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1.
Int J Pharm ; 499(1-2): 186-194, 2016 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-26768723

RESUMO

Leishmaniasis is a disease caused by parasites of Leishmania sp., which effects nearly 12 million people worldwide and is associated with treatment complications due to widespread parasite resistance toward pathogen-directed therapeutics. The current treatments for visceral leishmaniasis (VL), the systemic form of the disease, involve pathogen-mediated drugs and have long treatment regimens, increasing the risk of forming resistant strains. One way to limit emergence of resistant pathogens is through the use of host-mediated therapeutics. The host-mediated therapeutic AR-12, which is FDA IND-approved for cancer treatment, has shown activity against a broad spectrum of intracellular pathogens; however, due to hydrophobicity and toxicity, it is difficult to reach therapeutic doses. We have formulated AR-12 into microparticles (AR-12/MPs) using the novel biodegradable polymer acetalated dextran (Ace-DEX) and used this formulation for the systemic treatment of VL. Treatment with AR-12/MPs significantly reduced liver, spleen, and bone marrow parasite loads in infected mice, while combinatorial therapies with amphotericin B had an even more significant effect. Overall, AR-12/MPs offer a unique, host-mediated therapy that could significantly reduce the emergence of drug resistance in the treatment of VL.


Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Anfotericina B/administração & dosagem , Anfotericina B/farmacologia , Animais , Antiprotozoários/administração & dosagem , Medula Óssea/parasitologia , Dextranos/química , Feminino , Interações Hidrofóbicas e Hidrofílicas , Leishmaniose Visceral/parasitologia , Fígado/parasitologia , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Microesferas , Polímeros/química , Pirazóis/farmacologia , Baço/parasitologia , Sulfonamidas/farmacologia
2.
Clin Cancer Res ; 6(7): 2677-84, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10914709

RESUMO

Glycinamide ribonucleotide formyltransferase (GARFT) is a component of the de novo purine synthesis pathway. AG2034 is a specific inhibitor of GARFT that was designed based on the GARFT crystal structure. In conjunction with Phase I studies at four clinical centers in the United States and United Kingdom, AG2034 pharmacology was evaluated in 54 patients receiving 1-11 mg/m2 AG2034 as a 2-5 min injection. Blood samples were obtained just prior to and 5, 15, 30, and 45 min, and 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, and 96 h after bolus injection during course 1. Limited sampling was also performed on course 3. Plasma AG2034 was measured using a sensitive and reproducible ELISA assay. AG2034 demonstrated a trimodal elimination pattern over 24 h, with median half-life (t(1/2))alpha = 8.7 min, t(1/2)beta = 72.6 min, and t(1/2)gamma = 364.2 min. AG2034 systemic clearance ranged from 9.4-144.5 ml/min/m2, and volume of distribution was 1.2-7.6 liters/m2. Course 1 AG2034 area under the concentration versus time curve (AUC) had a linear relationship with dose (r(s) = 0.86). Accumulation of AG2034 was evident, because course 3 AUC was higher than course 1 in 23 of 23 evaluable patients, but was not associated with an increase in erythrocyte AG2034. AG2034 systemic exposure had an impact on toxicity, because course 1 and course 3 AG2034 AUCs were significantly higher for patients with grade III/IV toxicity than patients with less than grade II toxicity (P < 0.001 and P = 0.001 for course 1 and course 3, respectively). This study demonstrates rapid systemic clearance of AG2034 and suggests pharmacokinetic approaches that may minimize patient toxicity and aid the development of this interesting class of anticancer agents.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Glutamatos/efeitos adversos , Glutamatos/farmacocinética , Neoplasias/tratamento farmacológico , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Glutamatos/administração & dosagem , Humanos , Hidroximetil e Formil Transferases/antagonistas & inibidores , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Fosforribosilglicinamido Formiltransferase , Pirimidinas/administração & dosagem , Análise de Regressão , Reino Unido , Estados Unidos
3.
Cancer Chemother Pharmacol ; 45(5): 423-7, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10803927

