The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration. PATIENTS AND METHODS: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks. RESULTS: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76). CONCLUSIONS: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected.

Exposure of fallopian tube epithelium to follicular fluid mimics carcinogenic changes in precursor lesions of serous papillary carcinoma.

OBJECTIVES: Ovulation-related inflammation is suspected to have a causal role in ovarian carcinogenesis, but there are no human models to study the molecular pathways. Our aim is to develop such an ex-vivo model based on human fallopian tube (FT) epithelium exposed to human follicular fluid (FF). METHODS: FT epithelium was dissociated from normal surgical specimens. FF was obtained from donors undergoing in-vitro fertilization. The cells were cultured on collagen-coated Transwells and incubated with FF for various periods of time. The transcriptomic changes resulting from FF treatment were profiled using Affymetrix expression arrays. Specific characteristics of the FT pre-cancerous lesions were studied using immunohistochemistry, immunofluorescence, RT-PCR and XTT assay. RESULTS: We show that FF exposure causes up-regulation of inflammatory and DNA repair pathways. Double stranded DNA breaks are induced. There is a minor increase in cell proliferation. TP53, which is the hallmark of the precursor lesion in-vivo, is accumulated. Levels of expression and secretion of Interleukin-8 are significantly increased. CONCLUSIONS: Our model addresses the main non-genetic risk factor for ovarian cancer, namely the impact of ovulation. This study demonstrates the biological implications of in-vitro exposure of human FT epithelial cells to FF. The model replicates elements characterizing the precursor lesions of ovarian cancer, and warrants further investigation of the linkage between repeated exposure to ovulation-related damage and accumulation of neoplastic changes.

Pharmacokinetics and pharmacodynamics of neutrophil-associated ciprofloxacin in humans.

OBJECTIVE: To study the possibility that the penetration of the antibiotic ciprofloxacin into polymorphonuclear leukocytes (PMN) may be associated with some changes in cell reactivity. DESIGN: Superoxide anion and chemiluminescence generation induced by formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) were studied ex vivo in 12 healthy volunteers (mean age, 53.15 +/- 16.3 years; mean body weight, 71.23 +/- 6.9 kg) at fixed intervals up to 72 hours from the administration of a single oral dose of 250 mg ciprofloxacin. Cytosolic free calcium levels ([Ca2+]i) in resting and stimulated cells were also evaluated. The dynamic parameters of the effects on PMNs were compared with the kinetic profile of the drug in plasma and in PMNs. RESULTS: Superoxide generation induced by the stimulating agents increased significantly, reaching a peak after 12 hours (+116% [p < 0.001] for fMLP and +66% [p < 0.05] for PAF). Similarly, chemiluminescence production showed a threefold increase in the response to the stimulating agents 12 hours after drug administration (p < 0.001). The increase in [Ca2+]i in stimulated PMNs was significantly potentiated (p < 0.001). The mathematic analysis of the effects of ciprofloxacin showed that time to maximal activity was between 10.4 hours (PAF-dependent [Ca2+]i increase), and 15 hours (fMLP-induced superoxide anion and chemiluminescence production). The ratio of PMNs to plasma ciprofloxacin concentration increased progressively, from 0.5 at 30 minutes to 10.4 after 24 hours. In addition, time to maximal activity and half-life differed in PMNs and in plasma (4.66 versus 1.90 hours and 13.03 versus 7.28 hours, respectively). CONCLUSIONS: Ciprofloxacin administration induced a long-lasting enhancement of PMN reactivity to fMLP and PAF. The levels of the drug in the cells were greater and more sustained in the time than those in plasma.

Ultrastructural modifications of the platelet plasma membrane in vascular diseases and the effect of a carbochromen derivative as studied by freeze-fracture and computer measurement.

A high surface density of the openings of the surface connected canalicular system (SCCS) has been observed in the freeze-fractured plasma membrane of circulating platelets in rabbits fed an atherogenic diet and in hypercholesterolemic type IIa patients. In vitro tests have revealed a correlation between the increased surface density of the SCCS openings and the initial steps of platelet activation. 8-Chlorocarbochromen, a new drug which enhances the in vivo release of prostacyclin from the arterial wall, has been found to be effective in reducing the high surface density of SCCS openings in platelets of rabbits on an atherogenic diet. The present study shows that circulating platelets from patients with peripheral vascular disease present a high surface density of SCCS openings compared to that observed in control subjects. After a single oral administration of 8-chlorocarbochromen, a reduction of the high number of these openings has been observed. Likewise, beta-thromboglobulin levels were found to be high in the patients and to be significantly reduced after oral administration of the drug. This study shows ultrastructural modifications of platelets in conditions related to atherosclerosis and includes data on the effectiveness of 8-chlorocarbochromen in reducing the platelet activation of these patients.

