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Biomedical subjects

H Masur

Publications and source records attributed to H Masur.

At least 181 records · Page 10Linked to original sources
PubMed1988

Treatment of Pneumocystis carinii pneumonia with trimetrexate in acquired immunodeficiency syndrome (AIDS).

In vitro studies have shown that trimetrexate, a lipid-soluble analogue of methotrexate, is 1500 times more potent than trimethoprim as an inhibitor of dihydrofolate reductase from Pneumocystis carinii. Furthermore, trimetrexate is readily taken up by P carinii, while performed folates such as leucovorin are not. These observations suggest that the combination of trimetrexate plus leucovorin, which can specifically protect mammalian host tissues from the toxic effects of the antifolate, may be useful in the treatment of pneumocystis pneumonia. This concept was tested in a clinical study of 49 patients with acquired immunodeficiency syndrome (AIDS) and P carinii pneumonia who were treated for 21 days with trimetrexate and leucovorin. Patients were divided into three groups: 16 patients who were unable to tolerate or had failed both pentamidine isethionate and trimethoprim-sulfamethoxazole therapy were treated with trimetrexate plus leucovorin (Group I); 16 patients who were unable to tolerate sulfonamide therapy were treated with trimetrexate with leucovorin as initial therapy (Group II); and 17 patients in whom trimetrexate with leucovorin plus sulfadiazine was used as initial therapy (Group III). Response and survival rates were 69% and 69% in Group I; 63% and 88%, respectively, in Group II; and 71% and 76%, respectively, in Group III. Toxicity was minimal. The results indicate that trimetrexate with leucovorin is safe and effective for initial therapy in AIDS patients with P carinii pneumonia and in those intolerant or unresponsive to standard therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Treatment and prophylaxis of Pneumocystis carinii pneumonia.

Trimethoprim-sulfamethoxazole and parenteral pentamidine isethionate are effective in 60 to 80 per cent of AIDS patients with pneumocystis pneumonia. Adverse reactions are frequent with both agents, but because the adverse reactions are less severe with trimethoprim-sulfamethoxazole, this agent is the drug of choice for patients who are not known to be intolerant of it. The recommended duration of therapy is 21 days. Aerosolized pentamidine and intravenous trimetrexate are investigational agents that show considerable promise, but their role in the therapy of pneumocystis pneumonia will have to be demonstrated in controlled trials. For patients who fail to respond to conventional agents after 5 to 10 days of therapy, therapeutic alternatives to consider would be trimetrexate, DFMO, or high-dose corticosteroids, the latter given with conventional agents. Prophylaxis against pneumocystis pneumonia is appropriate for HIV-infected patients with fewer than 300 T4 lymphocytes per cu mm, even if they are receiving zidovudine (Retrovir). It also should be considered in patients with a prior history of this infection, irrespective of the T4 count. The efficacy of trimethoprim-sulfamethoxazole, pyrimethamine-sulfadoxine, or aerosolized pentamidine has not yet been substantiated. Many patients cannot tolerate the first two combinations chronically.

Acquired Immunodeficiency Syndrome↗
PubMed1988

[Methodology and normal values for the recording of evoked muscle potentials following stimulation over motor roots].

In 28 healthy subjects the peripheral nervous system was stimulated with brief high-voltage condenser discharges over the vertebral column. Latencies were correlated with the length of the extremity. The following normative data were obtained: M. biceps brachii 5.2 ms (SD 0.37 ms), M. abductor pollicis 14.2 ms (SD 0.86 ms), M. tibialis anterior 16.2 ms (SD 1.0 ms), M. extensor digitorum brevis 25.0 (SD 1.3 ms). Comparison of these latencies with those obtained by F-wave studies support the idea that motor roots are stimulated by this method.

Electric Stimulation↗
PubMed1988

[Findings in the peripheral motor system following stimulation of the motor nerve roots: polyradiculitis, amyotrophic lateral sclerosis and polyneuropathy].

