Indolylalkylthioureas and their tuberculostatic activity

The reaction of 5-methoxytryptamine with silicon tetraisothiocyanate has given N-[-(5-methoxy-3-indolyl)ethyl]thiourea, and N,N'-di[-(5-methoxy-3-indolyl)ethyl]thiourea has been synthesized by heating 2 moles of 5-methoxytryptamine hydrochloride with 1 mole of ammonium thiocyanate. The reaction of tryptamines with aryl isothiocyanates has given the unsymmetrical disubstituted N--3-indolylethyl-N'-phenylthioureas. All the thioureas have been converted by the action of methyl iodide into S-methylisothiouronium hydriodides. By the reaction of indolylalkyl bromides with thiourea, S-indolylalkylisothiouronium salts have been synthesized. The compounds obtained have been subjected to chemotherapeutic study.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 1, pp. 46–48, January, 1967.     

Physicochemical Properties of Salts of p-Aminosalicylic Acid. I. Correlation of Crystal Structure and Hydrate Stability

The potassium (K), sodium (NA), calcium (CA), and magnesium (MG) salts of p-aminosalicylic acid were obtained, and their thermal behavior was characterized by means of differential scanning calorimetry (DSC) and thermogravimetric analysis (TG). Their crystal and molecular structures were determined by single-crystal X-ray diffraction after powder patterns had shown them to be nonisomorphous. Different degrees of hydration were observed for the solid salts, and an assessment of hydrate stability to dehydration was made from thermogravimetric studies. The onset temperature of dehydration (T _t) of each salt varied within the series and exhibited correlation with X-ray determined structure. The observed onset of dehydration of MG and CA was higher than that of NA and is consistent with stronger ion-dipole interactions for the divalent salts. Crystallographic determination of the bond lengths between the metal ion and the water oxygens were 2.4 and 2.9 for NA, between 2.0 and 2.1 for MG, and 2.4 for CA. The open nature and presence of a channel feature in the structure of the sodium salt may have facilitated escape of water molecules from the crystal. Particle presentation (e.g., size, crystallinity) was also shown to affect dehydration behavior.     

Dissociation of Insulin Oligomers by Bile Salt Micelles and Its Effect on α-Chymotrypsin-Mediated Proteolytic Degradation

Bile salts have been found to be effective absorption promoters of insulin across mucosal barriers, i.e., nasal and gastrointestinal. One of the mechanisms proposed for absorption enhancement is the dissociation of insulin oligomers to monomers, rendering a higher insulin diffusivity. -Chymotryptic degradation and circular dichroism studies were used to characterize such a transition. When zinc insulin (hexamers) and sodium insulin (dimers) were subjected to -chymotryptic degradation, a 3.2-fold difference in the apparent first-order rate constants was observed (zinc insulin being slower than sodium insulin), representing the intrinsic difference in the concentration of total associated species in solution (three times). In the presence of a bile salt, sodium glycocholate (NaGC), the rate of degradation of both zinc and sodium insulin increased in an asymptotic manner. A maximum increase of 5.4-fold was observed for zinc insulin at a 30 mM NaGC concentration and a 2.1-fold increase was noted for sodium insulin at 10 mM NaGC, both values being close to the theoretical numbers of 6- and 2-fold as predicted by the complete dissociation of hexamers and dimers to monomers. The result indicates dissociation of insulin oligomers to monomers by bile salt micelles, probably by hydrophobic micellar incorporation of monomeric units. Circular dichroism studies also revealed progressive attenuation of molecular ellipticities at negative maxima of 276, 222, and 212 nm for zinc insulin solution in the presence of NaGC. Therefore, both -chymotryptic degradation and circular dichroism studies have consistently demonstrated that the bile salts may be capable of dissociating insulin oligomers to monomers, a fact which may play an important role in enhancing insulin bioavailability.     

