Vasodilation activity of dipfluzine metabolites in isolated rat basilar arteries and their underlying mechanisms.

Identifying the metabolites of a drug has become an indispensable task in the development of new drugs. Dipfluzine (Dip) is a promising candidate for the treatment of cerebral vascular diseases and has 5 metabolites (M1∼M5) in rat urine and liver microsomes, but their biological activity is still unknown. Because selective cerebral vasodilation is a main role of Dip, we investigated the vasodilation of Dip and its 5 metabolites in isolated Sprague-Dawley (SD) male rat basilar arteries preconstricted with high-K+ or 5-HT. The results showed that only M1 possessed concentration-dependent inhibitory activity on the vasoconstriction of arteries with or without the endothelium, and M1 has a more potent vasodilatory effect than Dip on both contraction models. Like Dip, the vasodilatory mechanisms of M1 may be not only related to receptor-operated and voltage-dependent calcium ion channels of smooth muscle cells but also to the release of NO and EDHF from endothelial cells and the opening of Ca2+-activated K+ channels and ATP-sensitive potassium ion channels. Unlike Dip, the vasodilation mechanism of M1 is also related to the opening of voltage-sensitive K+ channel. Together with more selectivity to non-VDCC than Dip, this may partially explain why M1 has stronger vasodilatory effects than Dip. The mechanisms of vasodilation of Dip and M1 may result from the combined action of these or other factors, especially blocking non-endothelium dependent non-VDCC and endothelium dependent IKCa channels. These results point to the possibility that M1 provides synergism for the clinical use of Dip, which may inform the synthesis of new drugs.

Cinnarizine as an alternative recommendation for migraine prophylaxis: a narrative review.

INTRODUCTION: Despite the available prophylactic and acute drugs for migraine management, this disabling disorder remains undertreated especially among pediatrics. In this review, the authors aim at assessing the preventive role cinnarizine plays in treating migraine based on previously published studies. AREAS COVERED: Randomized clinical trials, randomized controlled trials, non-randomized open-label trials, and retrospective studies concerning cinnarizine in migraine prevention in children and adults were reviewed. Especial attention was given to the response rate, migraine characteristics, and tolerability. EXPERT OPINION: The majority of reviewed trials demonstrated that cinnarizine is comparable to the conventional drugs used in migraine prophylaxis. However, most of the reviewed studies were limited by a non-controlled open-label design. Due to poor planning and possibility of high placebo responses, particularly in children and adolescents, the interpretation of open-label studies' results should be done cautiously. The evidence shows that cinnarizine's effectiveness was more promising in pediatric migraineurs and adults with migraine-associated vertigo such as vestibular migraine. Therefore, while the efficacy of cinnarizine cannot be dismissed, before reaching a definite conclusion on its effectiveness, it is necessary to do further high-quality RCTs among both children and adults.

Solubility of Pharmaceutical Ingredients in Natural Edible Oils.

Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.

Evaluating the Effect of Cinnarizine on Promastigotes and Amastigotes forms of Leishmania major.

As an important global disease, cutaneous leishmaniasis is associated with complications such as secondary infections and atrophic scars. The first line treatment with antimonials is expensive and reported to have serious side effects and enhance resistance development. The main objective of this study was to evaluate the effect of Cinnarizine on standard strains of Leishmania major because of paucity of information on this subject. METHODS: In this experimental study, four concentrations of the drug (5, 10, 15 and 20 µg/ml) were added to Leishmania major cultures at 24, 48 and 72 hours intervals. MTT assays were performed to determine parasite viability and drug toxicity. Leishmania major promastigotes were augmented to the in vitro cultured macrophages (J774 cells) and then incubated for 72 hours. Half maximal inhibitory concentration (IC50) was ascertained by counting parasites. The inhibitory effect of the drug was compared with that of Glucantime. Flow-cytometry was performed to investigate apoptosis. Each test was repeated thrice. RESULTS: The IC50 values of Cinnarizine after 72 hours were calculated to be 34.76 µg/ml and 23.73 µg/ml for promastigotes and amastigotes, respectively. The results of MTT assays showed 48 % promastigote viability after 72 hour-exposure to Cinnarizine at 20 µg/ml concentration. Programmed cell death in promastigote- and amastigote-infected macrophages was quantified to be 13.66 % and 98.7 %, respectively. Flow- cytometry analysis indicated that Cinnarizine induced early and late apoptosis in parasites. All treatments produced results which differed significantly from control group (P<0.05). CONCLUSION: Cinnarizine showed low toxicity with anti-leishmanial and apoptosis effects on both promastigote and intracellular amastigote forms. Therefore, we may suggest further assessment on animal models of this drug as candidates for cutaneous leishmaniasis therapy.

