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Biomedical subjects

T E Williams

Publications and source records attributed to T E Williams.

At least 55 records · Page 3Linked to original sources
PubMed1992

The evaluation of therapeutic responses in experimental keratomycosis.

Two different measures of response to therapy were evaluated in a model of keratitis caused by Aspergillus fumigatus in Dutch-belted rabbits. Combined pre and post-inoculation treatment with oral fluconazole 37.5 mg/kg bid or itraconazole 40 mg/kg bid was compared to post-inoculation treatment only and untreated controls using a standardized clinical disease severity score and quantitative isolate recovery techniques. For both drugs, there was no difference in isolate recovery rates among all three groups. However, a significant improvement in clinical disease was noted in the pre and post-inoculation treatment group compared to controls (p less than .01) and to the post-inoculation group (p less than .05) for fluconazole. A similar trend, though not statistically significant, was apparent with itraconazole treatment. This disparity highlights the difficulties associated with measuring responses to therapy in keratomycosis and emphasizes the need for more sensitive and specific measures.

Administration, Oral↗
PubMed1992

Nuclear and cytoplasmic localization of basic fibroblast growth factor in astrocytes and CA2 hippocampal neurons.

Fibroblast growth factors (FGFs) are known to stimulate mitogenesis in a variety of non-neuronal cell types and to support the survival in vitro of many neuronal cell types. The physiological role of FGFs in the CNS is currently not known. The present study determined the distribution in the rat CNS of a prominent member of the FGF family, basic FGF (bFGF). Immunohistochemical analysis showed that bFGF immunoreactivity was found predominantly in astrocytes throughout all regions of the CNS. In contrast, only a few neuronal populations were found to contain bFGF immunoreactivity, most prominent among them, neurons in the CA2 area of the hippocampus. This predominant localization of bFGF to astrocytes was confirmed by two other observations: (1) highly enriched cultures of astrocytes contained bFGF immunoreactivity and bioactivity, whereas highly enriched cultures of cerebral cortical neurons contained no detectable bFGF, and (2) neonatal rat cerebral cortex, which contains only a few differentiated astrocytes, also contained no detectable bFGF immunoreactivity and only low amounts of bFGF bioactivity. Immunocytochemical analysis also suggested that bFGF immunoreactivity was present in the nucleus as well as the cytoplasm of astrocytes and CA2 neurons. This nuclear localization was confirmed by EM analysis of the intracellular distribution of the immunoperoxidase reaction product. In addition, preparations of both nuclear and soluble fractions of brain extracts contained bFGF immunoreactivity and bioactivity. These data suggest that bFGF might be involved in mediating astrocytic influences on the late postnatal maturation and plasticity in the CNS, and that the nuclear localization of bFGF within astrocytes may play an important role in the differentiation of these cells. In addition, bFGF may play a similar role in a few specific neuronal populations, such as CA2 hippocampal neurons.

Animals↗
PubMed1991

Anomalous effect of subconjunctival miconazole on Candida albicans keratitis in rabbits.

After intrastromal injection of a standardized inoculum of Candida albicans blastoconidia in Dutch-belted rabbits, the efficacy of subconjunctival therapy with amphotericin B and miconazole was evaluated using a quantitative isolate recovery technique. The subconjunctival injection of miconazole resulted in the recovery of significantly more viable organisms compared to the number recovered in controls (2,000 micrograms daily, P less than .02; 3,000 micrograms daily, P less than .01, respectively). Amphotericin B, in contrast, in dosages of 500 or 1,500 micrograms daily, had a significant therapeutic effect (P less than .03). The anomalous response to subconjunctival therapy with miconazole seen in this model suggests an effect on host defense mechanisms.

Amphotericin B↗
PubMed1991

Influence of corticosteroid on experimentally induced keratomycosis.

To assess the effect of corticosteroid on the establishment of experimentally induced keratomycoses, rabbits were injected subconjunctivally with triamcinolone acetonide on two successive days before inoculation with Candida albicans, Aspergillus fumigatus, or Fusarium solanae. Whereas isolate recovery rates declined steadily in normal control corneas, they remained stable over 15 days in corticosteroid-treated corneas. Clinically, inflammation was equivalent (A fumigatus and F solanae) or significantly less (C albicans; P = .001) until the 10th day. At 15 days, inflammation in corticosteroid-treated corneas was significantly worse in animals infected with A fumigatus (P = .003) or F solanae (P = .02). Inflammatory signs correlated inconsistently with isolate recovery. Pathogenicity of the infecting organism appears to be important in determining the degree to which corticosteroid is able to mask clinical signs of infection while enhancing fungal replication.