RESUMO

PURPOSE: To identify a recommended phase II dose for the second generation glycinamide ribonucleotide transformylase (GARFT) inhibitor, AG2034, administered by intravenous bolus every 3 weeks without folate supplementation and to describe AG2034 pharmacokinetics. METHODS: Adults with advanced malignancies were enrolled in cohorts of three per dose level with expansion to six upon observation of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was defined as the dose at which two of up to six patients experienced DLT. Upon identification of an MTD and evidence of cumulative toxicity, a lower intermediate dose was explored as a candidate phase II dose. AG2034 plasma concentrations were measured using an ELISA assay. RESULTS AND CONCLUSIONS: The recommended phase II dose is 5.0 mg/m2. DLTs were anemia, thrombocytopenia, mucositis, diarrhea, hyperbilirubinemia, fatigue, and insomnia. Toxicities were modestly cumulative over three courses. Pharmacokinetic analysis showed a dose-AUC0-24 relationship and a progressive increase in AG2034 AUC0-24 over three courses. Both pharmacokinetic and pharmacodynamic factors may contribute to the modest cumulative toxicity observed with AG2034.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Glutamatos/uso terapêutico , Hidroximetil e Formil Transferases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Glutamatos/efeitos adversos , Glutamatos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Fosforribosilglicinamido Formiltransferase , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética
4.
Arthroscopy ; 15(7): 691-708, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10524817

RESUMO

A novel bioabsorbable suture anchor has been introduced for shoulder rotator cuff surgical repair made of the co-polymer 85/15 D,L lactide/glycolide. Previous clinical reports on the use of this material in anterior cruciate ligament reconstruction have described intraosseous edema at various time intervals following implantation. The purpose of this study was to analyze the implant's loss of physical properties and to correlate magnetic resonance imaging (MRI) finding with gross and histological observations at various time intervals after intraosseous implantation in the experimental animal. Six drill holes were made in the tibias of 11 dogs. The spherical implant was placed in 5 of the drill holes and the sixth was preserved as a sham control. The dogs were killed at 3, 4, 6, 9, 12, and 26 weeks for gross and microscopic inspection. Correlative MRIs were taken from the 4-, 12-, and 26-week specimens. Gross inspection showed that the overlying soft tissue healed to bone in 3 weeks. The implants were surrounded by new bone by 6 weeks. The implants maintained gross physical integrity for 6 to 12 weeks. Histologically, there was minimal inflammatory response to the degrading implant. The implant site had been completely replaced by bone at 12 weeks. Correlative MRI showed edema adjacent to the implant sites, but there was no correlative inflammation or cyst formation through the time necessary for complete absorption of the implant. Correlative MRI identified and differentiated the image of the intact and degrading implant.


Assuntos
Implantes Absorvíveis , Osso e Ossos/patologia , Osso e Ossos/cirurgia , Osseointegração/fisiologia , Polímeros , Suturas , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Cães , Feminino , Ácido Láctico , Imageamento por Ressonância Magnética , Masculino , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Valores de Referência , Sensibilidade e Especificidade , Tíbia/patologia , Tíbia/cirurgia
5.
Vet Clin North Am Equine Pract ; 15(2): 363-74, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10472117

RESUMO

Over the last decade, both the farriery and veterinary professions have greatly increased their collective experience and understanding of the treatment of acute laminitis. Many horses that would have not been considered candidates for treatment 10 to 15 years ago are now saved, and some progress to successful careers as athletes. Unfortunately, the difficulties over prediction of the course of the disease persist, which continues to complicate treatment decisions. By its nature, supportive therapy is designed to make the horse more comfortable and limit further laminar injury by countering adverse biomechanical forces. Therefore, the success of treatment depends on the degree of instability between the distal phalanx and the hoof when treatment is started as well as the effectiveness of medical and supportive therapy.


