Candicidin biosynthesis in Streptomyces griseus.

The biosynthesis of the aromatic polyene macrolide antibiotic candicidin, produced by Streptomyces griseus IMRU 3570, begins with a p-aminobenzoic acid (PABA) molecule which is activated to PABA-CoA and used as starter for the head-to-tail condensation of four propionate and 14 acetate units to produce a polyketide molecule to which the deoxysugar mycosamine is attached. Using the gene coding for the PABA synthase ( pabAB) from S. griseusIMRU 3570 as the probe, a 205-kb region of continuous DNA from the S. griseus chromosome was isolated and partially sequenced. Some of the genes possibly involved in the biosynthesis of candicidin were identified including part of the modular polyketide synthase (PKS), genes for thioesterase, deoxysugar biosynthesis, modification, transport, and regulatory proteins. The regulatory mechanisms involved in the production of candicidin, such as phosphate regulation, were studied using internal probes for some of the genes involved in the biosynthesis of the three moieties of candicidin (PKS, aromatic moiety and amino sugar). mRNAs specific for these genes were detected only in the production medium (SPG) but not in the SPG medium supplemented with phosphate or in the inoculum medium, indicating that phosphate represses the expression of genes involved in candicidin biosynthesis. The modular architecture of the candicidin PKS and the availability of the PKSs involved in the biosynthesis of three polyene antibiotics (pimaricin, nystatin, and amphotericin B) shall make possible the creation of new, less toxic and more active polyene antibiotics through combinatorial biosynthesis and targeted mutagenesis.

[Beneficial effect of ARB for ischemic stroke].

Angiotensin II plays a pathophysiological role for the development of cardiovascular disease. Angiotensin receptor blocker(ARB) is an antihypertensive drug that blocks the angiotensin II receptor. Recently, according to the reports of basic research, ARB has various cerebrovascular-protective-effects such as improvement of cerebrovascular auto-regulation, stroke prevention, reduction of brain edema, improvement of neurological outcome in cerebral ischemia and so on. There is no report of ARB being used for the acute stage of stroke. In an ongoing ACCESS(Acute Candesartan Cilexetil Evaluation in Stroke Survivors) trial, the ARB candesartan is being used to treat the acute stage of stroke. This trial is expected to clarify whether early treatment with candesartan during the acute stage of stroke is beneficial for the neurological outcome or prognosis.

[Radioprotective and antineoplastic activity of polyene antibiotics combined with dimethyl sulfoxide]. / Radioprotektornaia i protivoopukholevaia aktivnost' polienovykh antibiotikov v sochetanii s dimetilsul'foksidom.

Radioprotective and antineoplastic activity of polyene, its derivatives and combinations with dimethyl sulfoxide (DMSO) was studied. The most potent radioprotective effect was demonstrated by methylated levorin, original levorin and by its isomer--isolevorin. Survival rate of the animals on 12th day after X-ray exposure was 100, 60, 60 per cent, at the control group 33.6, 20 and 0 per cent consequently. Levorin and alkyl derivatives of amphotericin B--methamphocin and buthamphocin inhibited growth of ascites and solid tumors to 46.3-79.0 per cent when compared to control group. Polyen antibiotics combined with DMSO also demonstrated antineoplastic activity at the animals treated with carcinogenic agent--diethyl nitrosoamine (DENA). 5-month survival of the animals was 76 per cent at nystatin and levorin group and 35.7 per cent at the control group (animals treated with DENA only).

[Role of fungi belonging to the genus Candida in the etiology of nonspecific pulmonary diseases]. / Rol' gribov roda Candida v étiologii nespetsificheskikh zabolevanii legkikh.

The sputum specimens from 1363 patients at the age of 16 to 65 years with nonspecific pulmonary diseases and the pleural exudate specimens from 325 patients were tested for fungi in 1989-1994. The etiological significance of Candida was stated at a concentration of > 10(5) GFU per 1 ml of the sputum. The identification was performed by the routine methods. An increase in the rate of the fungi isolation was studied in the time course of the observation: 15.3 +/- 1.9 per cent in 1989 and 31.6 +/- 3.4 per cent in 1994. The fungi were more frequently isolated from the patients with lung abscesses (38.0 +/- 4.1 per cent of the cases). In the patients with pyothorax the fungi were isolated from the pleural exudate specimens only in 6.8 +/- 1.4 per cent of the cases. The groups of risk of the susceptibility to Candida were revealed. They included patients at the age of 21 to 30 years and above 60. Out of 484 Candida isolates 80.7 per cent belonged to C. albicans, 4.2 per cent to C. tropicalis, 2.1 per cent to C. kefyr and 1.8 per cent to C. krusei. The isolates of C. parapsilosis, C. guillermoudii, C. utilis and C. brumptii were rate. The isolates were highly susceptible to nystatin (91,8 per cent) and lowly susceptible to levorin (35.4 per cent), amphoglucamine (24.7 per cent) and ketokonazol (16.8 per cent).

