contrariwise, the final pH of medium including Maglax tablet was 2.5 and the dissolution rate of MgO was 77.1% after 60 min. These results indicate that the dissolution rate of MgO from tablets should be >81.1% to obtain significant acid neutralization action.

Video-assisted thoracic surgery for lung cancer: is it a feasible operation for stage I lung cancer?

OBJECTIVE: The objective of this study was to confirm the safety and feasibility of video-assisted thoracic surgery (VATS) for primary lung cancer and to compare prognoses with that of conventional procedures, and then to examine whether VATS would supplant a conventional thoracotomy for stage I lung cancer. METHODS: From September 1995 through March 2002, 144 patients with primary lung cancer, included 118 patients with postoperative stage I, underwent VATS lobectomy. We reviewed the previous cases whether they could be candidates for VATS lobectomy according to present indications. 166 cases were supposed to be candidates for VATS, and 121 cases of postoperative stage I disease were recruited into the "conventional thoracotomy" group. RESULTS: There was no mortality or major complication except one case, and mean follow-up was 31.8 months in VATS. The number of removed lymph nodes was not significantly less than the number by conventional thoracotomy (p=0.061). Five-year survival for patients with pathological stage IA adenocarcinoma was 92.4% (n=66) in VATS and 86.9% (n=50) in conventional thoracotomy, and a statistical significance could not be recognized (p=0.980). The length of hospital stay was significantly short in VATS lobectomy (p<0.0001). CONCLUSIONS: VATS lobectomy for stage I lung cancer can be performed safely with minimal morbidity, satisfying survival comparable with that of lobectomy through conventional thoracotomy. VATS approach is a feasible surgical technique for patients with stage I lung cancer.

[A case of multicentric Castleman's disease with multiple pulmonary nodules].

A 55-year-old woman visited our hospital for further examination of abnormal shadows on chest radiographs. Her routine chest radiograph showed two nodular shadows in the right lower lung field. A chest CT scan revealed other nodules, small patchy shadows in both lung fields, and enlargement of the mediastinal lymphnodes (#2, 3). Laboratory data showed polyclonal hyperimmunoglobulinemia. This case was initially considered on the basis of a transbronchial lung biopsy to be a plasma cell granuloma. However, serum gammaglobulin levels gradually increased, and video-assisted thoracoscopic surgery was performed to aid in making a definite diagnosis. Biopsy specimens revealed lymphoid follicles with plasma cells which were stained with both anti-kappa chain and anti-lambda chain antibodies. The patient was treated with prednisolone (50 mg/day), and the serum gammaglobulin level and the shadows on the chest CT were temporarily slightly improved. During the clinical course, her laboratory data and histological specimens were re-examined, and the final diagnosis was multicentric Castleman's disease.

Effect of ethanol on S-warfarin and diclofenac metabolism by recombinant human CYP2C9.1.

The effect of ethanol on the metabolism of S-warfarin and diclofenac by recombinant cytochrome P450 2C9.1 microsomes (CYP2C9.1) was studied. The 7-hydroxylation metabolism of S-warfarin was inhibited by as low as 0.1 vol% (17 mM) ethanol. Ethanol decreased the V(max)/K(m) and V(max) values of S-warfarin metabolism in a concentration-dependent manner, but the K(m) value was unchanged by ethanol. The inhibitory effect of ethanol on the 4'-hydroxylation metabolism of diclofenac was not observed even at 1.0 vol% (170 mM) ethanol. Ethanol at a concentration of 3.0 vol% (510 mM) increased the K(m) value of diclofenac metabolism without changes in the V(max), which indicates that diclofenac 4'-hydroxylation by CYP2C9.1 was competitively inhibited by ethanol. S-Warfarin metabolism by CYP2C9.1 was more sensitive to ethanol than diclofenac metabolism. These results suggest that ethanol inhibits the metabolism by CYP2C9.1 in a substrate-dependent manner.

Hydrogen-deuterium (h-d) exchange reaction of warfarin in D(2)O solution.

To prove the presence of a hydrogen-deuterium (H-D) exchange reaction, (1)H- and (13)C-NMR spectra of warfarin were measured in solvents containing D(2)O and H(2)O. In D(2)O or D(2)O/dimethyl sulfoxide (DMSO)-d(6) solvent, signal pattern changes were observed on H12 and H11 as well as 14 methyl protons over time while no changes were observed on H(2)O or H(2)O/DMSO-d(6) solvent. The observed changes in the solvents containing D(2)O were concluded to be caused by the H-D exchange reaction on H12, the process of CH(2)-->CHD-->CD(2). MS spectroscopy also confirmed these H-D exchanges. The kinetics of this reaction were analyzed as the successive reaction, and the mechanism was also proposed.

Effect of ethanol on the binding of warfarin enantiomers to human serum albumin.

Ethanol is widely used as a pharmaceutical excipient for the solubilization of many hydrophobic drugs for injections. However, there are only few studies about drug interaction with pharmaceutical excipients in the body after injection. In this study, the effect of ethanol (500 mM) or several alcohols (500 mM) on the stereoselective binding of warfarin enantiomers to fatty acid-free human serum albumin (HSA) or proteins of commercial albumin preparations was investigated. An ultrafiltration method was used for the separation of unbound warfarin enantiomers. By the addition of ethanol or 1-propanol, the unbound fraction of the S-enantiomer was decreased. On the other hand, the unbound fraction of the R-enantiomer was increased by the addition of ethanol or 1-propanol. Unbound fractions of both the S- and R-enantiomer were decreased by 2-propanol. In various commercial albumin preparations, unbound fractions of both the S- and R-enantiomer were increased by ethanol. The different effects of ethanol among fatty acid-free HSA and commercial albumin preparations were observed.