Biomedical subjects

A Martinez

Publications and source records attributed to A Martinez.

At least 109 records · Page 6Linked to original sources

PubMed2000

Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370.

OBJECTIVE: To compare the virologic activity of continued lamivudine (3TC) versus a switch to delavirdine (DLV) when initiating protease inhibitor therapy in nucleoside-experienced patients. DESIGN: Randomized, open-label, multi-center study. SETTING: Adult AIDS clinical trials units. PATIENTS: Protease and non-nucleoside reverse transcriptase inhibitor-naive patients who had received 3TC plus zidovudine (ZDV), stavudine (d4T), or didanosine (ddl) for at least 24 weeks. INTERVENTIONS: Patients with plasma HIV-1 RNA levels > 500 copies/ml who previously received d4T + 3TC or ddI + 3TC were randomized to ZDV + 3TC + indinavir (IDV) or ZDV + DLV + IDV. MAIN OUTCOME MEASURES: Primary endpoints were the proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at 24 weeks, and occurrence of serious adverse events. The proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at week 48 was a secondary endpoint. RESULTS: At week 24, 58% of subjects in the ZDV + 3TC + IDV arm and 73% in the ZDV + DLV + IDV arm had plasma HIV-1 RNA levels < or = 200 copies/ml (P = 0.29). At week 48, plasma HIV-1 RNA levels were < or = 200 copies/ml in 48% and 83%, respectively (P = 0.007). Rash and hyperbilirubinemia occurred more frequently in the DLV arm than in the 3TC arm. Steady-state plasma IDV levels were higher among patients in the DLV arm as compared with the 3TC arm. CONCLUSIONS: Substituting DLV for 3TC when adding IDV improved virologic outcome in nucleoside-experienced patients. This result might be explained, in part, by the positive effect of DLV on IDV pharmacokinetics.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Effect of alcohol compounds found in hemicellulose hydrolysate on the growth and fermentation of ethanologenic Escherichia coli.

Lignocellulose can be readily hydrolyzed into a mixture of sugars using dilute mineral acids. During hydrolysis, a variety of inhibitors are also produced which include aromatic alcohols from lignin and furfuryl alcohol from pentose destruction. Seven compounds were investigated individually and in binary combinations (catechol, coniferyl alcohol, furfuryl alcohol, guaiacol, hydroquinone, methylcatechol, and vanillyl alcohol). Aromatic alcohols and furfuryl alcohol inhibited ethanol production from xylose in batch fermentations primarily by inhibiting the growth of Escherichia coli LY01, the biocatalyst. The toxicities of these compounds were directly related to their hydrophobicity. Methylcatechol was the most toxic compound tested (MIC = 1.5 g/L). In binary combination, the extent of growth inhibition was roughly additive for most compounds tested. However, combinations with furfuryl alcohol and furfural (furaldehyde) appear synergistic in toxicity. When compared individually, alcohol components which are formed during hemicellulose hydrolysis are less toxic for growth than the aldehydes and organic acids either on a weight basis or a molar basis.

Alcohols↗

PubMed2000

Setup error in radiotherapy: on-line correction using electronic kilovoltage and megavoltage radiographs.