Comparisons of in vitro Fick's first law, lipolysis, and in vivo rat models for oral absorption on BCS II drugs in SNEDDS.

PURPOSE: The objective of this study was to compare the in vitro Fick's first law, in vitro lipolysis, and in vivo rat assays for oral absorption of Biopharmaceutical Classification Systems Class II (BCS II) drugs in self-nanoemulsifying drug delivery system (SNEDDS), and studied drugs and oils properties effects on the absorption. METHODS: The transport abilities of griseofulvin (GRI), phenytoin (PHE), indomethacin (IND), and ketoprofen (KET) in saturated water solutions and SNEDDS were investigated using the in vitro Madin-Darby canine kidney cell model. GRI and cinnarizine (CIN) in medium-chain triglycerides (MCT)-SNEDDS and long-chain triglycerides (LCT)-SNEDDS were administered in the in vivo SD rat and in vitro lipolysis models to compare the oral absorption and the distribution behaviors in GIT and build an in vitro-in vivo correlation (IVIVC). RESULTS: In the cell model, the solubility of GRI, PHE, IND, and KET increased 6-8 fold by SNEDDS, but their permeability were only 18%, 4%, 8%, and 33% of those of their saturated water solutions, respectively. However, in vivo absorption of GRI-SNEDDS was twice that of the GRI suspension and those of CIN-SNEDDS were 15-21 fold those of the CIN suspension. In the lipolysis model, the GRI% in aqueous and pellet phases of MCT were similar to that in LCT. In contrast, the CIN% in the aqueous and pellet phases were decreased but that of the lipid phase increased. In addition, an IVIVC was found between the CIN% in the lipid phase and in vivo relative oral bioavailability (F r). CONCLUSION: The in vitro cell model was still a suitable tool to study drug properties effects on biofilm transport and SNEDDS absorption mechanisms. The in vitro lipolysis model provided superior oral absorption simulation of SNEDDS and helped to build correlation with in vivo rats. The oral drug absorption was affected by drug and oil properties in SNEDDS.

A Proof of Concept for 3D Printing of Solid Lipid-Based Formulations of Poorly Water-Soluble Drugs to Control Formulation Dispersion Kinetics.

PURPOSE: The use of three-dimensional printing (3DP) in the development of pharmaceutical dosage forms is growing rapidly. However, the research is almost exclusively focussed on polymer-based systems with very little reported on 3D printing of lipid-based formulations. Thus, the aim of the work was to explore the feasibility of 3DP technology to prepare solid lipid-based formulations. Here, 3DP was applied for the preparation of solid self-microemulsifying drug delivery systems (S-SMEDDS) with defined surface area to volume (SA/V) ratios. METHODS: The S-SMEDDS formulations, comprised of Gelucire® 44/14, Gelucire® 48/16 and Kolliphor® P 188 were loaded with fenofibrate or cinnarizine as model drugs. The formulations were printed into four geometrical shapes - cylindrical, prism, cube and torus, and compared to a control cube manually prepared from bulk formulation. RESULTS: The printing process was not significantly affected by the presence of the model drugs. The as-printed S-SMEDDS formulations were characterised using differential scanning calorimetry and wide-angle X-ray scattering. The kinetics of dispersion depended on the SA/V ratio values. The digestion process was affected by the initial geometry of the dosage form by virtue of the kinetics of dispersion of the dosage forms into the digestion medium. CONCLUSIONS: This proof of concept study has demonstrated the potential of 3DP for the development of customised S-SMEDDS formulations without the need for an additional carrier or additive and with optimisation could elaborate a new class of dosage forms based on 3D printed lipids. Graphical abstract Lipid based formulations were 3D printed in various shapes to control the surface are to volume ratio and consequently the kinetics of dispersion.

