Additive Synergism Research Articles

Insecticide resistance in Culex quinquefasciatus from Zanzibar: implications for vector control programmes

BackgroundZanzibar has a long history of lymphatic filariasis (LF) caused by the filarial parasite Wuchereria bancrofti, and transmitted by the mosquito Culex quinquefasciatus Say. The LF Programme in Zanzibar has successfully implemented mass drug administration (MDA) to interrupt transmission, and is now in the elimination phase. Monitoring infections in mosquitoes, and assessing the potential role of interventions such as vector control, is important in case the disease re-emerges as a public health problem. Here, we examine Culex mosquito species from the two main islands to detect W. bancrofti infection and to determine levels of susceptibility to the insecticides used for vector control.MethodsCulex mosquitoes collected during routine catches in Vitongoji, Pemba Island, and Makadara, Unguja Island were tested for W. bancrofti infection using PCR. Insecticide bioassays on Culex mosquitoes were performed to determine susceptibility to permethrin, deltamethrin, lambda-cyhalothrin, DDT and bendiocarb. Additional synergism assays with piperonyl butoxide (PBO) were used for lambda-cyhalothrin. Pyrosequencing was used to determine the kdr genotype and sequencing of the mitochondrial cytochrome oxidase I (mtCOI) subunit performed to identify ambiguous Culex species.ResultsNone of the wild-caught Culex mosquitoes analysed were found to be positive for W. bancrofti. High frequencies of resistance to all insecticides were found in Wete, Pemba Island, whereas Culex from the nearby site of Tibirinzi (Pemba) and in Kilimani, Unguja Island remained relatively susceptible. Species identification confirmed that mosquitoes from Wete were Culex quinquefasciatus. The majority of the Culex collected from Tibirinzi and all from Kilimani could not be identified to species by molecular assays. Two alternative kdr alleles, both resulting in a L1014F substitution were detected in Cx. quinquefasciatus from Wete with no homozygote susceptible detected. Metabolic resistance to pyrethroids was also implicated by PBO synergism assays.ConclusionsResults from the xenomonitoring are encouraging for the LF programme in Zanzibar. However, the high levels of pyrethroid resistance found in the principle LF vector in Pemba Island will need to be taken into consideration if vector control is to be implemented as part of the elimination programme.

Atomistic simulations of aqueous griseofulvin crystals in the presence of individual and multiple additives

The production and stabilization of crystalline pharmaceutical suspensions, an area of great importance to the pharmaceutical industry, was investigated through exploration of the ability of surfactants and polymers to affect the growth and stability of poorly water soluble pharmaceutical crystals on a molecular scale using molecular dynamics simulations coupled with anti-solvent crystallizations. Griseofulvin, a model poorly soluble drug, was simulated in an aqueous system containing individual non-ionic surfactant Tween 80, polymer HPMC, polymer Pullulan, and anionic surfactant SDS, as well as binary surfactant–polymer mixtures. To evaluate the stability and growth potential of the crystals, the interfacial binding energies between three elementary faces were calculated and compared, based on which HPMC was determined to be the most effective individual additive of those tested. Additionally, the potential synergism of additives was evaluated by the simulation of binary mixtures containing each of the non-ionic additives with the anionic surfactant SDS at different starting configurations. The combination of HPMC with SDS proved to be the most effective and significantly greater than HPMC when used alone. Simulation results were validated by observing both crystal growth rates, as well as final particle sizes of griseofulvin crystals grown using an antisolvent crystallization in the presence of individual and mixtures of additives, suggesting that the simulation approach may be used as a screening tool for selection of additives.

Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats

The 5-hydroxytryptamine6 (5-HT6) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT6 antagonists compound (CMP) X and CMP Y and the reference 5-HT6 antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease, AD) was used as a positive reference compound. First, effects of the 5-HT6 antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1mg/kg, administered intraperitoneally, i.p., 30min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT6 antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT6 antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine.Donepezil (1mg/kg, oral administration, p.o.), GSK-742457 (3mg/kg, i.p.), CMP X (3mg/kg, i.p.) and CMP Y (30mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1mg/kg, i.p.) and CMP Y (10mg/kg, p.o.) with the AChEI donepezil (0.1mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT6 antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1mg/kg, p.o.), GSK-742457 (10mg/kg, p.o.) and CMP Y (30mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT.In conclusion, the 5-HT6 antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT6 receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil.