PURPOSE: We hypothesize that the difference in image quality between the traditional kilovoltage (kV) prescription radiographs and megavoltage (MV) treatment radiographs is a major factor hindering our ability to accurately measure, thus correct, setup error in radiation therapy. The objective of this work is to study the accuracy of on-line correction of setup errors achievable using either kV- or MV-localization (i.e., open-field) radiographs. METHODS AND MATERIALS: Using a gantry mounted kV and MV dual-beam imaging system, the accuracy of on-line measurement and correction of setup error using electronic kV- and MV-localization images was examined based on anthropomorphic phantom and patient imaging studies. For the phantom study, the user's ability to accurately detect known translational shifts was analyzed. The clinical study included 14 patients with disease in the head and neck, thoracic, and pelvic regions. For each patient, 4 orthogonal kV radiographs acquired during treatment simulation from the right lateral, anterior-to-posterior, left lateral, and posterior-to-anterior directions were employed as reference prescription images. Two-dimensional (2D) anatomic templates were defined on each of the 4 reference images. On each treatment day, after positioning the patient for treatment, 4 orthogonal electronic localization images were acquired with both kV and 6-MV photon beams. On alternate weeks, setup errors were determined from either the kV- or MV-localization images but not both. Setup error was determined by aligning each 2D template with the anatomic information on the corresponding localization image, ignoring rotational and nonrigid variations. For each set of 4 orthogonal images, the results from template alignments were averaged. Based on the results from the phantom study and a parallel study of the inter- and intraobserver template alignment variability, a threshold for minimum correction was set at 2 mm in any direction. Setup correction was applied by translating the treatment couch in the lateral, superior-to-inferior and vertical directions only. During treatment, kV open-field images were acquired for off-line treatment verification and analysis. Each patient study spanned 2-6 weeks. The 14 patient studies were completed with 8248 electronic images acquired and analyzed. RESULTS: Results from the phantom studies showed that the users were able to detect the applied translational shift to better than 2 mm, and mostly to within 1 mm. The intraobserver variability of template alignment was on the order of 1 mm using a sample of either MV or kV patient images. The difference between using MV or kV images was significant for only a few cases. However in most cases, interobserver alignment variability was larger when using MV images than kV. For on-line setup correction, the study procedure added 10 min. to conventional treatment time. Setup variation measured with either kV- or MV-localization images was similar. The initial magnitude of setup error was appreciable, with a mean displacement of about 6.6 +/- 2.4 mm for the 14 patients. On-line correction using either kV- or MV-localization images improved setup accuracy. Over all study patients, setup errors occurred with standard deviations greater than 2 mm in any direction with a frequency of 48% before correction, and were reduced to 16% after correction. On average, kV image-based correction reduced radial setup variation to 2.6 +/- 1.6 mm compared to the 3.3 +/- 1.8 mm attained using MV images. The difference detected between the kV and MV data was not statistically significant when averaged over all patients. However, for on-line corrections in the neck and thoracic regions, using kV-localization images reduced setup error significantly more than using MV images. CONCLUSIONS: In our anatomic template alignment study, interobserver variability was smaller using kV images than MV images. Intraobserver variability was smaller for alignments on kV images

Calibration↗

PubMed2000

Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy. METHODS: We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia. RESULTS: A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002). CONCLUSIONS: Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy.

AIDS-Related Opportunistic Infections↗

PubMed2000

Treatment of skin carcinomas of the face by high-dose-rate brachytherapy and custom-made surface molds.

PURPOSE: To analyze the results obtained in a prospective group of patients with basal or squamous cell skin carcinomas of the face treated by high-dose-rate (HDR) brachytherapy via custom-made surface molds. METHODS AND MATERIALS: A total of 136 patients with basal or squamous cell carcinomas of the face were treated between March 1992 and March 1997 by surface molds and HDR brachytherapy with iridium-192. Nineteen patients were treated with standard Brock applicators and 117 patients with custom-made polymethyl methacrylate applicators, built over a plaster mold obtained of the patient's face. Minimum dose administered to the tumor was 6000 to 6500 cGy in 33 to 36 fractions at 180 cGy/fraction in lesions of up to 4 cm. Lesions greater than 4 cm were boosted up to 7500-8000 cGy after a 3-week pause. RESULTS: With the custom-made surface molds, the dose distribution was uniform in the surface of the skin and at 5 mm depth in the whole area of the applicator. Differences between the areas of maximum and minimum dose at this depth never reached values higher than 5% of the prescribed dose. At the edges of the custom-made molds dose gradient was sharp, with the detected dose at 5 mm from the applicator being negligible. All the patients were complete responders. There were 3 local recurrences, 1/73 patients treated for primary tumor and 2/63 patients treated for recurrent tumor. Actuarial local control at 5 years for all patients was 98%, for those patients with primary tumors 99%, and for recurrent patients 87%. The treatment tolerance was excellent in all cases. No severe, early, or late, complications were detected. CONCLUSIONS: Radiotherapy is a highly effective treatment of skin carcinomas of the face. Custom-made molds, to be used in conjunction with HDR brachytherapy equipment, make possible a uniform dose distribution, with a sharp dose gradient in the limits of applicators. Custom-made surface molds are easy and safe to use, and they fit very accurately for daily treatment. Local control is excellent with minimal sequelae or complications. Probably they will become the standard way of treatment of face skin carcinomas in the near future.

Adult↗

PubMed2000

In search of the language switch: An fMRI study of picture naming in Spanish-English bilinguals.