Small molecules bind human mTOR protein and inhibit mTORC1 specifically.

Inhibition of mTOR activity (mechanistic target of rapamycin) is an anti-cancer therapeutic strategy. mTOR participates in two functional complexes, mTORC1 and mTORC2. Since mTORC1 is specifically activated in multiple tumors, novel molecules that inhibit mTORC1 could be therapeutically important. To identify potentially novel modulators of mTOR pathways, we screened 1600 small molecule human drugs for mTOR protein binding, using novel biolayer interferometry technology. We identified several small molecules that bound to mTOR protein in a dose-dependent manner, on multiple chemical scaffolds. As mTOR participates in two major complexes, mTORC1 and mTORC2, the functional specificities of the binders were measured by S6Kinase and Akt phosphorylation assays. Three novel 'mTOR general' binders were identified, carvedilol, testosterone propionate, and hydroxyprogesterone, which inhibited both mTORC1 and mTORC2. By contrast, the piperazine drug cinnarizine dose-dependently inhibited mTORC1 but not mTORC2, suggesting it as a novel mTORC1-specific inhibitor. Some of cinnarizine's chemical analogs also inhibited mTORC1 specifically, whereas others did not. Thus we report the existence of a novel target for some related piperazines including cinnarizine and hydroxyzine, i.e. specific inhibition of mTORC1 activity. Since mTOR inhibition is a general anti-cancer strategy, and mTORC1 is specifically activated in some tumors, we suggest the piperazine scaffold, including cinnarizine and hydroxyzine, could be proposed for rational therapy in tumors in which mTORC1 is specifically activated. Related piperazines have shown toxicity to cancer cells in vitro as single agents and in combination chemotherapy. Thus piperazine-based mTOR inhibitors could become a novel chemotherapeutic strategy.

A QbD approach for the fabrication of immediate and prolong buoyant cinnarizine tablet using polyacrylamide-g-corn fibre gum.

The main hurdle in the oral delivery of cinnarizine is its supersaturation, precipitation and re-dissolution process, influencing the oral bioavailability. To overcome this problem, an attempt was made to develop immediate and prolong buoyant tablet of cinnarizine. For this purpose, polyacrylamide-g-corn fibre gum (p-CFG) was synthesized as mucoadhesive cum swellable polymer and it was compared with already used HPMC K4M polymer. The central composite design with two numeric and one categorical factor was choosen to optimize conc. of p-CFG (X1), concentration of NaHCO3 (X2) and type of effervescent agents (X3). The bioadhesive strength of p-CFG tablet was 2.4 times higher than HPMC K4M containing tablet. The formulation composition comprises of p-CFG (64.3%), sodium bi­carbonate (12.9%) and citric acid (2%) (FCNZ) fulfilled the maximum requirement of an optimized formulation. The in-vivo animal pharmacokinetic performance revealed larger plasma half-life and reduced elimination rate as compared to CNZ suspension. Interestingly, the absorption of CNZ from optimized formulation was 3 times enhanced than from CNZ suspension. Overall, the enhancement in the oral bioavailability of CNZ was evident that is due to its prolonged gastric residence time. Furthermore, the swelling associated floating followed by mucoadhesive nature of tablet was observed by X-ray imaging studies.

Integrating virtual screening and biochemical experimental approach to identify potential anti-cancer agents from drug databank.