Assuntos
Doenças do Pé/veterinária , Casco e Garras , Doenças dos Cavalos/terapia , Doença Aguda , Animais , Doenças do Pé/fisiopatologia , Doenças do Pé/terapia , Casco e Garras/anatomia & histologia , Casco e Garras/irrigação sanguínea , Casco e Garras/fisiopatologia , Doenças dos Cavalos/fisiopatologia , Cavalos , Inflamação/fisiopatologia , Inflamação/terapia , Inflamação/veterinária , Sapatos
6.
J Shoulder Elbow Surg ; 6(3): 272-85, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9219132

RESUMO

The purpose of this study was to determine the initial effects of Holmium:YAG laser energy on the shoulder joint capsule. A new surgical procedure to correct shoulder joint instability uses Holmium:YAG laser energy to cause "shrinkage" of joint capsular tissues. To date there has been no information concerning an intraoperative measurable end point for the application of laser energy at surgery or the resultant depth and degree of tissue alteration. Seven greyhound dogs were used in this study. Preoperative intraarticular pressures (IAP) were measured on entry and after injection of 10 ml of solution. Laser energy was applied to the cranial medial glenohumeral ligament and joint capsule of all right shoulders with arthroscopic visualization. The unoperated left shoulders served as the control group. Six weeks after surgery pressure measurements were performed on both shoulders. A "second look" arthroscopy was performed on the shoulders. After euthanasia was performed, the anterior capsular tissues were harvested from both shoulders for histologic examination. The specimens were inspected by three blinded examiners. After 6 weeks the postoperative laser-treated IAP were higher than the same joint preoperative IAP in four of six dogs for both static nondistension and 10 ml distension measurements. At this same interval the marked tissue damage of the treated capsule was easily discerned by blinded observers. On histologic evaluation the laser-treated capsule showed synovitis and pericapsular tissue reactivity. The depth of the injury was beyond the joint capsule into the pericapsular tissue. It was not possible to determine the end point of the capsular "shrinkage" operation by combined pressure/volume intraoperative measurements. There was no uniform joint capsule compliance at 6 weeks. The histologic changes were extensive in both magnitude and depth. Future studies in this animal should include decreased laser energy plus other means of monitoring the intraoperative effects of laser use.


Assuntos
Terapia a Laser , Articulação do Ombro/cirurgia , Animais , Artroscopia , Cães , Ligamentos Articulares/patologia , Pressão , Articulação do Ombro/patologia , Articulação do Ombro/fisiopatologia , Membrana Sinovial/patologia
7.
Arthroscopy ; 12(1): 15-25, 1996 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8838724

RESUMO

Comparison of perilesional cartilage, lesional repair tissue, and subchondral bone activity 6 months after application of holmium-yttrium-aluminum-garnet (Ho:YAG) laser energy to chronic (10 week) induced 10-mm full-thickness (FT) circular articular cartilage craters followed by 6 months' intermittent active motion (IAM) in a free exercise environment was investigated. The 2.1-microns wavelength was delivered in hand-controlled near-contact mode by arthroscopic surgery in a saline medium. Bilateral arthroscopy was performed on normal antebrachiocarpal, intercarpal, and metacarpophalangeal joints of six adult horses. Full-thickness craters were created in nine sites per limb on weight-bearing articular surfaces with a motorized bur. Right limb craters served as sham operated controls. Animals were killed at 10 weeks after FT crater creation (n = 2), and at 24 weeks (6 months) after laser energy application (n = 4). Histological analysis using hematoxylineosin (HE) and Safranin-O staining consisted of a modified Mankin grading of perilesional cartilage and lesional repair tissue scoring. Biochemical analysis was performed for cellularity and glycosaminoglycan (GAG) synthesis. Histological analysis showed clustering of chondrocytes or perilesional zonal cloning (PZC) in 83% of laser-treated lesions and in no control lesions. No differences were observed between treated and control lesional repair activity. Laser-treated perilesional cartilage showed a significant (P < .02) decrease in GAG synthesis. No adverse effects to distant cartilage were observed after application of laser energy regarding cell proliferation or GAG synthesis. Significance of decreased GAG synthesis in treated perilesional cartilage and perilesional zonal cloning of chondrocytes in treated cartilage is unknown. Additional study of Ho:YAG laser energy application to cartilage and subchondral bone is needed before its application in the surgical management and repair of cartilage damage.


