Empirical "integrated disease management" in Ferrara during the Italian plague (1629-1631).

Plague, a highly infective disease caused by Yersinia pestis (Proteobacteria: Enterobacteriales), ravaged Europe from 1347 over the course of more than 450 years. During the Italian Plague (1629-1631), the disease was rampaging in the entire Northern Italy down to Tuscany, but the city of Ferrara was relatively spared, in spite that the economic activities were maintained with highly affected cities, such as Milan, through the relevant salt commerce. The aim of the study is to evaluate the hygiene rules that were effective in preventing the spread of the plague in Ferrara in 1630, by examining historical documents and reports. According to these documents, a kind of empirical "integrated disease management" was carried out, using remedies including compounds with bactericidal, anti-parasite and repellent activity, and by technical strategies including avoidance of possible plague carriers. The anti-plague remedies and technical strategies used in ancient Ferrara are critically analysed using a multidisciplinary approach (pharmaceutic, medical, epidemiologic and entomological) and compared to current prevention protocols.

Antidermatophytic Action of Resorcinol Derivatives: Ultrastructural Evidence of the Activity of Phenylethyl Resorcinol against Microsporum gypseum.

In this work, we evaluated the antidermatophytic activities of three resorcinol derivatives that have a history of use in dermo-cosmetic applications to discover molecules with multiple dermatological activities (i.e., multi-target drugs), thereby reducing the cost and time necessary for new drug development. The antidermatophytic activities of the three skin lighteners were evaluated relative to the known antifungal drug fluconazole on nine dermatophytes responsible for the most common dermatomycoses: Microsporum gypseum, Microsporum canis, Trichophyton violaceum, Arthroderma cajetani, Trichophyton mentagrophytes, Epidermophyton floccosum, Nannizzia gypsea, Trichophyton rubrum and Trichophyton tonsurans. Among the three tested resorcinols, only two showed promising properties, with the ability to inhibit the growth of all tested dermatophytes; additionally, the IC50 values of these two resorcinols against the nine dermatophytes confirmed their good antifungal activity, particularly for phenylethyl resorcinol against M. gypseum. Ultrastructural alterations exhibited by the fungus were observed using scanning electron microscopy and transmission electron microscopy and reflected a dose-dependent response to treatment with the activation of defence and self-preservation strategies.

A Multi-Target Approach toward the Development of Novel Candidates for Antidermatophytic Activity: Ultrastructural Evidence on α-Bisabolol-Treated Microsporum gypseum.

Multi-target strategies are directed toward targets that are unrelated (or distantly related) and can create opportunities to address different pathologies. The antidermatophytic activities of nine natural skin lighteners: α-bisabolol, kojic acid, ß-arbutin, azelaic acid, hydroquinone, nicotinamide, glycine, glutathione and ascorbyl tetraisopalmitate, were evaluated, in comparison with the known antifungal drug fluconazole, on nine dermatophytes responsible for the most common dermatomycoses: Microsporum gypseum, Microsporum canis, Trichophyton violaceum, Nannizzia cajetani, Trichophyton mentagrophytes, Epidermophyton floccosum, Arthroderma gypseum, Trichophyton rubrum and Trichophyton tonsurans. α-Bisabolol showed the best antifungal activity against all fungi and in particular; against M. gypseum. Further investigations were conducted on this fungus to evaluate the inhibition of spore germination and morphological changes induced by α-bisabolol by TEM.

[Malaria in endemic areas of Northern Italy and in the Italian context: remedies and substitutes in the nineteenth century medical practice]. / La malaria in aree ad elevata endemia del nord Italia e nel contesto italiano: rimedi e succedanei nella pratica medica dell'Ottocento.