The peripheral nervous system was stimulated over the vertebral column by brief, high-voltage condenser discharges. Potentials from proximal and distal muscles were recorded. We examined healthy subjects (N = 28), patients suffering from ALS (N = 5), from polyradiculitis (N = 6), and polyneuropathies (N = 8). In ALS latencies were slightly (in most cases less than 20%), in polyradiculitis latencies were markedly increased (30-40% on average). The latencies of patients suffering from polyneuropathies showed a variable pattern of vulnerability. Moreover, we could show that this method is frequently capable to quantify deficits in the peripheral nervous system when F-waves are absent.

Amyotrophic Lateral Sclerosis↗
PubMed1987

Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent.

The therapy of Pneumocystis carinii (PC) pneumonia is often unsuccessful, particularly in patients with acquired immune deficiency syndrome (AIDS). Because of difficulties in growing the organism in vitro or obtaining purified organisms, current treatment choices have been made with little information on the metabolic effects of therapeutic agents on PC. This report quantitates the effects of the commonly used antifolates as well as the classic antineoplastic antifolate methotrexate and a lipid-soluble analogue, trimetrexate, on the target enzyme, dihydrofolate reductase (DHFR), in the PC organisms. Trimethoprim and pyrimethamine were found to be weak inhibitors (ID50 = 39,600 and 2,800 nM, respectively), while methotrexate and trimetrexate were potent reductase inhibitors (ID50 = 1.4 and 26.1 nM, respectively). transport studies with radiolabeled compounds showed that compounds with the classic folate structure (methotrexate and leucovorin) were not taken up by the intact PC organisms. In contrast, trimetrexate exhibited rapid uptake. These results suggest a major therapeutic advantage may be gained by combining a potent, readily transported PC DHFR inhibitor such as trimetrexate with the reduced folate leucovorin to achieve a highly potent antiprotozoan effect while preventing toxicity to mammalian cells.

Biological Transport↗
PubMed1987

Combination chemotherapy of disseminated Kaposi's sarcoma in patients with the acquired immune deficiency syndrome.

Two clinical trials were conducted to assess the efficacy and safety of a combination chemotherapy regimen for the treatment of Kaposi's sarcoma in patients with the acquired immune deficiency syndrome (AIDS). Eighteen consecutive patients with disseminated Kaposi's sarcoma were treated with a six-drug regimen of doxorubicin (Adriamycin), vinblastine, bleomycin/actinomycin D, vincristine, dacarbazine (ABV/ADV). A brief partial or complete response was achieved in 13 patients. Most patients died of opportunistic infections. Eighteen consecutive patients with disseminated Kaposi's sarcoma were then randomly assigned to therapy with either recombinant alpha interferon or ABV/ADV. The treatment responses in these two groups were comparable to results of earlier trials, and the incidence of opportunistic infections during therapy did not differ between the two treatment arms. It is concluded that chemotherapy is effective and safe for use in palliative management of Kaposi's sarcoma in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Potent effect of trimetrexate, a lipid-soluble antifolate, on Toxoplasma gondii.

Trimetrexate, a lipid-soluble antifolate, has considerably greater activity in inhibiting the dihydrofolate reductase of Toxoplasma gondii than do the conventional antifolates pyrimethamine and trimethoprim. In an investigation of the effect of trimetrexate on T. gondii, in vitro and in vivo studies were undertaken with peritoneal macrophage cultures and acutely infected mice. Against T. gondii cultured in mouse peritoneal macrophages, 10(-7) M trimetrexate inhibited replication of the organism compared with 10(-6) M pyrimethamine and 10(-4) M trimethoprim. In acutely infected mice, trimetrexate alone prolonged survival and, when combined with sulfadiazine, allowed 93%-100% of mice to survive. These studies suggest that trimetrexate alone or combined with a sulfonamide may provide a safe and effective alternative to pyrimethamine plus sulfonamide for the treatment of T. gondii diseases.

Animals↗
PubMed1987

Cardiovascular effects and safety of intravenous and intramuscular pentamidine isethionate.

