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Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pentamidine is an aromatic diamidino compound synthesized originally for the therapy of trypanosomiasis. The pharmacologic effects of pentamidine vary, depending on its route of administration. In animals, the dominant effects have been a precipitous, transitory drop in blood pressure after injection and renal toxicity following repeated administration. To avoid the possibility of immediate toxic reactions associated with iv administration, we now usually give the drug im to humans. Further interest in pentamidine has been stimulated by its usefulness in the treatment of interstitial pneumonia caused by Pneumocystis carinii. In some patients receiving antineoplastic or immunosuppressive therapy who have superimposed P. carinii pneumonia, pentamidine may cause serious renal toxicity. Distribution and excretion studies in animals indicate pentamidine is deposited in tissues, with the greatest concentration in the kidneys, and gradually eliminated over a prolonged period. The mechanism of action of pentamidine against P. carinii or the means whereby fixation in tissues and subsequent toxicity occur have not been elucidated. Recent investigations to help clarify these points indicate that pentamidine inhibits dihydrofolate reductase in all tissues studied both in vitro and in vivo. In addition, pentamidine interacts and forms water-insoluble products with specific nucleotides and nucleic acids.
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PMID:Pharmacologic aspects of pentamidine. 101 18

Pneumocystis carinii pneumonia is a leading cause of morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). Much remains unknown about the basic biology of P. carinii and studies of this infection have been hampered by the lack of cultivation methods. We developed a sensitive and specific assay for P. carinii by utilizing DNA amplification of the P. carinii dihydrofolate reductase (DHFR) gene. By this method, P. carinii DNA was detected in the lungs of rats with experimentally induced P. carinii pneumonia 2 wk before the onset of histopathological changes. DNA amplification analysis of serum demonstrated that by 10 wk of corticosteroid treatment, 12 of 12 (100%) infected rats had circulating DHFR DNA. P. carinii DHFR DNA also was detected in the serum of patients with AIDS and active P. carinii pneumonia (12 of 14 sera collected prospectively). Patients with advanced AIDS but without a history of P. carinii pneumonia were negative by this assay (0 of 6 sera examined). Serum polymerase chain reaction may facilitate investigations into the natural history and epidemiology of P. carinii infection, provide insight into the pathogenesis of parasite dissemination, and offer a useful, noninvasive diagnostic test for the detection of human pneumocystosis.
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PMID:Application of DNA amplification to pneumocystosis: presence of serum Pneumocystis carinii DNA during human and experimentally induced Pneumocystis carinii pneumonia. 140 79

Infections with parasitic protozoa have always been problems for the developing world and are becoming of greater importance to the developed world in this age of easy international travel. The major human protozoal diseases are summarised with an emphasis on their presentation in normal hosts and in immunocompromised individuals and current US drug treatment recommendations are discussed. Present antiprotozoal regimens are based either on a pharmacokinetic rationale or on clinical trial and error. Regimens based on trial and error include amphotericin B against leishmaniasis and arsenic against African trypanosomiasis. Regimens which are to some extent driven by pharmacokinetic or biochemical considerations include paromomycin and metronidazole against amoebiasis, sodium stibogluconate against leishmaniasis, halofantrine and mefloquine against malaria, dihydrofolate reductase (DHFR) inhibitors against Pneumocystis carinii and toxoplasmosis and aerosolised pentamidine against P. carinii pneumonia. The majority of pharmacokinetic studies have been performed only on agents which have some therapeutic activity against other diseases of the developed world. Despite the trend toward rational treatment regimens, no studies have been performed that permit optimisation of antiprotozoal treatment regimens on the basis of clinical conditions such as renal failure.
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PMID:Pharmacokinetic justification of antiprotozoal therapy. A US perspective. 178 41

