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Controlled trial of natamycin in the treatment of allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis often requires treatment with oral corticosteroids to control the host response to Aspergillus fumigatus. In a double blind study 25 patients with allergic bronchopulmonary aspergillosis taking maintenance oral corticosteroids were randomly allocated to receive 5 mg natamycin or placebo by nebuliser twice daily for one year. The primary aim of the study was to assess the steroid sparing potential of natamycin. Standardised reductions in corticosteroid dosage were therefore undertaken every five weeks, unless clinically contraindicated. Five patients were withdrawn in the first four months: two (1 natamycin, 1 placebo) died, two (1 natamycin, 1 placebo) had suspected drug reactions, and one (natamycin) was non-compliant. The pretreatment characteristics of the 20 patients (10 in each group) who completed the study were similar, 17 (9 natamycin, 8 placebo) having evidence of recent disease activity. At the end of the study prednisolone dose had been reduced by a similar amount in each group (median natamycin 2.25 mg, placebo 2.5 mg). Evidence of disease activity during the study year (transient shadowing on the chest radiograph, blood eosinophilia, or increases in antibodies to A fumigatus, or any combination of these) was observed in similar numbers of patients in each group (5 natamycin, 7 placebo). There was no evidence that natamycin conferred benefit on these patients with allergic bronchopulmonary aspergillosis.

Adult

[The spectrophotometric determination of natamycin in cheese].

Derivative spectroscopy was used for quantitative determination of natamycin in cheese. When measuring a methanolic cheese extract against methanol, the second derivative of the UV-spectrum is measured between 340 and 290 nm. The natamycin concentration can be determined by measuring the vertical distance between the minimum at 318 nm and the maximum at 311 nm. Under these conditions the detection limit of natamycin in a pure methanolic solution lies at 20 ng/ml, in cheese extracts at 150 ng/ml. The latter corresponds to a natamycin concentration of 2.5 ppm in the case of a 3 g test sample or 0.03 mg/dm2 in the case of a 25 cm2 cheese surface. The introduction of derivative spectroscopy makes it possible to reduce the interference of cheese substances in the photometric measurements and to increase the sensitivity and selectivity of the detection process. Besides the advantage that work and expenses are reduced - as no pimaricin-free sample has to be extracted from the interior of the cheese - it is also possible to determine natamycin photometrically in cheese, in which it is distributed homogeneously.

Cheese

New high-molecular decomposition products of natamycin (pimaricin) with intact lactone-ring.

Mild acid treatment of natamycin (IV) results in biologically inactive aponatamycin (VI), an amphoteric substance with some natamycin-like chemical and physical properties. Aponatamycin contains one natamycin- and one natamycinolide-moiety. More drastic acid degradation of natamycin eliminates the aminosugar under formation of the dimer (VII) of the hypothetical aglycone of natamycin, natamycinolide (V) as well as a non-ionic compound, the dimer of the 12-decarboxy-11-anhydro analogue of natamycinolide.

Chemical Phenomena

[Natamycin (pimaricin) in the treatment of experimental keratomycosis].

The efficacy of natamycin (pimaricin) was studied and compared with the standard amphotericin B, using a reproducible model of keratomycosis from Candida albicans in the rabbit. C. albicans DSM 70010 (2.5 X 10(5) cells) was injected into the corneal stroma of both eyes. All eyes developed a corneal ulcer without pretreatment with immunosuppressive agents. Forty-eight hours after inoculation, the animals were divided into five groups: I (10 eyes) and II (12 eyes) receiving natamycin drops, 1%; groups III (12 eyes) and IV (12 eyes) receiving natamycin, 2.5%; the control group (14 eyes) receiving 0.9% NaCl. For better penetration of the drug, the epithelium of groups I and III was removed every 3rd day. Half of the control group was debrided as well. In a further series, the penetration of natamycin into the cornea and aqueous humor was studied. There was no difference between the treated eyes and the control eyes concerning complications (descemetocele or perforation). It is concluded that natamycin (pimaricin) is inferior to amphotericin B and not effective in controlling experimental keratomycosis.

