naphthoquinones and naftazone

There is an unmet need to better control motor complications in Parkinson's disease (PD). Naftazone, which exhibits glutamate release inhibition properties, has shown antiparkinsonian and antidyskinetic activity in preclinical models of PD and in a clinical proof of concept study.. We conducted a double-blind randomized placebo-controlled cross-over trial in PD patients with motor fluctuations and dyskinesia testing naftazone 160 mg/day versus placebo for 14 days. The two co-primary endpoints were the area under curve (AUC) of motor (MDS-UPDRS part III) and dyskinesia (AIMS) scores during an acute levodopa challenge performed at the end of each period. Secondary endpoints were UDysRS and axial symptoms scores during the challenge; AIMS, UDysRS, and time spent with or without dyskinesia the day before the challenge. The primary analysis was performed in the per protocol population.. Sixteen patients were included in the analysis. There was no difference between naftazone and placebo for the AUC of MDS-UPDRS III (-89, 95%CI[-1071; 893], p = 0.85), and AIMS (70, 95%CI[-192; 332], p = 0.57). At the end of treatment periods, AIMS score tended to be lower with naftazone than placebo (4.4 ± 3.4 versus 6.7 ± 4.4, p = 0.07), but UDysRS scores and other secondary outcomes were not different. Naftazone was safe and well tolerated.. This study did not confirm previous results on the efficacy of naftazone on dyskinesia nor motor fluctuations highlighting the problem of translating results obtained in preclinical models into clinical trials. Further investigation of naftazone may be conducted in PD with longer treatment duration.

Topics: Aged; Antiparkinson Agents; Cross-Over Studies; Dopamine Agents; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Male; Middle Aged; Naphthoquinones; Parkinson Disease; Treatment Outcome

To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson's disease (PD). Proof-of-concept, randomized, double-blind, placebo-controlled, multiple-cross-over n-of-1 study in patients with PD with wearing-off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single-blind dose-finding phase. Seven patients entered the placebo-controlled phase (four consecutive 28-day cross-overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48-h ON-OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven-point Likert scale to assess "patients' discomfort caused by dyskinesias" (Q1) and 'disability during OFF-periods' (Q2). A 'responder' analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross-over periods) was used. Treatment effects were derived from mixed-effects anova. On diaries, 5/7 patients responded to naftazone for 'ON-time with troublesome dyskinesia' (reduced time, treatment effect: -49 [95% CI: -93/-4] min, P = 0.03), 6/7 regarding 'ON-time without troublesome dyskinesia' (increased time, treatment effect: 35 [-19/88], P = 0.2). No trend was observed for 'OFF' time. There were 7/7 'responders' regarding UPDRSIII (reduced score, treatment effect: -2.1[-4.5/0.2], P = 0.08). The 7-point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.

Topics: Aged; Antiparkinson Agents; Cross-Over Studies; Double-Blind Method; Dyskinesias; Female; Humans; Male; Naphthoquinones; Parkinson Disease; Pilot Projects; Placebos; Single-Blind Method; Treatment Outcome

Topics: Dose-Response Relationship, Drug; Humans; Naphthoquinones; Venous Insufficiency

The authors carried out a double blind study of the action of naftazone in non-specific menometrorrhagias caused by a uterine device, the oral contraceptive and medroxyprogesterone, in 25 patients. They show a great improvement with the periods becoming normal and metrorrhagia disappearing in 12 out of 13 cases where naftazone was used and in only 1 out of 12 cases where the placebo was used.

Topics: Adult; Clinical Trials as Topic; Contraceptives, Oral; Double-Blind Method; Female; Humans; Intrauterine Devices; Middle Aged; Naphthoquinones; Random Allocation; Uterine Hemorrhage

Topics: Humans; Hydroquinones; Naphthoquinones; Semicarbazides; Semicarbazones; Solvents; Spectrometry, Fluorescence; Tablets

Topics: Animals; Cattle; Chromatography, Liquid; Dichlorvos; Food Analysis; Food Contamination; gamma-Aminobutyric Acid; Milk; Naphthoquinones; Ovum; Poultry; Red Meat; Tandem Mass Spectrometry; Time Factors

A simple, sensitive, stability-indicating HPLC method was developed and validated for the quantitative determination of the vasoprotective drug, naftazone in presence of its degradation products. The analysis was carried out on a Nucleosil 100-5 phenyl column (250 mm × 4.6 mm, 5 μm) using a mobile phase consisting of methanol-0.02 M sodium dihydrogen phosphate mixture (60:40, v/v) of pH 6.0. The analyses were performed at ambient temperature with a flow rate of 1.0 mL/min and UV detection at 270 nm. The method showed good linearity over the concentration range of 0.1-10.0 μg/mL with a lower detection limit of 0.032 and quantification limit of 0.096 μg/mL. The suggested method was successfully applied for the analysis of naftazone in its commercial tablets. Moreover, it was utilized to investigate the kinetics of alkaline, acidic and oxidative degradation of the drug. The apparent first-order rate constants, half-life times, and activation energies of the degradation process were calculated. The pH-rate profile curve was derived. Furthermore, the proposed method was successfully applied to the content uniformity testing of naftazone tablets.

