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The activities of 8 platinum drug complex salts were determined against Leishmania donovani promastigotes. The three most active salts were selected: [PtIVBr6]H2 (pentamidine); [PtIVBr6]H2 (stilbamidine), and [PtIVCl6]H2 (2-piperazinyl(1) ethyl amine), which induced growth-inhibition rates of more than 50% at 24 h of treatment and at the maximum dosage tested. The cytotoxicity assays on the macrophage cell line J-774 showed high cytotoxicity for the salt [PtIVBr6]H2 (stilbamidine) with a percentage of specific 51Cr release of 58.2% at 24 h of incubation and 100 microg/ml. Meanwhile, assays of the other compounds showed practically no cytotoxicity. The salt [PtIVBr6]H2 (pentamidine) notably inhibited the incorporation of 3H-thymidine in the treated parasites. The ultrastructural alterations observed in the flagellates treated with the salts [PtIVCl6]H2 (2-piperazinyl(1)ethyl amine) and [PtIVBr6]H2 (pentamidine) suggest that both act preferentially at the nuclear level and at the kinetoplast-mitochondrion complex. Both compounds showed a high in vivo activity in parasitized Wistar rats.

Stilbamidinium hexachloroiridiate was found trypanocidal in vitro against Trypanosoma brucei brucei IPP at 600 microM after a 1 h incubation period and 30 microM after 24 h. This activity was confirmed in mice with a subcutaneous treatment at 20 mg/kg in a single dose. It was then evaluated on T.b. brucei murine CNS model. At the early stage, a subcutaneous treatment at 2 mg/kg/day x 5 cured 50% mice where-as one single dose at 10 mg/kg was completely inactive. Higher doses failed to cure the mice. Nevertheless, hexachloroiridiate salt of stilbamidine was 3.3 fold less toxic than dihydrochloride salt. Although the compound appeared inactive at the late stage of the murine trypanosomiasis, the difference of toxicity justified its evaluation on the early stage of sheep trypanosomiasis. The compound was trypanocidal at 2 mg/kg in a single dose when administered 8 days after infection. The study of iridium serum kinetic showed that stilbamidinium hexachloroiridiate was distributed rapidly according to a monocompartmental model. Moreover, iridium persisted in serum for a long time. The compound in aqueous suspension with 1% carboxymethylcellulose acted therefore as a controlled release system with a bioavailability allowing its trypanocidal action at the early stage.

North American blastomycosis, first reported in 1894, and once thought to be a geographically localized disease, has now been reported worldwide. The greatest number of cases occur in the Mississippi, Missouri, and Ohio River basins. The organism enters the body via the lungs with subsequent dissemination to other organs, including the skin, eyes, bones, and genitourinary system. Patients most often present with cutaneous or pulmonary complaints. Demonstration of characteristic fungal morphology in microscopic smears or in histologic specimens is highly suggestive of Blastomyces dermatitidis. However, proof of the diagnosis is obtained only by mycologic culture. Some progress has been made using other laboratory methods to produce a rapid diagnosis. This paper reviews in detail the varied clinical presentations of blastomycosis, the laboratory diagnosis, and current treatment.

In a retrospective study of 51 cases of systemic North American blastomycosis 11 patients were found to have genitourinary tract involvement, the prostate and epididymis being most commonly affected. Diagnosis was made by culture of the fungus from urine, abscess or prostate secretions, morphologic identification of the characteristic organism in urine or secretions, or histologic examination of tissue specimens. Treatment with amphotericin B reduced the mortality rate of 90 per cent to as low as 10 per cent. Long-term followup is necessary because of a relapse rate of 10 to 15 per cent.

Pneumocystis carinii and Toxoplasma gondii are the two major parasitic protozoan pathogens in the immunocompromised host. Both organisms cause latent infection in humans and many animals. Cats are the definitive hosts for toxoplasmosis; the animal vector for pneumocystis (if any) has not been defined. Toxoplasma is an obligate intracellular parasite, whereas the available evidence suggests that Pneumocystis carinii exists primarily extracellularly. In compromised hosts, pneumocystis infection usually involves only lungs, whereas toxoplasma causes a generalized infection with encephalitis being the principal clinical manifestation. Both types of infection are treated with combinations of folate antagonists (trimethoprim or pyrimethamine with sulfonamide). Both parasites are associated with cytomegalovirus infection in immunosuppressed hosts, an association which may be due to symbiosis between parasites, or to an additive immunosuppressive effect of dual infection on the hosts.

A test system has been developed to evaluate the trypanosomicidal activity of large numbers of candidate drugs. Based on mortality of mice with blood induced Trypanosoma rhodesiense infections, it serves as a primary screen or as a secondary and confirmatory test for active compounds. Over 5,500 selected compounds have been tested; more than 6% were active.

Hydroxystilbamidine (OHSA), an inhibitor of DNA synthesis, was shown to induce the dyskinetoplastic forms (akinetoplastic forms, AK forms) of Trypanosoma gambiense. The mode of appearance of the AK forms after injection of various doses of OHSA into infected mice was examined. The results suggested that production of the AK form is due to the selective inhibition of kinetoplast duplication of the drug without any effect on nuclear and cytoplasmic multiplication. When the parasites were treated with moderate doses of OHSA, segmenting forms without stainable kinetoplasts, were occasionally seen but attempts to establish a clone of akinetoplastic parasite were unsuccessful. Electron microscopy of parasites obtained after OHSA treatment showed not only irregular division of the kinetoplast but also the disorganization of kinetonucleus with disappearance of its envelope. Therefore, it was concluded that the AK forms were also produced by OHSA through disappearance of the kinetoplast.