Chemical libraries constitute a reservoir of pharmacophoric molecules to identify potent anti-cancer agents. Virtual screening of heterocyclic compound library in conjugation with the agonist-competition assay, toxicity-carcinogenicity analysis, and string-based structural searches enabled us to identify several drugs as potential anti-cancer agents targeting protein kinase C (PKC) as a target. Molecular modeling study indicates that Cinnarizine fits well within the PKC C2 domain and exhibits extensive interaction with the protein residues. Molecular dynamics simulation of PKC-Cinnarizine complex at different temperatures (300, 325, 350, 375, and 400[Formula: see text]K) confirms that Cinnarizine fits nicely into the C2 domain and forms a stable complex. The drug Cinnarizine was found to bind PKC with a dissociation constant Kd of [Formula: see text]M. The breast cancer cells stimulated with Cinnarizine causes translocation of PKC-[Formula: see text] to the plasma membrane as revealed by immunoblotting and immunofluorescence studies. Cinnarizine also dose dependently reduced the viability of MDAMB-231 and MCF-7 breast cancer cells with an IC[Formula: see text] of [Formula: see text] and [Formula: see text]g/mL, respectively. It is due to the disturbance of cell cycle of breast cancer cells with reduction of S-phase and accumulation of cells in G1-phase. It disturbs mitochondrial membrane potentials to release cytochrome C into the cytosol and activates caspase-3 to induce apoptosis in cancer cells. The cell death was due to induction of apoptosis involving mitochondrial pathway. Hence, the current study has assigned an additional role to Cinnarizine as an activator of PKC and potentials of the approach to identify new molecules for anti-cancer therapy. Thus, in silico screening along with biochemical experimentation is a robust approach to assign additional roles to the drugs present in the databank for anti-cancer therapy.

Effect of common antivertiginous agents on the high velocity vestibulo-ocular reflex.

OBJECTIVE: It has long been suggested that antivertiginous medications exert their symptomatic effect through inhibition of the vestibulo-ocular reflex (VOR). We tested this hypothesis by directly measuring the VOR after administration of three agents from different substance classes: an antihistamine, a benzodiazepine and a calcium channel antagonist. METHODS: The gain and the variability of the high velocity VOR was assessed using video head impulses (vHIT) under the following conditions: baseline, after dimenhydrinate, after diazepam and after cinnarizine. RESULTS: We found that all three medications did not change any VOR gain or variability parameter: At 60ms, the gain was 0.95 at baseline, 0.99 under dimenhydrinate, 0.99 under diazepam and 0.96 under cinnarizine. The gain variability across repetitive head impulses remained also uninfluenced. CONCLUSIONS: The human high frequency VOR remains robust to pharmacological perturbations at common clinical doses and the assumption that symptomatic vertigo relief is achieved merely through impairment of the VOR requires re-examination. SIGNIFICANCE: Alternative mechanisms of pharmacological action might be operant, such as the modulation of vestibulo-cortical pathways, a differential effect on the low frequency VOR and an altered sensitivity to drugs in acute unilateral vestibulopathy.

Assessment of the Mechanistic Role of Cinnarizine in Modulating Experimentally-Induced Bronchial Asthma in Rats.

BACKGROUND/AIMS: Calcium influx, inflammatory infiltration, cytokine production, immunoglobulin E activation and oxidative stress play coordinated roles in bronchial asthma pathogenesis. We aim to assess the protective effect of cinnarizine against experimentally induced bronchial asthma. METHODS: Bronchial asthma was induced by ovalbumin sensitization and challenge. Rats were allocated into a normal control, an asthma control, a dexamethasone (standard) treatment, and 2 cinnarizine treatment groups. The respiratory functions tidal volume (TV) and peak expiratory flow rate (PEFR), the inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-5 (IL-5) in lung tissue, the allergic immunoglobulin IgE in serum, the absolute eosinophil count (AEC) in bronchoalveolar lavage fluid (BALF), as well as the oxidative and nitrosative markers glutathione reduced (GSH) and superoxide dismutase (SOD) in lung tissue and nitric oxide end products (NOx) in BALF were assessed, followed by a histopathological study. RESULTS: Cinnarizine administration significantly restored TV, PEFR, TNF-α, IL-5, IgE, AEC, GSH, SOD and NOx values back to normal levels, and significantly decreased perivascular and peribronchiolar inflammatory scores. CONCLUSION: Cinnarizine may protect against experimental bronchial asthma. Suppressant effect of cinnarizine on pro-inflammatory cytokines release, IgE antibody production, eosinophil infiltration as well as oxidative and nitrosative stress may explain its anti-asthmatic potential.