Intramuscular (im) pentamidine isethionate can cause substantial local pain and inflammation at the injection site. This drug is being used more frequently in recent years to treat Pneumocystis pneumonia, particularly in patients with acquired immunodeficiency syndrome. Clinicians began administering it iv despite warnings that iv administration might cause severe hypotension. We investigated the safety of im and iv pentamidine, monitoring hemodynamics after each dose in 11 patients with intra-arterial lines. Results showed only a small (but statistically significant) fall in mean arterial pressure after both im and slow (60 min) iv administration. A concomitant decrease in pulse occurred, but no change in cardiac output, pulmonary capillary occlusion pressure or systemic vascular resistance was noted. These results suggest that it may be safe to infuse pentamidine slowly intravenously. This route is more comfortable to patients than im administration.

Amidines↗
PubMed1987

Histoenzymological study of selected dehydrogenase enzymes in Pneumocystis carinii.

The metabolic activity of Pneumocystis carinii cysts was studied histochemically by a tetrazolium dye technique to assess substrate-specific dehydrogenase activity. Lactate dehydrogenase, succinate dehydrogenase, and glutamate dehydrogenase produced moderate-to-strong reactions in the cysts, whereas glucose-6-phosphate dehydrogenase had little if any reactivity. These results suggest that pneumocystis cysts have some of the enzymes necessary for glycolysis, Krebs cycle activity, and intermediary protein metabolism. These studies provide a method of directly assessing metabolic pathways in P. carinii which circumvents the uncertainties of specificity inherent in previous investigations with partially purified suspensions.

Animals↗
PubMed1987

Detection of Pneumocystis carinii by fluorescent-antibody stain using a combination of three monoclonal antibodies.

A combination of three monoclonal antibodies, two prepared against human and one against rat Pneumocystis carinii, was used in an indirect fluorescent-antibody stain (IFA) to diagnose P. carinii in both bronchoalveolar lavage and lung biopsy specimens. This combination of monoclonal antibodies was specific for P. carinii and yielded bright fluorescence of both P. carinii cysts and trophozoites. A total of 126 specimens from 93 patients were stained for P. carinii by a toluidine blue O stain and the monoclonal IFA. Forty-five (35.7%) of these were positive for P. carinii by toluidine blue O, and 43 (34.1%) were positive by IFA. There was 98.4% agreement between both methods, with no false-positive and two false-negative occurrences by IFA. An IFA procedure with monoclonal antibodies such as those used in these studies can provide a simple, fast, and sensitive method for diagnosing P. carinii pneumonia by microbiology laboratories.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Acquired immunodeficiency syndrome: Ga-67 citrate imaging.

All gallium-67 citrate scans obtained in patients with acquired immunodeficiency syndrome (AIDS) at the Clinical Center, National Institutes of Health (Bethesda, Md.) were retrospectively analyzed and correlated with the results of bronchoscopy, chest radiography, and endoscopy. There were 164 scans of 95 patients. Twenty scans were from patients with Pneumocystis carinii pneumonia; 19 were abnormal, for a sensitivity of 95%. Ga-67 uptake tended to be less in patients receiving therapy for P. carinii pneumonia. Chest radiographs were normal at least initially in three patients with abnormal scans and P. carinii pneumonia. Unusually prominent colonic activity was associated with infection in some patients. No lesions of Kaposi sarcoma showed tracer uptake. Gallium scanning is useful for detecting P. carinii pneumonia and other opportunistic infections in patients with AIDS, but it is not useful for localizing Kaposi sarcoma.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia.

To assess determinants of prognosis for 43 patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia, objective clinical and histopathologic characteristics were analyzed for acute and long-term prognostic significance. Severe abnormalities on initial chest radiographs and alveolar-arterial oxygen differences (AaPO2) greater than 30 mm Hg were associated with higher mortality during the period of treatment for the acute episode (p less than 0.05). Decreased long-term survival after the diagnosis of Pneumocystis pneumonia correlated with the severity of interstitial edema (a component of diffuse alveolar damage) on initial transbronchial biopsy and elevation of AaPO2 at the time of diagnosis (Cox proportional hazards analysis, p less than 0.05). The persistence of Pneumocystis cysts after 3 wk of therapy was associated with significantly decreased long-term survival (p less than 0.05) when follow-up biopsy was performed in 27 of the patients. Patients with a diagnosis of Pneumocystis pneumonia before July 1985 had more advanced disease at the time of diagnosis and a worse prognosis than did those in whom the diagnosis was made after July 1985 (p less than 0.05). This study demonstrates that important prognostic information can be derived from information obtained at initial presentation and follow-up bronchoscopic evaluation in patients with AIDS and Pneumocystis carinii pneumonia, and suggests that early detection and initiation of therapy may improve chances for survival.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate.

