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To compare the analgesic efficacy and toxicity of the nonsteroidal anti-inflammatory analgesic drug, ketorolac (Toradol, Recordati spa, Milan) 10 mg p.o. (t.i.d.) with diclofenac (Voltaren, Novartis Farma, Origglo, VA) 50 mg p.o. (t.i.d.) in cancer patients with moderate to severe chronic pain.The study was a multicenter randomized double-blind cross-over trial. Each treatment lasted 7 days, after which the patients crossed over to the other drug. Pain intensity was evaluated by the visual analogue scale (VAS) after the first dose and by the 5-point verbal rating scale (VRS) by the patient and by the physician following the 7-day treatment.A total of 138 advanced cancer patients were enrolled in the study. Overall 251 single-dose administrations (117 cross-over observations) and 257 multiple treatments (127 cross-over experiments) were assessable. After a single administration of ketorolac and diclofenac, no significant difference could be observed in analgesic activity, as indicated by the area under the pain-intensity time curve (AUC0-8), in the maximum efficacy, or the duration of efficacy of the two drugs. The Westlake confidence intervals of the AUC0-8 ratio (ketorolac: diclofenac) (1.07; 90% CI, 0.94-1.19), of the maximum efficacy ratio (1.03; 90% CI, 0.92-1.14), and the duration of efficacy ratio (1.05; 90% CI, 0.97-1.11) showed the bioequivalence of the two drugs. Satisfactory pain relief was reported for multiple 7-day treatments, with no significant differences between the two therapies: according to the physician's evaluation, in 93/128 (73%; 95% CI, 65-80%) ketorolac treatments and 91/129 (71%; 95% CI, 63-78%) diclofenac treatments; according to the patient's evaluation, in 83/128 cases (65%; 95% CI, 57-73%) after ketorolac and in 74/129 cases (57%; 95% CI, 49-66%) after diclofenac. Adverse symptoms were acceptable with both drugs. Interestingly, a pronounced sequence effect was found: gastric disturbances after ketorolac were observed mainly (10 out of 15 observed events) when the drug was given to patients pretreated with diclofenac.

The 5HT3 receptor antagonist Granisetron (GRA) is available on the market as a 1 mg vial in USA and as a 3 mg vial in Europe. This study aimed to compare the two i.v. doses of GRA (3 mg vs 1 mg), both of which combined with Dexamethasone (DEX) (20 mg) in the prevention of acute Cisplatinum (CP)-induced emesis.One hundred and ninety-eight consecutive chemotherapy-naive cancer patients, mainly suffering from lung and bladder cancer, were randomized at their first cycle to receive either GRA 1 mg + DEX or GRA 3 mg + DEX as i.v. bolus prior to chemotherapy and crossed-over to another GRA dose at the second cycle. The cytotoxic treatment included different multi-drug regimens containing CP (median dose 60 mg/m2, range 50-70) administered on day 1 and repeated every 21-28 days.Of the 192 evaluable patients complete protection from acute emesis with GRA 1 and GRA 3, was observed after the 1st + 2nd cycles as follows: nausea 70% and 74%, vomiting 90% and 94%, nausea and vomiting 67% and 74% respectively (no statistically significant difference). No carry-over effect was observed on the complete protection from emesis. The crossover analysis comprising 156 patients confirmed there were no differences between the two antiemetic treatments. Twenty-seven per cent of patients preferred GRA 1, 31% preferred GRA 3, while 42% expressed no preference (P = 0.75). Nor was any difference observed for tolerability, the only reported side-effects being mild headache (16% vs 17%) and constipation (18% vs 25%).This study shows that, under the above conditions, the 1 mg and 3 mg i.v. GRA doses are comparably effective when combined with DEX 20 mg in the prevention of acute CP-induced emesis.

In a multicenter randomized clinical trial 106 post-menopausal patients with progressive metastatic breast cancer were allocated to receive 500 mg or 1000 mg Aminoglutethimide (AG) per os daily. Cortisone Acetate (CA) replacement dose was 37.5 mg/day orally in both groups. In 91 fully evaluable patients, no statistically significant difference was observed between the two therapeutic regimens, neither in terms of overall response (28 vs 35%) and by site responses, nor in terms of median time to progression (10.5 vs 14.5 months) and median overall survival (20 vs. 22 months). The tolerability was satisfactory in both regimens. Although no statistically significant differences occurred, in the low dose regimen we observed fewer patients with side-effects (25% vs 6%) and induced grade 3 side-effects (4% vs 9%). Our results confirm that AG daily doses of 500 and 1000 mg associated with corticosteroids have a comparable effect. Because of its slight but clinically noticeable better tolerability, the lower dose is the preferable regimen in the treatment of advanced breast cancer.

