Studies on the adsorption and solubility of nalidixic acid

The adsorption of nalidixic acid on certain pharmaceutical additives was investigated and its extent estimated. Also, the effects of various surface-active agents and hydrophilic polymers on the solubility of the drug was determined. The adsorption isotherms have revealed that the degree of adsorption increased in the order; microcrystalline cellulose < ethyl cellulose < silicon dioxide < aluminium magnesium silicate. Studies on the solubility of nalidixic acid at 37°C using different concentrations of hydrophilic polymers have demonstrated that methyl cellulose, polvinylpyrrolidone and polyethylene glycol 6000 have comparable effects. Polyvinyl alcohol caused only a marginal increase in solubility. The surface-active agents, sodium lauryl sulphate and polysorbate 80, also increased solubility of the drug. The values of the heat of solution and the free energy changes were calculated from the Van't Hoff plots. The values of heat of solution for all systems were comparable, but the free energy changes indicate that sodium lauryl sulphate causes the most marked effect on solubility.     

In situ cross-linking of sodium alginate with calcium and aluminum ions to sustain the release of theophylline from polymeric matrices

Small matrices of calcium alginate or aluminium alginate have been investigated as possible controlled release systems for drugs. The objective of the present study was to sustain the release of theophylline from alginate matrices using different concentrations of aluminium chloride and calcium chloride in presence and absence of HPMC. Tablets containing differing concentrations of aluminium and calcium chloride were produced and the release rate of theophylline was tested using the basket dissolution apparatus over 8 h. Increasing amounts of aluminium chloride from 0.0001 to 0.00068 moles decreased the release of theophylline from 95.1 +/- 0.27 to 29.5 +/- 1.5, indicating a significant effect of aluminium ions on a reduction in the release rate of theophylline from sodium alginate matrices. In the case of matrices containing different concentrations of calcium ions, as the concentration of calcium chloride increased, the release rate increased to an optimum then declined after this. This was due to insufficient calcium ions being available to cross-link with the sodium alginate to form an insoluble gel. The effect of aluminium ions, as this is a trivalent ion compared to calcium, which is a divalent ion, aluminium ions are able to decrease the release rate with a smaller concentration compared to calcium ions. The results also showed that the presence of HPMC caused a reduction in release rate of theophylline from alginate matrices containing calcium chloride. Whereas, in the case of alginate matrices containing aluminium chloride the release rate of theophylline increased in presence of HPMC. For comparing the dissolution data, dissolution efficiency (DE) was used. The values of DE are consistent with the dissolution data. The results show that within a formulation series, DE values generally decrease when the cation concentration increases and this criterion can be used to describe the effect of calcium and aluminium ions on the release behaviour of theophylline from polymeric matrices.     

Pharmacokinetics of nalidixic acid associated with sodium citrate

A pharmacokinetic study of sachets containing nalidixic acid (0.66 g) associated with sodium citrate (3.75 g)--NSC--was carried out in 10 healthy volunteers in order to determine the influence of the urine alcalinization due to sodium citrate on the elimination of nalidixic acid (NA) and its 7-hydroxy (HNA) and 7-carboxy (CNA) derivatives. Urine alcalinization enhanced markedly the urinary excretion of HNA, but not of NA and CNA. The urinary concentrations of bacteriologically active compounds--NA + HNA--remained above five times their minimum inhibitory concentration for 10 h following each dose. After a 3-day treatment using NSC three times daily there was no significant accumulation of NA and derivatives in the plasma and no significant change in their kinetics. Finally, from a pharmacokinetic viewpoint, the daily administration of 3 sachets of NSC each containing 0.66 g of NA seems valuable in the treatment of urinary tract infections.     

Effect of various electrolytes upon cardiac and skeletal musculature

In rats kept on a low-potassium diet that contains only maintenance levels of magnesium, cardiac necroses and muscular cramps were readily induced by the oral administration of sodium perchlorate or disodium hydrogen phosphate. The precipitation of these cardiac and skeletal muscle changes by sodium chlorate was prevented by the prophylactic administration of either potassium or magnesium chlorides. The protective effect of these chlorides against the cardiotoxic and convulsive effects of disodium hydrogen phosphate has already been demonstrated by our earlier experiments. Sodium sulphate produced cardiac necroses in rats maintained on the same diet, and both potassium and magnesium chlorides had a prophylactic action. Unlike sodium perchlorate, however, sodium sulphate produced no muscular cramps under these conditions. Equimolecular amounts of sodium given in the form of sodium chloride (instead of sodium perchlorate, sodium sulphate, or disodium hydrogen phosphate) did not cause cardiac necroses or muscular cramps in rats maintained on the potassium-deficient diet. As the same three sodium salts, namely the perchlorate, the sulphate, and the hydrogen phosphate, produced cardiac necroses in rats sensitized by either a potassium-deficient diet or by certain corticoids, it seems that the anion must play a decisive rôle, since equivalent amounts of NaCl are ineffective.     

