Biomedical subjects
Publications and source records attributed to L Gradoni.
We report a case of gastric localization of Leishmania in a 29-year old man affected by AIDS. Gastric biopsies revealed macrophages infected with intracytoplasmic organisms attributable to Leishmania amastigotes. The authors emphasize the importance of performing random biopsies in the absence of endoscopic abnormalities.
Up-to-date information is given on the epidemiological situation of zoonotic visceral leishmaniasis (ZVL) in nine Mediterranean countries, and on drug regimens adopted in the management of ZVL patients in each country. Results of experimental and clinical trials on the efficacy and tolerability of liposomal amphotericin B in laboratory animals and in patients with ZVL are presented, as well as conclusions and recommendations on drug regimens to be used in the treatment of ZVL.
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Visceral leishmaniasis (VL) in pregnancy is rare in Mediterranean countries. We report here 2 cases of VL in pregnant women who acquired the infection in Italy. In the first case, the disease was diagnosed and treated with liposomal amphotericin B during the pregnancy. In the second case, diagnosis was established and treatment with meglumine antimoniate both undertaken shortly after delivery. The 2 infants were followed clinically and serologically for 8-9 months after birth, but no evidence of congenital VL was observed.
Visceral leishmaniasis (VL) is a public health problem in most countries bordering the Mediterranean sea. The disease has been found in central and southern Italy, Sicily, Sardinia; some pockets are present in Liguria. Dogs are the reservoirs and the vectors are some species of sandfly (Phlebotomus species). The incubation period is usually between 2 and 8 months; children and adults may become infected; lethality may be high and depends upon a correct diagnosis and treatment. The diagnosis should be suspected on the basis of the epidemiological data and clinical picture and confirmed by the detection of specific antibodies by appropriate techniques. Leishmaniasis can be detected in splenic or bone marrow aspirates. Patients with HIV infection and VL may lack specific antibodies; parasitological diagnosis is mandatory for these patients. Antimonials are the classic therapeutic agents for VL. Recently liposomal amphotericin B (Ambisome) has been successfully used, with negligible toxicity.
Thirty-one patients with visceral leishmaniasis (VL) caused by Leishmania infantum received liposomal amphotericin B (AmBisome) in a multi-centre study. Ten immunocompetent patients (six children) received 1-1.38 mg/kg/day for 21 days, and ten (nine children) received 3 mg/kg/day for 10 days. All were cured without significant adverse events and without relapse during 12-24 months of follow-up. Eleven immunocompromised adults, including seven co-infected with HIV (four with AIDS) received 100 mg (1.38-1.85 mg/kg) daily for 21 days. All were initially considered cured, but eight relapsed clinically and parasitologically at 3-22 months. Liposomal amphotericin B is a new, safe and effective drug for the treatment of VL.
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Although human visceral leishmaniasis (VL) is a notifiable disease in Italy, there is evidence that the actual number of cases is far higher than that notified. A programme for active surveillance of VL in the 14 Italian endemic regions was launched by the Istituto Superiore di Sanità. We report data collected during a 3-year period of active surveillance in Campania, a south Tyrrhenian region covering 4.5% of the Italian territory. Out of 120 clinically suspected cases referred to medical and diagnostic references centres, there were 52 confirmed VL cases (17.3/year), i.e. 10-fold more than previously notified. Most of the infection sites were in rural areas or peripheral districts of towns in hilly parts of Naples province. An epidemic cluster of 10 cases was identified in a microfocus of Caserta province. The biochemical analysis of 23 Leishmania stocks showed a zymodeme composition indicating Campania as an old and well-established focus of VL. The data obtained emphasize that the present notification system for VL in Italy is inadequate.
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Preliminary observations have shown that AmBisome, a liposomal formulation of amphotericin B (Vestar Inc.), is effective and non-toxic in animal and human visceral leishmaniasis. The activity of multiple doses of this drug on Leishmania infantum, in BALB/c mice was investigated, and amphotericin B concentration in liver and spleen was determined. Groups of infected mice were treated intravenously with 3, 5, or 7 doses of AmBisome (3 mg/kg) over 3, 10 and 25 days, respectively. The antileishmanial activity of the drug was compared with that of meglumine antimoniate (28 mg Sbv/kg per day over 21 days). Three consecutive daily doses of AmBisome were sufficient to clear all parasites from the liver of mice, while antimony did so only after 21 doses. Twenty-four-48 h after their last dose all the AmBisome-treated mice showed very high amphotericin B concentrations in liver (61.2-76.2 micrograms/g) and spleen (39.8-72.1 micrograms/g) with no overt signs of toxicity. Mice that received 2 or 4 doses at intervals of 5 to 8 days, maintained drug levels as high as those detected after 3 consecutive doses over 11 and 26 days, respectively. This should enable visceral leishmaniasis treatment on an intermittent or outpatient basis, thereby reducing overall treatment costs.