Trimetrexate, a highly lipid-soluble quinazoline antifolate now undergoing trials as an anticancer agent, was found to be a potent inhibitor of the dihydrofolate reductase (DHFR) isolated from Toxoplasma gondii. The concentration required for 50% inhibition of protozoal DHFR was 1.4 nM. As an inhibitor of this enzyme, trimetrexate was almost 600-fold (amount of antifolate required to inhibit catalytic reaction by 50%) and 750-fold (inhibition constant) more potent than pyrimethamine, the DHFR inhibitor currently used to treat toxoplasma infection. When the protozoan was incubated with 1 microM trimetrexate, the drug rapidly reached high intracellular concentrations. Since toxoplasma organisms lack a transmembrane transport system for physiologic folates, host toxicity can be prevented by co-administration of the reduced folate, leucovorin, without reversing the antiprotozoal effect. The effectiveness of trimetrexate against toxoplasma was demonstrated both in vitro and vivo. Proliferation of toxoplasma in murine macrophages in vitro was completely inhibited by exposure of these cells to 10(-7) M trimetrexate for 18 h. When used alone, trimetrexate was able to extend the survival of T. gondii-infected mice.

Animals↗
PubMed1987

Nonspecific interstitial pneumonitis in patients with AIDS: radiologic features.

Chest radiographic abnormalities in patients with AIDS usually are associated with opportunistic infection or neoplasm. One hundred five patients with AIDS and clinical evidence of pneumonitis had chest radiographs and underwent bronchoscopy with bronchoalveolar lavage, transbronchial biopsy, or open-lung biopsy. Chest radiographs were abnormal in 73 (70%). Pneumocystis carinii pneumonia was identified at bronchoscopy or open-lung biopsy in 52 (50%). Nonspecific interstitial pneumonitis occurring in the absence of an identifiable infection was documented histologically in 36 (34%). Twenty (56%) of these 36 patients had abnormal chest radiographs. No currently recognized infectious agents were recovered from lavage fluid or were seen histopathologically in patients with nonspecific interstitial pneumonitis. The results show that nonspecific interstitial pneumonitis is clinically and radiologically indistinguishable from Pneumocystis carinii pneumonitis and should be considered in the differential diagnosis of AIDS patients with interstitial infiltrates.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Nonspecific interstitial pneumonitis: a common cause of pulmonary disease in the acquired immunodeficiency syndrome.

During a 4.4-year period, nonspecific interstitial pneumonitis was seen in 41 of 110 (38%) patients with the acquired immunodeficiency syndrome and accounted for 32% (48/152) of all episodes of clinical pneumonitis. Diffuse alveolar damage was typically a feature of nonspecific interstitial pneumonitis, but neither lung biopsy nor bronchoalveolar lavage detected a pathogen. Of these 41 patients, 13 had no associated pulmonary tumor and had not been exposed to pulmonary toxins, whereas 28 patients had either concurrent pulmonary Kaposi sarcoma, previous experimental therapies, or a history of pneumocystis pneumonia or drug abuse. Of these 41, 23 had normal chest radiographs. The clinical features of patients with nonspecific interstitial pneumonitis were similar to those of patients with pneumocystis pneumonia, although histologic findings showed less severe alveolar damage in patients with nonspecific interstitial pneumonitis (p less than 0.001). Pathologic evaluation and clinical follow-up suggest that many clinical episodes of pneumonitis in patients with the acquired immunodeficiency syndrome are due to nonspecific interstitial pneumonitis of unknown cause.

Acquired Immunodeficiency Syndrome↗