A computerized, retrospective analysis of clinical and pharmacokinetic data relative to 380 cancer patients under medroxyprogesterone acetate (MPA) therapy has been carried out. A bioavailability:objective- response correlation was found only for mammary cancer patients with visceral metastases and a pain-control effect was observed in advanced cancer patients when MPA plasma levels were higher than 150-200 ng/ml. Discriminant analysis of the known prognostic factors for breast cancer indicates that receptorial status, site of predominant metastases, basal alkaline phosphatase and free interval are good predictors for possible clinical response, while the behavior of prolactin and previous treatments are predictors for non-response. There is no improvement in the efficacy of prediction in combining more than one prognostic factor.

A pharmacokinetic evaluation of medroxyprogesterone acetate (MAP, 6 alpha-methyl-17 alpha-hydroxyprogesterone acetate) was undertaken in 70 patients with advanced cancer treated either orally or im with single high doses. MAP plasma levels were determined by gas chromatography (63Ni electron capture detector) after derivatization with heptafluorobutyric anhydride, using 17 alpha-hydroxyprogesterone caproate as internal standard. Plasma levels after oral administration can be approximated by a triexponential function in agreement with a pharmacokinetic two-compartment open model with first-order absorption; peak levels are dose-related, but high interindividual variance is present. Following the administration, both decay phases are masked by prolonged absorption; peak levels are lower than after oral administration, but long-term bioavailability is higher, as demonstrated by comparison of the values for areas under curves in the 0-146-hour interval. The high interindividual ranges in the observed MAP plasma levels indicate that if any significant clinical evaluation is to be made, routine analysis of plasma MAP is mandatory.

Plasma and whole blood pharmacokinetics of epirubicin (4'-epidoxorubicin, epiDX), a new doxorubicin (DX) analogue with an improved spectrum of activity and lower toxicity, were investigated in advanced cancer patients after i.v. bolus administration. Drug decay is triphasic, with a long terminal half-life. Plasma and blood levels of the C-13 reduced epiDX metabolite, epirubicinol (epiDXol), are lower than those of the parent compound. Glucuronides of epiDX and epiDXol are also present in plasma, bile and urine; similar compounds are not described in the literature among the metabolites of DX. EpiDX plasma clearance is consistently higher and mean residence time lower than the corresponding DX parameters, thus indicating a more efficient disposition of the new drug. This behaviour is also reflected in a faster elimination of epiDXol with respect to the corresponding Dx metabolite, doxorubicinol. After an initial induction period, epiDX concentration is higher in whole blood than in plasma. Blood clearance is lower than plasma clearance; volume of distribution at steady state Vss is lower if blood concentration data are used in the pharmacokinetic analysis. Mean Residence Time is similar in plasma and blood. A statistically significant reduction of clearance parameters is observed in patients with liver metastases, even in the absence of altered bilirubin levels. Drug clearance problems induced by renal dysfunction become relevant only in severe renal failure.

A comparison has been made between the absorption of oral medroxyprogesterone acetate (MPA) in an aqueous suspension preparation and in syrup form. Plasma drug profiles were measured after a single administration of the two formulations in 17 advanced cancer patients. On average the standard form (aqueous suspension) gave peak levels which were lower than the syrup mixture. However, the wide intersubject spread in MPA plasma levels observed in both groups did not allow any statistical significance to be assigned to this difference.

Adriamycin, an anthracycline derived from Daunomycin, is widely used for intravesical instillation in the treatment of bladder tumors [1,2,3] and in the prophylaxis of relapses[4,5,6].

The high hepatic clearance of the new doxorubicin analogue epirubicin (4'-epidoxorubicin, epiDX) suggests a possible use of this drug in local and regional therapy where a first pass through the liver is required before the drug can reach systemic circulation. EpiDX pharmacokinetics was followed in advanced cancer patients with liver metastases or a primary tumour after single bolus administration in the hepatic artery, through a surgically implanted catheter and subcutaneous access port. The first-pass effect through the liver was appreciable and only a relatively low fraction of the drug reached systemic circulation. Mild leucopenia and alopecia were observed only in a patient with a hepatopulmonary shunt; this subject was actually exposed to higher epiDX plasma levels. Low intraperitoneal doses of epiDX were administered in a weekly schedule to advanced cancer patients with peritoneal metastases and ascites. Drug concentrations were monitored in the ascitic effusion and in plasma. A high concentration gradient was present between the peritoneal cavity and peripheral circulation. No relevant local or systemic toxicity was observed.