Animals

Spectrometric and liquid chromatographic determination of natamycin in cheese and cheese rind.

Methods for determining natamycin content of cheese rind and cheese are presented. Cheese and rind samples are extracted with methanol and the fat precipitated by cooling the sample solution in methanol-water at -15 to -20 degrees C for ca 1 h. Natamycin levels are measured by UV spectrometric detection at absorbance minimum 311 nm, maximum 317 nm, and at exactly 329 nm, or by LC separation over Lichrosorb RP-8 column with detection at 303 nm. For measuring low levels, a concentration step is provided. The method is applicable to natamycin in cheese rind and in the interior of the cheese. Detection limit is 0.5 mg/kg. The method is suitable for controlling a maximum tolerance of natamycin on the cheese rind, at a level of 1 mg/dm2, and for detecting migration of natamycin into the cheese.

Cheese

Results of a combination treatment with natamycin and butylscopolamine in cases of intestinal Candida colonization.

The findings described show that Candida species can be found in the feces of approximately half a population of nonselected test persons and in the mouths of approximately a third. Intestinal Candida colonization was found in most of these persons after one feces examination, and in practically all of them after a second examination. 10 d of therapy with 400 mg natamycin per day in sugar-coated tablet form and 40 mg natamycin in the form of tablets for sucking produced a negative fungus test for the feces in only 20% of the cases. Although a combination of this therapy with 3 x 10 mg butylscopolamine per day improved short-term results significantly, the long-term results were hardly influenced at all. Typifying results according to the Warnock method showed that we are dealing with recurrences in practically all cases and not with new infections. Minimal inhibition concentrations (MIC) of natamycin showed no marked changes as a consequence of the natamycin treatment.

Adult

Correlation of in vitro and in vivo susceptibility of Candida albicans to amphotericin B and natamycin.

The efficacy of topical 0.15% amphotericin B and 5% natamycin was examined in a model of Candida keratitis in rabbits and correlated with three tests of in vitro susceptibility: tube dilution minimal inhibitory concentration (MIC), minimal fungicidal concentration (MFC) and agar diffusion zones of inhibition. For a panel of 17 strains, the MIC classified precisely the same strains as resistant or susceptible to amphotericin B as did the in vivo response. Several strains were misclassified using the MFC and the zone of inhibition. For natamycin the MIC misclassified two strains but it was still superior to the other two tests. For all strains, amphotericin B was equal or superior in efficacy to natamycin in vivo. The tube dilution MIC for amphotericin B was a reliable indicator for natamycin efficacy in vivo.

Amphotericin B

A controlled trial of house dust mite eradication using natamycin in homes of patients with atopic dermatitis: effect on clinical status and mite populations.

In a controlled clinical trial, patients with atopic dermatitis carried out house dust mite eradication procedures on their mattresses, using natamycin or a matched placebo spray, with or without vacuum cleaning, for 4 months. For the two groups that used vacuum cleaning, mite numbers fell significantly both by comparison of mean initial and final numbers and by calculating mean rates of reduction from regression analyses (P less than 0.01 in all cases). There were no differences between the groups in the magnitude of the decreases. For the two groups that did not use vacuum cleaning, mite populations remained virtually unchanged. These results indicate vacuum cleaning not natamycin had the major effect on mite eradication. Mean symptom scores of patients in all four groups were slightly reduced by the end of the trial, but there was a greater reduction rate (P less than 0.01) in the combined scores of the groups that did not use vacuum cleaning, demonstrating a lack of correlation between improvement in clinical score and lowered mite numbers. No patients entered remission and the maximum improvement in clinical score was only 47%. Natamycin and vacuum cleaning neither alone nor in combination proved valuable in reducing mite numbers sufficiently to provide clinical benefit.