Plasma lipid lowering activity of acipimox in patients with type II and type IV hyperlipoproteinemia. Results of a multicenter trial.

A multicenter study was carried out in 130 out-patients to assess the plasma lipid lowering activity of acipimox in type IIa, IIb and IV hyperlipoproteinemia. The study consisted of two periods, an 8-week randomized, double-blind comparison of active drug versus placebo and a 16-week open follow-up with acipimox (400 mg and 250 mg t.i.d., respectively, in type II and IV patients). During the double-blind phase acipimox, compared to placebo, showed a highly significant triglyceride lowering effect in type IV patients (-43% vs. +4%, P less than 0.01), while reducing plasma cholesterol significantly in type II patients (-7% vs. -3%, P less than 0.05). Further reductions in plasma lipids were obtained in both types of hyperlipoproteinemia after the 16-week follow-up. In type II patients, total cholesterol fell by 9% in the former acipimox group and 17% in the former placebo group, whereas a 34% reduction in triglycerides was found in type IV patients previously treated with placebo. Treatment had to be discontinued in 4 patients during the double-blind phase and in 5 patients during follow-up, because of adverse events such as skin reactions and gastric disturbances. Statistical analysis of hematological and biochemical variables expressing safety did not show any significant change during treatment.

An equivalence study of the safety and efficacy of a fixed-dose combination of perindopril with indapamide versus fixed-dose combinations of captopril with hydrochlorothiazide and enalapril with hydrochlorothiazide in the treatment of hypertension.

OBJECTIVE: The aim of this multicenter, randomly allocated, double-blind, parallel-group study was to evaluate the equivalence of three fixed-dose combination drugs in mild to moderate hypertension: perindopril + indapamide (4 + 1.25 mg), captopril + hydrochlorothiazide (50 + 25 mg) and enalapril + hydrochlorothiazide (20 + 12.5 mg). PATIENTS AND METHODS: After a single-blind, 4-week, placebo run-in phase, 527 patients (mean +/- SD age 54.5 +/- 1.2 years) with a supine diastolic blood pressure of 101.2-101.7 mmHg were randomly assigned to one of the three treatments for 8 weeks. The main evaluation criteria were diastolic blood pressure and serum potassium concentration. Equivalence was assessed on an intention-to-treat basis, using Schuirmann's method, which involves performing two one-tailed statistical tests on the data. Thirty-five patients were withdrawn from the study but there were no differences between groups in the reasons for withdrawal. RESULTS: Diastolic blood pressure decreased by between 13.1 and 14.2 mmHg in the three groups. The 90% confidence intervals for the differences between perindopril + indapamide and the other treatments were -1.1, +1.7 mmHg for captopril + hydrochlorothiazide and -0.4, +2.6 mmHg for enalapril + hydrochlorothiazide. Schuirmann's test was highly statistically significant (P<0.001 for perindopril + indapamide versus captopril + hydrochlorothiazide; P<0.002 for perindopril + indapamide versus enalapril + hydrochlorothiazide), so that the two one-sided hypotheses that the treatments were not equivalent were rejected at the nominal level of alpha = 0.05. Similarly, the safety of the treatments was equivalent in terms of serum potassium. The 90% confidence intervals of the differences between perindopril + indapamide and the other treatments were -8.7, -1.6% for captopril + hydrochlorothiazide (P = 0.004) and -1.5, +2.7% for enalapril + hydrochlorothiazide (P<0.001). CONCLUSIONS: We conclude that the safety and efficacy of perindopril + indapamide, captopril + hydrochlorothiazide and enalapril + hydrochlorothiazide were equivalent after 8 weeks of treatment in patients with mild to moderate hypertension.

Adenosine system and cell calcium translocation: interference of calcium channel blockers.

Adenosine is able to inhibit in vitro neutrophil functions induced by formyl-methionyl-leucyl-phenylalanine (FMLP) and A23187, but not phorbol 12-myristate 13-acetate (PMA). The inhibiting activity on A23187 is reversed by increasing extracellular Ca2++ concentration. The calcium entry blocker flunarizine shows an activity very similar to that of adenosine. Both adenosine and flunarizine prevent Ca++ influx into activated neutrophils as detected by the fluorescent Ca++ chelator Quin-2. Finally, flunarizine binds to the neutrophil membrane and adenosine competitively inhibits flunarizine binding as assessed by 1H-Nuclear Magnetic Resonance (1H-NMR) technique, thus indicating that the two agents share a common binding site on the cell membrane.

