Necatoriasis: treatment and developmental therapeutics.

Two hookworm parasites, Necator americanus and Ancylostoma duodenale, infect approximately one billion people worldwide. These hookworms are one of the leading causes of iron-deficiency anaemia especially in children, resulting directly from intestinal capillary blood loss following the feeding activities of fourth-stage (L(4)) larva and adult worms. If ignored, human hookworm infections can retard growth and the intellectual development of children. Another clinical manifestation often associated with hookworm infections is cutaneous larva migrans (CLM). It is a well recognised, usually self-limiting condition caused by the infectious larvae of nematodes, especially Ancylostoma spp. CLM is characterised by skin eruption and represents a clinical description rather than a definitive diagnosis. Of the hookworm parasites, the dog and cat worm A. braziliense and A. caninum are the most common nematodes causing CLM, although many other species have also been implicated. The major subject of this review article will be discussion of the evolution of therapies and treatment of human necatoriasis and the development of experimental infections with N. americanus. Difference in the clinical efficacy of mebendazole and albendazole will be discussed along with drug resistance of N. americanus.

Parasitic infections. Treatment and developmental therapeutics. 1. Necatoriasis.

Necator americanus is a nematode hookworm of the family Ancylostomatidae, subfamily Necatorinae. This nematode parasite, which is distinguished by two chitinous cutting plates in the buccal cavity and fused male copulatory spicules, is the causative agent of necatoriasis, a hookworm disease prevalent in the Americas as well as in the tropical regions of Africa, southern Asia, and Polynesia. The adult parasites attached to the villi of the small intestines will suck blood causing abdominal discomfort, diarrhea and cramps, anorexia, wight loss, and in advanced disease, hypochromic microcytic anemia. Hookworm infections in man, especially in children, are one of the leading causes of iron-deficiency anemia resulting directly from intestinal capillary blood loss following the feeding activities of fourth-stage (L4) larva and adult worms. Another clinical manifestation often associated with hookworm infections is cutaneous larva migrans (CLM). It is a well recognized, usually self-limiting condition caused by the infectious larvae of nematodes. CLM is characterized by skin eruption and represents a clinical description rather than a definitive diagnosis. Of the hookworm parasites, the dog and cat worm Ancylostoma braziliense is the most common causing CLM, although many other species have been implicated. The major subject of this review article will be discussion of the evolution of therapies and treatment of human necatoriasis and the development of experimental infections with N. americanus. Difference in the clinical efficacies of mebendazole and albendazole will be discussed along with drug resistance of N. americanus.

Management of toxoplasmosis.

Toxoplasma gondii, an intracellular coccidian protozoan, is the causative agent of toxoplasmosis, a widespread infection affecting various birds and mammals including humans. In immunocompetent hosts, the infection is usually asymptomatic and benign. Toxoplasmosis is either congenital or acquired. In general, prenatal therapy of congenital toxoplasmosis is beneficial in reducing the frequency of infant infection. Therapies are based primarily on spiramycin because of the relative lack of toxicity and high concentrations achieved in the placenta. Clindamycin is the standard drug for chemoprophylaxis in newborn infants, and is directed at preventing the occurrence of retinochoroiditis as a late sequel to congenital infection. The standard treatment for acquired toxoplasmosis in both immunocompetent and immunodeficient patients is the synergistic combination of pyrimethamine and sulphonamides. Toxoplasmic encephalitis is the most common manifestation of acquired toxoplasmosis in immunocompromised patients and if not treated is fatal. However, because of toxicity, the therapeutic efficacy of pyrimethamine-sulphonamide combinations may be seriously limited in immunodeficient patients. A number of novel and less toxic agents are being currently studied in clinical settings, including macrolide antibiotics (clindamycin, clarithromycin and azithromycin) and atovaquone, as well as some older anti-infective drugs such as cotrimoxazole (trimethoprim/sulfamethoxazole). Maintenance or prophylactic therapy is essential in many patients with acquired immunodeficiency syndrome (AIDS) where toxoplasmosis is most often the result of a pre-existent latent infection.

Treatment and developmental therapeutics of Mycobacterium avium complex (MAC) infections.

Opportunistic infections associated with AIDS pose very serious problems because of their exceedingly high morbidity and mortality. For their part, Mycobacterium avium and M. intracellulare, two organisms belonging to M. avium complex (MAC), are the most often isolated bacteria from AIDS patients. Although in recent years, some progress has been made, by and large, there is no viable drug and /or combinations of drugs effective against MAC, especially in AIDS patients. Conventional therapies with multiple drug combinations involving isoniazid, rifampin, ethambutol, streptomycin, ethionamide, and cycloserine are still widely used, as well as prophylactic treatment with rifabutin. The use of clofazimine and ciprofloxacin has also been reported. Studies on new quinolones (sparfloxacin, difloxacin, WIN 57273), macrolides, folate antagonists and antimcobacterial anitbiotics are being actively pursued along with novel strategies involving drugs inhibiting mycobacterial cell wall biosynthesis. The role of various cytokines in enhancing host immune defenses against MAC infections is also discussed.

Treatment and developmental therapeutics in aspergillosis. 1. Amphotericin B and its derivatives.