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1. The sensitivity of ubiquinol:cytochrome c reductase to its most powerful inhibitors has been characterized in mitochondria from three ciliate and two trypanosome protozoans and compared with that in mitochondria of animals and plants. 2. Mitochondria of ciliates, particularly those of Tetrahymena pyriformis, are resistant to antimycin. 3. Mitochondria of trypanosomes are quite resistant to stigmatellin, as they exhibit a 40-fold higher titer than that in ciliate or animals mitochondria. 4. Both ciliates and trypanosomes are highly resistant to myxothiazol. 5. Correlations have been drawn between the natural resistance of the protozoan mitochondria to antimycin, stigmatellin and myxothiazol and peculiar features in the structure of their apocytochrome b, on the basis of an accurate alignment of the sequences of this protein.
A 196 bp fragment of cloned kinetoplast (k) DNA of Leishmania infantum has been sequenced and shown to be diagnostic for this species. The DNA from 10(4)-10(5) promastigotes was routinely and specifically detected in crude dot blots of whole cells lysed in situ, and there was no cross-hybridization with 10(6) cells of L. major, L. tropica, L. killicki, L. aethiopica, L. braziliensis and L. mexicana. A low degree of hybridization was found with L. donovani and L. chagasi. This probe will be of particular use in Mediterranean countries, such as Italy, in which dermotropic zymodemes of L. infantum can be difficult to isolate and grow in numbers sufficient for isoenzyme typing.
Although unresponsiveness to antimonial drugs in human leishmaniasis appears to be increasing, resistance to antimony in Leishmania is not well documented. Treatment of leishmaniasis in dogs, the domestic reservoir of L. infantum, with meglumine antimoniate (Glucantime) is a common practice in many Mediterranean countries. The dogs, however, remain highly infective to the phlebotomine vectors, even after several courses of treatment. A study was therefore carried out to test the comparative susceptibility to meglumine antimoniate of L. infantum stocks isolated from four naturally-infected dogs, before (BT) and after treatment (AT) with three to six courses of the drug, and used to infect Balb/c mice. Significant differences in suppression between the BT and AT stocks were observed in the infected mice when they were given the drug at a rate of 0.01-10 mg kg-1 day-1 for five days. Each AT stock was between eight and 41 times more resistant to meglumine antimoniate than the BT stock from the same dog, in terms of the ratios of the AT ED50 values to the corresponding BT values, which were calculated as indices of resistance. This result underlines the futility and danger of repeated antimonial treatments of dogs with signs of leishmaniasis, as these may produce a permanent reservoir of parasites unsusceptible to the drugs in human clinical use.
Purified maize polyamine oxidase bound to hydroxylapatite was utilized as an enzymatic reactor to produce oxidized spermidine and spermine. The oxidation products showed a consistent inhibitory activity on Leishmania infantum in mice. 1,3-diaminopropane showed a much lower activity. Moreover chemically prepared 4-aminobutyraldehyde had a similar ED50 to that of oxidized spermidine. It is concluded that among the compounds arising from polyamine oxidation those with the greatest anti-leishmanial effect are 4-aminobutyraldehyde and 1-(3-aminopropyl)-4-aminobutyraldehyde.
An autochthonous case of leishmaniasis of tongue and palate is reported from Sardinia, Italy. The parasite isolated from the lingual lesion was typed through the electrophoretic analysis of 14 isoenzymes and it was identified as Leishmania infantum zymodeme MON 27.
Several new derivatives of 4-amino-, 4,6-diamino- and 4-hydrazino-[3,4-d]pyrimidine dihydroxyalkyl substituted in the 1 or 2 positions, or dihydroxyalkoxy substituted in the 3 position have been synthesized. Some of these compounds were evaluated for their activity against Leishmania infantum in mice. The highest degree of antileishmanial activity was displayed by the 4-amino-1-(dihydroxyalkyl) derivatives which yielded parasite inhibition values nearly comparable with that of glucantime in a standard 5-day test.