Heparin inhibition of polymorphonuclear leukocyte activation in vitro. A possible pharmacological approach to granulocyte-mediated vascular damage.

The "in vitro" effects of heparin on different functions of human polymorphonuclear leukocytes were studied. Granulocyte aggregation, enzyme release induced by FMLP and zymosan-activated serum and superoxide anion and chemiluminescence generated by FMLP were assessed. Heparin (25-500 micrograms/ml) was able to inhibit in a dose-dependent way cellular aggregation and degranulation induced either by FMLP or by zymosan-activated serum. FMLP-dependent superoxide anion generation and chemiluminescence were specifically inhibited by heparin at the concentration of 25 micrograms/ml. Our results showed that heparin "in vitro" inhibits all the aspects of the functional and metabolic granulocyte activation. A possible protecting effect of the drug on leukocyte-mediated tissue injury and vascular damage is discussed.

Nitroprusside in vitro inhibits platelet aggregation and intracellular calcium translocation. Effect of haemoglobin.

The biologically final active compound of nitrovasodilators is now supposed to be nitric oxide (NO), a labile substance identical to EDRF. The effects of nitroprusside on platelet functions were studied in vitro. Platelet aggregation induced by several stimuli (ADP, collagen, arachidonic acid and PAF) was inhibited by increasing concentrations of the drug (1-50 uM); interestingly, the potency of nitroprusside is higher when PAF is employed as stimulating agent in comparison with the other agonists (ED50 = 2 uM for ADP, 2.5 uM for A.A., 4.5 uM for collagen and 0.3 uM for PAF-induced aggregations). The concomitant addition of haemoglobin is able to reverse the inhibitory effect of nitroprusside, according to the view that haemoglobin possesses a high affinity for NO, thus antagonizing the effect of this compound. Nitroprusside was also able to inhibit intracellular calcium translocation, as studied with the Quin 2 technique, induced by PAF and arachidonic acid. Fron these observations the hypothesis may be suggested that nitroprusside inhibits platelet functions by mimicking the endogenous NO, and that the intracellular calcium metabolism is involved in the inhibitory activity of the drug.

Increase in plasma adenosine during brain ischemia in man: a study during transient ischemic attacks, and stroke.

Adenosine is a "retaliatory metabolite" which accumulates during experimental brain ischemia and has vasodilatory and putative neuroprotective effects. The aim of this study was to assess whether human cerebral ischemia and necrosis-evaluated in the clinical models of transient ischemic attack (TIA) and stroke, respectively-acutely raise plasma adenosine levels. We studied 20 patients: 10 with TIA and 10 with stroke. In all, blood was serially sampled for assessment of plasma adenosine by an high-performance liquid chromatography method. Sampling occurred on peripheral blood during TIA and stroke upon admission, and serially thereafter every day up to 7 days and every other day up to 20 days. We found that in TIA and stroke patients, peripheral adenosine levels were increased to a similar extent upon admission (TIA = 264 +/- 53 vs. stroke = 257 +/- 60 nM, p = ns), peaked on the day 2 for TIA (300 +/- 60) and on day 3 for stroke (289 +/- 43) patients, and steadily decreased towards the normal range, reached by all TIA patients by day 5 and by stroke patients by day 15. Stroke and TIA are associated with a rapid increase in circulating plasma adenosine concentration in man, detectable in peripheral vein. The adenosine surge likely mirrors an increased production from the ischemic brain, and it lasts days (for TIA) and weeks (for stroke) after the acute event.

Selective 1H-NMR relaxation investigations of membrane-bound drugs in vitro. 3. Calcium-entry blockers and adenosine.

Selective proton relaxation rates (SPRR) were measured for selected protons of nimodipine or diltiazem in the presence of neutrophils, allowing detection of binding to the cell membrane. Fast exchange exchange of drug molecules between bound and free environments was shown to be the main factor determining the enhancement of SPRR, whereas viscosity effects could be neglected. The SPRR enhancement was almost completely cancelled out by the presence of adenosine as a cosolute in a dose-dependent fashion, leading to the suggestion that the endogenous mediator 'adenosine' affects binding of calcium-entry blockers to the neutrophil surface.