In recent years, the frequency of infections caused by Aspergillus sp. has been on the rise. Immunocompromised patients are especially vulnerable to such infections. The polyene antibiotic amphotericin B is currently considered to be therapeutically the most effective drug against Aspergillus-induced infections. In the present review, the clinical efficacy of amphotericin B, its toxicities and various routes of applications, are discussed. Different combinations of amphotericin B with other drugs have also been reviewed, along with the anti-Aspergillus activity of various other antibiotics and some ester derivatives of amphotericin B.

Treatment and developmental therapeutics in aspergillosis. 2. Azoles and other antifungal drugs.

The present article surveys the anti-Aspergillus activity of various azole derivatives as well as a number of miscellaneous other antifungal agents. The drawbacks of sodium (potassium) iodide therapy in the management of pulmonary aspergilloma are discussed along with current efforts at treatment of allergic bronchopulmonary aspergillosis and Aspergillus-induced otomycosis.

Studies on antifungal agents. Novel cis-5-alkyl (or alkenyl)-3-phenyl-3-(1H-azol-1-ylmethyl)-2-methyl-isoxazolidine derivatives.

The preparation and in vitro antifungal activity of a novel series of cis-5-alkyl (or alkenyl)-3-phenyl-3-(1H-azol-1-ylmethyl)-2-methylisoxazol idines are described. The overall activity of the 3-(1H-imidazol-1-ylmethyl) analogues was higher than that of the corresponding 3-(1H-1,2,4-triazol-1-ylmethyl) derivatives. Compound 4b emerged as the most potent derivative. When compared to ketoconazole, several of the analogues tested demonstrated equipotent or superior activity against Trichophyton and Candida sp.

Studies on antifungal agents. 19. Effect of the C-5-aromatic substitution on the in vitro activity of novel 3,5-substituted isoxazolidines.

The influence of the C-5-aromatic substitution on the in vitro antifungal activity of novel cis-3,5-substituted isoxazolidine derivatives was investigated. Compounds having a C-5-(substituted phenoxy)methyl group were found to be the most active against Trichophyton rubrum, Aspergillus fumigatus and Candida albicans with MIC values ranging from 0.7 to 70.0 micrograms/ml. Replacing the phenoxymethyl group with either naphthyl or 2-oxo-1,3-benzoxathiol-6-yl groups resulted in a diminished in vitro activity.

Drug-induced modifications of the immune response. 12. 4,5-Dihydro-4-oxo-2-(substituted amino)-3-furancarboxylic acids and derivatives as novel antiallergic agents.

The synthesis of a series of novel 4,5-dihydro-4-oxo-2-(substituted amino)-3-furancarboxylic acids, salts, esters, and amides is described. The title compounds when tested in the mediator-induced dermal vascular permeability and active anaphylaxis assays in rats demonstrated moderate to potent antiallergic activity. The [2-trans-(4-methylphenyl)cyclopropyl]amino analogue 53 emerged as the most active derivative. Thus, when administered intraperitoneally to rats at a dose of 100 mg/kg, it inhibited the action of the mediators serotonin, histamine, and bradykinin by 100%. In the active anaphylaxis assay in rats, compound 30 suppressed the edema by 81% at a dose of 100 mg/kg, following intraperitoneal administration.

Studies on antifungal agents. 23. Novel substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)- 2-alkylisoxazolidine derivatives.

The synthesis and antifungal activity of a novel series of substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)-2-alkylisoxazolidine derivatives (15-30) are described. The synthesis of the title compounds was accomplished via a 1,3-dipolar cycloaddition reaction of alpha-substituted ketonitrones with appropriate styrene precursors. The compounds when tested in vitro in solid agar cultures exerted a very potent antifungal activity against a wide variety of yeast and systemic mycoses and dermatophytes, especially Trichophyton and Microsporum sp., Epidermophyton floccosum and Candida stellatoidea. The in vitro activity against Aspergillus fumigatus and Candida albicans was moderate to potent. Overall, the two bis(4-chlorophenyl) analogues 18 and 19 were the most potent in vitro compounds, showing MIC values ranging between 0.2 and 7.0 microgram/mL, as compared to 0.2-20.0 micrograms/mL for ketoconazole, which was used as the positive standard in all assays. When tested in vivo in the rat vaginal candidiasis model, derivative 18, although showing significant antifungal activity when compared to controls, was less effective than ketoconazole. The title 3,5-substituted isoxazolidine compounds represent a novel class of potent antifungal agents.

Substituted spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1(3,7)]decane] derivatives.

The preparation and potential anti-inflammatory activity of a series of novel substituted spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1(3,7)]decanes] (7, 11-30) are reported. The synthesis of the title compounds was accomplished via a 1,3-dipolar cycloaddition reaction of nitrones with appropriate olefins.

Synthesis and immunomodulating activity of 5H-thiazolo[2,3-b]quinazolin-3(2H)-one.

The synthesis and immunomodulating activity of 5H-thiazolo[2,3-b]quinazoline-3(2H)-one (7) are described. When tested in the Kennedy plaque assay, 7 exerted immunosuppressive activity on IgM production in female C3H mice sensitized with sheep erythrocytes.