Assuntos
Artroscópios , Cartilagem Articular/cirurgia , Endoscópios , Terapia a Laser/instrumentação , Amplitude de Movimento Articular/fisiologia , Suporte de Carga/fisiologia , Animais , Cartilagem Articular/patologia , Divisão Celular/fisiologia , Glicosaminoglicanos/metabolismo , Cavalos , Cicatrização/fisiologia
8.
J Clin Oncol ; 11(10): 1888-93, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8410114

RESUMO

PURPOSE: A prospectively randomized trial was performed to determine whether the combination of fluorouracil (FU) plus leucovorin (FU-LV) administered orally is more effective than equitoxic FU for patients with metastatic colorectal cancer. PATIENTS AND METHODS: A double-blind, placebo-controlled trial design was used to eliminate observer bias. An escalating FU dosing schedule was used to achieve equal toxicity. End points were response, time to treatment failure (TTF), and eight quality-of-life (QL) parameters. A crossover arm allowed FU-treated patients to receive FU-LV combination treatment after treatment failure. RESULTS: Response rate was 32% for FU-LV versus 23% for FU (P = .15). Median TTF was 22 versus 16 weeks (P = .27). Median survival time was 44 versus 54 weeks (P = .26). QL was the same for both treatments, except for days of hospitalization, which was greater for FU-LV (P < .001). Toxicities were similar to those previously reported for FU-LV and FU alone. CONCLUSION: Oral LV-FU produces the same efficacy and toxicity pattern as has been reported for intravenous LV-FU. When FU-LV is compared with equitoxic doses of FU, there is no difference in patient outcome. These results suggest that patients with advanced disease should receive FU at doses adequate to produce toxicity.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Adenocarcinoma/secundário , Idoso , Neoplasias Colorretais/patologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Análise de Sobrevida , Resultado do Tratamento
9.
Arthroscopy ; 9(5): 536-45, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8280326

RESUMO

This study was performed to investigate the effects of holmium:yttrium-aluminum-garnet (Ho:YAG) laser energy on articular cartilage and subchondral bone adjacent to traumatically created cartilage lesions in a continuous weight-bearing model. The 2.1-microns wavelength was delivered efficiently and precisely in hand-controlled contact and near-contact hard tissue arthroscopic surgery in a saline medium. Bilateral arthroscopy was performed on normal antebrachiocarpal and intercarpal joints of four adult horses. One hundred twenty traumatic lesions were created on three weight-bearing articular surfaces with a knife, curet, or motorized burr. Depths of the lesions were partial and full thickness. Configurations of the lesions were lacerations, scrapes, and craters. Left limbs were used as controls. Right limb lesions were treated with various intensities of laser energy: 0.1. 0.16, and 0.2 J. Animals were killed at intervals of 1, 3, and 8 weeks. Gross microscopic anatomy was documented, and tissue sections were subjected to blind review by a pathologist. Mankin grading for cellularity and proteoglycan content was used to qualitatively evaluate cartilage response. Cartilage adjacent to all lesions exposed to laser energy had better cellularity and proteoglycan content (p < 0.05) than did corresponding controls by Mankin grading. Mankin grades for levels of 0.16 and 0.2 J were lower (p < 0.05) than were those of controls or lesions exposed to 0.1 J. There was loss of cellularity and necrosis in subchondral bone at higher energy levels (0.16 and 0.2 J). This study examined the effects of Ho:YAG laser on articular cartilage and subchondral bone in terms of depth of damage and healing response over time in a weight-bearing model. Additional research to define dose-response curves for Ho:YAG laser treatment of cartilage and subchondral bone are indicated.