Some areas of Northern Italy, especially Ferrara during the nineteenth century, represent privileged observatories regard to malaria, a disease that affected the poor, but did not spare the rich and powerful people. The so called Delta of the River Po, as well as the Maremma and other lowland areas in Italy, was particularly noted for its marshland environment (mosquito breeding grounds). Spared from Malaria because of the better hygienic conditions of the city that restricted the proliferation of anopheles, Ferrara represented an important study centre due to the presence of renowned physicians and scientists who exchanged knowledge and findings in the medical academies. Among these, Antonio Campana was very attentive to the latest scientific findings, and wrote about antimalarial remedies in his famous Ferrarese Pharmacopoeia. This paper analyses the main remedies listed in the various editions of Campana Pharmacopoeia since 1798 and particularly that of 1841, in the reports from the Accademia Medico Chirurgica di Ferrara and of Argenta physicians of the mid nineteenth century and in the Reports (1871 and 1876) from Alessandro Bennati, director of Arcispedale Santa Anna and concerned with hospital practice. Other printed documents referring to the town of Argenta are discussed.

Antidermatophytic activity of pyrazolo[3,4-c]isothiazoles: a preliminary approach on 4-chlorophenyl derivative for evaluation of mutagenic and clastogenic effects on bacteria and human chromosomes in vitro.

The antifungal activity of eight pyrazolo[3,4-c]isothiazole derivatives was evaluated on five dermatophytes: three were of an anthropophilic species (i.e., Epidermophyton floccosum, Trichophyton rubrum, and Trichophyton tonsurans) and two were of a geophilic species (i.e., Microsporum gypseum and Nannizzia cajetani). The new compounds proved to be unlikely effective in inhibiting the growth of the different strains. In general, the fungi parasitic on man were more sensitive than the geophilic species. This fact can be positive for a possible practical-therapeutic utilization of this class of compounds. To verify their possible use against fungi of medical interest, the most interesting substance at low doses, 6-(4-chlorophenyl)-4-methyl-6H-pyrazolo[3,4-c]isothiazol-3-amine, was chosen to perform in vitro genotoxicity tests using the following: Salmonella/microsome test (SAL), sister chromatid excange test (SCE), cytokinesis-blocked micronucleus test (CBMN), and its improvement (Ara-C/CBMN). The compound showed no mutagenic activity at low doses, whereas at the highest dose (100 µg/mL), it caused a generalized cytotoxic effect. The high growth inhibition exerted on fungi at the lowest dose and the concomitant lack of genotoxicity, at least until the dose of 50 µg/mL, might suggest the compound as a safe candidate as an antidermatophytic substance.

Pyrazolo[3,4-c]isothiazole and isothiazolo[4,3-d]isoxazole derivatives as antifungal agents.

CONTEXT: The diseases of plants and humans due to pathogenic fungi are increasing. Among the substances used to combat fungi, the azoles are of primary interest, both in agricultural field both in health. To avoid fungal resistance phenomena, the synthesis and tests of new derivatives are necessary. OBJECTIVE: This article discusses the synthesis and the antifungal activity of pyrazolo[3,4-c]isothiazole and isothiazolo[4,3-d]isoxazole derivatives against three fungi that are pathogenic only for plants and two fungi that are opportunistic in humans and plants. MATERIALS AND METHODS: The compounds were prepared starting from 2-cyano-3-ethoxy-2-butenethioamide. The antifungal activity of the compounds was determined by measuring the inhibition of growth of the fungi tested at 20, 50, and 100 µg/mL in comparison with the controls. RESULTS: Results demonstrated that several compounds were able to control the mycelial growth of the tested fungi, even if they showed different sensitivity to the different azole-derivatives. In general Magnaporthe grisea (T.T. Hebert) Yaegashi & Udagawa was the most sensitive fungus, being blocked almost entirely by 4-chloro derivative even at 20 µg/mL, a concentration at which the reference commercial compound tricyclazole was nearly ineffective. DISCUSSION AND CONCLUSION: These findings demonstrate that the pyrazolo[3,4-c]isothiazole derivatives have a wide spectrum of activity on phytopathogenic and opportunistic fungi. In particular the 4-chloro derivative seems to have a great potential as new product to combat M. grisea in the agricultural field.

Antifungal activity of essential oil from fruits of Indian Cuminum cyminum.