Topics: Chromatography, High Pressure Liquid; Drug Stability; Kinetics; Naphthoquinones; Quality Control; Tablets

We have investigated the antitumor functions and mechanisms of 1,2-naphthoquinone-2-thiosemicarbazone (NQTS) and its metal complexes (Cu(2+), Pd(2+), and Ni(2+)) against MCF-7 human breast cancer cells. The cells were dosed with these complexes at varying concentrations, and cell viability was measured by a sulforhodamine B (SRB) method. To study mechanisms of action, the complexes were incubated with topoisomerase II (topo II) and supercoiled DNA, linear DNA, nicked open DNA, and relaxed DNA were detected by agarose gel electrophoresis. The results revealed that these complexes are effective antitumor chemicals in inhibiting MCF-7 cell growth, with Ni-NQTS being the most effective among the complexes studied. Our data also indicated that Ni-NQTS is more effective than the commercial antitumor drug, etoposide, based on IC(50) values. The mechanistic study of action showed that metal complexes of NQTS, NQ, and NQTS can only stabilize the single-strand nicked DNA, but not double-strand breakage intermediates. In addition, metal derivatives of these ligands, but not the parent NQ and NQTS, exerted an antagonizing effect on topoisomerase II activity. In summary, chemicals with or without metal derivatives might possess different chemical-topoisomerase II-DNA interactions.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; DNA, Neoplasm; Dose-Response Relationship, Drug; Female; Humans; In Situ Nick-End Labeling; Indicators and Reagents; Metals; Naphthoquinones; Topoisomerase II Inhibitors

It is well known that an excessive release of glutamate in the mammalian brain plays a major role in several neurological diseases. Naftazone (Etioven) is a currently used vasoprotectant drug that is metabolized in humans by reduction and glucuronidation. In the present study naftazone was found to decrease glutamate levels in the cerebro spinal fluid (CSF) of rats treated for 15 days, as determined by a chemiluminescent glutamate assay reaction. Naftazone and its glucuronide derivative also reduced respectively spontaneous and high K+-evoked glutamate release from mouse cerebellum synaptosomes. It is likely that naftazone and its glucuronide metabolite contribute in vivo to decrease glutamate levels in the CSF through their inhibitory actions on glutamate release.

Topics: Animals; Cerebellum; Cerebrospinal Fluid; Female; Glutamic Acid; Luminescent Measurements; Male; Mice; Microscopy, Electron; Naphthoquinones; Nerve Fibers; Potassium; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Synaptosomes

It has been demonstrated that hyperproduction of nitric oxide (NO) plays a major role in the vasodilatation of cirrhosis; thus, the vasodilatation might be reversed by an inhibition of NO production. Experimental studies in isolated aortic rings showed that naftazone inhibits the effects of NO production. The aim of this study was to evaluate the haemodynamic effects of acute and chronic administration of naftazone in rats with portal hypertension. Haemodynamic values were measured either before and 10 min after intravenous administration of 432 microg/kg of naftazone or after 4 days of oral administration of 10 mg/kg per day. Acute administration of naftazone significantly reduced portal pressure in portal vein-stenosed and cirrhotic rats. This reduction was related to a decrease in the resistance of the liver and collateral circulation and it was associated with an increased cardiac output. Oral administration of naftazone significantly decreased portal pressure in rats with portal vein stenosis; this decrease depended on a significant reduction of portal blood flow. In both groups, arterial pressure did not change significantly. These haemodynamic effects differed from those observed following prazosin or propranolol administration. However, these effects were similar but less marked than those observed following N-nitro-L-arginine administration in systemic and splanchnic arterial territories. In conclusion, acute and oral administration of naftazone significantly reduces portal pressure by two different mechanisms in portal hypertensive rats. The exact mechanism has, however, to be elucidated.