Synthesis of 5-(n-isopropylthiocarbamoyl)-spinaceamines: Analogs of antisecretory and antiulcer derivatives of spinaceamine

A series of 5-(N-isopropylthiocarbamoyl) derivatives of spinaceamine and spinacine have been synthesized for pharmacological testing. N-Phenacylium salts were obtained via the interaction of 1-and 1,2-substituted imidazo[4,5-c]pyridines with p-methoxyphenacyl bromide. The reduction of N-phenacylium salts with sodium borohydride in alcohol leads to the formation of 5-(β-hydroxy-β-p-methoxyphenetyl)spinaceamines, and subsequent boiling with concentrated hydrochloric acid leads to cleavage of the terminal C-N⁵ bonds with the formation of 1-substituted and 1,2-disubstituted spinaceamines. Final treatment with isopropylisothiocyanate converts these intermediate compounds into the target 5-(N-isopropylthiocarbamoyl) derivatives. Lithium and potassium salts of spinacine were reacted with isopropylisothiocyanate to obtain the corresponding thioureas, which were converted into hydrochlorides by treatment with hydrogen chloride saturated ether. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 2, pp. 5–9, February, 2006.     

Monosulfonyl-cyclopentadiene

Monosulfonylcyclopentadienes Addition of sulfonyl bromides to cyclopentadiene ( 1 ) yields a mixture of cis- and trans-3-bromo-5-sulfonylcyclopentenes 7 and 8 . The stereochemistry of 7 and 8 was elucidated by ¹-NMR spectroscopy and chemical transformations. With sodium hydride 7 and 8 are converted into the sodium sulfonylcyclopentadienides 15 . By cation exchange the more stable salts 16 were obtained. Protonation of 15 or 16 gives rise to the monosulfonylcyclopentadienes 17 which are rather unstable and tend to form the Diels-Alder dimers 6 immediately. Only 1-(phenylsulfonyl)cyclopentadiene ( 17a ) could be intercepted and characterized by analysis and spectroscopy.     

Sodium pump inhibition by sulfhydryl inhibitors and myocardial contractility

Summary In order to determine whether the positive inotropic action of cardiac glycosides is related to the inhibition of sodium pump activity, the actions of known inhibitors:N-ethylmaleimide,p-chloromercuribenzoate (PCMB),p-chloromercuribenzene sulfonic acid (PCMBS) and digitoxin, were studied in isolated guinea pig hearts. In electrically driven left atrial preparations, all these agents increased isometric contractile force. The inotropic effect ofN-ethylmaleimide was only partially reduced in the presence of propranolol or by reserpine pretreatment, whereas the inotropic effects of PCMB and PCMBS were unaffected by reserpine pretreatment. (±)-Propranolol markedly delayed the development of the inotropic action of PCMB and PCMBS without affecting the magnitude of the peak inotropic response. Similar effect was observed with (+)-propranolol indicating that the delayed development of the inotropic action is probably due to the action of propranolol unrelated to -adrenergic blockade. Among sulfhydryl blocking agents, the development of the inotropic effects was fastest withN-ethylmaleimide and slowest with PCMBS. Effects of these sulfhydryl inhibitors on resting potential and action potential were unrelated to the inotropic action. These agents caused a decrease in ouabain-sensitive⁸⁶Rb uptake, an estimate of sodium pump activity, in sodium-loaded ventricular slices obtained from drug-perfused Langendorff preparations. Quantitative comparisons between the degree of inotropic response and sodium pump inhibition caused by these agents were not possible because of the difference in experimental conditions. These results, however, are consistent with the hypothesis that Na⁺, K⁺-ATPase inhibitors cause positive inotropic effects associated with sodium pump inhibition.Supported by U.S. Public Health Service Grants HL-16052 and HL-16788 and a grant from the National Science Foundation, BMS 74-19512     