Anti-platelet actions of salicylates: in vivo, ex vivo and in vitro effects of choline salicylate

Effects of choline salicylate, sodium salicylate, choline chloride and acetylsalicylic acid on platelet aggregation in vivo, ex vivo and in vitro in mice were studied. These drugs all inhibited adenosine diphosphate (ADP)-induced respiratory depression, which is closely related to platelet aggregation in vivo, with choline salicylate showing the strongest inhibitory effect. Choline salicylate had a tendency to reduce the mortality of animals injected intravenously with endotoxin, but the other drugs had no such effect. The inhibitory effects of these drugs on ADP-induced platelet aggregation ex vivo were in the order of choline salicylate greater than acetylsalicylic acid congruent to sodium salicylate greater than choline chloride congruent to no effect, and plasma concentrations of protein-unbound salicylic acid at 1 hr after oral administration of drugs were in the order of choline salicylate greater than acetylsalicylic acid congruent to sodium salicylate. The in vitro effects of these drugs were in the order of choline salicylate congruent to sodium salicylate greater than choline chloride congruent to acetylsalicylic acid congruent to no effect. Therefore, it was considered that salicylic acid played an important role on the in vivo, ex vivo and in vitro effects of choline salicylate and that choline increased plasma concentrations of salicylic acid and consequently enhanced the in vivo and ex vivo effects of salicylic acid. Furthermore, the ex vivo effects of choline salicylate were found when ADP-induced platelet aggregation was measured with platelet-rich plasma prepared from blood collected with heparin as anti-coagulant, but not when blood was collected with citrate.(ABSTRACT TRUNCATED AT 250 WORDS)     

盐酸曲马多与枸橼酸芬太尼在氯化钠注射液中的稳定性研究

目的考察盐酸曲马多与枸橼酸芬太尼注射液在0.9%氯化钠注射液中的配伍稳定性。方法在室温条件下,观察两药配伍后的外观及pH值变化,盐酸曲马多与枸橼酸芬太尼的含量测定采用SinoChrom ODS-BP色谱柱,以乙腈-0.05 mol/L磷酸二氢钾水溶液（25∶75）为流动相,流速为1.0 ml/min。结果配伍液中盐酸曲马多与枸橼酸芬太尼的含量均大于98%,72 h内外观与pH值均未见明显变化。结论在室温条件下,盐酸曲马多与枸橼酸芬太尼注射液在0.9%氯化钠注射液中72 h内保持稳定。     

Antineoplastic agents 460. Synthesis of combretastatin A-2 prodrugs

The original synthesis of combretastatin A-2 (1a) was modified to provide an efficient scale-up procedure for obtaining this antineoplastic stilbene. Subsequent conversion to a useful prodrug was accomplished by phosphorylation employing in situ formation of dibenzylchlorophosphite followed by cleavage of the benzyl ester protective groups with bromotrimethylsilane to afford the phosphoric acid intermediate 11. The latter was immediately treated with sodium methoxide to complete a practical route to the disodium phosphate prodrug (2a). The phosphoric acid precursor (11) of phosphate 2a was employed in a parallel series of reactions to produce a selection of metal and ammonium cation prodrug candidates. Each of the phosphate salts (2a-q) was evaluated with respect to relative solubility behavior, cancer cell growth inhibition and antimicrobial activity.     

The effect of media composition on the thermal resistance of Bacillus stearothermophilus

Spores of Bacillus stearothermophilus ATCC 7953 were developed at 62 degrees C on 32 media composed of various amounts of 11 components: D-glucose, L-glutamic acid, yeast extract, peptone, sodium chloride, magnesium sulfate, ammonium phosphate, potassium phosphate, calcium chloride, ferrous sulfate and manganese sulfate. Statistical models were used and demonstrated a strong interaction of yeast/peptone/ammonium phosphate, contributing positively to the best sporulation yield (6-7 log10 spores). The most influential medium components on the thermal resistance (at 121 degrees C) of spores in suspension (calcium acetate, pH 9.7) were yeast extract (positively) and potassium phosphate (negatively), both creating the positive interaction, for spores from a 6-day incubation period. However, the strong negative effect of sodium chloride decreased the D-value from 1.81 min to 0.57 min upon increasing the incubation period (62 degrees C) from 3 days to 6 days. The D-glucose and peptone exhibited greater effects than the yeast extract and potassium phosphate interaction on D-values for 3-day spores on strip, just as the highly joint-positive peptone/sodium chloride effect maintained the thermal resistance of 6-day spores on strips. The spores on strip system showed less stability than the spores in suspension. The most stable spore system confirmed D-values at 121 degrees C at a range between 1.5 min and 1.9 min, which were obtained by keeping sodium chloride and potassium phosphate at minimum concentrations and yeast extract and peptone at maximum concentrations, regardless of the 3- to 6-day sporulation.     