[Intensive combined therapy of patients with urogenital tuberculosis]. / Opyt intensifikatsii kombinirovannogo lecheniia bolnykh mochepolovym tuberkulezom.

More rapid attenuation of urogenital inflammation achieved in 41.65% of nephrophthiasis patients treated with combination levorin + furadonin + nitroxoline compared to control illustrates the validity of introducing tuberculostatic--potentiating drugs in chemotherapy of urogenital tuberculosis.

[Synthesis and biological activity of aminophenylphosphonic derivatives of levorin]. / Poluchenie i biologicheskaia aktivnost' aminofenilfosfonistykh proizvodnykh levorina.

Reactions of levorin, a polyenic macrolide antibiotic, with aromatic aldehydes and hypophosphorous acid resulted in formation of its amino phenylphosphonium derivatives. Physicochemical and biological properties of the derivatives were studied. The levorin amino phenylphosphonium derivatives were shown to be low toxic and have antifungal and antiviral activities.

Candicidin in treatment of benign prostatic hypertrophy.

In a prospective, double-blind, placebo-controlled multicenter study, candicidin (a polyene macrolide) was investigated in the treatment of benign prostatic hypertrophy. Seventy-six patients were included in the study--34 in the candicidin group and 42 in the placebo group. Patients treated with 270 mg. of candicidin daily for 6 months had a significant decrease in residual urine, voided volume and bladder volume. No significant increases were found in flow rates. Symptoms improved significantly in both the candicidin and the placebo group, but no differences in improvement were found between the groups. The results of candicidin treatment are less satisfactory than those following surgery.

[Sensitivity of Candida strains to polyenic antibiotics in the treatment of oral candidiasis]. / Izuchenie chuvstvitel'nosti gribov roda Candida k polienovym antibiotikam v protsesse lecheniia kandidoza slizistoi polosti rta.

Sensitivity of 146 clinical strains of Candida albicans to nystatin, levorin and amphoglucamine was studied on solid media with the replica method. The strains were isolated from 79 patients with candidiasis of the oral mucosa. It was found that sensitivity of the fungi to the polyenic antibiotics was different which should be considered in treatment of candidiasis. On the basis of the mean MICs for the clinical strains and their distribution by the MICs it was shown that the activity level of levorin and amphoglucamine was higher than that of nystatin. During the treatment resistance of the Candida strains to the polyenic antibiotics increased and cross resistance developed which required application of other treatment means.

[Effect of levorin on the intracellular pool of free amino acids in Ehrlich ascites carcinoma cells]. / Vliianie levorina na vnutrikletochnyi fond svobodnykh aminokislot v kletkakh astsitnoi kartsinomy Erlikha.

Levorene, a polyenic antibiotic, lowered the concentration of amino acids in the cells of Ehrlich carcinoma. The decrease in the intracellular level of the amino acids was due not only to inhibition of their entrance to the cells but also to their increased leaching from the cells. The effect of levorene on the intracellular level of the neutral amino acids was higher than that on the main amino acids which was associated with different sensitivity of the amino acid transport systems to the antibiotic.

Candicidin treatment of prostatism: a prospective double-blind placebo-controlled study.

The polyene macrolide candicidin was investigated in the treatment of benign prostatic hyperplasia (BPH). Forty-one unselected patients with BPH and prostatism were admitted to a prospective, double-blind placebo-controlled clinical trial. Patients treated with 270 mg candicidin daily for 6 months had a significant decrease in residual urine and a significant increase in maximum flow rate after correction for differences in corresponding bladder volume. Symptoms improved significantly in both the candicidin and the placebo group but no differences in improvement were found between the two groups. The mechanism of the drug's effect is unknown and positive results are much less pronounced than those obtained with surgery. Candicidin appears valuable in the treatment of BPH patients who are a poor surgical risk.

[Effect of polyene antibiotics on the development of alcoholic-dietary fatty degeneration of the liver in rats]. / Vliianie polienovykh antibiotikov na razvitie alkogol'no-alimentarnoi zhirovoi distrofii pecheni u krys.

The effect of the sodium salts of levorin, isolevorin, nystatin and amphotericin B prepared with the use of sodium desoxycholate and amphoglucamine on the development of fatty degeneration of the liver was studied in rats. Fatty degeneration of the liver was induced in the animals by the diet deficient in choline and administration of alcohol (10 g/kg). Most of the studied antibiotics inhibited the development of the liver fatty degeneration. The only exclusion was amphotericin B prepared with the use of sodium desoxycholate which did not influence the level of the liver fatty degeneration. Sodium levorin (10 mg/kg) produced the most pronounced normalizing effect on the lipid metabolism in the liver. Complication of mycoses with fatty degeneration of the liver should not be considered as a contraindication to their treatment with polyenic antibiotics.