Effects of Goniopora toxin on the membrane currents of bullfrog atrial muscle

Summary The effects of Goniopora toxin (GPT), isolated from the Goniopora species, on the action potential and membrane currents of bullfrog atrial muscle were studied using the double sucrose-gap method. GPT at concentrations above 10 nmol/l prolonged the duration of the action potential and sometimes induced arrhythmias. The prolongation was also induced in the presence of Ca channel blockers (Mn or verapamil). These effects were not reversed by continuous superfusion of GPT-free solution, but were rapidly antagonized by tetrodotoxin (1 mol/l). The resting potential was not affected by GPT. Voltage clamp experiments revealed that sustained inward current flows following the fast sodium current upon depolarization, in the presence of GPT. The current was elicited by the toxin in Mn-treated fibers and abolished in the presence of TTX. The delayed outward current (I _x) was slightly reduced; the background K current (I _K1), inward background current (I _b) and slow inward current (I _slow) were not altered by GPT. These results suggest that GPT acts on sodium channels to give rise to a prolonged sodium current which is in turn responsible for the prolongation of the action potential.This work was supported in part by a Grant-in Aid for Special Project Research (No. 58110007) from the Ministry of Education, Science and Culture, Japan (M.F.)     

2-β-(N-arylpiperazino) ethyl indandiones-1,3 and indandiols-1,3

Conclusion By the action of N-arylpiperazines on the tosylates of 2--hydroxyethyl-2-phenyl and 2-methylsubstituted indandiones-1,3 one obtains 2--(N-arylpiperazino) ethyl derivatives of 2-substituted indandiones-1,3 which are reduced by sodium borane to the corresponding indandiol-1,3 derivatives. The arylpiperazino derivatives of 2-substituted indandiones-1,3 and indandiols-1,3 have neurotropic properties. A certain association between structure, toxicity, and pharmacological action of these compounds was noted.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 10, pp. 25–29, October, 1968.     

Water-in-Oil Microemulsions Containing Medium-chain Fatty Acids/Salts: Formulation and Intestinal Absorption Enhancement Evaluation

Purpose. Water-in-oil (w/o) microemulsions have been developed which, in addition to non-ionic medium-chain glycerides, incorporate ionic lipids, primarily medium-chain fatty acids, such as caprylic (C₈) capric (C₁₀) and lauric (C₁₂) acids and their corresponding sodium salts. The absorption enhancing activity of w/o microemulsions incorporating these lipids was evaluated in the rat using Calcein (MW = 623) a water-soluble and poorly absorbed marker molecule. Methods. Phase diagrams were constructed where C₈/C₁₀ or C₁₂ fatty acids were treated as lipophilic surfactants and their sodium salts as hydrophilic ones. The anesthetised rat model was employed to evaluate Calcein absorption upon a single intraduodenal administration from a solution and the various w/o microemulsions. Results. A wide range of clear and transparent w/o microemulsions were obtained at ambient temperature either in liquid or solid form when a fixed blend of medium chain fatty acid/salt was titrated by a fixed ratio of the oil containing the oil-soluble mono- and diglycerides and deionized water or physiological saline. Upon intraduodenal administration in the anesthetised rat, the absorption of Calcein was improved from about 2% in aqueous solution up to about 37% in w/o microemulsions. Solid and liquid formulations were equally effective in improving bioavailability. The absorption enhancement activity of the fatty acids/salts followed the order C₈ C₁₀ > C₁₂. Absorption enhancement of Calcein was significantly reduced in the absence or presence of low levels of C₈/C₁₀ mono-/diglycerides. Conclusions. These results further support the use of medium-chain glycerides and fatty acids/salts in microemulsion formulations to improve intestinal absorption of water-soluble compounds.     

Nicorandil shortens action potential duration and antagonises the reduction of V max by lidocaine but not by disopyramide in guinea-pig papillary muscles