Topics: Animals; Blood Pressure; Enzyme Inhibitors; Hemodynamics; Hypertension, Portal; Male; Naphthoquinones; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Regional Blood Flow

Because of the considerable interest in the role of platelets and antiplatelet therapy in cardiovascular disease, including the aggregation of platelets to each other during arterial thrombosis and atherogenesis, we have studied the effect of naftazone (Etioven), an original vasculotropic drug on platelet aggregation. Rat and human platelets were prepared and incubated in-vitro with different concentrations of naftazone. We found that naftazone inhibited both platelet secretion and aggregation in platelet-rich plasma (PRP) and washed platelets after stimulation with thrombin or ADP. Rats were also treated intraperitoneally for five days with various naftazone doses (0.125-10 mg kg-1) and ex-vivo platelet aggregation compared, at various times after the last injection, with that of control animals. Inhibition by naftazone was dose-dependent in both PRP and isolated platelets. The inhibition was transient, a maximum value (approximately 50%) being obtained about 3-6 h after the last injection, with a return to near-control values after 24 h. Naftazone also facilitated platelet deaggregation after in-vitro stimulation with thrombin or ADP. In another series of experiments, rats were treated intraperitoneally for five days with 10 mg kg-1 of aspirin, ticlopidine, dipyridamole or naftazone. Platelets were prepared and tested for aggregation 90 min after the last injection. Thrombin-induced aggregation in PRP and washed platelets was significantly reduced after in-vivo treatment with ticlopidine and naftazone. Except for dipyridamole, all the drugs inhibited ex-vivo ADP-induced aggregation in PRP. In isolated platelet preparation, only naftazone induced a significant inhibition of ADP- or thrombin-stimulated aggregation. We conclude that naftazone inhibits platelet aggregation in-vitro and ex-vivo.

Topics: Adenosine Diphosphate; Animals; Blood Platelets; Humans; In Vitro Techniques; Male; Naphthoquinones; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Serotonin; Thrombin

Restoration of a haemocompatible surface after endothelial damage induced by treatments such as embolectomy, angioplasty, endarterectomy or irradiation or following vascular graft implantation is an important factor for the ultimate success of these interventions. The development of substances which enhance endothelial cell growth and accelerate their proliferation is therefore of great interest in such situations. In the present work naftazone was shown to accelerate human saphenous vein endothelial cell proliferation in vitro at concentrations which did not alter the hemostatic balance, resulting in a cell density at confluence 20% higher than in controls. This compound was able to partially substitute for serum requirements and further displayed additive effects in the presence of fibroblast growth factors. Thus naftazone, an original synthetic molecule distinct from growth factor peptides, is a promising candidate drug for the amelioration of vascular repair.

Topics: Cell Division; Cell Membrane; Cells, Cultured; Endothelium, Vascular; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Heparin; Humans; Kinetics; Naphthoquinones; Saphenous Vein; Thrombomodulin; Thromboplastin

Reduction and glucuronidation of the vasoprotectant drug, naftazone, by human and rat liver microsomes and by recombinant UDP-glucuronosyltransferases (UGT) stably expressed in V79 cells were studied. The oxo group was first reduced in the presence of NADPH or NADH, and was subsequently readily glucuronidated on the phenolic moiety leading to a 1 beta-O-glucuronide, as revealed from MS and by proton and 13C-NMR. Glucuronide extracted from the urine of rats treated with the drug presented the same structure. In all enzyme systems tested, NADH was the most efficient electron donor, when compared with NADPH. The reaction was strongly inhibited by quercitrin, a specific inhibitor of carbonyl reductase. Attempts to isolate the reduced intermediate were unsuccessful because of its marked instability. In humans, a large interindividual variation for the formation of glucuronide was observed with microsomes of seven different liver samples (3.98 +/- 3.22 nmol/min.mg). In rat, glucuronidation of reduced naftazone was strongly induced (12-fold) by 3-methylcholanthrene and, to a lesser extent (2.6-fold) by phenobarbital, but was not affected by clofibrate. In addition, liver microsomes from Gunn rats, which present a genetic defect in bilirubin and phenol UGTs could not form glucuronide of reduced naftazone. The drug, after addition of NADH, was a substrate of the human liver recombinant UGT1*6 that presents a strict specificity toward planar phenolic substances, but not that of UGT2B4 and UGT2B1 expressed in V79 fibroblasts. The reducing step by the endogenous V79 cellular reductase was rate-limiting. In conclusion, the powerful inducing effect exerted by 3-methylcholanthrene, the lack of glucuronidation in the Gunn rat and the ability of UGT1*6 encoded by the UGT1 gene to glucuronidate reduced naftazone suggest that, in humans and in the rat, the compound is metabolized by a UGT isoform (UGT1*6 and the rat orthologous form) belonging to family 1, with a restricted specificity toward the drug.