Adolescent

Corneal penetration of topical amphotericin B and natamycin.

The corneal uptake and penetration of 14C-labelled 0.15% amphotericin B and 5% natamycin were studied in Dutch-belted rabbits. Corneal levels of natamycin were substantially higher than amphotericin B. For both drugs, these levels were influenced by corneal contact time. In corneas debrided of epithelium, both agents entered the corneal stroma and levels were detected in aqueous in the therapeutic range. However, in corneas with intact epithelium, penetration was negligible for amphotericin B (0.23 microgram/gm at 2 mins). By contrast, although penetration of natamycin was greatly reduced, 7.0 micrograms/gm were present at 2 mins.

Administration, Topical

Optimal efficacy of a fungicide preparation, natamycin, in the control of the house-dust mite, Dermatophagoides pteronyssinus.

The efficacy of a fungicidal preparation, natamycin, for the effective control of Dermatophagoides pteronyssinus (Trouessart), was determined at different concentrations on mattress-dust microsites, including ticking. One treatment with the commercially available natamycin concentration (Tymasil) resulted in a 65% reduction of house-dust mite populations within 4 weeks of treatment. The acaricidal control could be proven despite the protective role of mattress fibres such as ticking. However, mite fecundity was much more affected after treatment with twice the commercial concentration, which then assured a long-term control. Concentrations below the commercially available one were not effective. In a maritime climate, six sequential treatments three times a year would be effective for an adequate long-term control because of the high growth of house-dust fungi and the close interaction between the mite and the mould Aspergillus penicilloides.

Animals

Natamycin in genital candidosis in men.

In a trial of natamycin, an antifungal antibiotic in a vanishing cream base, assessment was possible in 66 men with genital or anal candidosis. The overall cure rate was 82 percent, In 43 patients with culturally proven candidosis it was 98 percent. but in 23 patients treated solely on clinical impression it was only 52 percent. Symptoms were rapidly relieved in those who responded and there were no side-effects. In our hands, natamycin 2 per cent cream has proved to be a valuable preparation in the treatment of candidal balanitis.

Administration, Topical

Treatment of vaginal candidosis with natamycin and effect of treating the partner at the same time.

Thirty-three patients with vaginal candidosis were treated with natamycin vaginal tablets for 10 days and their partners were treated double-blind with natamycin cream/placebo cream. Follow-up examinations were carried out one week after the treatment was discontinued and again about one month later. The cure rate in patients having actively treated partners was 94%, not differing significantly from the cure rate of 88% in patients whose partners had been treated with placebo. One month after the treatment there was a high recurrence/re-infection rate, about 30% in both groups. Thus, treating the partners of patients with vaginal candidosis has no influence upon the therapeutic outcome or recurrence rate. The recurrence is presumably due to re-infection from the patient herself.

Adult

[Therapeutic results achieved through the advantage of a combination of oral metronidazole and vaginal natamycin tablets in urogenital protozoan, trichobacterial and blastomyces infections].

Vaginal inflammations caused by Trichomonas, Leptothrix vaginalis or Candida and other less common organisms respectively, were treated very successfully with a combination of metronidazole orally and a natamycin preparation vaginally (Pimafucin vaginal tablets). In women with urogenital Trichomoniasis a cure was obtained in 96,1% of the cases (microbiologically controlled); Candida mycoses of the vagina were cured clinically in 89% of the cases after the first course of treatment and mycologically in 79% of the cases. Of special importance is the rapid and successful elimination of the mixed infection before birth, because this diminishes perinatal morbidity of the fetus. The combination treatment of bilateral, constantly interchanging Candida and Trichomonas infections of the vagina is of importance to both sexes, especially with respect to the elimination of sterility. From the onco-gynecological point of view the combination treatment with metronidazole and natamycin appeared to be of value as it limits the incidence of dyskariosis of the epithelial cells, which occur frequently in cases of inflammation of the vagina or cervix uteri. No teratogenic effect was observed with this combination when applied during pregnancy.

