Toxicity of 1,1'-alkyl-4,4'-bipyridylium salts in the rat

Methyl (paraquat), propyl, isopropyl, butyl, methyl-pentyl, hexyl, octyl and benzyl viologens (1,1'-Alkyl-4,4'-bipyridylium salts) were administered subcutaneously to female Sprague-Dawley rats to determine relative toxicities. These compounds all produce the spectrum of effects previously reported for paraquat and additionally produce a focal necrosis at the injection site, nonemptying of the stomach and adrenal enlargement. A lethal dose of propyl, hexyl or benzyl viologen often produced a yellow to red serous fluid in the pleural cavity. Many of the signs observed with viologen poisoning are similar to adrenal hormone effects and the suggestion is made that the adrenals may be contributing to toxicity.     

The effects of 24% paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride) on hemodynamics, blood gases, plasma lactate and plasma catecholamines in dogs

The cause of death after ingestion of a large dose of paraquat is unclear. We investigated the cardiovascular effects of paraquat injection in 7 dogs that were anesthetized with urethane and alpha-chloralose and maintained on controlled ventilation. After control measurements, paraquat (20 mg/kg) was injected iv. Average concentrations of plasma paraquat were 128 micrograms/ml at 15 min (point 1) and 44 micrograms/ml at 4 hr. The average time of survival was 5.5 +/- 2.2 hr. Comparison was made of control values, 15 min (point 1), and 2.5 +/- 1.0 hr before death (point 2). Pulmonary capillary wedge pressure (+33%) and pulmonary vascular resistance (PVR) (+28%) increased, but no change occurred in mean arterial pressure (MAP) or cardiac output (CO) at 15 min. Mean arterial pressure (-50%) and cardiac output (-61%) decreased, while total vascular resistance (+56%) and PVR (+256%) were increased at point 2. Arterial pH decreased from 7.394 and 7.307 (point 1) to 7.143 (point 2). The concentration of plasma catecholamines and lactic acid increased significantly at both points 1 and 2. Renal, adrenal and myocardial tissues were studied by light and electron microscopy. The outstanding feature was early swelling of mitochondria and disruption of the contents in the presence of intact mitochondrial membrane.     

Response to marijuana as a function of potency and breathhold duration

The present study examined the effects of systematic manipulation of breathhold duration (0 and 20 s) on the physiological and subjective response to active (M; 2.3% delta-9-THC) and placebo (P; 0.0% delta-9-THC) marijuana in a group of ten regular marijuana smokers. During the eight-session experiment, subjects were exposed twice to each of four experimental conditions (P0, P20, M0, M20), scheduled according to a randomized block design. A controlled smoking procedure was used in which the number of puffs and puff volume were held constant. Expired-air carbon monoxide (CO) levels were used to monitor smoke intake. Breathhold duration affected CO absorption; significantly more CO was absorbed from both P and M smoke after 20 s of breathholding (mean CO boost=6.9 ppm) than after no breathholding (mean=4.4 ppm). Heart rate was minimally affected by the breathhold manipulation. Effects of marijuana on mood were not consistently affected by breathhold duration. The results confirm previous findings that prolonged breathholding does not substantially enhance the effects of inhaled marijuana smoke.     

Dielectric constants of solid-liquid and liquid-liquid systems as a function of composition.

The dielectric constant of a solid substance in the dissolved state may be found by using a solvent with a dielectric constant that remains invariable when the solid substance is dissolved. The slope values obtained from dielectric constant versus concentration plots of the solid substance in two solvents with different dielectric constants are extrapolated or interpolated. The dielectric constant of a solid substance in the dissolved state also can be found directly from the dielectric constants of solutions of the solid in one solvent at two concentrations. The dielectric constants are converted to polarizations, and the two values allow calculations of the polarizations of the solvent and solute separately. From the polarization of the solute, one can calculate its dielectric constant (in dissolved state). Such a procedure is correct only if the dielectric constant is concentration independent.     

Skin penetration behaviour of liposomes as a function of their composition

Deformable liposomes have been developed and evaluated as a novel topical and transdermal delivery system. Their mechanism of drug transport into and through the skin has been investigated but remains a much debated question. The present study concerns ex vivo diffusion experiments using pig ear skin in order to explain the penetration mechanism of classical and deformable liposomes. Classical and deformable vesicles containing betamethasone in the aqueous compartment through the use of cyclodextrin inclusion complexes were compared to vesicles encapsulating betamethasone in their lipid bilayer. Deformable liposomes contained sodium deoxycholate as the edge activator. Liposomes were characterised by their diameter, encapsulation efficiency, deformability, stability (in terms of change in diameter) and release of encapsulated drug. Exvivo diffusion studies using Franz diffusion cells were performed. Confocal microscopy was performed to visualise the penetration of fluorescently labelled liposomes into the skin. This study showed that liposomes do not stay intact when they penetrate the deepest layers of the skin. Betamethasone is released from the vesicles after which free drug molecules can diffuse through the stratum corneum and partition into the viable skin tissue.     

