Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis.

Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

Chemical composition and antidiabetic activity of Opuntia Milpa Alta extracts.

Three new compounds, 1-3, and 20 known compounds were isolated from the AcOEt and BuOH extract of edible Opuntia Milpa Alta. The petroleum ether extract was examined by GC and MS. A total of 26 compounds were identified, representing 95.6% of the total extract, phytosterol (36.03%) being the most abundant component, and polyunsaturated fatty acids (18.57%) represented the second largest group, followed by phytol (12.28%), palmitic acid, palmitate (13.54%), vitamin E (4.51%), and other compounds (7.47%). The effects of various extracts from edible Opuntia Milpa Alta (petroleum ether extract, AcOEt extract, BuOH extract, aqueous extract, H2O parts) and the positive control (received dimethylbiguanide) were tested on streptozotocin (STZ)-induced diabetic mice. The results indicated that all the treatment groups could significantly decrease blood glucose levels in STZ-induced diabetic mice compared to the model control group (P<0.01), except the aqueous extract group (P<0.05). Especially, the petroleum ether extract group and the positive control group showed remarkable decrease of blood glucose levels. Taken together, the results indicate that the petroleum ether extract is the major hypoglycemic part in edible Opuntia Milpa Alta, which may be developed to a potential natural hypoglycemic functional ingredient.

Anomaly and correlation of killing in the therapeutic properties of silver (I) chelation with glutamic and tartaric acids.

OBJECTIVES: To investigate whether silver chelates or silver ions are more effective as therapeutic agents, and to examine their mode of action so that safer and stable compounds that have a broad spectrum of therapeutic activities can be developed. METHODS: Efficacy was investigated against Pseudomonas aeruginosa (ATCC 15442) by determining MIC via a broth macrodilution procedure using NCCLS methods for antibiotic susceptibility testing. RESULTS: It was found that the responsible agent for silver therapeutic properties is the silver chelates rather than silver ions, contradicting previous findings, and the efficacy profiles mimic that of free silver ions present in solution. CONCLUSIONS: Silver therapeutic activities seem to be more effective as complexes-an intracellular package-rather than free silver ions, demonstrating that the effect of silver is linked to cells' DNA unwinding, and not respiratory or membrane functionality as was traditionally recognized.

Effect of an oral bulking agent and a rectal laxative administered alone or in combination for the treatment of constipation.

OBJECTIVES: The aim of the present study was to search for a synergetic action between psyllium and a defecation-inducing drug, Eductyl, for symptom relief in patients suffering from chronic constipation. METHODS: Twenty healthy volunteers and 20 patients complaining of chronic constipation were included in a randomized crossover study. The study was divided into four 2-weeks periods: pre-inclusion and three periods of treatment with psyllium, Eductyl, and Eductyl + psyllium respectively. Colonic transit time was determined at the end of each period of treatment. During each of the four periods, a self-administered questionnaire was used to assess symptoms of constipation. RESULTS: For constipated patients, treatment with Eductyl and Eductyl-psyllium improved clinical symptoms of constipation: increased stool frequency, resulted in fewer hard stools and less sensation of incomplete evacuation and less straining to defecate. The improvement was associated with a decrease in total and segmental colonic transit time. The Eductyl-psyllium combination did not exhibit any synergetic effect. CONCLUSION: Treatment with Eductyl alone is more efficient than with psyllium alone in providing symptom relief. Combination with psyllium is not synergetic.

The oral anti-volatile sulphur compound effects of zinc salts and their stability constants.