Administration, Oral

[Natamycin-S treatment of ringworm in cattle. Epidemiological aspects (author's transl)].

At a test centre for bulls the progress of a ringworm infection was studied. By treating only the affected animals with natamycin-S the progress of the disease as well as the spreading of the infection among untreated animals could be studied. By treating only the affected animals with natamycin-S the progress of the disease as well as information could be gathered on the difference of progress of the infection in both groups and also of the role of possible immunity.

Animals

Effects of natamycin and potassium sorbate on growth and aflatoxin production in olives.

Aspergillus flavus NRRL 6555 was inoculated onto whole olives and olive paste samples containing variable amounts of either natamycin or potassium sorbate and incubated at 15 degrees, 25 degrees, and 35 degrees C for 7, 14 and 21 days for whole olives and at 15 degrees and 25 degrees C for 8 and 16 days for olive pastes. The initiation time of growth was parallel to the concentrations of either preservatives applied. However, at 15 degrees C, natamycin at 160 and 320 micrograms/g (ppm) completely inhibited the growth of mold on whole olives for 21 days and olive paste for 7 and 15 days, respectively. All levels of potassium sorbate inhibited mold growth at 15 degrees C, but at 25 degrees C, 6000 micrograms/g (ppm) only, delayed growth for 15 days. The extent of growth at the end of the incubation periods was parallel to the temperatures of incubation. The analyses for aflatoxin B1 production in all samples at all levels of preservatives and control were negative.

Aflatoxins

Determination of natamycin in cheese and cheese rind: interlaboratory collaborative study.

A collaborative test on the determination of natamycin in cheese and cheese rind was conducted. Participants were from 37 laboratories in 13 countries. Eight samples, consisting of 4 duplicates, were investigated by a spectrometric method and a liquid chromatographic (LC) method. The spectrometric method gave good results (coefficient of variation [CV] = 12%) and the LC method with ultraviolet detection gave reasonable results (CV = 25%) for levels down to 15 mg/kg (0.9 mg/dm2). For very low levels, a preconcentration step is necessary, but even then quantitation is poor (CV = 35-37%) for both methods at 1.7 mg/kg, although the presence of natamycin can be detected qualitatively. For a level of 0.3 mg/kg, quantitation is poor (CV = 39%) for the LC method and impossible (CV = 60%) for the spectrometric method.

Cheese

Liquid chromatographic determination of natamycin in cheese at residue levels.

A high performance liquid chromatographic method, with special reference to the cleanup procedure, is described for the measurement of natamycin in cheese. Co-extracted fats and proteins are removed by cooling the methanol extract of the cheese. Amounts as low as 1 ng natamycin can be detected; the limit of determination is better than 0.05 mg/kg. Recovery at the 1 mg/kg level is better than 90%. Reproducibility at the 0.4 mg/kg level shows a coefficient of variation of 10%. Some results obtained with Dutch cheese samples from the local market are reported.

Cheese

House dust mite allergen levels and an anti-mite mattress spray (natamycin) in the treatment of childhood asthma.

Natamycin, a fungicide marketed as Tymasil, is claimed to reduce house dust mite numbers and would therefore be expected to improve asthma in children with mite sensitivity. We have tested this assertion by a double-blind, placebo-controlled trial. There was no significant effect on levels of Der p I in mattress dust between active and placebo groups at the end of the spraying period. Histamine inhalation challenge PC20, clinic visit symptom scores and lung function tests reflecting either large or small airways obstruction were also unchanged. Therefore this product is not a therapeutic option for mite-allergic patients using the manufacturer's recommended dose and method of administration. Other factors influencing the Der p I levels were also investigated. Of these, only month of measurement and bedroom wall humidity showed any association.

Adolescent