The essential oil of fruits of Cuminum cyminum L. (Apiaceae), from India, was analyzed by GC and GC-MS, and its antifungal activity was tested on dermatophytes and phytopathogens, fungi, yeasts and some new Aspergilli. The most abundant components were cumin aldehyde, pinenes, and p-cymene, and a fraction of oxygenate compounds such as alcohol and epoxides. Because of the large amount of the highly volatile components in the cumin extract, we used a modified recent technique to evaluate the antifungal activity only of the volatile parts at doses from 5 to 20 microL of pure essential oil. Antifungal testing showed that Cuminum cyminum is active in general on all fungi but in particular on the dermatophytes, where Trichophyton rubrum was the most inhibited fungus also at the lowest dose of 5 microL. Less sensitive to treatment were the phytopathogens.

The treatment of syphilis in Ferrara (Italy) in the 19th century: the example of the Ferrarese pharmacopoeia.

The authors have taken the Italian city of Ferrara as an example of the remedies against syphilis, commonly used worldwide in the 1800s. After having identified the terminologies used to diagnose syphilis, they evidence the legislative behaviours of the government authorities in 19th century in Italy and, in particular, the social and sanitary measures taken in Ferrara to limit the spread of the syphilis epidemic. Historical sources permitted description of the remedies employed in Ferrara from the beginning to the end of that century, not only to treat conditions linked directly to the malady itself, but also its complications and secondary pathologies. The pharmacopoeia written for the apothecaries of Ferrara by Antonio Campana, a famous Professor of Pharmaceutical Chemistry and Botany, won a great reputation and distribution in the international medical world not only of the first half of the 1800s. His authoritative work was much appreciated in Italy and abroad.

The treatment of tuberculosis in Ferrara (Italy) in the 19th century.

The present work is a review of the remedies in use in Ferrara against tuberculosis in the 1800s. The work started from the discovery of accounts describing methods and remedies. These remedies were also in use world wide. Of particular interest is the work by Antonio Campana, a famous professor of Pharmaceutical Chemistry and Botany in Ferrara, who wrote a pharmacopoeia which had several editions between 1797 and 1841. The Farmacopea Ferrarese was addressed to the apothecaries of Ferrara. Nevertheless, due to its great reputation it had an international distribution. It provided us with an exhaustive view about the medical field in Ferrara in the early 1800s. The remedies adopted in the city in the second half of the century were in line with those present abroad. The work was also supported by the discovery of statistical accounts of the Sant'Anna hospital from 1871. The manuscript written by Alessandro Bennati enabled elucidation of the methods used to treat tuberculosis in the second half of the century. Bennati's work is an historical document completed by the work of the physician Cesare Minerbi.

Three new species of Aspergillus from Amazonian forest soil (Ecuador).

From an undisturbed natural forest soil in Ecuador, three fungal strains of the genus Aspergillus were isolated. Based on molecular and morphological features they are described as three new species, named A. quitensis, A. amazonicus, and A. ecuadorensis.

Synthetic pyrazole derivatives as growth inhibitors of some phytopathogenic fungi.

The present study was carried out to investigate the antifungal activity of pyrazole/isoxazole-3-carboxamido-4-carboxylic acids, 4-oxo-5-substituted pyrazolo[3,4-d]pyrimidine-6-thiones, and N-alkyl/aryl-N'-(4-carbethoxy-3-pyrazolyl)thioureas against Pythium ultimum, Botrytis cinerea, and Magnaporthe grisea. The results on growth inhibition showed differences in the sensitivity of the three fungi to the tested substances, and in general P. ultimum was shown to be the most sensitive. On all phytopathogens the best results within the pyrazole/isoxazolecarboxamide series are given by the compounds with the carboxamide and carboxylic groups in positions 3 and 4; the presence of these groups seems to be critical for biological activity in this series of compounds. Among the pyrazolopyrimidines the derivative supplied with the benzylic group was the most active on the three fungi and in particular against P. ultimum. Several compounds belonging to the thiourea series are able to inhibit selectively M. grisea at 50 and 10 microg mL(-1), doses at which the reference commercial compound tricyclazole had low or no effect.

Pyrazole derivatives as photosynthetic electron transport inhibitors: new leads and structure-activity relationship.