For many years, researchers investigating the brain bases of bilingualism have concentrated on two basic questions. The first concerns the nature of language representation. That is, are a bilinguals' two languages represented in distinct or overlapping areas of the brain. The second basic question in the neuropsychology of bilingualism concerns the neural correlates of language switching, that is, the areas that are active when bilinguals switch from one language to the other. Performance between single-language and dual-language picture naming was compared in a group of six Spanish-English bilinguals using behavioral measures and functional magnetic resonance imaging. Participants showed slower reaction times and increased activation in the dorsolateral prefrontal cortex in the mixed language condition relative to single language condition. There was no evidence that each language was represented in different areas of the brain. Results are consistent with the view that language switching is a part of a general executive attentional system and that languages are represented in overlapping areas of the brain in early bilinguals.

Adult↗

PubMed2000

Characterisation with stable isotopes of the presence of a lag phase in the gastric emptying of liquids.

BACKGROUND: Gastric emptying of non-nutrient liquids usually lacks the presence of an initial delay phase (lag phase), and so it has been considered to be monoexponential with an initial rapid phase followed by a slower emptying phase. However a lag phase in the gastric emptying of liquids can be found if there is a high caloric density in the liquid meal. AIM OF THE STUDY: To characterise with stable isotopes the presence of a lag phase in the gastric emptying of non-solid meals. METHODS: Healthy volunteers ingested a low caloric liquid meal (345 KJ/ 200 mL) (LCLM), a high caloric liquid meal (1135 KJ/180 mL) (HCLM) or a semisolid meal (1403 KJ/500 mL) (SSM). Test meals were labelled with 13C-acetate. Breath samples were collected for 13CO2 measurement and data were fitted to a power exponential function. RESULTS: Non-solid meals can have different behaviour related to the initial emptying. The presence of a lag phase in the gastric emptying of liquids was not masked by the processing of the tracer previous to its detection in breath. While the LCLM and SSM showed a rapid initial emptying phase (no lag phase), the HCLM has an initial slow emptying phase. The slower gastric emptying of the HCLM compared to the SSM was related to the presence of a lag phase in the gastric emptying of the HCLM. CONCLUSIONS: The 13C-acetate breath test is very accurate to identify and study the lag phase if present of liquid meals.

Acetates↗

PubMed2000

N-Benzylpiperidine derivatives of 1,2,4-thiadiazolidinone as new acetylcholinesterase inhibitors.

A new family of 1,2,4-thiadiazolidinone derivatives containing the N-benzylpiperidine fragment has been synthesised. The acetylcholinesterase (AChE) inhibitory activity of all compounds was measured using Ellman's method and some of them turned out to be as potent as tacrine. Furthermore, compound 13 was as active as tacrine in reversing the blockade induced by tubocurarine at rat neuromuscular junction. Additionally, receptor binding studies provided new lead compounds for further development of alpha2-adrenergic and sigma-receptor antagonists. Molecular dynamic simulation using X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new compounds.

Acetylcholinesterase↗

PubMed2000

Down-regulation of AP1 activities after polarization of vas deferens epithelial cells correlates with androgen-induced gene expression.

Vas deferens epithelial cell subcultures were used to study the sequential regulation of jun/fos proto-oncogene expression and AP1 activities during cell proliferation, polarization and androgen-induced expression of a terminal differentiation marker, i. e. the mvdp gene. Proliferation of epithelial cells is associated with a high expression in the nucleus of most Jun and Fos oncoproteins. After cell seeding on an extracellular matrix which allows polarization and expression of the mvdp gene in response to androgens, AP1 protein accumulation is greatly altered and consists in a loss of JunB, Fra1, FosB and a decrease in c-Fos, c-Jun and Fra2, while JunD remained at the same level. This was correlated with a drop in AP1 binding activity as evaluated by gel shift assay using either AP1 consensus sequence or AP1 binding sites of the mvdp gene promoter region, and in AP1 transactivating activity, as estimated by stable transfection experiments using an AP1 responsive promoter (TRE-TK-luc). Androgens did not significantly influence AP1 activities. On the contrary, stimulation of AP1 proteins by the tumor-promoting phorbol ester caused a decrease in androgen-induced mvdp mRNA accumulation, and this effect was reversed by staurosporine, a potent inhibitor of PKC. Our data suggest that a down-regulation of AP1 activities induced by epithelial cell differentiation is a prerequisite to androgen-induced mvdp gene expression. The high AP1 activities observed during proliferative state or induced in TPA-treated polarized cells, exert a repressive effect on androgen action.