In vitro antimicrobial activity of econazole and miconazole sulfosalicylate

The in vitro activities of new sulfosalicylic salts of econazole (E.SSA) and miconazole (M.SSA) have been investigated in comparison with the respective nitrate (NIT) salts and sulfosalicylic acid (SSA) alone. The results reveal good antimicrobial activity of M.SSA and E.SSA against different strains of Candida, dermatophytes, moulds, Gram-positive bacteria and Trichomonas vaginalis. The MIC values demonstrate that M.SSA is more active than M.NIT on Candida and T. vaginalis. E.SSA was also more active than E.NIT on T.vaginalis. Both SSA and sodium sulfosalicylate (NaSSA) were practically without activity by themselves. Finally, the pH variations did not significantly modify the activity of the SSA salts, suggesting that their greater activity could be due to better lipophilic activity of these compounds with respect to the nitrate salts.     

Compatibility of calcium chloride and calcium gluconate with sodium phosphate in a mixed TPN solution

The maximum concentrations of phosphate that will remain soluble in a parenteral nutrient solution containing various concentrations of calcium chloride or calcium gluconate were determined. Various concentrations of sodium phosphate were mixed with FreAmine II (McGaw Laboratories), and the resulting solutions were mixed with 50% dextrose solutions containing various concentrations of calcium chloride or calcium gluconate. The final solutions were sealed and stored at 30 degrees C for 24 hours and then were inspected visually for precipitate formation. It was found that higher equivalent concentrations of phosphate are attainable when calcium gluconate, instead of calcium chloride, is used as the calcium source. Factors found to influence the concentrations of calcium and phosphate that are compatible in amino acid solutions are the calcium salt used, temperature and duration of storage, dextrose concentration, amino acid composition, pH, and other additives.     

Chemical reactivity of aluminium-based pharmaceutical compounds used as phosphate-binders

Several aluminium-containing substances, including antacids used as phosphate-binders in treating renal failure, have been analysed in-vitro under different pH conditions for the release of Al3+ ions and for binding of phosphate. Control experiments on different forms of pure aluminium hydroxide validated the methods. At pH 2 it was the most amorphous forms which released Al3+ most rapidly. These aluminium ions, available for absorption by the patient, were released from all antacids tested, but no firm phosphate-binding was detected while the pH remained at 2. Phosphate was bound at pH 8, by adsorption onto the surface of aluminium hydroxide. No significant amounts of free Al3+ exist in solution at pH 8, since at that pH aluminium hydroxide is precipitated. The most amorphous forms of this solid were the most efficient phosphate-binders. Alumino-silicate salts require prior exposure to acid to produce free Al3+ before they can act as phosphate-binders, whereas amorphous aluminium hydroxide acts as an efficient phosphate-binder without prior exposure to acid. Chemical principles are employed to show why aluminium release and phosphate-binding are separate and independent processes. Methods are proposed for maximizing the activity of phosphate- binders in-vivo, while minimising aluminium release.     

CHLORIDE ION INGESTED WITH SODIUM AFFECTS THE DEVELOPMENT OF CEREBRAL LESIONS IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. To determine the effect of chloride ion on the development of hypertension and the incidence of cerebral lesions in stroke-prone spontaneously hypertensive rats (SHRSP), groups of 10 rats were administered chronically with either 171 mmol/L sodium chloride or equimolar sodium provided as sodium citrate in the drinking water from the age of 12 weeks. 2. The life span was significantly extended in SHRSP given sodium citrate (336 +/- 28 vs 246 +/- 26 days, mean +/- s.e.m., P less than 0.05) but their development of hypertension was not different from SHRSP given sodium chloride. 3. In order to determine the role of calcium homeostasis, calcium in urine was collected. Urinary calcium in SHRSP given sodium citrate was significantly decreased (1.0 +/- 0.12 vs 1.8 +/- 0.18 mg/24 h urine, P less than 0.05). 4. If the normal life span is 320 +/- 35 days, this suggests that chloride ion ingested with sodium accelerates the development of cerebrovascular diseases, and that increased urinary calcium excretion may be related to this adverse chloride effect on the development of hypertension in SHRSP.     

