A pharmacodynamic and pharmacokinetic study of fluoropyrimidines in a nude mouse system and in postoperative patients with gastric cancer

To evaluate the effect of the oral fluoropyrimidines, tegafur and uracil (UFT) and 5-fluorouracil (5-FU), a pharmacodynamic analysis was conducted using a nude mouse system and patients. In the nude mouse system, UFT and 5-FU showed similar marginal effects against the human tumor xenograft Co-4, and the concentration of 5-FU in serum 1 h after the last administration being 0.04 g/ml, which was assumed to be the minimum effective concentration. (MEC). Postoperative patients were subdivided into three groups, being: those who underwent subtotal gastrectomy and received UFT; those who underwent subtotal gastrectomy and received 5-FU; and those who underwent total gastrectomy and received UFT. In the UFT groups, the concentration of 5-FU in the portal and peripheral blood showed similar elimination in terms of the peak concentration (Cmax) and the area under the curve (AUC). In the 5-FU groups, the AUC and Cmax were significantly higher in portal blood than peripheral blood. The concentrations in the portal blood of the 5-FU group and in the portal and peripheral blood of the UFT group were significantly higher than the MEC (0.04 g/ml). From these pharmacodymamic data, it was concluded that postoperative chemotherapy with oral fluoropyrimidines can achieve the MEC in portal and peripheral blood.This paper was presented, in part, at the 28th and 29th Congresses of the Japan Society for Cancer Therapy in Tokyo and Osaka.     

Unusual immunologic properties of the uveitogenic interphotoreceptor retinoid-binding protein-derived peptide R23

Peptide R23, consisting of residues 1091-1115 of bovine interphotoreceptor retinoid-binding protein (IRBP), had some unusual immunologic properties in Lewis rats. The peptide induced experimental autoimmune uveoretinitis and pinealitis in these rats, but only at high doses. The minimal immunopathogenic dose was found to be 100 nmol/rat. On the other hand, R23 was highly immunogenic in Lewis rats, producing cellular immunity, as measured by the lymphocyte proliferation assay, with a minimal dose of 1 nmol/rat. This unusual dissociation between the uveitogenic and immunogenic activities of R23 was attributed to different sites on the peptide, stimulating either the lymphocytes which induce disease or those which vigorously proliferate in culture. The potent immunogenicity of R23 was consistent with the peptide being immunodominant, as demonstrated by its capacity to be recognized by lymphocytes sensitized against whole IRBP and to stimulate these cells in culture to proliferate and acquire uveitogenic capacity. Likewise, lymphocytes sensitized against R23 are stimulated in culture by whole IRBP. Unexpectedly, peptide R23 was inferior to whole IRBP in its capacity to stimulate uveitogenicity in R23-sensitized lymphocytes. This finding also was attributed to the preferential stimulation by R23 of the lymphocytes specific for the putative "nonuveitogenic" site on the peptide. Peptide R23 also differs from the other tested bovine IRBP-derived peptides in the specificity of its antibodies. Unlike antibodies to the other peptides, those to R23 showed a strong cross reactivity toward whole IRBP.     

Geranylgeranylacetone, a non-toxic inducer of heat shock protein, induces cell death in fibroblast-like synoviocytes from patients with rheumatoid arthritis

Fluvastatin (Fluv) is reported to induce apoptosis in rheumatoid arthritis (RA) synoviocytes through the blocking of protein geranylgeranylation. We report here our investigation of whether geranylgeranylacetone (GGA) induces cell death in RA synoviocytes. Synovial tissues were obtained from patients with RA at the time of total knee arthroplasty. Fibroblast-like synoviocytes (FLS) cultured in three passages were used for the experiments. The FLS were then cultured for 48 h in 48-well flat-bottomed plates containing various concentrations of GGA (0.1–4.0 μg/ml) and either 0.1 or 0.5 μM Fluv. We also examined the effect of GGA and Fluv in human fibroblasts from normal skin (CCD-25SK) and FLS from patients with osteoarthritis (OA). Cells demonstrating cell death were counted following trypan blue staining. In the absence of GGA, there was no apparent cell death, as evidence by trypan blue staining. Concentrations of GGA between 0.1 and 4.0 μg/ml induced cell death in RA FLS, but not in skin fibroblasts (CCD-25SK) nor OA FLS. The number of synoviocytes demonstrating cell death induced by 0.1 or 0.5 μM Fluv was significantly higher than that by the medium alone. In summary, we found that GGA induced cell death in RA FLS, suggesting that GGA may be a potential new therapeutic agent for RA as well as osteoporosis.     