Volatile sulphur compounds (VSC) produced in the oral cavity, are a major cause of oral malodour. Zinc (Zn) ions inhibit VSC formation. The objective of this study was to examine whether Zn salts with low stability constants were more suitable as sources of Zn in lozenges than salts with high stability constants. The former provide free Zn ions upon dissolution in water, whereas the latter provide almost no free Zn. Identical lozenges containing Zn-acetate and -gluconate, which have low stability constants, and Zn citrate and amino acid-chelated Zn, which have extremely high stability constants, were tested. All the lozenges contained 0.9% w/w Zn. Ten volunteers sucked the lozenges until dissolved, and oral VSC were measured by gas chromatography. Zn-acetate, -gluconate and -chelate had an impressive anti-VSC effect even 3 h after the lozenges were taken. Zn citrate had significantly less effect than the other lozenges except Zn acetate after 2 and 3 h. It was concluded that the anti-VSC effect was not related to the stability constants of the Zn compounds tested. Alternative ligands. with stronger affinity for Zn than the ligands in the lozenges, must be present in the oral cavity to explain these results. It is suggested that the sulphide ion may serve this function.

Lack of effectiveness of several chelators in removing internally deposited strontium from mice following repeated parenteral strontium administration.

Diethylenetriaminepentaacetic acid (DTPA), ethylenglycolbis-(beta-amino-ethylether)-N,N-tetraacetic acid (EGTA), tartaric acid, KRYPTOFIX 222, and KRYPTOFIX 5 were evaluated for their efficacy in mobilization of strontium from the body of mice which had received 20 sc injections of strontium nitrate (95 mg/kg/injection) for 4 w. Twenty-four hours after the last strontium injection, ip administration of 1 of the various chelators or 0.9% saline was initiated and continued daily for 5 d. Mice were housed in metabolic cages, and urine and feces were collected daily for 5 d. After this period, the animals were killed and tissues removed. Tartaric acid, KRYPTOFIX 222, and KRYPTOFIX 5 had no effect on urinary or fecal strontium elimination, whereas DTPA and EGTA significantly decreased the fecal strontium excretion. The concentration of strontium in bone was only lowered in tartaric-treated mice. This study indicates the use of the above chelators is not an effective treatment to enhance the removal of strontium following repeated parenteral strontium administration.

Penicillamine as an adjuvant to antimonial therapy of schistosomiasis: effect on liver function tests in rabbits and on antischistosomal activity.

Earlier work has shown that penicillamine reduces the acute toxicity of antimonyl potassium tartrate (APT) as well as the abnormal ECG changes it induces. In the present study, the possible protective effect of penicillamine on the hepatic toxicity of APT was investigated. Tests of liver function showed changes in the level of serum aspartate and alanine aminotransferase and of alkaline phosphatase, and in the beta-/alpha-lipoprotein ratio, in response to antimony treatment. The changes were significantly reduced by penicillamine, though the effect depended on the dose. Penicillamine was found to give the best overall protection without affecting the antischistosomal efficacy of the antimonial when a 1:2 APT/penicillamine ratio was used. The findings provide further evidence of the potential usefulness of penicillamine in the antimonial treatment of schistosomiasis.

The action of certain antibiotics and ether on swine enzootic pneumonia.

The susceptibility of Mycoplasma hyopneumoniae to the action of three antibiotics and diethyl ether was determined. Infected swine were used in an in vivo sensitivity detection system. The parameter of susceptibility was lesion prophylaxis. In vivo, Mycoplasma hyopneumoniae appeared to be resistant to diethyl ether, tylosin tartrate, and erythromycin, but was susceptible to the action of chlortetracycline. Chlortetracycline was effective in preventing the development of lesions when given at levels which would be practical in commercial swine operations.

The use of penicillamine as an adjuvant to tartar emetic in the treatment of experimental schistosomiasis.

One of the principal drawbacks of antimonial therapy in schistosomiasis has been the prevalence of annoying, and sometimes dangerous, side-effects. The adjuvant administration of chelating agents offers a possible solution to this problem, providing this can be achieved without appreciably decreasing the therapeutic effect of the drug.The authors found that the chelating agent penicillamine lowered the toxicity of tartar emetic for mice and hamsters without affecting the tissue uptake of antimony. When administered in a similar manner to hamsters infected with Schistosoma mansoni there was no effect on the uptake of antimony by the parasites, or on the cure rate. This suggests a potential usefulness of penicillamine in antimony therapy.