Topics: Adult; Animals; Chromatography, High Pressure Liquid; Enzyme Induction; Female; Glucuronates; Glucuronosyltransferase; Humans; In Vitro Techniques; Isoenzymes; Magnetic Resonance Spectroscopy; Male; Microsomes, Liver; Models, Molecular; Naphthoquinones; Oxidation-Reduction; Quercetin; Rats; Rats, Wistar; Recombinant Proteins; Spectrophotometry, Ultraviolet

In the present study, the potential involvement of lipid peroxidation and disruption of lysosomal integrity in the pathogenesis of different experimental models of inflammation was examined. The chosen models were carrageenan-induced paw oedema, carrageenan granuloma pouch (acute phase) and Freund's adjuvant-induced arthritis in rats. The pharmacological and biochemical effects of naftazone, a lysosomal membrane stabilizer and indomethacin, a standard anti-inflammatory agent were evaluated with regard to paw oedema volume, serum and exudate activities of the lysosomal enzyme N-acetyl-beta-D-glucosaminidase (NAG), in addition to serum and liver lipid peroxide (LP) levels. Intraperitoneal administration of the test drugs, in rats subjected to inflammation, produced: (1) a significant inhibition of carrageenan-induced paw oedema, (2) a marked reduction of the paw oedema of the Freund's adjuvant arthritis animals, (3) a remarkable decrease of lysosomal leakage of NAG into the exudate of carrageenan granuloma pouch, (4) a slight, but significant, reduction of NAG activity in the serum of rats subjected to carrageenan inflammation, and (5) a reduction of the serum level of LP that was elevated in adjuvant-induced arthritic rats. The level of liver LP was altered by either drugs in an opposite manner; while naftazone lowered hepatic LP, indomethacin markedly elevated its level. The results of the present investigation revealed that lipid peroxidation and disruption of lysosomal integrity are implicated in the pathogenesis of inflammatory processes, and the protection against these deleterious effects imparted both drugs significant anti-inflammatory activity.

Topics: Acetylglucosaminidase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Carrageenan; Edema; Foot; Freund's Adjuvant; Granuloma; Indomethacin; Inflammation; Lipid Peroxidation; Lysosomes; Male; Naphthoquinones; Rats; Rats, Sprague-Dawley

The preparation of hydrophilic matrix tablets able to release naftazone, a water-insoluble drug, into an aqueous medium at a constant rate (zero-order dissolution) is described. Enhancement of dissolution rate of the drug was achieved using cross-linked carmellose sodium, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin. Hypromellose was used as a water-gelling polymer. Tablets could be prepared that released naftazone at a constant rate over 16 h.

Topics: Calorimetry, Differential Scanning; Delayed-Action Preparations; Drug Carriers; Naphthoquinones; Photomicrography; Solubility; Tablets; Water

Topics: Animals; Dogs; Female; Kinetics; Naphthoquinones

Assays are proposed for sulpiride and other benzamides, vincamine and naftazone in plasma (or blood) and urine with direct UV reflectance spectrophotometry on this are applied directly on TLC along with a calibration curve on each plate. Plasma (or total blood) samples are extracted, and an internal standard is added before aplication; slopes of the obtained calibration curves do not change significantly from plate to plate, thus allowing several determinations on the same plate. The sensitivity is 2 microgram in a 1-ml sample (amount applied 30 ng) for sulpiride and related compounds and about the same for vincamine. Naftazone is determined in plasma with simultaneous reflectance and transmittance spectrophotometric measurements at 520 nm on chromatoplates sprayed with lead acetate, the sensitivity reached is 10 ng in a 1-ml sample (amount applied 0.5 ng). For all drugs studied, the proposed techniques are specific, reliable and sensitive enough and can be used to perform pharmacokinetic studies in human or in animal after administration of doses in the therapeutic range.

Topics: Animals; Benzamides; Chromatography, Thin Layer; Dogs; Humans; Kinetics; Naphthoquinones; Semicarbazones; Spectrophotometry, Ultraviolet; Sulpiride; Vinca Alkaloids; Vincamine

Topics: Contraceptives, Oral; Contraceptives, Oral, Hormonal; Female; Humans; Naphthoquinones; Plethysmography; Varicose Veins; Venous Pressure

Topics: Humans; Naphthoquinones; Varicose Veins