Inhibitors of aspartic proteases in human diseases: molecular modeling comes of age.

The family of aspartic proteases such as cathepsin D, gastricin, pepsin, renin, HIV protease and others have been the subject of molecular modeling in the field of drug design in the last years. The first aspartic protease inhibitor was reported thirty years ago as a renin inhibitor. The success of HIV protease inhibitors in preventing progression to AIDS was based on the transition state analogs of renin inhibitors. Taking these three decades into consideration, an astonishing variety of chemical classes, in vitro and in vivo activities and species specificities of inhibitors of aspartic proteases have been reported. Especially inhibitors of renin, HIV protease and secreted aspartic protease of Candida albicans are covered.

Persistent oral candidosis by non-albicans Candida strains including Candida glabrata in a human immunodeficiency virus-infected patient observed over a period of 6 years.

A 38-year-old woman infected with human immunodeficiency virus (HIV) presented with persistent oral candidosis in which non-albicans Candida strains were the predominant yeasts in most of the examinations performed over a period of 6 years. Oral treatment with fluconazole had no effect on clinical signs of oral candidosis. In 8 of a total of 11 specimens, Candida glabrata, Candida parapsilosis and Candida tropicalis were at least suspected as the causative pathogens of oral candidosis. The non-response to fluconazole in our patient could be explained by in vitro resistance to fluconazole of detected Candida glabrata and Candida tropicalis isolates.

HIV protease inhibitors influence the prevalence of oral candidosis in HIV-infected patients: a 2-year study.

The introduction of HIV protease inhibitors was accompanied by reduction in HIV-associated opportunistic infections. Therefore, we performed a retrospective study of HIV-infected patients to evaluate the effects of therapy with an HIV protease inhibitor (PI) on oral candidosis. This was of special interest, because an important virulence factor of Candida albicans is the secreted aspartic protease (SAP), which is assigned to the same class of aspartic proteases as HIV protease. Sixty-two patients were examined five times over a period of 2 years. There was a hint at a difference in the frequencies of C. albicans carrier state and manifest oral candidosis in favour of treatment with a PI. In addition, loss of Candida colonization and manifest oral candidosis was observed only in patients with elevation of CD4 cells upon PI. This might explain the effect, which also might go back to a direct inhibition of yeast SAP.

Shift from persistent oral pseudomembranous to erythematous candidosis in a human immunodeficiency virus (HIV)-infected patient upon combination treatment with an HIV protease inhibitor.

A 45-year-old human immunodeficiency virus (HIV)-infected patient has suffered for a period of 4 years from recurrent and, later on, persistent oral pseudomembranous candidosis. The Candida isolates proved to be resistant to azole derivates in vitro and in vivo. Treatment with amphotericin B parenterally was successful in February 1996, but had to be stopped when chemotherapy for lymphoma was started. In August 1996, the patient showed a shift from the pseudomembranous to the erythematous type of oral candidosis; antiretroviral combination therapy including the HIV protease inhibitor saquinavir had been started 4 months previously. In July 1997, the patient was still suffering from a persistent oral candidosis of the erythematous type.

[Inpatient behavioral medicine in chronic skin diseases]. / Stationäre Verhaltensmedizin bei chronischen Hautkrankheiten.

Behavioral medicine is a newer approach in the management of various diseases. In the last years, special programs have been developed for atopic dermatitis, psoriasis vulgaris and other chronic skin diseases. An increase in the patient's self-control could be achieved by optimizing the patient's skills in dealing with their skin disease. The article summarizes the principles and procedures of in-patient behavioral medicine, especially the strategies employed by dermatological training groups and psychotherapeutical groups to help the patient deal with their skin disorder.

Candida sake: a relevant species in the context of HIV-associated oropharyngeal candidosis?

Candida sake is routinely identified in the oral cavity of patients infected with the human immunodeficiency virus (HIV) using the commercial identification system ATB 32 C. To establish the prevalence of C. sake and to evaluate this designation repeatedly found using the ATB 32 C system, 94 HIV-infected patients were investigated for the presence of oral candidosis based on clinical and microbiological grounds. A total of 186 Candida isolates from 62 patients were obtained. Using the assimilation assay, C. sake was suspected in 49 isolates, but only seven strains were positively identified according to ATB 32 C. With respect to antifungal susceptibility and clinical parameters the 49 strains did not differ markedly from the other strains. Only antifungal susceptibility to amphotericin B, ketoconazole, and flucytosine was increased in C. sake strains when the positively and equivocally identified strains by ATB 32 C were taken together. In addition, amplifying genomic DNA with primers T3B and AP3, C. sake could not be identified in four strains and in one strain, respectively. Therefore biochemical identification of C. sake seems to be misleading and clinical relevance may be lacking.

Molecular diagnosis of deep nodular bacillary angiomatosis and monitoring of therapeutic success.

