To evaluate the changes in platelet function in connection with aging, spontaneous platelet aggregation in whole blood (SPAWB) from healthy aged people was measured and compared to that in the whole blood of young subjects as well as patients with old cerebral infarction. SPAWB was determined by the fall in non-aggregated single platelet count by stirring without adding platelet aggregating agents to whole blood. SPAWB in the aged subjects was significantly higher than that in the young volunteers. In patients with old cerebral infarction taking no platelet suppressive agents, SPAWB was also high but was suppressed to the level of that in young subjects by prescription of ticlopidine. Although when aspirin or a mixture of phosphocreatine and creatine phosphokinase (CP/CPK) was added in vitro to whole blood obtained from the aged subjects, SPAWB was inhibited to 50%, addition of the specific PAF (platelet activating factor) inhibitor TCV-309 induced only partial inhibition of SPAWB. Only CP/CPK showed more than 50% inhibition of SPAWB in the young volunteers. These findings suggest that platelet function in aged subjects is in a hyperaggregable state in vivo due to increased thromboxane A(2).

Journal Article↗

PubMedDate not supplied

Age-related augmentation of stroke tendency evaluated using plasma P-selectin levels.

Plasma soluble P-selectin is thought to be a useful marker for thrombotic diseases. To evaluate the thrombotic state and risk of stroke in aged healthy subjects, we investigated plasma P-selectin levels in healthy subjects and ischemic stroke patients. Plasma P-selectin was measured in 67 healthy subjects and 35 aged (>or= 65 years of age) patients with chronic ischemic stroke using a sandwich enzyme-linked immunosorbent assay (ELISA). Plasma P-selectin was significantly higher in aged (>or= 65 years of age) healthy subjects than in young (< 65 years of age) healthy subjects. Significant difference did not exist between aged healthy subjects and aged stroke patients who were not receiving anti-platelet agents. Anti-platelet agent had no significant effect on plasma P-selectin levels in aged stroke patients. The amounts of P-selectin released from platelets into the plasma after stimulation with adenosin diphosphate in young and aged healthy subjects were not significantly different. Elevated levels of P-selectin in aged healthy subjects suggests the existence of a subclinical thrombotic state which can result in a stroke. Elevated P-selectin levels are not thought to be due to platelet hyperfunction.

Journal Article↗

PubMedDate not supplied

Age related elevation of serum macrophage colony stimulating factor (M-CSF) level.

We recently reported that the serum level of macrophage colony-stimulating factor (M-CSF) was elevated in patients with cerebral infarction. In the present study, we measured serum M-CSF level, as well as coagulo-fibrinolytic markers and general laboratory tests in adult healthy subjects of various ages, and investigated the relationship between age and M-CSF level. M-CSF in aged subjects (>or=65 years of age) was significantly higher than that in the younger subjects (<65 years of age), and a significant positive correlation between age and M-CSF was found. Significant positive correlations between M-CSF, and plasma levels of thrombomodulin (TM), von Willebrand factor antigen (vWF), thrombin-antithrombin III complex (TAT), prothrombin fragment 1+2 (F1+2), d-dimer products cross-linked fibrin degradation products (d-dimer) and plasmin-antiplasmin complex (PAP) were also found. Among the general laboratory tests, there was only a significant correlation between M-CSF and serum creatinine; however, no significant correlation was found between M-CSF and other tests including blood cell counts. From these results, age-related elevation of serum M-CSF level was confirmed, and was suggested not to indicate the alteration of hemopoietic condition in aged subjects but to be related to thrombotic state or systemic damaged blood vessel in the apparently healthy aged people.

Journal Article↗

PubMedDate not supplied

A phase I/II trial of cisplatin, docetaxel and ifosfamide in advanced or recurrent non-small cell lung cancer.