Assuntos
Artroscópios , Osso e Ossos/lesões , Cartilagem Articular/lesões , Terapia a Laser/instrumentação , Cicatrização/fisiologia , Animais , Osso e Ossos/patologia , Osso e Ossos/cirurgia , Cartilagem Articular/patologia , Cartilagem Articular/cirurgia , Contagem de Células , Cavalos , Proteoglicanas/metabolismo , Suporte de Carga/fisiologia
10.
J Invest Surg ; 5(4): 343-59, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1472487

RESUMO

An in vivo biopsy technique was developed to harvest cylindrical osteochondral core samples (2 mm diameter x 2 mm depth) from the articular surfaces of radial carpal bones in adult horses for use in osteoarthritis drug kinetic studies. A 25 degree arthroscope was introduced into the midcarpal joint through the dorsolateral surface, and a custom-built motorized core drill was introduced through the dorsomedial surface to create the osteochondral core samples. A total of 24 core samples were sequentially harvested in vivo, and 16 at postmortem, from eight horses on four different occasions within a 96-h period. Cores ranged in weight, from 5.0 to 19.0 mg with a median of 13.25 mg, mostly due to the amount of subchondral bone present. No evidence of carpal bone fractures was observed associated with core sample sites at postmortem. No tissue distortion or thermal damage occurred to the osteochondral core samples. No detrimental effects on the tissue surrounding the biopsy sites was detected on microscopic examination. This technique offers a simple and effective procedure for obtaining multiple in vivo osteochondral core samples at various time intervals for cartilage or osteoarthritis research or analysis of clinical joint disease in the horse.


Assuntos
Biópsia/métodos , Carpo Animal/cirurgia , Pé/cirurgia , Animais , Artroscópios , Artroscopia/métodos , Artroscopia/veterinária , Biópsia/instrumentação , Cartilagem/patologia , Estudos de Avaliação como Assunto , Membro Anterior , Cavalos
11.
Vet Surg ; 21(5): 351-4, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1413468

RESUMO

In an attempt to prevent neuroma formation and digital reinnervation after sharp palmar digital neurectomy in 10 adult horses with navicular disease, 18,426 W/cm2 of CO2 laser energy was applied to the proximal nerve stump. Clinical follow-up was 4 to 23 months. In two horses, palmar digital nerve biopsies were taken at month 4 (four nerves) and month 7 (two nerves). Nine horses were sound immediately and at all follow-up examinations. None had clinical evidence of painful neuroma or digital reinnervation. Histologically, there was minimal scar tissue at the surgical site; axonal sprouts were comingled with fibrous tissue.


Assuntos
Axônios/fisiologia , Cavalos/cirurgia , Terapia a Laser/veterinária , Neuroma/veterinária , Nervos Periféricos/cirurgia , Animais , Seguimentos , Doenças do Pé/cirurgia , Doenças do Pé/veterinária , Casco e Garras/cirurgia , Doenças dos Cavalos/etiologia , Doenças dos Cavalos/prevenção & controle , Doenças dos Cavalos/cirurgia , Regeneração Nervosa , Neuroma/etiologia , Neuroma/prevenção & controle
12.
Ann Oncol ; 3(1): 79-81, 1992 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-1606074