QTc interval prolongation during infusion with dipyridamole or adenosine.

The aim of our study was to discover whether there was a relationship between the QTc interval prolongation on the standard 12-lead electrocardiogram (ECG) and provoked myocardial ischemia. Since the increase of adenosine plasma levels, obtained either with adenosine or dipyridamole (an adenosine reuptake inhibitor) infusion, has been used to test the coronary artery reserve in patients affected by coronary artery disease, the QTc interval modifications during dipyridamole or adenosine echocardiographic stress test were evaluated. Twenty-five patients admitted to our Institute for evaluation of chest pain of suspected myocardial origin underwent an echocardiographic dipyridamole stress test (0.84 mg/kg over 10 min) after discontinuation of antianginal treatment. Of these patients, 10 underwent an echocardiographic adenosine stress test (scalar doses of 50, 75, 100, 140 micrograms/kg/min) after 48-72 h. The Bazett formula was used to evaluate the QTc interval. After dipyridamole and adenosine administration, a significant prolongation of the QTc interval was observed only in those patients who had positive test results. Our data suggested that QTc interval prolongation during pharmacological stress tests might be considered a marker of myocardial ischemia.

Pharmacological preconditioning of ischemic heart disease by low-dose dipyridamole.

Fourteen patients affected with coronary artery disease underwent two consecutive dipyridamole echocardiographic stress tests, in basal conditions and after repeated low doses of intravenous dipyridamole, following the observation that pulse increases in adenosine plasma levels due to repeated intravenous administration of dipyridamole mimic the mechanism of ischemic preconditioning. Echocardiographic, electrocardiographic, haemodynamic parameters, and adenosine plasma levels were measured. After the second test, six patients were completely negative, and in those eight still positive the onset of dyssynergy was delayed.

Use of extract of Ruscus aculeatus in venous disease in the lower limbs.

The effectiveness and tolerability of a venotropic drug (RAES) composed of an extract of Ruscus aculeatus (16.5 mg), hesperidin (75 mg) and ascorbic acid (50 mg) were evaluated in 40 patients (30 female, 10 male) aged between 28 and 74 years, suffering from chronic phlebopathy of the lower limbs. The cross-over, double-blind trial involved two periods of treatment of 2 months with the drug (2 capsules, 3 times/day) or with placebo, and an interim period of 15 days for wash-out. An overall tendency for improvement occurred that was more distinct during the periods of treatment with the drug. In fact, symptoms and plethysmographic parameters (in particular MVIV 40 and 60) immediately changed significantly in correspondence with the administration of RAES. The biological and clinical tolerability were excellent.

Stimulation of endogenous adenosine release by oral administration of quercetin and resveratrol in man.

Epidemiological evidence indicates that moderate alcohol consumption is associated with a significant decrease in the incidence of certain cardiovascular disorders, which can lead to impaired quality of life and to death. However, there are no objective data suggesting a cause-effect relationship and detailed research based on definitive working hypotheses is needed. We tested two flavonoids in man and found that these substances can belong, at least in part, to a wine-dependent mechanism, which leads to increased adenosine plasma levels. If these results could be confirmed by analyzing all the possible influences leading to blood nucleoside increase, a hypothesis of diet-dependent cellular preconditioning could be discussed.

Effect of cefodizime (HR 221) on immunological defects induced by surgical stress.

Cefodizime, a new aminothiazolylcephalosporin, has been shown to possess immunomodulating activity in many experimental models in vivo and in vitro. The in-vivo effect of the drug was evaluated in a model represented by the surgical patient, being surgical practices usually associated with an immunological impairment involving many aspects of the immune response. Two groups of ten subjects were treated respectively with cefodizime (2 g i.v. daily) and another cephalosporin (ceftriaxone) at the same dosage. Aspecific immunity (complement activity, neutrophil phagocytosis, chemiluminescence and superoxide anion production) and cell-mediated reactivity (lymphocyte subpopulations and E-rosette-forming cells) were evaluated before, and at predetermined intervals after, surgery and antibiotic treatment. In the control group an important immunological derangement is observed, involving both lymphocytes and neutrophil functions and complement system. The treatment with cefodizime displays a positive effect with a significant improvement of impaired functions. The effect of the drug particularly influences neutrophil phagocytosis, explored with both the NBT test and determinations of chemiluminescence, and the complement system, through both the classic and the alternative pathways. A slight effect is observed on lymphocyte functions.