Summary Conventional microelectrode techniques were used to examine whether or not nicorandil, which shortens action potential duration (APD), modifies the lidocaine- or disopyramide-induced time-dependent reduction of V _max in guinea-pig papillary muscles. First, effects of 0.1 and 1 mmol/l nicorandil were examined on the frequency dependence of V _max and on the recovery process of V _max. Second, the frequency-dependent reduction of V _max by 20 mol/l antiarrhythmic drugs was examined in the presence and absence of 1 mmol/l nicorandil at stimulation frequencies of 1/120 Hz–5 Hz. Third, the recovery process of V _max in the presence of 20 mol/l antiarrhythmic drugs was examined, with and without 1 mmol/l nicorandil, by applying test stimuli at various diastolic intervals after conditioning stimuli. 1 mmol/l nicorandil greatly shortened APD₉₀ to 30–40% of control without changing the frequency dependence of V _max, the recovery process of V _max, and the resting potential. The lidocaine-induced, frequency-dependent reduction of V _max was significantly antagonised by 1 mmol/l nicorandil, but the disopyramide-induced reduction was not. The recovery process of V _max slowed in the presence of lidocaine was antagonised by 1 mmol/l nicorandil as follows: the time to get the full recovery of V _max was shortened by nicorandil with a significant decrease in the zero time-intercept (from 0.54 to 0.38) but with an insignificant change in the recovery time constant (from 130 ms to 121 ms). In contrast, the recovery process of V _max slowed in the presence of disopyramide (a zero time intercept of 0.13 and a recovery time constant of 50 s) was not significantly antagonised by 1 mmol/l nicorandil. In conclusion, nicorandil having an action potential-shortening action antagonises the lidocaine-induced, time-dependent reductions of V _max, but not the disopyramide-induced reductions. These results suggest that: (1) lidocaine and disopyramide preferentially bind to inactivated and activated sodium channels, respectively, because lidocaine's effects are dependent on and disopyramide's effects are independent of APD (during which sodium channels are in the inactivated state); and (2) nicorandil is a useful drug for estimating whether a sodium channel-blocking action of class I antiarrhythmic drugs is due to an inactivated channel block or an activated channel block. These time-dependent reductions of V _max by both lidocaine and disopyramide were well simulated by the guarded receptor hypothesis. Send offprint requests to M. Kojima     

Effective Inhibition of Mannitol Crystallization in Frozen Solutions by Sodium Chloride

Purpose. The purpose of this work was to study the possibility of preventing mannitol crystallization in frozen solutions by using pharmaceutically acceptable additives. Methods. Differential scanning calorimetry (DSC) and low-temperature X-ray diffractometry (LTXRD) were used to characterize the effect of additives on mannitol crystallization. Results. DSC screening revealed that salts (sodium chloride, sodium citrate, and sodium acetate) inhibited mannitol crystallization in frozen solutions more effectively than selected surfactants, -cyclodextrin, polymers, and alditols. This finding prompted further studies of the crystallization in the mannitol-NaCl-water system. Isothermal DSC results indicated that mannitol crystallization in frozen solutions was significantly retarded in the presence of NaCl and that NaCl did not crystallize until mannitol crystallization completed. Low-temperature X-ray diffractometry data showed that when a 10% w/v mannitol solution without additive was cooled at 1°C/min, the crystalline phases emerging after ice crystallization were those of a mannitol hydrate as well as the anhydrous polymorphs. In the presence of NaCl (5% w/v), mannitol crystallization was suppressed during both cooling and warming and occurred only after annealing and rewarming. In the latter case however, mannitol did not crystallize as the hydrate, but as the anhydrous polymorph. At a lower NaCl concentration of 1% w/v, the inhibitory effect of NaCl on mannitol crystallization was evident even during annealing at temperatures close to the Tg (–40°C). A preliminary lyophilization cycle with polyvinyl pyrrolidone and NaCl as additives rendered mannitol amorphous. Conclusion. The effectiveness of additives in inhibiting mannitol crystallization in frozen solutions follows the general order: salts > alditols > polyvinyl pyrrolidone > -cyclodextrin > polysorbate 80 polyethylene glycol poloxamer. The judicious use of additives can retain mannitol amorphous during all the stages of the freeze-drying cycle.     