RESUMO

To increase the complete remission (CR) rate achieved with two cycles of cisplatin, continuous infusion fluorouracil (5-FU) and oral leucovorin (PFL) we added two antifolate drugs, methotrexate (MTX) and the lipophilic piritrexim (PTX), to the combination (PFL-MP). Twenty-eight patients with previously untreated Stage IV squamous cell carcinoma of the head and neck received 2 cycles of cisplatin 100 mg/m2 on day 1 followed by a 5-day continuous infusion of 5-FU at 800 mg/m2/day and 100 mg of leucovorin administered orally every 4 hours. MTX was administered at 40 mg/m2 IV on day 15 and PTX at 75 mg orally twice daily on days 22 to 26, with cycle 2 starting on day 36. After 2 of the first 5 patients had tumor progression between days 15 and 35, the regimen was intensified to MTX 50 mg/m2, PTX 100 mg twice daily and a cycle duration of 28 days. Local therapy consisted of surgery and/or radiotherapy with concomitant 5-FU and hydroxyurea (FHX) administered every other week. Eleven patients (39%, 95% confidence intervals 21-57%) had a CR, 9 (32%) had a PR, and four patients had no response. Four patients were unevaluable for response to PFL-MP. Patients with poor performance status or N3 disease were less likely to achieve a CR. Mucositis following PFL was the dose-limiting toxicity. Local therapy included surgery in 15 patients and FHX chemoradiotherapy in 19 patients. The administration of FHX in this setting proved feasible and the regimen was given near the intended dose intensity in the majority of patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Cisplatino/administração & dosagem , Terapia Combinada , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Leucovorina/administração & dosagem , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem
13.
J Am Vet Med Assoc ; 199(7): 909-12, 1991 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-1769881

RESUMO

A 5-hole T-plate was used to repair an unstable compound depression fracture of the nasal bones in a horse. Substantial bone loss was evident as a result of severe trauma. Satisfactory bone healing, facial contour, and airway function were achieved. The use of a T-plate can be an alternative means of repair of a nasal bone fracture in a situation in which instability and/or bone loss exists.


Assuntos
Placas Ósseas/veterinária , Fraturas Ósseas/veterinária , Cavalos/lesões , Osso Nasal/lesões , Animais , Parafusos Ósseos/veterinária , Fraturas Ósseas/cirurgia , Cavalos/cirurgia , Masculino , Osso Nasal/cirurgia
14.
Cancer ; 67(9): 2253-7, 1991 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-2013031

RESUMO

Thirty patients with recurrent and/or metastatic head and neck cancer were treated with sequentially administered methotrexate (MTX) and piritrexim (PTX). The treatment schedule consisted of intravenous (IV) MTX (50 mg/m2) administered on day 1 and oral PTX (75 mg/m2) administered twice daily on days 8 to 12. Courses were repeated every 21 days with dose escalation in subsequent courses aimed at achieving Grade 1 toxicity. Two patients were not evaluable for response, 5 (17%; 95% confidence interval, 4% to 30%) had a partial response (PR), 10 had stable disease, and 13 had progressive disease. All five responses were seen in patients with regional lymph nodes as measurable disease. The median time to progression for all patients was 1.4 months, and the median survival was 6.7 months. Generally, this regimen was well tolerated with only mild toxicity seen during cycle 1 in the majority of patients. Dose escalation in subsequent cycles was possible in a high percentage of patients. Although the overall response rate and survival figures in this Phase II trial were disappointing, the doses and schedule used in this trial may have been suboptimal as reflected by the low incidence of moderate to severe toxicity. Additional evaluation of this combination of drugs in a more aggressive schedule may be warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Contagem de Células Sanguíneas/efeitos dos fármacos , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Humanos , Metástase Linfática , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem
15.
J Am Vet Med Assoc ; 198(4): 663-4, 1991 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-2019539

RESUMO

A one-year-old Thoroughbred filly was examined because of poor body condition and reluctance to move its neck. Complete blood count revealed leukocytosis (15,700 WBC/microliters) and hyperproteinemia (8 g/dl). Radiography of the cervical vertebrae revealed multifocal lesions of bone lysis surrounded by zones of sclerosis. The horse was euthanatized and necropsied. Granulomatous lesions were identified in the heart, spleen, lungs, bones, and lymph nodes. The multifocal granulomatous inflammatory lesions in this horse were suggestive of mycobacteriosis.