Investigation on synergism of composite additives for zinc corrosion inhibition in alkaline solution

The synergism of imidazole (IMZ) and poly(ethylene glycol) 600 (PEG) for zinc corrosion inhibition in 3 mol L −1 KOH solution was investigated using a combination of electrochemical and gravimetric methods, and the surface morphology of the zinc was observed by scanning electron microscopy. It is found that there is a synergistic effect between IMZ and PEG for the zinc corrosion inhibition. The difference in molecular structure, ring for IMZ and chain for PEG, and in binding atoms with zinc, nitrogen in IMZ and oxygen in PEG, contributes to this synergistic effect. IMZ inhibits zinc corrosion by mainly depressing the anodic reaction, whereas PEG by depressing the cathodic reaction. The storage performance of the zinc–manganese dioxide batteries using IMZ and/or PEG as inhibitors was determined by discharge test, with a comparison of the battery using mercury as the inhibitor. The battery containing 0.05% IMZ + 0.05% PEG exhibits better performance than the mercury-containing battery, especially when discharged at high rate.

Corrosion Inhibitive Effect of Ocimum Gratissimum Extract on Zinc – Aluminium Alloy in Hydrochloric Acid

The inhibitive effect of ocimum gratissimum by seed extract on the corrosion of zinc – aluminium (ZA) alloy in 2 M hydrochloric acid (HCl) solution has been studied using gravimetric methods. Inhibition increases with concentration of extract but decreases with temperature. This observation implies that ocimum gratissimum seed extract is an effective and non toxic inhibitor of the corrosion of zinc – aluminium alloy. Adsorption of the extract on the surface obeyed the Freundlich adsorption isotherm. The calculated rate constant (k) shows a first order kinetics in the absence and presence of the inhibitor. The kinetic parameter B, measured for the reaction has a high negative value which implies that ocimum gratissimum becomes more effective as the temperature increases. Synergistic effect of halide additives shows an increase in the efficiency of the extract. However synergism parameter shows that synergism of halide additives decreases with increased concentration of inhibitor.

Synergistic and Antagonistic Interactions of Phenolic Compounds Found in Navel Oranges

Phenolic compounds are known to have antioxidant and antimicrobial properties. These properties may be useful in the preservation of foods or beverages. The interactive antioxidant capacity of phenolic compounds within foods has not been well explored. Interactions of individual phenolic compounds (chlorogenic acid, hesperidin, luteolin, myricetin, naringenin, p-coumaric acid, and quercetin) at the concentrations found in navel oranges (Citrus sinensis) were analyzed for their antioxidant capacity to observe potential antagonistic, additive, or synergistic interactions. Mixtures of 2, 3, and 4 phenolic compounds were prepared. The Oxygen Radical Absorbance Capacity (ORAC) assay was used to quantify the antioxidant capacities of these combinations. Three different combinations of 2 compounds and 5 combinations of 3 compounds were found to be synergistic. One antagonistic combination of 2 was also found. No additional synergism occurred with the addition of a 4th compound. A model was developed to explain our results. Reduction potentials, relative concentration, and the presence or absence of catechol (o-dihydroxy benzene) groups were factors in the model. Practical Application: Understanding how combinations of fruit antioxidants work together will support their future use in preservation of foods and/or beverages.

Modeling the effect of immobilization of microorganisms on the rate of biodegradation of phenol under inhibitory conditions

The main objective of this research is to model the effect of biodegradation process of phenol at high initial concentrations using a well known immobilization technique of the biomass. This work focused on testing the effect of activated carbon and clay while considering the diffusive internal mass transfer limitations. Biodegradation of phenol was performed by using enriched microorganisms from a compost of agricultural wastes. The average phenol biodegradation rate (uptake) of free biomass system was 235.3 mg g −1 h −1 at initial concentration range of 212–260 mg/L. However, the values for the systems of immobilized biomass in alginate and activated carbon (1 mm), alginate, activated carbon (4 mm), alginate, activated carbon and clay (1 mm) and alginate, activated carbon and clay (4 mm) were 64.9, 27.6, 27.5, and 8 mg g −1 h −1 respectively. The effective diffusion factors in different matrix were obtained using an intra-particle diffusion-based mathematical model. Diffusion limitation was observed when the matrix contained clay in addition to activated carbon. The diffusion coefficient was decreased from 1.6 × 10 −8 to 1.2 × 10 −9 cm 2/s when clay was added to the matrix of 1 mm of alginate and activated carbon. Also, slight differences between the diffusion factors were observed for larger beads. The combination of clay and AC contributes to better mineralization of phenol at high concentrations. This could be attributed to the synergism of both additives.