This trial was initiated to evaluate the toxicity and activity of combination chemotherapy employing cisplatin (CDDP), docetaxel (DCT) and ifosfamide (IFX) in non-small cell lung cancer (NSCLC), and to determine the maximum tolerated dose (MTD) of IFX. Chemotherapy-naive patients with advanced or recurrent NSCLC received 60 mg/m(2) DCT followed after a 3-h interval by 60 mg/m(2) CDDP on chemotherapy day 1, and IFX at an escalating dose with mesna protection on days 2-4. The chemotherapy was repeated every 3 weeks. Granulocyte colony-stimulating factor (GCSF) was administered in the event of grade 3 leukopenia/neutropenia. The patients tolerated the treatment well up to level 4 of IFX dosing 1.5 g/day, but not the IFX dose at level 6 (2.0 g/day). Additional patients were enrolled in level 5 (IFX 1.7 g/day) to evaluate the toxicity of the drugs around the MTD. Level 5 was also judged as having exceeded the MTD, with febrile neutropenia and hepatic toxicity being observed as the dose-limiting toxicities. No toxicity-related deaths occurred. The majority of the chemotherapy courses were supported by GCSF administration. A total of 33 eligible patients were entered into the trial; the overall response rate was 10/33 or 30% among all eligible cases, and the rate for patients treated with the MTD or higher (levels 4-6) was 8/24, or 33% (90% confidence limit: 18-52%). The MTD of IFX was 1.5 g/m(2) administered for 3 days in this triplet combination. The clinical activity does not seem to justify the toxicity profile.

Adolescent↗

PubMedDate not supplied

Evaluation of novel platinum complexes, inhibitors of topoisomerase I and II in non-small cell lung cancer (NSCLC) sublines resistant to cisplatin.

We determined the in vitro cytotoxicities of promising new platinum complexes, an inhibitor of topoisomerase I, and novel anthracycline derivatives, and examined using clonogenic assay whether these compounds are cross-resistant in CDDP-resistant sublines derived from human non-small cell lung cancer (NSCLC) cell lines. Cytotoxicities were evaluated by means of the relative antitumor activity (RAA = peak plasma concentration/IC50 values), which we reported previously as a model for predicting antitumor activity. Of the CDDP analogues tested, including carboplatin (CBDCA), [(glycolate-0,0') diammineplatinum (II) (254-S)], ormaplatin [tetrachloro-(d,1-trans)- 1,2-diaminocyclohexaneplatinum (IV) (OP)] and oxaliplatin [oxalato (trans-1-1,2-diaminocyclohexane) platinum (II) (1-OHP)], no agent showed superior antitumor activity compared to CDDP. ME2303 [7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl) adriamycinone-14-O -pimelate], a new anthracycline derivative, showed higher antitumor activity than adriamycin (ADM). The CDDPresistant sublines, PC-9/CDDP and PC-14/CDDP, were 18.3- and 7.7-fold more resistant to CDDP compared to the respective parent cell lines. The CDDP analogues were all cross-resistant to CDDP and the order of relative resistance values was CBDCA > 254-S > 1-OHP > OP for PC9/CDDP and 254-S > CBDCA > 1-OHP > OP for PC-14/CDDP. Although OP showed cross-resistance to CDDP, OP was the most active against the CDDP-resistant sublines with relative resistance values of 3.8 and 1.6 for PC-9/CDDP and PC-14/CDDP, respectively. ME2303 and CPT-11, [7-ethyl-10-(4-[1-piperidino]-1-piperidino) carbonyloxycamptothecin], an inhibitor of topoisomerase I, was active against CDDP-resistant human NSCLC cell lines. These results suggest that OP, ME2303 and CPT-11 could be active in patients with, NSCLC clinically resistant to CDDP.

Adenocarcinoma↗

PubMedDate not supplied

Chronopharmacology of etoposide given by low dose prolonged infusion in lung cancer patients.

We examined the chronopharmacology of prolonged etoposide administration by intravenous infusion over 14 days in 9 patients with lung cancer. Blood samples were obtained every 4 hours between 24 hours and 48 hours after initiation of the infusion. Using the unpaired t-test, the percentage plasma etoposide concentration at 09:00 hours calculated from the 24 hour average value, was significantly higher than that at 21:00 hours (p = 0.024). However, neither ANOVA nor cosinor analysis revealed any significant effect of sampling time (ANOVA: p = 0.29, cosinor analysis: p = 0.46).

Adult↗