Assuntos
Granuloma/veterinária , Doenças dos Cavalos/patologia , Inflamação/veterinária , Infecções por Mycobacterium/veterinária , Animais , Feminino , Granuloma/etiologia , Granuloma/patologia , Doenças dos Cavalos/etiologia , Cavalos , Inflamação/etiologia , Inflamação/patologia , Infecções por Mycobacterium/etiologia , Infecções por Mycobacterium/patologia , Osteólise/etiologia , Osteólise/patologia , Osteólise/veterinária
17.
Am J Vet Res ; 48(7): 1082-6, 1987 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-3631690

RESUMO

A monopolar electrode was implanted surgically in the canine tooth dentine layer to evaluate pain threshold responses of horses. A constant-current stimulator was used to deliver a known electrical current to the tooth pulp nerve. A single stimulus of 2-ms duration, repeated at greater than or equal to 20-s intervals, was used to elicit a head lift response. The lowest current level that produced 3 positive head lift responses was recorded as the pain threshold of the horse. The testing technique, dental dolorimetry, was easily performed. Tooth pulp pain thresholds (TPPT) were established on 8 nonmedicated adult male horses. Electrodes were nonreactive and remained functional for up to 98 days. Base-line TPPT values were consistent with repeated measurements on the same day and measurements on subsequent test days. The quantity of electrical current necessary to elicit the TPPT was increased after administration of xylazine HCl as a test analgesic.


Assuntos
Analgésicos/uso terapêutico , Polpa Dentária/fisiologia , Cavalos/fisiologia , Medição da Dor/veterinária , Tiazinas/uso terapêutico , Xilazina/uso terapêutico , Animais , Eletrodos Implantados/veterinária , Masculino , Medição da Dor/métodos
18.
NCI Monogr ; (5): 111-20, 1987.
Artigo em Inglês | MEDLINE | ID: mdl-3431588

RESUMO

Piritrexim (PTX), 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin e, formerly called BW 301U, is a potent small-molecule inhibitor of dihydrofolate reductase (DHFR) that enters cells rapidly by passive diffusion and thus does not depend upon the transport-mediated uptake that can limit cell entry of methotrexate (MTX). PTX is as active as MTX in inhibiting DHFR and mammalian cell growth. In vivo, PTX is active against Walker 256, L1210, P388, Sarcoma 180, and Ehrlich ascites tumors. After iv administration of [14C]PTX to rats, the elimination profile of intact drug from plasma was first order with a half-life (t1/2) of 38 minutes. PTX penetrates extensively into tissues and its tissue:plasma concentration ratios are generally 10-fold higher than those reported for MTX. When administered systemically, PTX inhibits the DHFR-dependent conversion of sepiapterin or 7,8-dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4), demonstrating that PTX enters brain at pharmacologically relevant concentrations. Pharmacokinetic studies in the dog indicated a mean plasma t1/2 (after iv dose) of 2.15 hours, total body clearance of 0.625 liters/hr/kg and steady-state volume of distribution of 1.82 liters/kg; the absolute bioavailability was 0.64. Toxicologic studies were conducted in rats and dogs that received daily doses for 1, 5, or 90 days. In dogs, oral doses of 480 (single dose), 25 (5 daily doses), and 2.5 mg/kg (90 daily doses) were lethal, whereas 240 (single dose), 2.5 (5 daily doses), and 0.5 mg/kg (90 daily doses) produced reversible alterations in clinical toxicity and histopathologic parameters. The lethal toxicity of PTX in dogs given 25 mg/kg/day for 5 days is prevented by oral calcium leucovorin rescue with either 0.75 or 3.0 mg/kg every hour for 4 hours on any of the 5 treatment days. The general pharmacologic profile indicates that PTX should be free of CNS, cardiovascular, and respiratory side effects at clinically useful doses.


Assuntos
Antagonistas do Ácido Fólico , Pirimidinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Cães , Coração/efeitos dos fármacos , Taxa de Depuração Metabólica , Metotrexato/farmacocinética , Camundongos , Músculo Liso/efeitos dos fármacos , Neoplasias Experimentais/tratamento farmacológico , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , Ratos , Solubilidade , Distribuição Tecidual , Células Tumorais Cultivadas
19.
J Am Vet Med Assoc ; 187(10): 1040-3, 1985 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-3877713

RESUMO

A delayed union metacarpal stress fracture was repaired in a horse, using lag-screw fixation in conjunction with dc electrical stimulation. Twelve weeks after surgery, radiographic and scintigraphic evaluations revealed that the fracture line was not discernible and that there was a decrease in radiopharmaceutic uptake, as compared with that in previous bone imaging studies. In this horse, DC stimulation of a delayed union stress fracture in a bone resulted in a healing pattern similar to that in human beings with delayed union fractures when treated with electrical stimulation.