Pirmenol,a new antiarrhythmic drug with potassium- and sodium-channel blocking activity; a voltage-clamp study in rabbit Purkinje fibres

Summary The target of this study was to characterize the effect of pirmenol hydrochloride on the electrophysiological properties of cardiac cells.Action potential studies were carried out using the standard microelectrode technique in isolated rabbit Purkinje fibres. Information about the effect of pirmenol on the fast sodium current was obtained by V _max measurement. Furthermore the delayed rectifying current i_x was studied by the two microelectrode voltage clamp technique.In concentrations of 0.5–5 mol/l pirmenol caused a marked prolongation of the action potential duration in isolated rabbit Purkinje fibres. Measurements of the delayed rectifying current i_x displayed a strong depression with a K _D-value of 1 mol/l pirmenol. The steady-state current voltage relation showed that pirmenol also caused a reduction of the steady-state sodium window current and/or of the slowly decaying components of the sodium current. In concentrations of 10 mol/l pirmenol the action potential duration was diminished again and V_max was depressed in a use-dependent manner. Furthermore pirmenol caused a depression and a negative shift of the V_max/E_m- relation. Pirmenol blocked sodium channels which recovered from block with a time constant of 6.7 s at a holding potential of –105 mV. Similar to quinidine and sotalol the prolongation of the action potential duration under pirmenol is essentially caused by a diminution of the delayed rectifying current i_x The depression of V_max is mainly independent from the action potential duration indicating the dominance of an open channel block. Pirmenol is a new drug with class la antiarrhythmic action. Send offprint requests to O. Hauswirth at the above address     

Choleresis and hepatic transport mechanisms

Summary To investigate, whether binding to micelles has a function in hepatic transport, biliary excretion of three organic anions, phenolphthalein-\-D-glucuronide (PG), dibromosulphthalein (DBSP) and indocyanine green (ICG) was studied in rats during saline, taurocholate or dehydrocholate administration. Taurocholate causes a weak choleresis with formation of biliary micelles, dehydrocholate a strong choleresis with little micelle formation. The two bile salts did not uniformly influence biliary excretion of the organic anions: biliary excretion of ICG (12.9 moles/kg) and DBSP (75.0 moles/kg) was stimulated by both bile salts: ICG excretion most pronounced by taurocholate and DBSP excretion most strongly by dehydrocholate. Biliary output of PG (25.8 and 200 moles/kg) was not stimulated by bile salt administration. Binding of PG, DBSP and ICG to biliary micelles was studied in sedimentation experiments by ultracentrifugation. PG, DBSP and ICG in bile showed a similar sedimentation pattern as ³H-taurocholate in bile, which indicates an association of all three anions with biliary micelles.Thus, the influence of bile salts on biliary transport of organic anions varies with the compound studied and the bile salt used, effects which cannot be explained by differences in binding to biliary micelles.The previously published paper of Vonk et al. (1974) is regarded as paper I in this series.     

Renal effects of adenosine and their inhibition by theophylline in dogs

Summary The action of adenosine on renal blood flow and kidney function in dogs was studied with bolus injections and infusion of adenosine into the renal artery. Simultaneous infusions of theophylline, 1–5×10^–6 mol/min into the renal artery which did not affect renal function by itself inhibited the adenosine induced vasoconstriction. From the bolus injection studies a dose response curve (DRC) was constructed. Theophylline shifted the DRC to the right in a parallel manner. pA₂-pA₁₀ was 0.98 indicating that theophylline inhibition of the adenosine effects may be interpreted as a competitive antagonism. Infusions of adenosine (0.3–1.1 mol/min) caused a reduction of urine volume, sodium excretion and glomerular filtration rate (GFR). The decrease of GFR after adenosine infusion by 31.4% could be diminished by theophylline. It is suggested that adenosine action is based mainly on a constriction of the vasa afferentia in the outer zone of the cortex.with the technical assistance of O. JacobsPart of this work was presented on the 14. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft, Mainz, 18.–21. 3. 1973.Supported by Deutsche Forschungsgemeinschaft.     