Effect of chloride ion on dissolution of different salt forms of haloperidol, a model basic drug

The effect of chloride ion (Cl-) on dissolution rates of hydrochloride, mesylate (methanesulfonate) and phosphate salt forms of a model drug, haloperidol, was investigated. The dissolution rates of the salts in 0.01 M HCl from rotating disks followed the order of mesylate>phosphate>hydrochloride. With additional chloride ion, a decrease in dissolution rate of the hydrochloride salt was observed due to the common ion effect. Dissolution rates of mesylate and phosphate salts also decreased due to their conversion to the HCl salt form on the surfaces of dissolving disks, however, the dissolution rates of mesylate and phosphate salts under identical chloride ion concentrations were still higher than that of the HCl salt. In powder dissolution studies, it was observed that kinetics of nonhydrochloride-to-hydrochloride salt conversion play a major role in dissolution; the mesylate dissolved completely (<5 min) before its dissolution rate could be impeded by its conversion to the hydrochloride salt form. Therefore, despite the potential for conversion to a hydrochloride salt form, certain nonhydrochloride salt forms may still be preferred for dosage form development due to kinetic advantages during dissolution, such as higher apparent dissolution rate of a nonhydrochloride salt before it could completely convert to the hydrochloride form.     

The effect of sucrose and salts in combination on the drug release behaviour of an HPMC matrix

Previous work has shown how high concentrations of sugars can accelerate drug release from hydroxypropyl methylcellulose (HPMC) matrices by suppressing polymer hydration. This study investigates the effects of combining sugar and salts, using sucrose, sodium chloride and trisodium citrate, soluble ingredients commonly found in foods. A factorial study showed that each solute suppressed HPMC solution sol–gel transition temperature (a sensitive measure of molecular hydration) independently, and their effects reflected their rank order in the Hofmeister series. In mixtures, the effects were purely additive, with no evidence of antagonism or synergy. In dissolution tests, both salts significantly reduced the threshold sugar concentration required to elicit an acceleration of drug release, and when used in combination, 0.15 M sodium chloride with 0.015 M trisodium citrate reduced the threshold sucrose concentration from 0.7 M to 0.35–0.4 M, a reduction of almost 50%. The results show that food salts can significantly reduce the concentration required for sugar effects on HPMC matrices, and this may be a factor to consider when interpreting their in vivo behaviour in the fed state.     

The effect of sucrose and salts in combination on the drug release behaviour of an HPMC matrix

Previous work has shown how high concentrations of sugars can accelerate drug release from hydroxypropyl methylcellulose (HPMC) matrices by suppressing polymer hydration. This study investigates the effects of combining sugar and salts, using sucrose, sodium chloride and trisodium citrate, soluble ingredients commonly found in foods. A factorial study showed that each solute suppressed HPMC solution sol–gel transition temperature (a sensitive measure of molecular hydration) independently, and their effects reflected their rank order in the Hofmeister series. In mixtures, the effects were purely additive, with no evidence of antagonism or synergy. In dissolution tests, both salts significantly reduced the threshold sugar concentration required to elicit an acceleration of drug release, and when used in combination, 0.15 M sodium chloride with 0.015 M trisodium citrate reduced the threshold sucrose concentration from 0.7 M to 0.35–0.4 M, a reduction of almost 50%. The results show that food salts can significantly reduce the concentration required for sugar effects on HPMC matrices, and this may be a factor to consider when interpreting their in vivo behaviour in the fed state.     

Norfloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use

Norfloxacin is one of the new 4-quinolone antibacterial agents. A fluorinated piperazinyl-substituted congener of nalidixic acid, it demonstrates a much wider in vitro antibacterial spectrum and greater potency than the parent compound. Its antibacterial activity against most Gram-negative pathogens is enhanced in comparison to nalidixic acid, but is similar to that of some of the other new 4-quinolones like enoxacin, and slightly less than that of ciprofloxacin. Unlike nalidixic acid, norfloxacin is also active against Pseudomonas aeruginosa and some Gram-positive organisms. In acute or uncomplicated urinary tract infections, norfloxacin has repeatedly been shown to be as effective as co-trimoxazole. Single studies have demonstrated a significantly better bacteriological cure rate with norfloxacin than with pipemidic acid, and similar cure rates with norfloxacin and both a nalidixic acid/sodium citrate mixture and amoxycillin. Similar results were found in a few studies comparing norfloxacin to pipemidic acid or amoxycillin in patients with chronic and/or complicated urinary tract infections. Norfloxacin is as effective as spectinomycin in gonorrhoea due to penicillin-resistant N. gonorrhoeae, and cures bacterial gastroenteritis caused by several gastrointestinal pathogens. Norfloxacin appears to be well tolerated and may have a low propensity to select for bacterial resistance during clinical use, although the latter needs further confirmation.     