Amplification of DNA by the polymerase chain reaction (PCR) offers a highly sensitive and specific method for detecting DNA sequences in biological samples. We applied this technology to develop an assay for the P. carinii dihydrofolate reductase (DHFR) gene. This assay was found to be sensitive enough to detect as little as 1 organism-'equivalent' of DHFR DNA. In rats with experimentally-induced P. carinii pneumonia, DHFR DNA amplification demonstrated the presence of pulmonary P. carinii 2 wk prior to the onset of histopathological changes. When rat serum was analyzed by PCR, serum P. carinii DNA was found in 5 of 14 experimental rats. Finally, P. carinii DNA was detected in the serum of 7 of 18 patients (39%) with AIDS and active P. carinii pneumonia. These results suggest that circulating serum P. carinii DNA can be detected frequently in the course of pulmonary infection and may represent a blood-borne phase of infection. The PCR detection of P. carinii DNA provides a useful tool to study the natural history of P. carinii infection and may offer a non-invasive diagnostic procedure in some patients with P. carinii pneumonia.
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PMID:Detection of Pneumocystis carinii in serum of AIDS patients with Pneumocystis pneumonia by the polymerase chain reaction. 181 86

This is a case report of a 31-yr-old homosexual male with AIDS, admitted to our clinic with a relapse P. carinii pneumonitis (PCP) and a previous history of severe adverse reactions to currently used therapy. He was treated successfully with trimetrexate (TMTX), a dihydrofolate reductase inhibitor combined with leucovorin rescue. Adverse reactions, current therapy and prophylaxis of PCP in AIDS are discussed.
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PMID:Relapse Pneumocystis carinii pneumonitis and adverse reaction to current therapy in patients with AIDS: trimetrexate as an alternative. 214 21

Trimetrexate and BW301U (piritrexim isethionate), lipid-soluble inhibitors of dihydrofolate reductase, are potent inhibitors of the growth of Pneumocystis carinii in culture with WI-38 cells. Inhibition was observed with 0.1 microgram of trimetrexate or BW301U per ml. Trimethoprim is ineffective at 100 micrograms/ml in this culture system. Both trimetrexate and BW301U were effective as prophylactic agents against P. carinii pneumonia in rats; trimetrexate at 7.5 mg/kg protected 9 of 10 rats, and BW301U at 5 mg/kg protected 4 of 10.
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PMID:Activity of lipid-soluble inhibitors of dihydrofolate reductase against Pneumocystis carinii in culture and in a rat model of infection. 244 81

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.
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PMID:Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent. 295 Feb

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.
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PMID:Treatment of Pneumocystis carinii pneumonia with trimetrexate in acquired immunodeficiency syndrome (AIDS). 296 85

Trimetrexate is a lipid-soluble antifolate that has been shown in vitro to be a much more potent inhibitor of Pneumocystis carinii dihydrofolate reductase than the conventionally used inhibitor trimethoprim. To evaluate the in vivo efficacy of trimetrexate, steroid-treated rats which spontaneously develop P. carinii pneumonia were used. Rats treated with trimetrexate (25 mg/kg/d) plus sulfamethoxazole (250 mg/kg/d) orally responded at least as well as rats treated with trimethoprim (50 mg/kg/d) plus sulfamethoxazole. Trimetrexate alone administered orally was ineffective in treating P. carinii infection, but subcutaneous (sc) trimetrexate (7 mg/kg/d) significantly decreased the intensity of infection compared to controls. Trimetrexate is a potent antifolate that may provide an effective alternative to pentamidine and trimethoprim-sulfamethoxazole for treatment of P. carinii pneumonia in humans.
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PMID:Efficacy of trimetrexate, a potent lipid-soluble antifolate, in the treatment of rodent Pneumocystis carinii pneumonia. 297 55

To gain further insight into the genetic variability between different isolates of Pneumocystis carinii of rat and human origin, we sequenced three DNA regions from the mitochondrial rRNA gene, the 5S rRNA gene and the dihydrofolate reductase gene (DHFR) of microorganisms isolated from three different immunosuppressed rat sources and from one HIV + patient with P. carinii pneumonia. Some point mutations and deletions were found among rat isolates in two regions (mitochondrial rRNA gene and 5S rRNA gene). Nucleotide sequence variations in these conserved regions support the hypothesis of the existence of several Pneumocystis strains infecting the same host species.
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PMID:Genetic variability in different Pneumocystis isolates from man and rats. 755 73


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