Cinnarizine: Comprehensive Profile.

Cinnarizine is a piperazine derivative with antihistaminic, antiserotonergic, antidopaminergic, and calcium channel-blocking activities. A comprehensive profile was performed on cinnarizine including its description and the different methods of analysis. The 1H NMR and 13C one- and two-dimensional NMR methods were used. In addition, infrared and mass spectral analyses were performed which all confirmed the structure of cinnarizine.

In vitro efficacy of cinnarizine against lymphoma and multiple myeloma.

BACKGROUND/AIM: Multiple myeloma, a well-known but still incurable disease, is a hematological malignancy of B-lymphocytes. While standard chemotherapy regimens have been used for years, novel agents, such as lenalidomide and bortezomib, have become an essential part of today's therapies. Nevertheless, new therapeutical strategies are required in the future. Aberrant activation of wingless-related integration site (WNT)/ß-catenin signaling promotes the development of several types of cancer. Recently, it has been demonstrated that the WNT pathway is also activated in lymphoma and myeloma. Thus, the WNT signaling molecules are attractive candidates for the development of targeted therapies. To this extent, we recently confirmed that the diuretic agent ethacrynic acid (EA) and the antifungal agent ciclopirox olamine (CIC) inhibit WNT signaling. Cinnarizine has similar chemical features to those of CIC. MATERIALS AND METHODS: Thus, in this study the antitumor effect of cinnarizine on myeloma and lymphoma cells was investigated by DiOC6 and propidium iodide (PI)-staining in flow cytometry. RESULTS: Cinnarizine triggered a significant apoptotic activity in all tested myeloma and lymphoma cell lines in a concentration-dependent manner. Interestingly, healthy cells were mainly unaffected. CONCLUSION: These results reveal a significant selective induction of apoptosis by cinnarizine that might result from an inhibition of WNT signaling and suggest an in vivo efficacy against lymphoma and myeloma.

An in vivo antilymphatic screen in zebrafish identifies novel inhibitors of mammalian lymphangiogenesis and lymphatic-mediated metastasis.

The growth of new lymphatic vessels (lymphangiogenesis) in tumors is an integral step in the metastatic spread of tumor cells, first to the sentinel lymph nodes that surround the tumor and then elsewhere in the body. Currently, no selective agents designed to prevent lymphatic vessel growth have been approved for clinical use, and there is an important potential clinical niche for antilymphangiogenic agents. Using a zebrafish phenotype-based chemical screen, we have identified drug compounds, previously approved for human use, that have antilymphatic activity. These include kaempferol, a natural product found in plants; leflunomide, an inhibitor of pyrimidine biosynthesis; and cinnarizine and flunarizine, members of the type IV class of calcium channel antagonists. Antilymphatic activity was confirmed in a murine in vivo lymphangiogenesis Matrigel plug assay, in which kaempferol, leflunomide, and flunarizine prevented lymphatic growth. We show that kaempferol is a novel inhibitor of VEGFR2/3 kinase activity and is able to reduce the density of tumor-associated lymphatic vessels as well as the incidence of lymph node metastases in a metastatic breast cancer xenograft model. However, in this model, kaempferol administration was also associated with tumor deposits in the pancreas and diaphragm, and flunarizine was found to be tumorigenic. Although this screen revealed that zebrafish is a viable platform for the identification and development of mammalian antilymphatic compounds, it also highlights the need for focused secondary screens to ensure appropriate efficacy of hits in a tumor context.

Efficacy and safety of cinnarizine in the prophylaxis of migraine in children: a double-blind placebo-controlled randomized trial.