[Changes in the state of plasma membrane proteins of tumor cells exposed to a polyene antibiotic and cyclophosphamide]. / Izmenenie sostoianiia belkov plazmaticheskikh membran opukholevykh kletok pod vozdeistviem polienovogo antibiotika i tsiklofosfana.

The fractional composition of the proteins of the plasmatic membranes of the Ehrlich's tumor cells treated with various drugs was studied with the use of electrophoresis in polyacrylamide gel. It was shown that the character of the changes in the fractional composition of the plasmatic membrane proteins under the effect of levorin and cyclophosphamide was different. When the drugs were used in combination, summation of the changes induced by every drug alone was observed. Possible causes of the changes in the fractional composition of the membrane proteins are discussed.

[Characteristics of a strain of C. albicans resistant to polyene antibiotics]. / Kharakteristika shtamma C. albicans, ustoichivogo k polienovym antibiotikam.

It was found that a resistant strain R2 of C. albicans obtained as a result of passages on media containing increasing concentrations of amphotericin B differed from the initial strain by its lower pathogenicity. Treatment of the infection caused by the resistant strain on modeling of candidiasis in mice was not successful. The decrease in the average life span of the mice infected with the resistant strain R2 and treated with amphotericin B was lower than that in the control animals and such indices of the disease as the levels of the kidney dissemination and the cell vegetation even increased under the effect of amphotericin B. The results of the study suggest that the resistant strain R2 of C. albicans depend on amphotericin B in the host. The data obtained emphasize the necessity of determinining the antibiotic sensitivity of C. albicans strains isolated from patients.

[Effect of levorin on the chromatin of the prostate of dogs in its hypertrophy]. / Izuchenie vliianiia levorina na khromatin predstatel'noi zhelezy sobak pri ee gipertrofii.

The effect of prolonged oral use of levorin on chromatin from the hypertrophic prostate of old dogs was studied. It was found that the chromatin from the hypertrophic prostate of old animals was characterized by a decrease in the relative content of non-histone proteins, the melting temperature and hyperchromism value. The results of the electrophoretic analysis of the histone fraction composition showed its proteolytic degradation. The matrix activity of chromatin in the RNA-polymerase system remained unchanged. Administration of levorin had no effect on the structural and functional characteristics of the chromatin isolated from the hypertrophic prostate of the old dogs.

Short-term topical treatment of vulvovaginal candidiasis with the combination of 5-fluorocytosine and candicidin.

A combination of 5-fluorocytosine (1000 mg) and candicidin (5 mg) was compared with clotrimazole (100 mg) in the treatment of 112 non-pregnant volunteers with vulvovaginal candidiasis. Seventy-two (75%) of the 96 patients treated with 1 or 2 vaginal tablets of the combination product and 10 (62%) of the 16 women treated with clotrimazole for 6 days were cured. The efficacy of the treatments was assessed mycologically and clinically 1 week and 1 month after the therapy. Both treatments were well tolerated and no side-effects could be detected. It is concluded that a short-term vaginal treatment with a 5-fluorocytosine and candicidin combination is effective in vaginal moniliasis, and the brevity of the treatment is an advantage compared with others now available.

[Effect of levorin on the rat liver plasma membranes in experimental fatty dystrophy]. / K voprosu o vliianii levorina na plazmaticheskie membrany pecheni krys pri éksperimental'noi zhirovoi distrofii.

Activity of Na+, K+-ATP- ase and 5'-nucleotidase, the lipid composition of the liver plasmic membranes with toxic and alimentary-alcohol fat dystrophy were studied on rats exposed to water-soluble sodium levorin. It was found that the above forms of the liver fat dystrophy did not change the activity of the enzymes in the membranes but caused significant shifts in the composition of the membrane lipids. The shifts were evident from an increased level of phospholipids in the plasmic membranes. Administration of levorin at the very beginning of the development of both the toxic and the alimentary-alcohol liver fat dystrophy aggravated the increase in the phospholipid level in the membranes. It was supposed that the increase in the phospholipid level due to levorin in the membranes of the liver with fat dystrophy was one of the mechanisms of the drug therapeutic effect in case of such pathology type. Levorin increased the amount of phospholipids in the dystrophic membranes and thus changed the membrane permeability resulting in decreased accumulation of neutral lipids in the hepacytes and subsequently in decreased levels of the liver fat dystrophy.