Blockage of the fast sodium current by dimetindene in frog auricular fibres

Summary The effect of dimetindene (DMI) on action potential and fast inward Na current (I _Na) of frog atrial fibres was studied using double sucrose gap voltage-clamp technique. DMI reduced the amplitude and maximum rate of rise of the action potentials without altering the resting membrane potential. The drug inhibited the fast Na conductance in a concentration-dependent manner, without changing the reversal potential. The shape of the current-voltage curve along the voltage axis remained unchanged in the presence of DMI. The time to peak of the I_Na was not significantly altered by the drug whereas the rate of the I_Na inactivation (_h) was slowed. DMI shifted the steady-state inactivation curve of I _Na (h) to more negative potentials, and increased the reactivation time constant of the sodium system (_r). The inhibition of I_Na was use-dependent. The results suggest that DMI interacts with the inactivation mechanism of the sodium channel of the frog myocardium, and explain its favourable antiarrhythmic activity.     

Noradrenaline transport by rat heart sympathetic nerves: A re-examination of the role of sodium ions

Summary The effect of sodium ion on ³H-(–)-noradrenaline (0.0875 to 0.5 M) transport by rat heart atrial hemi-appendages incubated in vitro has been studied, and the following observations made: a) When sodium was omitted (choline and lithium substitution) there was no evidence for active noradrenaline transport, and only a component that did not show saturation kinetics up to 1 M noradrenaline, remained. b) Omission of sodium or addition of 4×10^–5 M desipramine inhibited noradrenaline transport to exactly the same extent, and their effects were not additive. Alprenolol did not reduce this sodium-independent transport, but tropolone lowered it somewhat. c) No evidence for corticosterone-sensitive noradrenaline transport (uptake-2) was found in this preparation at the low amine concentrations used. d) In control medium, the kinetic parameters of transport were: K _m: 0.59 ± 0.063 M and V _max: 2.44 ± 0.43 (pmoles/mg protein/min). With 26 mM sodium and the rest substituted by choline, K _m:2.26 ± 0.70 M (P0.001) and V _max: 2.74 ± 0.43 (pmoles/mg protein/min) (not significant). Also with 26 mM sodium, but with sucrose substitution, K _m: 0.76 ± 0.13 M (N.S.) and V _max: 1.06 ± 0.13 (pmol/mg/min) (P<0.05). Such results indicate that sodium only modifies the affinity of the transport system for noradrenaline, without changing V _max, and that changes in the latter are only a consequence of a reduction of the ionic strength. e) When noradrenaline transport was studied at different concentrations of external sodium, at constant ionic strength and with precautions to minimize the noradrenaline-releasing effect of low sodium, it was found that the data could be best represented by two hyperbolas placed in series. This suggests that the noradrenaline carrier has two sites for sodium, that do not interact with each other. When the same experiments were repeated in the absence of chloride, it was found that the noradrenaline transport system had lost virtually all its affinity for sodium. f) The effect of prolonged tissue incubation in the absence of sodium was found to produce a relatively small inactivation of noradrenaline transport. Such phenomenon was enhanced by raising the calcium concentration to 2 mM.     

Freeze-Concentration Separates Proteins and Polymer Excipients Into Different Amorphous Phases

Purpose. To study the miscibility of proteins and polymer excipients in frozen solutions and freeze-dried solids as protein formulation models. Methods. Thermal profiles of frozen solutions and freeze-dried solids containing various proteins (lysozyme, ovalbumin, BSA), nonionic polymers (Ficoll, polyvinylpyrrolidone [PVP]), and salts were analyzed by differential scanning calorimetry (DSC). The polymer miscibility was determined from the glass transition temperature of maximally freeze-concentrated solute (T_g) and the glass transition temperature of freeze-dried solid (T_g). Results. Frozen Ficoll or PVP 40k solutions showed T_g at –22°C, while protein solutions did not show an apparent T_g. All the protein and nonionic polymer combinations (5% w/w, each) were miscible in frozen solutions and presented single T_gs that rose with increases in the protein ratio. Various salts concentration-dependently lowered the single T_gs of the proteins and Ficoll combinations maintaining the mixed amorphous phase. In contrast, some salts induced the separation of the proteins and PVP combinations into protein-rich and PVP-rich phases among ice crystals. The T_gs of these polymer combinations were jump-shifted to PVP's intrinsic T_g at certain salt concentrations. Freeze-dried solids showed varied polymer miscibilities identical to those in frozen solutions. Conclusions. Freeze-concentration separates some combinations of proteins and nonionic polymers into different amorphous phases in a frozen solution. Controlling the polymer miscibility is important in designing protein formulations.     