Assuntos
Fraturas não Consolidadas/veterinária , Doenças dos Cavalos/cirurgia , Metacarpo/lesões , Animais , Parafusos Ósseos , Terapia por Estimulação Elétrica , Fixação de Fratura , Fraturas não Consolidadas/diagnóstico por imagem , Fraturas não Consolidadas/cirurgia , Fraturas não Consolidadas/terapia , Doenças dos Cavalos/diagnóstico por imagem , Doenças dos Cavalos/terapia , Cavalos , Masculino , Metacarpo/diagnóstico por imagem , Radiografia
20.
Am J Vet Res ; 46(3): 600-9, 1985 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-3873189

RESUMO

Electrically induced osteogenesis exhibits a dose response curve and can induce bone formation in the absence of trauma and in nonunions. Electrically induced osteogenesis, using direct electric current (DC) in a third metacarpal diaphyseal osteotomy model, in conjunction with internal fixation and postoperative loading, was investigated. Twelve young adult ponies of mixed sex were divided into 2 treatment groups (A and B) of 3 stimulated and 3 controls each and evaluated, using a specifically designed procedure. Stimulated ponies in both groups were given 20 microA of DC via an implanted bone growth stimulator (BGS); group A ponies were stimulated for 60 days and group B ponies for 120 days. Biocompatibility of the BGS was excellent in all ponies. Radiographically, there was more advanced healing with better vascular development in the ponies stimulated for 60 days compared with controls, but no discernible difference was seen at 120 days. Nuclear medical bone imaging revealed a peak uptake at 4 weeks in stimulated groups and the uptake decreased after 8 weeks. Radiopharmaceutical uptake in stimulated ponies was consistently below control uptake throughout the study. Mean specific gravity (SG) of specimens prepared for testing materials properties for group A and B controls were 2.044 +/- 0.119 and 1.939 +/- 0.065, respectively. The SG for group A and group B stimulated were 1.992 +/- 0.049 and 1.876 +/- 0.031, respectively. The SG of specimens obtained from metacarpi of age-matched control ponies was 2.194 +/- 0.166. The ultimate bending strengths and the flexural moduli of elasticity in 60-day control ponies and stimulated ponies were 57 +/- 8.4, 59 +/- 23.9 MN/m2 and 89 +/- 3.5, 106 +/- 6.5 MN/m2 and in 120-day control ponies and stimulated ponies were 13 +/- 1.0, 13 +/- 3.2 GN/m2 and 13 +/- 2.89, 15 +/- 0.577 GN/m2, respectively. Sixty-day samples and 120-day samples had pending strengths (SU) of 25% and 50% that of unfractured cortex, respectively. These findings indicate that 20 microA of DC stimulation on a diaphyseal osteotomy model may not stimulate sufficient bone production to affect the mechanical properties of the bone. Therefore, based on our research, clinical use of BGS in fresh fracture management cannot be recommended.


Assuntos
Terapia por Estimulação Elétrica/veterinária , Fraturas Ósseas/veterinária , Doenças dos Cavalos/terapia , Metacarpo/lesões , Osteogênese , Cicatrização , Animais , Modelos Animais de Doenças , Terapia por Estimulação Elétrica/métodos , Feminino , Fixação Interna de Fraturas/veterinária , Fraturas Ósseas/cirurgia , Fraturas Ósseas/terapia , Doenças dos Cavalos/cirurgia , Cavalos , Masculino , Metacarpo/diagnóstico por imagem , Osteotomia/veterinária , Radiografia , Cintilografia
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