Aldehyde Reductase↗

PubMed2000

Autologous stem cell transplantation for advanced Hodgkin's disease in children. Spanish group for BMT in children (GETMON), Spain.

This study evaluates the outcome of myeloablative chemo-radiotherapy and autologous stem cell transplantation (ASCT) in children with Hodgkin's disease (HD). Twenty children aged 5 to 18 years (median 10.8 years) at diagnosis, with relapsed, refractory or very poor prognosis HD, underwent ASCT in eight hospitals of our country. Status at transplant was: second complete remission (CR2): n = 12; further CR (CR >2): n = 3, partial remission (PR): n = 2, relapse: n = 2 and first CR (CR1): n = 1. Eighteen patients received chemotherapy-based conditioning regimens: cyclophosphamide, carmustine and etoposide (CBV): 11 (55%), carmustine, etoposide, cytarabine and melphalan (BEAM): 5, other: 2; and two patients were conditioned with TBI/Cy. Peripheral blood (PB) was the source of progenitor cells in 12 patients, BM in seven, and BM plus PB, in one. All patients engrafted. One patient died of sepsis and multiorgan failure at day 28 after transplantation. All four patients with measurable disease (PR or relapse) at transplantation attained complete remission. Five patients relapsed 5-34 months after transplant (median: 11 months). Eighteen children remain alive with a median survival time of 40 months. The projected 5-year overall survival and event-free survival (EFS) rates were 0.95 and 0.62. High-dose therapy with stem cell rescue can lead to durable remissions in children with advanced HD. Bone Marrow Transplantation (2000) 25, 31-34.

Adolescent↗

PubMed2000

Lipoatrophic panniculitis and chromosome 10 abnormality.

We report a 3-year-old girl with a 12-month history of an acquired lipoatrophy that was rapidly progressive. Her karyotype revealed additional material on chromosome 10 at the 10q26 location. The human pancreatic lipase gene maps to chromosome 10q24-26, and we postulate an association. Lipoatrophic panniculitis describes the panniculitides in which atrophy is a feature. The classification of these diseases is confusing in the literature and the precise diagnosis still relies on a combination of clinical and laboratory assessment. Our finding of a chromosomal abnormality on chromosome 10q26 has not been described previously.

Child, Preschool↗

PubMed2000

Morphological and structural study of pseudowollastonite implants in bone.

In vitro experiments show that pseudowollastonite (alpha-CaSiO3) is a highly bioactive material that forms a hydroxyapatite surface layer on exposure to simulated body fluid and also to human parotid saliva. This finding is very significant, as it indicates that the pseudowollastonite can be physically and chemically integrated into the structure of living bone tissue, and therefore could be suitable for repair or replacement of living bone. The physical and chemical nature of the remodelled interface between the pseudowollastonite implants and the surrounding bone has been studied after in vivo implantation of 20 pseudowollastonite cylinders into rat tibias. The interfaces formed after 3, 6, 8 and 12 weeks of implantation were examined histologically using an optical microscope and also by analytical scanning electron microscopy. SEM and X-ray elemental analysis showed that the new bone was growing in direct contact with the implants. Other examinations found that the bone was fully mineralized. The ionic exchange taking place at the implant interface with the body fluids was essential in the process of the implant integration through a dissolution-precipitation-transformation mechanism. The study found the interface biologically and chemically active over the 12-week implantation period. The rate of new bone formation decreased after the first 3 weeks and reached constant value over the following 9 weeks. The osteoblastic cells migrated towards the interface and colonized the surface at the contact areas with the cortical regions and also bone marrow.

Animals↗

PubMed2000

Titanium for removable denture bases.

The aim of the present study was to compare titanium-base and resin-base maxillary complete dentures. In 13 patients with a maxillary complete denture with a titanium base (group I) and in 12 patients with a maxillary complete denture with a resin base (group II), the (a) patient's adaptation to the denture, (b) denture retention and (c) appearance of the mucosa under the denture were evaluated. In all cases, the adaptation was assessed with a questionnaire, while the retention and the appearance of the mucosa were assessed by clinical examination. None of the three measures considered (adaptation, retention and mucosa appearance) differed significantly between patients with titanium-base dentures and patients with resin-base dentures. Titanium bases are suitable for dentures likely to be subject to severe mechanical stresses (as in the case of maxillary complete dentures opposing natural teeth), and in patients who show hypersensitivity responses to other materials.