Toxicity of Lithium to Three Freshwater Organisms and the Antagonistic Effect of Sodium

Lithium (Li) is the lightest metal and occurs primarily in stable minerals and salts. Concentrations of Li in surface water are typically <0.04mg l^–1 but can be elevated in contaminated streams. Because of the general lack of information concerning the toxicity of Li to common toxicity test organisms, we evaluated the toxicity of Li to Pimephales promelas (fathead minnow), Ceriodaphnia dubia, and a freshwater snail (Elimia clavaeformis). In the laboratory, the concentration of Li that inhibited P. promelas growth or C. dubia reproduction by 25% (IC25) was dependant upon the dilution water. In laboratory control water containing little sodium (2.8mg l^–1), the IC25s were 0.38 and 0.32mg Li l^–1 and in ambient stream water containing 17mg Na l^–1, the IC25s were 1.99 and 3.33, respectively. A Li concentration of 0.15mgl^–1 inhibited the feeding of E. clavaeformis in laboratory tests. Toxicity tests conducted to evaluate the effect of sodium on the toxicity of Li were conducted with fathead minnows and C. dubia. The presence of sodium greatly affected the toxicity of Li. Fathead minnows and Ceriodaphnia, for example, tolerated concentrations of Li as great as 6mg l^–1 when sufficient Na was present. The interaction of Li and Na on the reproduction of Ceriodaphnia was investigated in depth and can be described using an exponential model. The model predicts that C. dubia reproduction would not be affected when animals are exposed to combinations of lithium and sodium with a log ratio of mmol Na to mmol Li equal to at least 1.63. The results of this study indicate that for most natural waters, the presence of sodium is sufficient to prevent Li toxicity. However, in areas of historical disposal or heavy processing or use, an evaluation of Li from a water quality perspective would be warranted.     

Arsenic uptake,cytotoxicity and detoxification studied in mammalian cells in culture

The cytotoxicity of trivalent and pentavalent inorganic arsenic salts was determined in mouse fibroblasts in vitro. Concentrations of As (III) in the M range led to a reduction of proliferation and viability with a concomitant increase in LDH release and stimulation of lactic acid production. Similar effects were noted with approximately 10-fold greater molar concentrations of As(V). Cells pretreated with a low As(III) concentration are less sensitive to toxic doses of As(III) or As(V).Uptake of As(III) by the fibroblasts is greater than that of As(V). Both forms of inorganic arsenic are converted intracellularly to monomethylarsonic (MMA) and dimethylarsinic (DMA) acids, which are then released into the culture medium. In As-pretreated cells, which are more resistant to As toxicity, biotransformation of inorganic arsenic to MMA and DMA is increased.     

Application of a Brain-Targeting Chemical Delivery System to 9-Amino-1,2,3,4-Tetrahydroacridine

Several chemical delivery systems (CDS) were synthesized for the cholinesterase inhibitor 9-amino-l,2,3,4-tetrahydroacridine (THA). The derivatives prepared were substituted with a 1,4-dihydropyridine pyridinium salt redox system at the amino functionality. These compounds were synthesized by acylation of the 9 amino group of THA with nicotinic anhydride under forced conditions, followed by a selective N-alkylation of the pyridine ring and regioselective reduction of the resulting quaternary salts. Lipophilicity parameters indicated increased lipophilic indices for various CDS's compared to the THA. Oxidation studies showed that dihydronicotinamides readily converted to the quaternary salt, both chemically and enzymatically. The transport forms of THA were also shown not to interact with acetylcholinesterase in vivo. In vivo distribution studies in the rat indicated that high and sustained levels of the pyridinium quaternary ion derivative were present in the central nervous system (CNS). In addition, THA was produced in the CNS from the quaternary salt precursor in low concentrations, indicating a slow but sustained release. The CDS for THA were found to be less acutely toxic than THA.