Animals↗
PubMed1991

An evaluation of intrastromal injection of antifungal agents.

The effect of the intrastromal injection of a mixture of amphotericin B, miconazole, natamycin, and nystatin and the component agents alone was studied in Dutch-belted rabbits by standard bioassay. Twenty-four hours following injection, the inhibiting effect of the mixture was equivalent to that of nystatin alone. All other agents exhibited inferior activity. The intrastromal injection of this mixture appears to offer no therapeutic advantage.

Amphotericin B↗
PubMed1991

Toxicity and pharmacokinetics of subconjunctival amphotericin B. An experimental study.

The pharmacokinetics and toxicity of subconjunctival (S/C) amphotericin B (AmB) were evaluated in Dutch-belted rabbits. Following the S/C injection of 1,500 micrograms of AmB, corneal and aqueous levels were determined by bioassay. The highest levels were present in the periphery of debrided corneas at 1 h (90.12 +/- 2.4 micrograms/g). The debrided central cornea contained 30.84 micrograms/g, almost double the amount present in the intact central cornea. These levels were transient; in the central intact cornea only 2.08 micrograms/g could be detected at 2 h. Peak aqueous levels were low (0.95 +/- .24 micrograms/mL in debrided corneas at 1 h). The S/C injection of 1,500 micrograms of AmB in sodium deoxycholate produced a severe inflammatory response in the conjunctiva, episclera, iris, anterior chamber, and superior rectus muscle that persisted 10 days. Injection of sodium deoxycholate alone produced a similar but less severe response.

Amphotericin B↗
PubMed1991

Differences in response in vivo to amphotericin B among Candida albicans strains.

A group of ten Candida albicans strains previously determined to be resistant or susceptible to topical amphotericin B in vivo and in vitro were exposed to treatment with different concentrations of the drug in a quantitative model of candidal keratitis in Dutch-belted rabbits. After 5 days of topical treatment with amphotericin B eye drops in concentrations of 0.3%, 0.03%, or 0.003%, quantitative isolate recovery in treated animals was compared with that of untreated controls. A dose response was observed for all five susceptible strains. The two strains that were most sensitive to amphotericin B in vitro also were the most susceptible in vivo. At each dose level there was a two- to eightfold reduction in isolate recovery among highly susceptible strains compared with less susceptible strains (P less than 0.05). The five resistant strains remained so even when the 0.3% concentration was used. Among strains of C. albicans susceptible to amphotericin B, there appeared to be a variation in degree of susceptibility in vivo that correlated with the minimum inhibitory concentration.

Administration, Topical↗
PubMed1990

Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule.

Piritrexim, a new nonclassical antifolate, was evaluated in a multiinstitutional phase I trial in children. The starting dose was 290 mg/m2/day, administered p.o. every 12 h for 5 consecutive days, with courses repeated every 21 days. Dose reduction, initially to 200 mg/m2/day and subsequently to 140 mg/m2/day, was required because dose limiting myelosuppression and mucositis were encountered at the 290- and 200-mg/m2/day dose levels. Non-dose limiting toxicities included transient elevations in liver function tests, mild nausea, and skin rashes. The maximum tolerated dose was 140 mg/m2/day for 5 days. Pharmacokinetic monitoring was performed at steady state during the first course. For the 140-, 200-, and 290-mg/m2/day dose groups, the mean +/- SE peak plasma concentrations were 5.3 +/- 0.84, 9.3 +/- 1.7, and 10.2 +/- 2.3 microM, respectively, and occurred at a median of 1.5 h following the p.o. dose. The mean area under the plasma concentration-time curves were 18.1 +/- 2.3, 45.4 +/- 8.9, and 56.9 +/- 16.3 microM.h, respectively. Absolute bioavailability in two patients who were also monitored following a single i.v. dose of 140 and 200 mg/m2/day of piritrexim was 35 and 93%, respectively. Dose limiting toxicities were observed in 9 of 10 patients with 12-h trough piritrexim concentrations greater than 0.5 microM, whereas only 2 of 7 patients with trough concentrations less than 0.5 microM experienced dose limiting toxicities. A limited pharmacokinetic sampling strategy that allowed the area under the plasma concentration-time curve to be accurately predicted from the 3- and 6-h plasma drug concentration was developed. The recommended dose for future phase II trials is 140 mg/m2/day administered p.o. every 12 h for 5 consecutive days. Pharmacokinetic monitoring at 3, 6, and 12 h postdose may be useful for estimating bioavailability and for predicting which patients are at greatest risk for developing toxicity.