Abstract 5398: Drug combination synergy quantification in animals and clinics using computerized combination index method

Abstract Drug combination has been used for thousand of years, and currently widely used in the treatments of cancer, AIDS, and other diseases. Drug combination studies have been carried out mostly in vitro but rarely in animals and clinics due to cost, efficiency, ethical considerations, etc. However, the “definition of synergy” is universal and can be quantitatively determined as indicated by Chou & Talalay in (i). Adv. Enz. Regul. 22: 27-55, 1984 and by Chou in (ii). Pharmacol. Rev. 58: 621-681, 2006, (iii). Leukemia & Lymphoma 49: 2059-2080, 2008, and (iv). Cancer Res. Perspective Article 2009 (in press). By definition, synergism is more than the additive effect, however, additive effect cannot be determined by the arithmetic sum of effect, nor by the fractional product method, nor by statistics, p value, but rather by the combination index (CI) where CI = 1, < 1, and > 1 indicate additive effect, synergism, and antagonism, respectively. The theory, experimental design, and computerized simulation have been discussed or illustrated in (i-iii), and in (iv) outlined the pitfalls, common errors, and frequently asked questions. The CI method of Chou-Talalay has been cited in over 400 journals and in (i) alone has been cited over 1,916 times with citations over 1,000-fold higher than the journal's impact number. The CI method, based on the median-effect principle of the mass-action law, is quantitative, efficient, simple and economical which allows using small number of data points. This paper will illustrate how synergism of two anticancer drugs can be determined in nude mice bearing mammary carcinoma MX-1, and why two similar anti-HIV clinical trials, where both used surrogate markers and fractionated doses, were published and had different results; one used 366 patients (N. Engl. J. Med. 333: 1662-1669, 1995) but was unable to determine synergism due to the experimental design, and another, which applied the CI method, used only 36 patients (Antivir. Ther. 1: 77-88, 1996), and yet was able to quantitatively determine synergism. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5398.

Synergism of Complex Additives of DTAB+KTL for Zinc Corrosion Inhibition in KOH Solutions

Synergism of Complex Additives of DTAB+KTL for Zinc Corrosion Inhibition in KOH Solutions

The Effects of GDF-5 and Uniaxial Strain on Mesenchymal Stem Cells in 3-D Culture

Recent endeavors in tissue engineering have attempted to identify the optimal parameters to create an artificial ligament. Both mechanical and biochemical stimulation have been used by others to independently modulate growth and differentiation, although few studies have explored their interactions. We applied previously described fabrication techniques to create a highly porous (90%-95% porosity, 212-300 microm), 3-D, bioabsorbable polymer scaffold (polycaprolactone). Scaffolds were coated with bovine collagen, and growth and differentiation factor 5 (GDF-5) was added to half of the scaffolds. Scaffolds were seeded with mesenchymal stem cells and cultured in a custom bioreactor under static or cyclic strain (10% strain, 0.33 Hz) conditions. After 48 hours, both mechanical stimulation and GDF-5 increased mRNA production of collagen I, II, and scleraxis compared to control; tenascin C production was not increased. Combining stimuli did not change gene expression; however, cellular metabolism was 1.7 times higher in scaffolds treated with both stimuli. We successfully grew a line of mesenchymal stem cells in 3-D culture, and our initial data indicate mechanical stimulation and GDF-5 influenced cellular activity and mRNA production; we did not, however, observe additive synergism with the mechanical and biological stimuli.

Soybean Oil-Based Lubricants: A Search for Synergistic Antioxidants

Vegetable oils can contribute toward the goal of energy independence and security due to their naturally renewable resource. They are promising candidates as base fluids for ecofriendly lubricants because of their excellent lubricity, biodegradability, good viscosity−temperature characteristics, and low evaporation loss. Their use, however, is restricted due to low thermo-oxidative stability and poor cold-flow behavior. This paper presents a systematic approach to improve their oxidation behavior by searching for a suitable additive combination. The study of antioxidant/antiwear additive synergism was investigated on a set of four antioxidants and three antiwear additives in vegetable oils using pressure differential scanning calorimetry (PDSC) and a rotary bomb oxidation test (RBOT). The results indicate that dialkyldithiocarbamate antioxidant performed better than diphenylamine and hindered phenol. The zinc dialkyldithiocarbamate antioxidant showed excellent synergism with antiwear additive antimony dit...