Some correlates of marihuana self-administration in man: A study of titration of intake as a function of drug potency

Previous research has suggested that psychosocial rather than strictly pharmacological factors may play a dominant role in the subjective response to socially relevant (i.e., low) doses of marihuana. The insensitivity of experienced marihuana users to pharmacological factors was studied in an ad lib self-administration situation. Subjects tested repeatedly with varying drug potencies were asked to smoke a sufficient amount to achieve a predefined subjective state of intoxication. Several indices of amount consumed suggested that effective titration of intake did not occur. Rather, subjects consumed more total THC the greater the potency of the material. Doses which produced a subjectively optimal high had significant behavioral and physiological effects. The results are consistent with the hypothesis that psychosocial variables may be more significant than pharmacological variables in determining the recreational intake of marihuana.     

Antiaggregatory activity of imidazoline drugs and chemicals as a function of their structure

The concentration-response curves were constructed for 18 azole derivatives (including seven imidazoline drugs) as the inhibitors of the adrenaline-induced human blood platelet aggregation. It was demonstrated by the quantitative structure-activity relationships analysis that the less hydrophobic agents started to act as effective inhibitors at lower concentrations but that stronger effects could be obtained with the more hydrophobic derivatives. The conclusion was drawn that the inhibitory activity observed was the result of nonspecific hydrophobic interactions of the agents with both an andrenergic platelet receptor and a site of loss on serum albumin.     

N-acetylation pharmacogenetics. Michaelis-Menten constants for arylamine drugs as predictors of their N-acetylation rates in vivo

Michaelis-Menten constants for two in vivo monomorphically N-acetylated substrates, p-aminobenzoic acid and p-aminosalicylic acid, and two in vivo polymorphically N-acetylated substrates, sulfamethazine and procainamide, were determined with an improved assay procedure using liver N-acetyltransferase from rapid and slow acetylator rabbit. The slow rabbit liver isozyme proves to be a Vmax and a Km variant for p-aminobenzoic acid and p-aminosalicylic acid. Mean differences in the apparent Vmax for rapid acetylators were 39-fold greater for p-aminobenzoic acid and 16-fold greater for p-aminosalicylic acid. The apparent Km values for the slow acetylator enzyme were lower than 5 microM, whereas the apparent Km values for the rapid acetylator phenotype were at least 15 times higher, with a value of 105 +/- 21 microM for p-aminobenzoic acid and 74 +/- 16 microM for p-aminosalicylic acid. In contrast, for the polymorphic substrates, sulfamethazine and procainamide, rapid rabbit liver N-acetyltransferase was only a Vmax variant with a mean specific activity that was 13-fold higher than that for slow acetylator.     

Ecotoxicological assessment of industrial effluent using duckweed (Lemna minor L.) as a test organism

This study aimed at assessing the toxic effects of industrial effluents using duckweed (Lemna minor L.) plants as a test system. Growth inhibition test according to standardized protocol (ISO 20079) was performed. The suitability of the Comet assay (indicates DNA damage) and certain parameters such as peroxidase activity and lipid peroxidation level, as biomarkers for environmental monitoring was evaluated. The water samples were collected monthly over a 3-month period from the stream near the industrial estate of Savski Marof, Croatia. All samples caused inhibition of growth rates based on frond number and biomass as well as decrease of chlorophylls content. In contrast, peroxidase activity, malondialdehyde content and tail extent moment (measure of DNA strand breaks) markedly increased. Obtained data demonstrate the relevance of duckweed as sensitive indicators of water quality as well as the significance of selected biological parameters in the reliable assessment of phyto- and genotoxic potential of complex wastewaters.     

3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides as ATP-sensitive potassium channel openers: effect of 6,7-disubstitution on potency and tissue selectivity

A series of 6,7-disubstituted 4H-1,2,4-benzothiadiazine 1,1-dioxides bearing a short alkylamino side chain in the 3-position were synthesized. These compounds were tested on rat pancreatic islets and on rat aorta rings. In vitro data indicated that in most cases substitution in the 6 and the 7 positions increased their activity as inhibitors of insulin secretion, while the myorelaxant potency of the drugs was maintained or enhanced according to the nature of the substituent in the 7-position. The presence of either chlorine or bromine atoms in the 6 and 7 positions did not improve the apparent selectivity of the drugs for the pancreatic tissue. By contrast, the introduction of one or two fluorine atoms, as well as the presence of a methoxy group in the 7-position, generated potent and selective inhibitors of insulin release. Radioisotopic and fluorimetric experiments performed with the most potent compound inhibiting insulin release (34, BPDZ 259, 6-chloro-7-fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide) confirmed that the drug activated K(ATP) channels. 34 was found to be one of the most potent and selective pancreatic potassium channel openers yet described.     

Protection from shock-induced seizures as a measure of hypnotic potency of drugs

Mice injected with drug or vehicle were administered a 13 mA shock via corneal electrodes. The number of mice in which the shock produced a tonic seizure was recorded. The dose that blocked seizures in 50% of mice (ED₅₀) was determined for each drug. The drugs evaluated consisted of 15 hypnotics, two antidepressants and two antihistamines. All hypnotics and antidepressants, and one antihistamine, caused a dose-dependent suppression of seizures. The ED₅₀'s were highly correlated with hypnotic potency in man. The advantages of this procedure, as compared to others currently used for the evaluation of hypnotic potential of novel compounds, are discussed.     