The type of fungal infection and the immunologic status of the patient determine whether drug therapy should be used. Amphotericin B is the single most important antifungal agent for the treatment of systemic mycoses. Flucytosine is given adjunctively with amphotericin B. Miconazole, a new parenteral agent, may be useful in treating candidiasis, cryptococcosis, paracoccidioidomycosis and coccidioidomycosis. Potassium iodide is used to treat lymphocutaneous sporotrichosis, bronchopulmonary geotrichosis and chromoblastomycosis. Nystatin, tolnaftate, clotrimazole and haloprogin are used for mucocutaneous infections. Griseofulvin is limited to the treatment of skin and nail infections caused by dermatophytes.

The past 40 years have brought great advances in the knowledge of morphology, immunology and epidemiology of fungal infections in man. Each general advance in the science of medicine has had its counterpart in man's improved facility to deal with these infections therapeutically. Although satisfactory control of fungal infections of man is still lacking, productive paths of investigation seem to have been found and the continued application of rigorous discipline to research efforts should provide even more efficient treatment in the future.

The clinical courses of 14 children with acute pulmonary blastomycosis were studied. All the patients had a remarkably similar illness limited to the lungs with fever, malaise, and respiratory symptoms (cough, sputum production, chest pain, and vomiting). Despite eventual recovery with treatment in all instances, 13 of the 14 children persisted in having abnormal roentgenograms. Three children have demonstrated persistent mild obstructive airway disease for two to 12 months after completion of therapy. These data suggest that the initial illness following childhood infections with Blastomyces dematitidis is usually an acute pulmonary disease without systemic dissemination. Evidence of residual lung abnormalities conflicts with the recent concept of this being a benign, self-limited illness. Our findings suggest the importance of long-term follow-up as well as a need for more complete understanding of the full clinical spectrum and prognosis of acute pulmonary blastomycosis.

Two children, aged 3 months and 4 years, respectively, were treated with ten weeks of amphotericin B for culture proved pulmonary blastomycosis. Organisms were easily demonstrated in nasopharyngeal or sputum specimens on admission. Although organisms were present until the 12th and 19th days of therapy, respectively, they were viable through only the seventh and 12th days of therapy. Both patients had thrombophlebitis, anemia, neutropenia, hypokalemia, fever, and vomiting develop during therapy. The less toxic drug hydroxystilbamidine isethionate, given for only 17 to 30 days, has been used successfully in at least six previously reported cases. Long courses of amphotericin B therapy may not be necessary for the treatment of pulmonary blastomycosis in selected children.

Successful chemotherapy of the systemic mycoses now covers a span of more than 75 years and dates to the first reported use of potassium iodide for treatment of sporotrichosis. The second drug with efficacy was stilbamidine, and its currently available successor, hydroxystilbamidine isethionate, still has a role in therapy of some patients with nonprogressive blastomycosis of the skin. The introduction in 1957 of amphotericin B marked the first time there was an effective agent for such diseases as cryptococcosis, histoplasmosis, candidosis, and with lesser success, for coccidioidomycosis, mucormycosis, and aspergillosis. However, amphotericin B is nephrotoxic, depresses bone marrow (especially erythropoeisis), and, if patients are not monitored and controlled closely, the drug produces hypokalemic muscle weakness and cardiotoxicity. Flucytosine has a narrower spectrum of activity (cryptococcosis, candidosis, cladosporiosis, and chromomycosis) but a preferable route of administration (oral). Newer agents presently available are miconazole and clotrimazole; the latter is for topical use only.

Six cases of pulmonary sporotichosis were observed in 2 institutions in Oklahoma City, Okla. Three of the patients were treated with iodides with or without surgery. Although one patient required a second course of iodides, the patients have remained well after at least 34 months of follow-up. Three patients treated with amphotericin B, single course as well as multiple courses, and other antifungal agents (hydroxystilbamidine and miconazole) have all relapsed. These cases and a reviewed of more than 40 cases of pulmonary sporotrichosis susceptibilities of Sporothrix schenckii that we observed in vitro suggest that amphotericin B is not an effective agent for the treatment of pulmonary sporotrichosis. It is our opinion that the treatment of choice for pulmonary sporotrichosis is a supersaturated solution of potassium iodide. If the patient is allergic to the medication or fails to respond, then a combination of amphotericin B plus flucytosine may be tried.

Ten pediatric patients with systemic blastomycosis in Arkansas are reviewed. No particular age predisposition in childhood is apparent and there has been no change in incidence over the previous 40 years. Six of the 10 cases were male and 8 were black. Organ systems most commonly involved were pulmonary, skeletal and skin. With current therapy, usually amphotericin B as a single agent, the case fatality rate is less than 10%. Early recognition and institution of appropriate antifungal treatment remain the most important factors for survival and prevention of chronic pulmonary disease.

The main antifungal agents used for deep-seated mycotic infections are the broad-spectrum antifungal drug amphotericin B, the narrow-spectrum agent flucytosine, and the newer broad-spectrum agents miconazole and ketoconazole. Amphotericin B remains the cornerstone of antifungal therapy. For the treatment of cryptococcal meningitis, the current recommendation is for the combined use of amphotericin B and flucytosine. 2-Hydroxystilbamidine is used only in indolent cases of blastomycosis; however, this condition is usually treated with amphotericin B. Clinical experience with the newer agents is limited. Not all patients from whom fungal agents have been isolated require treatment; the extent of the fungal infection should be determined, when possible, for evaluation of the need for treatment.