Quantitative Structure–Activity Relationships for Predicting the Joint Toxicity of Substituted Anilines and Phenols to Algae

Aniline, phenol, and their derivatives are widely used industrial chemicals that consequently have a high potential for environmental pollution. The toxicity of these chemicals has been investigated extensively using fish, Tetrahymena pyriformis and Vibrio fischei (Cronin and Schultz, 1996; Konemann and Musch, 1981; Lu et al., 2003). However, in aquatic ecosystems, there often are many coexistent chemicals, and information on the joint toxicity of a mixture of aniline and phenol derivatives is scarce. Quantitative structure–activity relationships (QSARs) are powerful tools for predicting the toxicologic effect of chemicals. In the past two decades, QSARs for the toxicity of single compounds have been developed fleetly. The joint toxicity of organic chemicals can be assessed objectively by QSAR studies, and the toxicologic effect of coexistent pollutants on aquatic organisms can be predicted. In an early study analyzing the joint toxicity of binary mixtures, Placket and Hewlett (1967) identified four types of actions: simply additive, more than additive (synergism), less than additive (partial addition), and no interaction (independent). These actions have been quantitatively classified using the Toxic Unit (TU), the Additivity Index (AI), the Similarity Parameter (k), and the Mixture Toxicity Index (MTI). Recently, joint toxicity prediction based on QSARs has been attempted. Xu and Nirmalakhandan (1998) applied QSAR models derived from single chemical toxicity assays to predict the joint toxicity of mixtures of organic chemicals to microorganisms. Yuan et al. (2002) determined the joint toxicity of binary mixtures of 2,4-dinitrobenzne, 8 nitrobenzenes, and anilines to Vibrio fischeri according to an equiconcentration ratio (1:1) and developed a QSAR for joint toxicity using ELUMO as the structural descriptor. Huang et al. (2003) measured the joint toxicity of phenol derivatives to tadpoles (Rana japonica) and predicted mixture toxicity using logP. This study aimed to determine experimentally the toxicity of single substituted anilines and phenols and related binary mixtures to the algae Scenedesmus obliquus, and to assess, model, and predict joint toxicity using molecular structural descriptors.

Interaction between noradrenergic and glucocorticoid brain systems: Probable involvement in the development of depression

Electrophysiological and biochemical experiments on slices of the rat dorsal hippocampus demonstrated that dexamethasone (100 nM) augmented and prolonged the depressive effect of noradrenaline on synaptic transmission in the CA1 zone; this effect is related to weakening of the uptake of noradrenaline by neurons. The effect of dexamethasone is mediated by glucocorticoid receptors. Inhibitors of presynaptic translocase of noradrenaline, cocaine and imipramine, increased, similarly to dexamethasone, the effects of noradrenaline; an additive synergism was observed upon combined applications of dexamethasone and cocaine. The effect of dexamethasone decreased with an increase in the extracellular concentration of glucose, but increased upon application of the Na/K-ATPase inhibitor strophantin. The potentiating influence of dexamethasone on the effects of noradrenaline was weaker in slices obtained from rats with behavioral depression induced by social isolation or chronic introduction of dexamethasone. We hypothesize that glucocorticoids stabilize noradrenergic neurotransmission in the brain under the action of stressogenic influences. The role of glucocorticoid mechanisms in the development of depression is discussed.

Effect of nociceptin and [Phe1Ψ (CH2–NH) Gly2]-nociceptin-(1–13)-NH2 on tonic activity of rat hypothalamic neurons

The effect of nociceptin, an endogenous ligand for a unique member of the cloned opioid receptor family ORL1-receptor, on tonic activity of neurons in the preoptic area/anterior hypothalamus (PO/AH) has been examined in rat brain slices using extracellular recordings. Nociceptin (1, 10 and 100 nM) decreased dose-dependently tonic activity of PO/AH neurons. This effect was not significantly different from the effect of [Phe1Ψ (CH2–NH) Gly2]-nociceptin-(1–13)-NH2 (1, 10 and 100 nM), recently proposed as a selective antagonist of the nociceptin receptor. Thus, [Phe1Ψ (CH2–NH) Gly2]-nociceptin-(1–13)-NH2 appears to be an agonist rather than an antagonist of nociceptin (ORL1) receptor in rat PO/AH neurons. However, there was neither antagonism nor additive synergism when nociceptin and [Phe1Ψ (CH2–NH) Gly2]-nociceptin-(1–13)-NH2 were applied simultaneously at equimolar concentrations. The effect of nociceptin on tonic activity of rat PO/AH neurons was not blocked by selective μ-, κ- and δ-opioid receptor antagonists (d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), nor-binaltorphimine and naltrindol, respectively) at 10 times higher concentrations than nociceptin. These data suggest that the effect of nociceptin on tonic activity of PO/AH neurons is not due to an action on μ-, κ-, or δ-opioid receptors but results from a specific effect on the ORL1-receptor.