A 51-year-old human immunodeficiency virus (HIV)-positive male patient (CDC stage 3C) had had a painful nodule on his external ankle joint for 10 months. A biopsy suggested bacillary angiomatosis, but Kaposi's sarcoma could not be excluded. Rods were detectable in lesional skin by a Warthin-Starry stain. A 298 base pair (bp) gene fragment specific for Bartonella species was amplified from lesional skin and direct nucleotide sequence analysis of the amplification product clearly identified Bartonella quintana. Kaposi's sarcoma-associated herpes virus specific DNA was not amplifiable by polymerase chain reaction (PCR) in our patient, suggesting that the lesion represented bacillary angiomatosis alone, despite clinical and histopathological features which suggested the coexistence of bacillary angiomatosis and Kaposi's sarcoma. The lesion regressed after erythromycin was prescribed. However, 4 and 9 weeks after initiation of therapy, PCR still yielded a positive result in material obtained by a swab. After complete healing, following 12 weeks of antibiotic therapy, PCR became consistently negative. The optimal length of antibiotic treatment in HIV-positive patients with bacillary angiomatosis is not yet known and inadequate therapy may be followed by disseminated disease and a fatal outcome. PCR-based monitoring of the success of treatment is valuable for determining the duration of treatment resulting in a cure.

Single dose, dose-escalating trial with fozivudine tidoxil (BM 21.1290).

BACKGROUND AND OBJECTIVES: In vitro and in vivo experimental data for fozivudine tidoxil [BM21.1290 (FZD) an ether-lipid conjugate of zidovudine] have shown better efficacy, no myelotoxicity and better tolerability compared with zidovudine. Therefore, the objectives of our study were to evaluate the safety of FZD in patients with human immunodeficiency virus (HIV) infection and to establish basic pharmacokinetic data. PATIENTS AND METHODS: In a Phase I dose-escalating trial, seven different single dose applications were studied in 39 patients: 50, 100, 300, 600, 900, 1200 and 1800 mg in capsule and tablet formulations. Inclusion criteria were HIV infection, CD4 count > 100 cells/mm3 and informed consent. Exclusion criteria were active opportunistic manifestations, concomitant zidovudine therapy and neutropenia (< 750 neutrophils/mm3). Safety parameters, 24 h plasma levels and urinary excretion were determined. RESULTS: The tolerance of FZD was excellent up to single doses of 1800 mg. In only one case, a single episode of loose stool was reproducible in a second treatment period and was therefore considered to be a probable drug-related event. In an amendment to the trial, a tablet formulation of FZD did not induce diarrhoea in this patient. FZD was available in measurable concentrations after 2 to 4 h. Maximum concentrations were reached after 4 to 8 h. After normalization for a dose of 100 mg/patient, the mean AUC was 8.6 mg x h/l and the mean Cmax was 1.13 mg/l; t1/2 was 3.78 h. Interestingly, plasma concentrations of zidovudine and zidovudine glucuronide were much lower than with equimolar zidovudine doses. CONCLUSIONS: The zidovudine conjugate FZD is safe and well tolerated at the seven doses tested. Phase II trials are warranted.

The role of Candida albicans secreted aspartic proteinase in the development of candidoses.

Although Candida albicans infections in humans are increasingly frequent, our understanding of the host-parasite relationship is limited. The secreted aspartic proteinase of C. albicans was first described in 1965 and has proved to be a major factor in virulence. This enzyme belongs to the class of aspartic proteinases which includes pepsin and renin in humans. Although found in some fungi, secreted aspartic proteinase is rare in these organisms. While the existence of several isoenzymes may not be fully established, it is now obvious that at least seven different genes encode for secreted aspartic proteinase. Within Candida cells it is located in membrane-bound vesicles. Upon fusion of these subcellular structures within the plasma membrane, the enzyme is released to the environment. In the context of human mucosal diseases it is responsible both for adhesion and invasion. Strains from HIV-infected patients with oral candidosis generally exhibit higher enzymatic activity than control strains. In future secreted aspartic proteinase may prove a prime target for new types of antimycotics.

[Porphyria cutanea tarda (type 1) in HIV infection]. / Porphyria cutanea tarda (Typ 1) bei HIV-Infektion.

A HIV-infected patient in stage CDC 3A with porphyria cutanea tarda (type I) was treated with chloroquin for some months and this led to full remission. The patient course is compared with earlier reports on HIV-infected patients with porphyria cutanea tarda. Possible provocation factors for porphyria cutanea tarda in HIV infection are considered. The increased prevalence of porphyria cutanea tarda in HIV infection, the interaction of HIV and UV irradiation as a prediposing factor for porphyria cutanea tarda and the photosensitivity present in HIV infection are discussed.

[Historical development of skin surface microscopy]. / Historische Entwicklung der Auflichtmikroskopie.

Within the last decade, skin surface microscopy has been rediscovered as an useful technique for preoperative diagnosis of pigmented skin lesions. This method was originally developed early this century as one component of "functional diagnosis" in constitutional pathology.