新型手性螺环季铵盐的合成及其在不对称烷基化中的应用(英文)

以L-脯氨酸为起始物设计了一类新型手性相转移催化剂,并基于对映选择性催化的结果对催化剂的结构进行优化,最终合成了8个新型手性螺环季铵盐类相转移催化剂,用于催化N-二苯亚甲基甘氨酸叔丁酯的不对称烷基化反应,高产率得到烷基化产物,ee值最高达21%。     

Determination of the protonation constants of pipecuronium bromide on the basis of optical rotation as a function of pH values]

Pipecuronium bromide molecule contains two slightly basic nitrogen atoms in its two piperazine rings. Their pK values are quite similar to each other in consequence of their almost equivalent surroundings. Although the potentiometric titration used mostly for determination of pK values of organic compounds can be performed in this case too, but the polarimetric titration applied by us is more advantageous. Change of pH considerably influences the values of optical rotation; consequently, the curve obtained in this way is more utilizable than that of potentiometric titration. Protonation of two nitrogen atoms one after the other changes the optical rotation of the molecule in opposite direction. Consequently, a minimum can be seen on the curve of optical rotation versus pH value. The exact pK values were determined on the basis of the estimated parameters of a curve established corresponding to an equation and fitted to the measuring points. The sequence of deprotonation of nitrogen atoms could only be ascertained on the basis of the curves of polarimetric titration of compounds containing one piperazine ring; on the basis of the pK values and of the changing direction of optical rotation.     

Cellular accumulation and distribution of uranium and lead in osteoblastic cells as a function of their speciation

Uranium (U) and lead (Pb) are accumulated and fixed for long periods in bone, impairing remodeling processes. Their toxicity to osteoblasts, the cells responsible for bone formation, is poorly documented. It has been previously shown that cytotoxicity and phenotypic effects of both metals on osteoblasts are highly influenced by metal speciation. Differences in sensitivity between cell types have been underlined as well. In this paper, cellular accumulation of U and Pb in cultured and primary osteoblastic cells was assessed by trace element analysis. Distribution of different species at the cell scale was investigated by electron microscopy. Internalization of both metals was shown to be correlated to cytotoxicity and population growth recovery after exposure. For each metal, the amount of metal uptake leading to 50% cell death was shown to be speciation-dependent. Scanning and transmission electron microscopy showed the formation of precipitates with phosphate in lysosomes for both metals, whose role in toxicity or cell defence remains to be clarified. Although a clear link was established between cytotoxicity and accumulation, differences in sensitivity observed in terms of speciation could not be fully explained and other studies seem necessary.     

Comparative study of the uterotrophic potency of 14 chemicals in a uterotrophic assay and their receptor-binding affinity

We performed an immature rat uterotrophic assay of 14 chemicals having various receptor-binding affinities in order to assess the relationship between their uterotrophic potency and receptor-binding affinity. The chemicals tested were phthalic acid di-n-hexyl ester, phthalic acid di-n-amyl ester, phthalic acid di-n-propyl ester, 2-ethylhexyl-p-hydroxybenzoate, 4,4'-biphenol, 4,4'-sulfonyldiphenol, 4,4'-dihydroxydiphenylmethane, 2,4-dihydroxybenzophenone, 4,4'-cyclohexylidenebisphenol, 4-t-butylpyrocatechol, clomiphene citrate, 4,4'-(1,3-phenylenediisopropylidene)bisphenol, p-t-butylphenol, and diallylterephthlate. Two of the 14 chemicals, phthalic acid di-n-propyl ester and diallylterephthlate, exhibited no receptor-binding affinity, and the receptor-binding affinity of phthalic acid di-n-hexyl ester and phthalic acid di-n-amyl ester was lower than that of the other chemicals. Ten of the chemicals showed uterotrophic potency, the exceptions being phthalic acid di-n-propyl ester, diallylterephthlate, phthalic acid di-n-hexyl ester, and phthalic acid di-n-amyl ester. The results of the present study demonstrate that the affinity of the chemicals in the receptor-binding assay correlated well with their potency in the uterotrophic assay except for a few chemicals with very low receptor-binding affinity.     

3,3'-bi-1,3-thiazolidine]-4,4'-dione system. III. Evaluation of the antimicrobial and antitumor properties of 2,2'-disubstituted derivatives and their 1,1'-disulfones

A series of dl and meso 2,2'-disubstituted-[3,3'-bis-1,3-thiazolidine]-4,4'-diones and their 1,1'-disulfone derivatives have been tested for their antimicrobial activity against gram-positive, gram-negative and Candida strains and for antitumor activity against leukemic P.388 tumor system in mice. None of the tested bi-thiazolidinones showed any significant antitumor properties; only few 1,1'-disulfones exhibited some antibacterial activity.