Nociceptin/orphanin FQ: effects on thermoregulation in rats.

Nociceptin/orphanin FQ is a 17 amino acid peptide which acts as a potent endogenous agonist of the opioid receptor-like 1 (ORL1) receptor. ORL1 receptor is a G protein-coupled unique member of the cloned opioid receptor family. We have investigated the effects of nociceptin (1, 10 and 100 nM) on the temperature sensitivity of neurons from the preoptic area of the anterior hypothalamus (PO/AH) in rat brain slices. The body temperature of male Wistar rats was measured after intrahypothalamic application of nociceptin (1 nM) via cannulas in the PO/AH. Low dose nociceptin (1 nM) significantly increased (p < 0.05) temperature sensitivity (TC) of warm-sensitive PO/AH neurons, while the high concentration (100 nM) decreased TC in both warm-sensitive and temperature-insensitive neurons. Similar agonistic activity was obtained after addition of [Phe1 psi (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 (1, 10 and 100 nM), recently proposed to be a selective antagonist of the nociceptin receptor. Neither antagonism nor additive synergism were observed when nociceptin and [Phe1 psi (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 were applied simultaneously in equimolar concentrations. The selective opioid OP3 receptor antagonist CTOP, the selective opioid OP2 receptor antagonist nor-binaltorphimine and selective opioid OP1 receptor antagonist naltrindol had no influence on the effects of nociceptin on temperature sensitivity in PO/AH neurons. In vivo experiments showed that nociceptin (1 nM; 1 microliter/rat) significantly decreased body temperature (p < 0.05) between 30 and 60 min after intrahypothalamic application. These data are in agreement with the hypothesis that the specific action of endogeous substances on body temperature appears to be closely related to a specific change in the temperature sensitivity of warm-sensitive PO/AH neurons.

Effect of process conditions on co-liquefaction kinetics of waste tire and coal

Thermal and catalytic liquefactions of waste (recycled) tire and coal were studied both separately and using mixtures with different tire/coal ratios. Runs were made in a batch tubing bomb reactor at 350–425°C. The effect of hydrogen pressure on the product slate was also studied. Mixtures of tire components and coal were used in order to understand the role of the tire as a solvent in co-liquefaction. In the catalytic runs, a ferric-sulfide-based catalyst impregnated in situ in the coal was used. Both the tire components and the entire tire exhibit a synergistic effect on coal conversion. The extent of synergism depends on temperature, H 2 pressure and the tire/coal ratio. Experiments with coal and tire components show that the synergistic effect of tire is due to the rubber portion of the tire and not the carbon black. The synergism mainly leads to an increase in the yields of asphaltenes, which are nearly double those in the coal-only runs at 400°C. The conversion of coal increases dramatically using the catalyst, but the catalytic effect is attenuated somewhat in the presence of tire, especially at high tire/coal ratios. The data were analyzed using a consecutive reaction scheme for the liquefaction of coal to asphaltenes and thence to oil+gas, both reactions being of second order; a second-order conversion of tire to oil+gas; and an additional synergism reaction when both coal and tire are present, first-order in both coal and tire. Parallel schemes were assumed for thermal (uncatalyzed) and catalyzed reactions. The uncatalyzed liquefaction of coal has a low apparent activation energy, 36 kJ/mol, compared to those for the synergism reaction (84 kJ/mol) and the catalytic coal liquefaction (158 kJ/mol). The conversion of asphaltenes to oil+gas is relatively independent of temperature and of the presence of the catalyst. The catalyst appears to play a significant role in the conversion of coal to asphaltenes, but a negligible role in the synergism reaction.

Anticonvulsant and sodium channel blocking effects of ralitoline in different screening models.