Acrylic Resins↗

PubMed2000

Skeletal muscle kinetics of propofol in anaesthetized sheep: effect of altered muscle blood flow.

1. The kinetics of propofol were studied in vivo in a skeletal muscle bed of the hindlimb of the anaesthetized sheep at normal and low rates of blood flow. 2. Propofol kinetics in muscle were determined during and after a 20-min i.v. infusion of propofol (10 mg min-1) via paired arteriofemoral venous blood sampling. One-and-a-half hours later, the study was repeated but with a concurrent left femoral artery infusion of adrenaline (0.004 mg min-1) to lower the muscle blood flow by vasoconstriction. 3. Muscle blood flow in the low flow state was 28% of that in the normal state. The kinetics were poorly described by a single flow-limited compartment model, but were better described by a model with a flow-limited component and a deeper distribution component. There were no significant differences in muscle retention of propofol between normal and low flow states. 4. There was an apparent arteriovenous shunt of approximately 24% of total muscle blood flow for the low flow state, but not for the normal blood flow state.

Adrenergic Agonists↗

PubMed2000

Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response.

The effects of 1 year of zidovudine, lamivudine, and ritonavir treatment on immune reconstitution were evaluated in 34 human immunodeficiency virus (HIV)-infected individuals. After 48 weeks of therapy, 20 (59%) subjects had <100 copies HIV RNA/mL. CD4+ T cells increased from a median of 192/mm3 at baseline to 362/mm3 at week 48. Lymphocyte proliferative responses to Candida normalized within 12 weeks, but responses to HIV and tetanus remained depressed throughout therapy. Alloantigen responses increased within 12 weeks and then declined to baseline levels. Recovery of delayed-type hypersensitivity responses occurred after 12 weeks for Candida and after 48 weeks for mumps. The magnitude of virologic suppression was correlated with numeric increases in CD4+ T cells, but not with measures of functional immune reconstitution. Plasma virus suppression <100 copies/mL was not significantly correlated with increases in CD4+ T cells or functional immune reconstitution.

Anti-HIV Agents↗

PubMed2000

Prolonged duration of response to infliximab in early but not late pediatric Crohn's disease.

OBJECTIVES: Tumor necrosis factor-alpha plays a central role in chronic intestinal inflammation of Crohn's disease. Targeting this cytokine with the chimeric monoclonal antibody infliximab has emerged as an effective form of therapy in adult Crohn's disease patients. We sought to determine whether infliximab treatment would benefit pediatric patients with medically refractory Crohn's disease. We also assessed the duration of response, comparing children with early disease to children with long-standing (late) Crohn's disease. METHODS: Fifteen consecutive children (mean age 12.8 +/- 3.2 yr) with medically refractory Crohn's disease were enrolled in a prospective, open-label trial of a single, 5-mg/kg infliximab intravenous infusion. Medically refractory disease was defined as an inability to taper steroids, lack of response to immunomodulator therapy over 4 months, and active disease as measured by the Pediatric Crohn's Disease Activity Index (PCDAI). Primary endpoints included measurements of disease activity (PCDAI), steroid use, and duration of clinical response. RESULTS: In all, 14/15 children (94%) improved after infliximab infusion, with a significant decrease of both PCDAI and daily steroid use by 4 wk. Ten patients (67%) achieved complete remission by 10 wk. Among the 14 patients who responded, three of six children (50%) with early disease maintained clinical response through the 12-month trial period, compared to none of eight children with late disease. There were no serious complications associated with the use of infliximab in any of the patients. CONCLUSIONS: Infliximab is safe and effective in the short-term treatment of medically refractory pediatric Crohn's disease. More importantly, there is a remarkably prolonged duration of response after infliximab therapy in children with early compared to late Crohn's disease.

Antibodies, Monoclonal↗

PubMed2000

Activities of sordarins in experimental models of candidiasis, aspergillosis, and pneumocystosis.