Permissive hypercapnia during thoracic anaesthesia

BACKGROUND: While permissive hypercapnia is commonly practised in critical care, it remains unclear if the comparable manoeuvres are clinically acceptable during anaesthesia. This retrospective study aimed at describing the anaesthetic implications of hypercapnia associated with deliberate hypoventilation during thoracic surgery in patients with severe emphysema. METHODS: Thirteen patients with emphysema who required thoracic surgery under similar anaesthesia were reviewed: 3 patients were managed to maintain normocapnia (normocapnia group) whereas 10 patients developed hypercapnia (PaCO2 >70 mmHg) as a result of restricting peak airway pressures (hypercapnia group). RESULTS: In the normocapnia group (PaCO2: 45+/-1 mmHg, mean+/-SD), no event which required therapeutic intervention during the surgery was seen, whereas 2 of 3 patients showed postoperative air leakage which persisted over 5 days. In the hypercapnia group, the maximum PaCO2 during anaesthesia ranged between 70 mmHg and 135 mmHg (98-21 mmHg). During anaesthesia, all 10 patients required inotropic support to prevent hypotension, 4 patients required tracheal gas insufflation of oxygen to the operated lung to avoid hypoxaemia and 3 patients required lidocaine to treat ventricular arrhythmia. However, the trachea was extubated in the operation theatre in 9 of 10 patients and no organ dysfunction was observed postoperatively. Four patients showed postoperative air leak on the first postoperative day, one of which persisted over 5 days. CONCLUSION: Although there are some limitations, this preliminary study indicates that hypercapnia around 100 mmHg during anaesthesia for thoracic surgery may not be associated with serious consequences.     

A case of microscopic polyangiitis with severe cardiac and respiratory muscle involvement]

A 66-year-old female was admitted to our hospital in January, 1998, complaining of low grade fever and muscle weakness of her legs. Physical examination revealed muscle weakness of her neck (4/5) and proximal skeletal muscles of her bilateral legs (3/5-4/5). She showed proteinuria and microhematuria. Her serum levels of ureanitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, creatinekinase, aldolase and myoglobin were all within the normal ranges. Antinuclear antibodies were negative, but her serum levels of pANCA (743 EU) and C reactive protein (18.0 mg/dl) were elevated. Neuroconduction velocity of her left common peroneal nerve was decreased to 40.8 m/sec and electric myograph showed neurogenic changes. Magnetic resonance images (MRI) of her bilateral thigh depicted high signal intensity in quadriceps by T 2 weighed images, but the signals were not enhanced by gadolinium injection. Muscle and renal biopsies revealed necrotizing vasculitis of the small arteries. Crescentic glomerulonephritis was also observed by renal biopsy. These findings supported the diagnosis of microscopic PN. On 16 th admission day, she developed acute cardiac and respiratory failures due to cardiac and respiratory muscle involvements with PN, and was assisted by mechanical ventilation. She was treated with methylprednisolone pulse therapy (500 mg/day, three consecutive days) on 18 th admission day, followed by 40 mg of oral prednisolone daily. However, her symptoms deteriorated, and herserum creatinine levels increased to 2.4 mg/dl. On 24 th admission day, intravenous cyclophosphamide pulse therapy (500 mg/day) was instituted. Her cardiac wall motion on echocardiography and serum creatinine levels gradually improved, but her skeletal and respiratory muscle weakness did not improve. On 38 th admission day, she was complicated with respiratory infection by methicillin resistant Staphylococcus aures. On 62 th admission day, she died of endotoxic shock. This is the first report describing respiratory muscle involvement with PN, and the second report describing MRI findings of muscle involvement by PN. Therefore, our case provides important clinical information for the diagnosis and treatment of the disease.     

Travoprost 0.004%/timolol 0.5%-fixed combination with and without benzalkonium chloride: a prospective, randomized, doubled-masked comparison of safety and efficacy

Purpose

The purpose of this study is to compare the safety and intraocular pressure (IOP)-lowering efficacy of travoprost/timolol in a benzalkonium chloride (BAK)-free fixed combination preserved with polyquaternium-1 (TRA/TIM BAK-free), with travoprost/timolol-fixed combination preserved with BAK (TRA/TIM), in patients with open-angle glaucoma or ocular hypertension.