Ralitoline, a thiazolidinone derivative chemically distinct from known antiepileptic drugs, possesses remarkable anticonvulsant properties as demonstrated in various animal models of epilepsy. The efficacy of this compound seems to be comparable or even better than that of conventional antiepileptics. In the present study, the activity of ralitoline was investigated in four seizure models in rodents in order to characterize the anticonvulsant profile of action further. In the maximal electroshock seizure test (mice), this compound showed marked anticonvulsant effects (ED50 2.8 mg/kg i.p.). The efficacy of clinically established anti-epileptics was significantly increased when ralitoline was given as co-medication. In the strychnine seizure test (mice), ralitoline (5 and 10 mg/kg) prolonged the latency of tonic seizures as well as the survival time. On the other hand, in the subcutaneous pentylenetetrazol seizure threshold test (mice), this drug revealed limited protective actions at higher doses and increased the effectiveness of ethosuximide. In unrestrained rats with chronically implanted electrodes, ralitoline (5 mg/kg) significantly reduced the duration of electrically-evoked hippocampal discharges and raised the focal stimulation threshold (10 mg/kg). In the rotorod ataxia test (mice), a TD50 value of 14.5 mg/kg i.p. was determined for ralitoline (protective index TD50/MES-ED50 5.2). With regard to the possible mode of action, whole-cell voltage-clamp experiments on cultured neonatal rat cardiomyocytes showed that ralitoline may act specifically on voltage-sensitive sodium channels. The compound inhibited the fast sodium inward current in a frequency- and voltage-dependent manner. In conclusion, the findings confirm the potent anticonvulsant effects of ralitoline, especially against generalized tonic-clonic and complex partial seizures. Moreover, in combination with antiepileptics, an additive synergism can be found at lower concentrations. Regarding the mode of action, this drug was capable of depressing the fast sodium inward current in cultured heart ventricular cells, suggesting that the local anesthetic properties may be important for the anticonvulsant activity of ralitoline.

An LH-RH antagonist inhibits the behavioral effects of the agonist D-TRP-6-LH-RH in mice

The effects of a potent LH-RH receptor antagonist, [Ac-4-Cl-D-Phe 1,2, D-Trp 3,D-Arg 6,D-Ala 10]LH-RH (ORG 30276), on the behavioral actions of the LH-RH agonist, D-Trp-6-LH-RH, were studied in mice. The subcutaneous (SC) administration of 100 μg/kg D-Trp-6-LH-RH inhibited ambulation in an open-field, produced analgesia in the hot-plate and tail-flick tests. These effects of the agonist were totally antagonized by pre-treatment with ORG 30276 at a dose of 100 μg/kg SC. In the apomorphine-induced cage-climbing test, both the agonist and the antagonist alone or together suppressed the duration of stereotyped behaviod in dose-dependent manner, but, as there was no additive synergism after combined treatments, it seems that the two substances mutually diminish each other's effects. The results indicate that the behavioral effects of the LH-RH agonist can be antagonized by pretreatments with a potent LH-RH antagonist designed to block pituatary LH-RH receptors, with the exception of the suppression of apomorphine-induced cage-climbing, where special type of receptors and/or mechanisms might be involved.

Analysis of Synergism/Antagonism Between HIV-1 Antibody-Positive Human Sera and Soluble CD4 in Blocking HIV-1 Binding and Infectivity.

We tested human immunodeficiency virus type 1 (HIV-1) antibody-positive human sera and sCD4, alone and in combination, for synergistic, additive, or antagonistic effects on blocking of HIV binding and infectivity. Data were analyzed by an application of the median effect principle derived from the law of mass action. This allows the assessment of synergism/antagonism at any desired level of effect. Using three assays (whole virus binding to CD4 cells, neutralization of HIV infectivity, and binding of purified gp120 to solid-phase sCD4), we generally observed additive effects or slight synergism between antibody and sCD4 in inhibiting gp120-CD4 interaction. We used a fourth assay to measure the irreversible inactivation of HIV infectivity by sCD4, a property that can also be mediated by antibody but with considerably less potency than sCD4. The reduction in HIV infectivity mediated by mixtures of sCD4 and antibody was always equal to or greater than the arithmetic sum of the reductions by either agent alone. The relevant antiviral effects of sCD4 and anti-HIV sera may include reversible blockage of receptor binding, irreversible inactivation of HIV infectivity, and in the case of antibody, additional reactions that are independent of receptor binding. Although predictions concerning the in vivo situation are speculative, we find no evidence in vitro for antagonism between sCD4 and antibody with respect to the net effect of the two in blocking HIV binding and infectivity.

Some fundamental aspects of levelling and brightening in metal electrodeposition

This review concerns fundamental aspects of levelling and brightening in the electrodeposition of metals. The most important effects of additives, such as the grain refinement of the deposit, polarization of the cathode, incorporation of additives in the deposit, the change of the orientation of crystals and the synergism of additives are presented. The mechanisms proposed to explain the action of additives in metal electrodeposition are classified taking into account the rate determining step of the process. The main mechanisms are discussed.