BACKGROUND: In spite of the high occurrence of migraine headaches in school-age children, there are currently no approved and widely accepted pharmacologic agents for migraine prophylaxis in children. Our previous open-label study in children revealed the efficacy of cinnarizine, a calcium channel blocker, in migraine prophylaxis. A placebo-controlled trial was conducted to demonstrate the efficacy and safety of cinnarizine in the prophylaxis of migraine in children. TRIAL DESIGN: A double-blind, placebo-controlled, parallel-group study conducted in a tertiary medical center in Tehran, Iran. METHODS: Children (5-17 years) who experienced migraines with and without aura, as defined on the basis of 2004 International Headache Society criteria, were recruited into the study. Children were excluded if they had complicated migraine, epilepsy, or a history of use of migraine prophylactic agents. Each participant was randomly assigned to receive cinnarizine (a single 1.5 mg/kg/day dose in children weighing less than 30 kg and a single 50 mg dose in children weighing more than 30 kg, administered at bedtime) or placebo. The frequency, severity, and duration of headaches over the trial period were assessed and adverse effects were monitored. RESULTS: A total of 68 children (34 in each group) with migraine were enrolled and 62 participants completed the study. After 3 months of taking cinnarizine or placebo, children in both groups experienced significantly reduced frequency, severity, and duration of headaches compared with baseline measurements (P < 0.001). However, compared with 31.3% of children in the placebo group, 60% of children in the cinnarizine group reported more than 50% reduction in monthly headache frequency (P = 0.023), suggesting that cinnarizine was significantly more effective than placebo in reducing the frequency of headaches. No serious adverse effects of the medications were observed in the treated children, including no abnormal weight gain or extrapyramidal signs. CONCLUSION: Our results indicate that the use of cinnarizine at doses administered in this study is effective and safe for prophylaxis of migraine headaches in children.

Evaluation of the effects of anti-motion sickness drugs on subjective sleepiness and cognitive performance of healthy males.

This study aimed to investigate the clinical and cognitive side effects of baclofen (10 mg), meclizine (25 mg), dimenhydrinate (40 mg) plus cinnarizine (25 mg) and promethazine (25 mg) plus d-amphetamine (10 mg). The study had a double-blind, placebo controlled, repeated measures design and was conducted on healthy male volunteers. The psychomotor vigilance test, the Sternberg working memory task, the implicit memory test and the automated Operation Span (Ospan) task were performed. The Stanford, the Karolinska and the Epworth Sleepiness scale determined the degree of sleepiness. The Profile of Mood States (POMS) evaluated mood states and adverse effects were reported on a 22-item questionnaire. Letter recalls and time for solving mathematical problems, recorded during the Ospan task, were impaired by baclofen and dimenhydrinate-cinnarizine respectively, suggesting an influence of these drugs on the working memory. Significant side effects for baclofen were: sleepiness, tiredness, blurred vision, concentration problems and dizziness whereas for dimenhydrinate-cinnarizine only sleepiness and blurred vision were reported. Meclizine decreased the accuracy on the Sternberg working memory task and thus seemed to affect short-term memory. A reported side effect was increased sleepiness. Promethazine plus d-amphetamine did not affect any of the tested cognitive functions. However, many side effects such as sleepiness, dry mouth, dizziness, vertigo, confusion, insomnia and tremors were reported. The results show that meclizine and dimenhydrinate combined with cinnarizine were the two drugs with the most acceptable combination of side effects.

Circumvention of inherent or acquired cytotoxic drug resistance in vitro using combinations of modulating agents.