Methods

In this prospective randomized controlled trial, subjects with IOP of at least 22 mm Hg in one or both eyes at 0900 h, and IOP of at least 21 mm Hg in one or both eyes at 1100 h and 1600 h at two eligibility visits were randomly assigned to receive either TRA/TIM BAK-free (n=195) or TRA/TIM (n=193), dosed once daily in the morning (0900 h) for 6 weeks. IOP was assessed at 0900 h, 1100 h, and 1600 h at each scheduled visit (baseline, 2 and 6 weeks after randomization).

Results

Mean IOP reduction across all visits and time points was 8.0 mm Hg in the TRA/TIM BAK-free group and 8.4 mm Hg in the TRA/TIM group (P=0.0943). The difference in mean IOP between groups ranged from 0.2 to 0.7 mm Hg across visits and time points, with a mean pooled difference of 0.4 mm Hg (95% CI: −0.1 to 0.8), demonstrating equivalence of the two formulations. The most common drug-related adverse event was hyperemia of the eye (ocular hyperemia and conjunctival hyperemia combined), occurring in 11.8% of the TRA/TIM BAK-free group and 13.0% of the TRA/TIM group.

Conclusion

Travoprost/timolol BAK-free demonstrated equivalence to travoprost/timolol preserved with BAK in efficacy. No clinically relevant differences in the safety profiles of travoprost/timolol BAK-free and travoprost/timolol preserved with BAK were identified.     

Combined irinotecan (CPT-11) and nedaplatin (254-S) therapy for advanced and/or recurrent cervical cancer

We performed combination therapy with irinotecan (CPT-11) plus nedaplatin (254-S) for patients with cervical cancer. A total of 9 patients with cervical cancer (5 patients treated in neoadjuvant setting and 4 patients for recurrent disease) were administered 80 mg/m(2) of 254-Sintravenously on day 1 and 50 mg/m(2) of CPT-11 intravenously on day 1, 8 and 15. Treatment was repeated every 4 weeks. The average number of courses administered was 3.8 (range, 2-6). Grade 3 or 4 adverse events were leukopenia in 4 patients, thrombocytopenia in 1 patient and vomiting in 1 patient. The response rate was 40% in the neoadjuvant setting (2 PRs) and 75% in recurrent disease (3 PRs).     

Activation of a neutrophil-derived inflammatory response in the airways during cardiopulmonary bypass

Cardiopulmonary bypass (CPB) is believed to cause postoperative lung dysfunction. To more closely examine the inflammatory processes occurring in the airways during CPB, we serially measured inflammatory mediators, with the assistance of a new bronchoscopic microsample probe, in 11 patients undergoing repair of aortic arch aneurysms. Epithelial lining fluid (ELF) and arterial blood were sampled simultaneously after induction of anesthesia, at the time of pulmonary reperfusion, and at the end of surgery. A decrease in the PaO2/FiO2 ratio was observed at the end of surgery (P = 0.029). Although the ELF concentrations of interleukin (IL)-8, IL-6, and neutrophil elastase had increased significantly at the end of surgery (median = 23,200, 1818, and 12,900 microg/mL, respectively), they did not correlate with the degree of hypoxemia. Neutrophil elastase increased significantly at the time of pulmonary reperfusion, before IL-8 and IL-6, and independently of blood transfusions. At the end of surgery, IL-6 in ELF correlated with total blood transfusion volume (rho = 0.731, P = 0.011). These results indicate that a neutrophil-derived inflammatory response is activated in the airway in the early phase of CPB.     

Bladder cancer with skin metastasis: a case report

Bladder carcinoma with skin metastasis is extremely rare. We herein report a case of a bladder tumor with skin metastasis. A 68-year-old man was referred to our hospital with macroscopic hematuria. Cystoscopy revealed a trigone papillary tumor. Transurethral resection of bladder tumor (TURBT) was performed and the pathological diagnosis was transitional cell carcinoma (TCC), pT1, G3. Thereafter, he received several courses of TURBT, intravesical chemotherapy (pirarubicin, bacillus Calmette-Guerin and mitomycin C) and intra-arterial chemotherapy because of recurrence. Thirteen years later, he underwent total cystoprostatectomy with neobladder formation. Histological examination revealed muscle-invasive bladder cancer with a staging of T3bNOM0. Two years and three months later, multiple firm nodules with eruptions appeared on the skin in several regions; they were resected and the histological findings revealed TCC. This indicated metastatic spread from the primary bladder TCC. He received only supportive treatment during this period due to renal dysfunction. He died four months after the manifestation of the skin metastasis due to multiple metastases.