Aluminium concentrations in the brain and bone of rate fed citric acid,aluminium citrate or aluminium hydroxide

Male Sprague-Dawley rats were treated daily by gastric intubation (6 days/wk) with 100 mg alumunium/kg body weight in the form of aluminium hydroxide (9 wk) or aluminium citrate (4 wk), with citric acid (4 wk) or with tap-water (control, 9 wk). Young adult and aged Wistar rats were treated with 100 mg aluminium/kg body weight as aluminium hydroxide or with carboxymethylcallulose (vehicle controls). The cerebral cortex, hippocampusm, cerebellum and samples of bone from each rat were analysed for aluminium, after digestion with nitric acid, using graphite furnace atomic absorption spectroscopy. The mean aluminium concentrations detected in the control Sprague-Dawley rats were 0.013–0.022 μg/g wet weight in the various brain regions and 0.355 μg/g in the bone. No significant increase in tissue aluminium concentrations was observed in Sprague-Dawler or Wistar after treatment with aluminium hydroxide. However the rats treated with aluminium citrate showed significantly increased concentrations of aluminium in all the brain regions studied (0.057–0.121 μg Al/g) and in the bone (12.9 μg Al/h). Elevated aluminium concetrations in the cerebral cortex and bone were also observed in the animals fed citric acid suggesting possible absorption of the citrate chelate presumably formed with the traces of aluminium present in the diet.     

不同浓度柠檬酸钠对肺炎克雷伯菌生物被膜形成的抑制作用

目的 探讨不同浓度柠檬酸钠对肺炎克雷伯菌生物被膜(biofilm, BF)形成的抑制作用。方法 体外构建肺炎克雷伯菌BF模型;分别添加15%和7.5%的柠檬酸钠溶液,运用结晶紫法连续4d检测肺炎克雷伯菌BF的吸光度;采用扫描电镜观察其对BF的抑制情况。结果 肺炎克雷伯菌BF体外培养后其570nm吸光度值由0.2逐天升高,至第4天达到高峰0.6以上;而在添加柠檬酸后肺炎克雷伯菌BF的吸光度显著下降。其中15%的柠檬酸钠对肺炎克雷伯菌BF的抑制效果优于7.5%的柠檬酸钠溶液。结论 7.5%和15%的柠檬酸钠溶液均可抑制肺炎克雷伯菌BF的形成,且随柠檬酸钠浓度增高,抑制效果增强。     

不同浓度柠檬酸钠对肺炎克雷伯菌生物被膜形成的抑制作用

目的 探讨不同浓度柠檬酸钠对肺炎克雷伯菌生物被膜(biofilm, BF)形成的抑制作用。方法 体外构建肺炎克雷伯菌BF模型；分别添加15%和7.5%的柠檬酸钠溶液，运用结晶紫法连续4d检测肺炎克雷伯菌BF的吸光度；采用扫描电镜观察其对BF的抑制情况。结果 肺炎克雷伯菌BF体外培养后其570nm吸光度值由0.2逐天升高，至第4天达到高峰0.6以上；而在添加柠檬酸后肺炎克雷伯菌BF的吸光度显著下降。其中15%的柠檬酸钠对肺炎克雷伯菌BF的抑制效果优于7.5%的柠檬酸钠溶液。结论     

The effect of piperidinoethylesters of n-alkoxyphenyl-carbamic acids on bacterial cells

The inhibitory effect of local anaesthetic agents of this type on the bacteria Escherichia coli were evaluated. The dependence between antimicrobial activity and structure (log 1/MIC = f/m) was studied with the use of a bilinear model. In the positional paraisomers a lower effect of spherical and electron effects than in the case of ortho- and meta-isomers is assumed. The efficacy of these agents depends on their lipophilicity. Membrane activity of these agents was confirmed. In subinhibitory concentrations they cause leakage of cytoplasmic material lysis of spheroplasts, they increase the permeability of the membrane for protons and inhibit dehydrogenase activity of cells. The mode of action of heptacainium chloride and its positional isomers on cells is identical and is similar as in organic ammonium salts and amine oxides.