BACKGROUND/AIM: Modulating agents are used to circumvent drug resistance in the clinical setting. However achievable serum concentrations are often lower than those which are optimal in vitro. Combination of modulating agents with non-overlapping toxicities may overcome this obstacle. We have investigated combinations of three modulating agents (quinine, verapamil, and cinnarizine) to circumvent inherent or acquired resistance to the cytotoxic drugs doxorubicin, vincristine and paclitaxel. MATERIALS AND METHODS: Dose-response curves to cytotoxic drugs in the presence/absence of modulating agents were determined using colony formation and cell proliferation assays. Doxorubicin accumulation into cell monolayers was measured by fluorescence spectrophotometry. RESULTS: Greater (1.9-fold) sensitisation to particular cytotoxic drugs was observed for certain combinations of modulating agents compared to individual effects. The most effective combination was quinine-plus-verapamil with the cytotoxic drug doxorubicin. This increase in sensitivity was associated with increased doxorubicin accumulation. Such enhanced activity was, however, not observed for all combinations of modulating agents or for all studied cytotoxic drugs. CONCLUSION: The findings of the present study suggest certain combinations of modulating agents to have a clinical role in circumventing drug resistance. Particular combinations of modulating agents must be carefully chosen to suit particular cytotoxic drug treatments.

Peculiarities of heart rhythm variability in narcotized and immobilized wakeful rats during blockade of calcium channels.

In narcotized rats, verapamil and cinnarizine modified some heart rate variability (HRV) indices and heart rate (HR) indicating up-regulation of parasympathetic tone in contrast to nifedipine that elevated activity of sympathetic subdivision of ANS producing no influence on HR. In wakeful stressed rats, the time-domain and geometric analysis established that verapamil decreased HR and up-regulated sympathetic tone; nifedipine elevated sympathetic tone and produced no effect on HR, while cinnarizine enhanced parasympathetic tone without any effect on HR. Spectrum analysis of HRV revealed probable activation of some other neurohumoral mechanisms by the employed calcium blockers.

No effects of anti-motion sickness drugs on vestibular evoked myogenic potentials outcome parameters.

OBJECTIVE: To investigate the effects of meclizine (50 mg), baclofen (10 mg), cinnarizine (20 mg) + dimenhydrinate (40 mg), and promethazine (25 mg) + dextro-amphetamine (5 mg) on the parameters of the vestibular evoked myogenic potential (VEMP) test. STUDY DESIGN: Double-blind placebo-controlled prospective randomized trial. SETTING: University hospital. SUBJECTS: Twenty-four (first block: baclofen versus placebo) and 20 healthy male subjects (second block: meclizine, cinnarizine + dimenhydrinate and promethazine + dextro-amphetamine versus placebo). INTERVENTIONS: VEMP test. MAIN OUTCOME MEASURES: Threshold, p13 and n23 latencies, p13-n23 latency difference, p13-n23 peak-to-peak amplitude, mean rectified voltage of the sternocleidomastoid muscle contraction and the corrected amplitude. RESULTS: There were no clinically significant pharmacologic effects on the VEMP outcome parameters. However, there was a statistically significant left-right asymmetry after intake of the combination promethazine + d-amphetamine for the parameters p13 and latency difference. CONCLUSION: The absence of clinically significant effects can be explained by the predominant presence of the target receptors for the applied drugs in the medial vestibular nucleus, which receives the lowest grade of saccular projections. It also can be hypothesized that the VEMP methodology and techniques in general do not allow determining pharmacologic effects in a healthy group of subjects because of a too small discriminative power. The left-right asymmetry can be explained by a depressive action of the drugs on the central compensation mechanisms. Because there were no significant differences between the VEMP parameters obtained after intake of the placebos of both blocks, we concluded that there were no training effects.

Melanogenesis inhibitory activity of two generic drugs: cinnarizine and trazodone in mouse B16 melanoma cells.

More than 200 generic drugs were screened to identify the inhibitory activity on melanogenesis in mouse B16 melanoma cells. Cinnarizine and trazodone were identified as melanogenesis inhibitors. The inhibitory effects of the two drugs on cell survival, melanogenesis, and tyrosinase activity were investigated. The results showed that both cinnarizine and trazodone inhibited melanogenesis in B16 cells by a dose-dependent manner at the non-cytotoxic concentrations. Based on the results of the present study, seeking new melanogenesis inhibitors from generic drugs is an alternative approach to developing new depigmenting agents in cosmeceuticals. Moreover, cinnarizine and trazodone were proven to be good candidates as skin-whitening agents for treatment of skin hyperpigmentation.