Adolescent↗
PubMed1990

Ocular uptake of fluconazole following oral administration.

The ocular penetration and distribution of oral fluconazole was studied in Dutch-belted rabbits. Measured by high-pressure liquid chromatography, fluconazole readily penetrated all ocular tissues and fluids. No difference was observed between the levels obtained in phakic and aphakic eyes. Four hours after a single oral dose of 20 mg/kg, the mean levels and SEs were as follows: cornea, 13.3 +/- 1.4 micrograms/g; aqueous, 7.4 +/- 0.3 mg/L; vitreous, 9.8 +/- 0.9 mg/L; and choroid/retina, 5.2 +/- 0.4 micrograms/g. These levels were approximately twice those obtained with a 10-mg/kg dose. The corneal concentrations correlated highly with serum levels (r = .89). A steady accumulation in both normal corneas and corneas infected with Candida albicans was noted when 17.5 mg/kg of fluconazole was administered twice daily over a 5-day period. Drug levels did not increase in the cornea when fluconazole was administered as a single daily dose of 35 mg/kg. In view of its excellent ocular pharmacokinetic profile, fluconazole merits further attention as an orally administered agent for ocular fungal infections.

Administration, Oral↗
PubMed1990

Measurements of antifungal levels in corneal tissue: a simplified bioassay for amphotericin B.

Measuring precise antifungal levels in the cornea with broth-dilution bioassays is difficult, as standard techniques involving visual determination of endpoints are hindered by corneal debris. To increase the precision of the measurement, we modified the sample preparation for bioassay of rabbit corneas treated with subconjunctival amphotericin B. Endpoint determination and variance were compared for a freshly thawed corneal suspension and the supernatant after 24 h equilibration; bioassay of the corneal suspension after 24 h equilibration served as an additional control. All endpoints were read visually in a masked fashion and were verified by culture. The three methods gave comparable endpoint values with equivalent degrees of variance. Amphotericin B levels were consistent by both visual and culture determination; however, endpoints were clearly visible and easier to read for the supernatant. Visual determination of the endpoints for the supernatant following 24 h equilibration simplified and ensured the precision of the bioassay technique.

Amphotericin B↗
PubMed1989

Photodynamic therapy for esophageal tumors.

Between 1982 and 1987, 40 patients with esophageal tumors (19 adenocarcinomas, 19 squamous carcinomas, and two melanomas) in whom conventional treatments were unsuccessful were treated with photodynamic therapy (PDT) after injection with either hematoporphyrin derivative or dihematoporphyrin ether. Patients underwent endoscopy again two to three days and one month after PDT and as needed when symptoms recurred. At one month, the average minimal diameter opening of 28 assessable tumors increased from 6 to 9 mm. Of the 35 patients who could be evaluated one month after PDT, the average improvement in food intake was from a liquid to a soft diet. Average survival time (from time of first treatment) was 7.7 months (n = 17) for adenocarcinoma, 5.8 months (n = 12) for squamous cell carcinoma, and 25 months (n = 2) for melanoma. Two patients with stage I adenocarcinoma were alive with no evidence of disease at 11 and 23 months. One patient with stage I squamous cell cancer died 18 months after PDT, with recurrence of tumor above the treated area noted eight months after treatment. One patient with stage I melanoma died of a synchronous colon cancer 31 months after PDT, with no evidence of residual melanoma.

Adenocarcinoma↗
PubMed1988

Aortobrachiocephalic reconstruction.

Aortobrachiocephalic reconstruction was studied in 26 patients. Nine had suffered a previous stroke, and seven had residual deficity. A previous carotid endarterectomy or carotid-to-subclavian bypass had been performed in eight patients. The ascending aorta was the proximal anastomotic site in all cases. Bypass grafting to a single distal site was performed in 11 patients (42 percent), to 2 distal sites in 14 patients (54 percent) and to 3 distal sites in 1 patient (4 percent). The carotid artery, innominate arteries, or both were involved in all reconstructions. Concomitant carotid or subclavian endarterectomy was performed in 14 patients, 1 of whom also had a coronary bypass at the same time. Two patients (7 percent) died in the postoperative period. Twenty-three of 24 survivors (96 percent) had relief of symptoms after operation. Only one patient had worsening of symptoms postoperatively, which was secondary to intracerebral hemorrhage. Results of this study indicate that direct revascularization of the arch branches can be carried out with minimal morbidity and mortality. Relief of presenting symptoms is to be expected, and long-term results suggest that the operation is durable.