Action of S 5682 on the complement system. In vitro and in vivo study.

Activation of the complement system during the early phase of inflammation is partly responsible for increased vascular permeability, white blood cell margination and stimulation of phagocytosis. The aim of this study was to evaluate the anti-inflammatory action of S 5682 in terms of inactivation of the serum complement system. Serum complement was measured by the method of Mayer modified. In vitro, S 5682 was tested on human and rabbit sera with increasing concentrations from 10 to 5.10(-8) g in the presence of different complement pathways activators. In vivo, serum anticomplement activity was evaluated is the N.Z. rabbit after administration of a single dose (100 mg/kg) of S 5682. In vitro, the anticomplement action of S 5682 was effective, starting at the concentration 1.10(-9) g for both classical (IC50 = 6.19.10(-9) g) and alternative pathways (IC50 = 7.69.10(-9) g). This dose-dependent anticomplement action was statistically significant (p less than 0.01) and involved fraction Clq and C3. In vivo, there was a statistically significant decrease (p less than 0.01) of complement activation which reached a maximum of 74%, 180 minutes after the administration of S 5682. This decrease was still significant after 5 hours (p greater than 0.01). These data suggest that the anti-oedematous effect of S 5682 can be partly explained by anti-inflammatory properties in relation with an anticomplement action.

A simple computational approach to model parameter estimation.

The desire to describe biological data using mathematical models has led to the rapid development of various analytical techniques for model identification and parameter estimation. The procedures used may be non-linear and complex, and require long calculation periods. Thus, the aid of a personal computer renders efficient the application of these rather complicated procedures. In this study we developed a simple identification programme for heparan sulfate pharmacodynamics which can be easily and rapidly implemented on a personal computer. The programme is based on an iterative algorithm performing a non-linear regression analysis by the least-square method. This programme was applied to a clinical measured variables with which it was possible to quantify the pharmacodynamic effect of heparan sulfate.

Differentiated dosage of microporous colestyramine and its double-blind comparison with a placebo in hypercholesterolaemic patients.

A double-blind trial of microporous colestyramine (MPC) at different dosages was undertaken on 18 hypercholesterolaemic patients (Fredrickson classification Type II A) in three groups. During the attack phase of four weeks, three dosage regimens of MPC were used, 9 g, 12 g and 18 g for six patients in each group. During the maintenance phase of eight weeks, the patients were divided into two groups of nine each, one group receiving MPC 9 g/day and the other a placebo. The attack phase demonstrated the efficacy of the MPC therapy at all three dosage levels with minimal side-effects and the maintenance phase showed significant adverse variations in the total and HDL-cholesterol levels and in the intraratio in the placebo group, and in the physician's and patients judgement of the efficacy of the MPC therapy compared with the placebo. It is considered that MPC provides an excellent alternative therapy for prolonged treatment of hypercholesterolaemia, where a specific diet therapy is unacceptable.

Pharmacokinetics and pharmacodynamics of dermatan sulfate after intravenous and intramuscular administration to healthy volunteers.

The pharmacokinetics and pharmacodynamics of dermatan sulfate (DS) was investigated in healthy volunteers (two groups, namely group A: 6 subjects, group B: 8 subjects). The subjects of group A received 100 mg of DS both i.v. and i.m. and the subjects of group B received 400 mg of DS both i.v. and i.m. in two different days. The resulting anticoagulant activities were assessed by the activated partial thromboplastin time (aPTT) and the pharmacokinetic parameters were calculated from the plasma concentrations of DS measured by a chromogenic assay. The plasma concentrations of DS were fitted by linear and non-linear elimination models (i.e. assuming that the drug elimination follows Michaelis-Menten kinetics). Some evidence of non-linear kinetics was given by the observation that the mean terminal half-life and clearance estimated by the linear model were not independent of the i.v. dose (0.83 +/- 0.1 and 1.74 +/- 0.21 hours and 4.94 +/- 0.64 and 2.67 +/- 0.27 l/h after 100 and 400 mg i.v. respectively. Moreover the mean half-lives estimated after i.m. administrations were much higher than the values estimated after the i.v. dose (2.03 +/- 0.74 and 3.54 +/- 1.3 hours after 100 and 400 mg) and linear models failed to fit simultaneously the DS plasma concentrations after both the administration routes. Using the linear model, the mean drug bioavailability after i.m. administration was estimated to be about 30% and 80% after the 100- and the 400-mg dose respectively.(ABSTRACT TRUNCATED AT 250 WORDS)