Four series of new pyrazoles, namely, 5 4-carboxypyrazolo-3-tert-butylcarboxamide and 6 4-carboxypyrazolo-3-cyclopropylcarboxamide derivatives and 10 pyrazolo[3,4-d][1,3]thiazine-4-one and 9 pyrazolo[3,4-d][1,3]thiazine-4-thione derivatives, were synthesized and screened as potential inhibitors of photosynthetic electron transport. The structures were confirmed by 1H NMR, elemental, and IR analyses. Their biological activity was evaluated in vitro as the ability to interfere with the light-driven reduction of ferricyanide by isolated spinach chloroplasts. Only a few compounds exhibited excellent inhibitory properties in the micromolar range, comparable to those of commercial herbicides sharing the same target, such as diuron, lenacil, and hexazinone. Nevertheless, most of the remaining molecules exerted a remarkable inhibition in the millimolar range. Combined with previous results on 6 pyrazolo[1,5-a][1,3,5]triazine-2,4-dione and 4 pyrazolo[1,5-c][1,3,5]thiadiazine-2-one derivatives, these data allowed a comprehensive analysis of structure-activity relationship. Molecular modeling studies were undertaken to rationalize the structural determinants of activity in terms of shape, size, and molecular fields. Results suggested that the inhibitory potential of these compounds is associated mainly with their electrostatic properties.

Synthesis of pyrazole derivatives and their evaluation as photosynthetic electron transport inhibitors.

Two series of new pyrazoles, namely six pyrazolo[1,5-a][1,3,5]triazine-2,4-dione and four pyrazolo[1,5-c][1,3,5]thiadiazine-2-one derivatives, were synthesized as potential inhibitors of the photosynthetic electron transport chain at the photosystem II level. The compounds were confirmed by 1H NMR, elemental, and IR analyses. Their biological activity was evaluated in vivo upon both the growth of blue-green algae and the photosynthetic oxygen evolution by eukaryotic algae and in vitro as the ability to interfere with light-driven reduction of ferricyanide by isolated spinach chloroplasts. Some compounds exhibited remarkable inhibitory properties, comparable to those of the reference commercial herbicides lenacil, diuron, and hexazinone. Results suggest that the substitution of triazine with thiadiazine ring may act as amplifier for herbicidal activity.

Synthesis and antifungal action of new tricyclazole analogues.

Melanins are very important pigments for the survival and longevity of fungi, so their biosynthesis inhibition is a new biochemical target aiming at the discovery of selective fungicides. In this work is described the synthesis of new pyrazolo-thiazolo-triazole compounds, analogues of tricyclazole (a commercial antifungal product that acts by inhibiting melanin synthesis), and their biological activity was studied on some dermatophytes and phytopathogens. The compounds poorly inhibited the growth and pigmentation of fungi tested and were less efficient than tricyclazole. Electron microscopy on Botrytis cinerea showed that treatment with the most active compound caused abnormally thickened and stratified walls in fungi, whose ultrastructure was, in contrast, generally normal. The fungus treated with tricyclazole, on the other hand, appeared to be drastically altered, so as to become completely disorganized. These results suggest that the new azole compounds employ an action mechanism similar to that of other azoles, but dissimilar to that of tricyclazole.

Development of new fungicides against Magnaporthe grisea: synthesis and biological activity of pyrazolo[3,4-d][1,3]thiazine, pyrazolo[1,5-c][1,3,5]thiadiazine, and pyrazolo[3,4-d]pyrimidine derivatives.

Some pyrazolo[3,4-d]pyrimidin-4(5H)-thione, pyrazolo[3,4-d][1,3]thiazin-4-one/thione, and pyrazolo[1,5-c][1,3,5]thiadiazine-4-one/thione derivatives were synthesized and screened for antifungal activity against the causal agent of rice blast disease, Magnaporthe grisea. In all cases a remarkable inhibition of fungal growth was found in the range from 10 to 200 microg x mL(-1). Several compounds were able to control mycelium growth at a rate of 10 microg x mL(-1), a concentration at which the reference compound tricyclazole was completely ineffective. At least in the case of the most active substance, at the same dose the growth of seedlings or cultured cells of rice was substantially unaffected. Results allowed definition of structural requirements either to maintain or to enhance mycotoxic activity.