Spectroscopic evidence (e.s.r.) has been obtained to show that the spin-adduct of a radical ·CX2Y (where X is Cl or Br) with nitrosobutane is converted into a carbonyl nitroxide (YC:O)N(But)O·. A radical mechanism is outlined which can accommodate this.When Y in the carbonyl nitroxide is F, Cl, or Br, it can be displaced by methanol, ethanol, or dimethylamine to give alkoxycarbonyl or aminocarbonyl nitroxides. The structure of these is compared with that of vinyl nitroxides.Attempts to trap propenyl radicals from crotonyl peroxide using nitrosobutane led to a dialkyl nitroxide tentatively formulated as (7).

The dehydrogenation of some diazoamino-compounds with lead tetra-acetate in aromatic solvents has been shown to give rise to mixtures of biaryls and azo-compounds. The reaction of diazoaminobenzene, in monosubstituted benzene derivatives as solvents, gives azobenzene and mixtures of isomeric biphenyls as products. The isomer ratio for the biphenyls suggests that they are formed by substitution of intermediate phenyl radicals in the aromatic solvent. The dehydrogenation of 1,1-di-2-naphthyltriazen in benzene led to 2-phenylnaphthalene and dibenzo[a,h]phenazine as products. The latter product is also obtained from the thermal decomposition of 2-naphthyl azide. These latter results indicate the intervention of nitrenes as intermediates. The electron paramagnetic resonance spectrum of the reaction mixture of 1,3-diphenyltriazen with lead tetra-acetate exhibited a triplet with a coupling constant of about 10 gauss, which may be indicative of an intermediate triazenyl radical, which would break down to afford a phenyl radical, phenylnitrene, and nitrogen.

The phenylation of thiophen, carried out with several phenylating agents, afforded in each case a mixture of 2- and 3-phenylthiophens the proportions of which were in the range 90—95 : 10—5. The rates of substitution of thiophen relative to benzene by substituted phenyl radicals, generated by the aprotic diazotization of the anilines with pentyl nitrite have been found to follow, qualitatively, the order expected on the basis of the theory of polarized aryl radicals. A linear correlation has been found to hold between the partial rate factors for the 2-position of thiophen, and the substituent σ° parameters.

The reaction of thiophen with phenylazotriphenylmethane has been investigated. The percentage of the 2-phenyl-thiophen relative to that of the 3-isomer is considerably lower than those obtained with other phenylating agents and is highly dependent on the experimental conditions as well as on the working-up of the reaction mixtures. This is attributed to the trapping of the σ-complex leading to the 2-phenylthiophen by the triphenylmethyl radical to give two isomeric 2,5-dihydro-2-phenyl-5-triphenylmethylthiophens.

The spectrum of the title compound is reported. This radical can be viewed as a triarylmethyl radical in which one of the aryl groups is electrically charged.

We described the optimization, by molecular modelling, of small pyrazole derivatives, as kinase inhibitors, obtained through a 1,3-dipolar cycloaddition between nitrile imines and functionalized acetylenes. The two compounds, selected as potential agents active against hepatocellular carcinoma (HCC) were then evaluated in vitro for their biological activity on HCC-derived cell lines. The compounds show a promising inhibitory growth efficacy (IC 50 50–100 μM) in SNU449 cell line, as well as block of cell cycle progression and induction of apoptosis, and can be considered as lead compounds for further SAR developments.

12003 Background: Cape is an efficient oral prodrug of 5FU in MBC and CRC. Unexpected severe toxicity in older patients (pts) was reported after standard dose of 2500mg/sm/day. About 70% of drug and metabolites are excreted with the urine and a 25% reduction of the dose is recommended if the pt has a creatinine clearance (CrCl) th, 8th, 12th and 14th days in the morning. Plasma levels of Cape, 5DFUR, 5DFCR and 5FU were determined by a validated HPLC method and UV detection. Results: At present PK data after the first administration of Cape are available for 13 pts (9 elderly; 4 younger). The mean Cape and 5DFCR AUC0–8hr are higher in older patients (Cape 6653±2564.8 vs. 4427±2714.5; P=0.09; 5DFCR 8635±5197.1 vs. 6292±3813.6; P=0.26), while no evident differences are present for 5DFUR and 5FU. The same results are obtained both in pts with CrCl < and ≥ 50 ml/min. The ratios of DFUR_AUC to Cape_AUC and 5FU_AUC to Cape_AUC are conversely higher in younger than in older pts (mean: 2.2 vs 1.62). A large interindividual variability in the concentration/time curves is present for Cape and metabolites. Cape dose reduction because of G3 toxicity (2 hand-foot syndrome, 1 stomatitis) was performed in 3 elderly pts. Drug systemic exposure was higher in 2 of these pts independently of CrCl. Conclusions: The preliminary results of this PK study suggest that elderly patients treated with Cape at 1000 mg/sm/bid are more drug-exposed than younger patients, independently of renal function. PK analysis is ongoing for the remaining patients. No significant financial relationships to disclose.