Sordarin derivatives represent a new class of antifungal agents that act as potent inhibitors of fungal protein synthesis and possess a broad spectrum of activity. The in vivo activity of GM193663 and GM237354 was studied in mouse models of disseminated candidiasis and aspergillosis and in a rat model of pneumocystosis. The pharmacokinetic behavior of both sordarin derivatives was studied in mice and rats. In all studies, compounds were administered by the subcutaneous route. After a subcutaneous dose of 50 mg/kg of body weight to mice, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for GM193663 and GM237354 were 51.8 and 23 microg/ml, 79.5 and 46 microg. h/ml, 0.8 and 0.85 h, and 21 and 25 ml/h, respectively. Systemic candidiasis and aspergillosis were established in CD-1 male mice infected with Candida albicans or Aspergillus fumigatus. For systemic candidiasis, compounds were given three times per day for seven consecutive days at 15, 30, 60, or 120 mg/kg/day. GM193663 and GM237354 showed dose-related efficacy against C. albicans, with 50% effective doses, 1 month after infection, of 25.2 and 10.7 mg/kg/dose, respectively. In experimental infections with A. fumigatus, GM237354 was given three times per day at 30, 60, or 120 mg/kg/day for five consecutive days. Animals treated with GM237354 demonstrated irregular responses. The survival of animals treated with GM237354 was 0, 30, and 0% at 30, 60, and 120 mg/kg/day, respectively. The therapeutic efficacy of GM193663 and GM237354 against Pneumocystis carinii was studied in an experimental P. carinii pneumonia (PCP) rat model. After a subcutaneous dose of 10 mg/kg given to rats, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for GM193663 and GM237354 were 6.6 and 7.2 microg/ml, 8.5 and 11.8 microg. h/ml, 0.7 and 0.8 h, and 230 and 133 ml/h, respectively. To induce spontaneous PCP, rats were chronically immunosuppressed with dexamethasone. Infected animals were treated twice daily for 10 days at 0.2, 2, or 10 mg/kg/day. The therapeutic effect was estimated by the reduction in the number of cysts in the lungs of treated versus untreated animals. GM193663 and GM237354 significantly reduced the mean (+/- standard deviation) log number of cysts from 7.6 +/- 0.2 in the untreated group to 4.7 +/- 0.2 and 4.6 +/- 0.1, respectively, when the drugs were administered at a dose of 2 mg/kg/day. The log number of cysts was also reduced in infected animals given lower doses of the compounds (0.2 mg/kg/day). In summary, GM193663 and GM237354 are new sordarin derivatives that may potentially play a major role in the treatment of candidiasis and PCP. Further testing with Aspergillus in other animal models is warranted.

Animals↗

PubMed2000

In vitro pharmacodynamic parameters of sordarin derivatives in comparison with those of marketed compounds against Pneumocystis carinii isolated from rats.

Pneumocystis carinii pneumonia remains one of the most serious complications of immunosuppressed patients. In this study, the in vitro pharmacodynamic parameters of four sordarin derivatives (GM 191519, GM 237354, GM 193663, and GM 219771) have been evaluated by a new quantitative approach and compared with the commercially available drugs pentamidine, atovaquone, and trimethoprim-sulfamethoxazole (TMP-SMX). In vitro activities and in vivo therapeutic efficacies of sordarin derivatives against P. carinii were also evaluated. In vitro activity was determined by the broth microdilution technique, comparing the total number of microorganisms in treated and drug-free cultures by using Giemsa staining. The in vitro maximum effect (E(max)), the drug concentrations to reach 50% of E(max) (EC(50)), and the slope of the dose-response curve were then estimated by the Hill equation (E(max) sigmoid model). Sordarin derivatives were the most potent agents against P. carinii, with EC(50)s of 0.00025, 0.0007, 0.0043, and 0. 025 microg/ml for GM 191519, GM 237354, GM 193663, and GM 219771, respectively. The EC(50)s of pentamidine, atovaquone, and TMP-SMX were 0.025, 0.16, and 26.7/133.5 microg/ml, respectively. The results obtained with this approach showed GM 237354 and GM 191519 to be approximately 35- and 100-fold more active in vitro than pentamidine, the most active marketed compound. All sordarin derivatives tested were at least 5,000-fold more active in vitro than TMP-SMX. The three sordarin derivatives tested in vivo-GM 191519, GM 237354, and GM 219771-showed a marked therapeutic efficacy, defined as reduction of cyst forms per gram of lung. GM 191519 was the most potent (daily dose reducing 50% of the P. carinii burden in the lungs [ED(50)], 0.05 mg/kg/day) followed by GM 237354 and GM 219771 (ED(50)s, 0.30 and 0.49 mg/kg/day, respectively). Good agreement between in vitro parameters and in vivo outcome was obtained when P. carinii pneumonia in rats was treated with sordarin derivatives.

Animals↗