Adult↗
PubMed1987

Hemodialysate composition and intradialytic metabolic, acid-base and potassium changes.

We compared the effects of dialysate composition on changes in intermediary metabolites, acid-base balance, and potassium removal during hemodialysis. Patients were dialyzed against dialysates containing acetate or bicarbonate, each with or without glucose, in a four-way cross-over study. Dialysates containing acetate were associated with significant perturbations in intermediary metabolism, including increases in blood citrate, acetoacetate and beta-hydroxybutyrate and a decrease in pyruvate. In contrast, bicarbonate-containing dialysates caused minimal perturbations in intermediary metabolism. Addition of glucose to the dialysate decreased the changes in intermediary metabolites; however, the magnitude of this effect was less than that observed for the change from acetate to bicarbonate. Use of acetate also resulted in lower post-dialysis blood-concentrations of base equivalents than obtained with bicarbonate; this difference was unaffected by the presence or absence of glucose. Although pre- and post-dialysis potassium concentrations were unaffected by the dialysate formulation, total potassium removal was significantly greater when glucose was omitted from the dialysate. Our results suggest that both bicarbonate and glucose should be included in the dialysate, particularly for those patients whose capacity for metabolism may be limited because of highly efficient dialysis, intercurrent illness, or starvation. However, addition of glucose to the dialysate may require a reduction in dialysate potassium to maintain proper potassium homeostasis.

Acetates↗
PubMed1987

Fascioliasis in cattle in Louisiana: development of a system to predict disease risk by climate, using the Thornthwaite water budget.

A system correlating climate with the annual risk of fascioliasis in cattle in central Louisiana was developed, using the Thornthwaite water budget and a 6-year data base that included records on herd prevalence rates, transmission to fluke-free sentinel calves, and snail population dynamics. The system developed was compared with modifications of the wet-day and Mt forecasting systems previously developed for use in the oceanic climate zone of western Europe. The wet-day system correlated poorly with transmission data, whereas the Mt and Thornthwaite water budget-derived systems correctly ranked 5 of the 6 years in terms of annual numbers of flukes transmitted to sentinel calves. Compared with the Mt system, the water budget-based system more closely correlated with transmission data, on the basis of statistical regression analysis. The water budget system was calculated by use of a microcomputer software program, and provided a means of measuring the effect of moisture stress and flooding in snail habitats that serve as foci of transmission of Fasciola hepatica to cattle on pastures.

Animals↗
PubMed1986

Photodynamic therapy of endobronchial tumors.

After presensitization with IV hematoporphyrin derivative (HpD), neoplasms in the tracheobronchial tree of 18 patients were treated by photodynamic therapy (PDT) with 630-nm light from a tunable dye argon laser system delivered through quartz fibers passed through the biopsy channel of a flexible bronchoscope under local anesthesia. Tumor effect was measured by complete response (CR)--no visible tumor in area treated, partial response (PR)--tumor size or degree of obstruction reduced by more than 50% and some response (SR)--tumor or degree of obstruction reduced by more than 20% but less than 50%. One month or less after 30 treatments to 26 areas in 18 patients, there was 40% CR, 57% PR, and 3% SR. All tumors showed at least some response. Since many of these patients had end-stage disease, the effect on the clinical condition and symptoms were evaluated using the Karnofsky Performance Status (KPS), oxygen requirements, and the presence or absence of respiratory symptoms. One month after treatment, 61% were clinically improved, with an increase of the average KPS from 48 to 61. Three patients with stage III primary lung cancer improved from being severely disabled requiring hospitalization to normal activity with effort and lived an average of 3.5 months. One patient with metastatic colon cancer was palliated from bedrest with continuous oxygen to normal activity with no oxygen for 12 months. A patient with hemoptysis and carcinoma in situ remains biopsy- and symptom-free for 34 months. A patient with hemoptysis and cough from breast cancer metastases maintained CR, biopsy- and symptom-free for 7 months. A patient with hemoptysis from recurrence at the bronchial stump maintained CR, biopsy- and symptom-free for 13 months. Six patients with Stage III primary lung cancer with average KPS of 27 (severe) died in the hospital and lived an average of 5 weeks (two CR, two PR, two SR). One patient with atelectasis of the right lower lobe re-expanded 14 days after treatments began.

Bronchial Neoplasms↗
PubMed1986

Aflatoxins and kwashiorkor: clinical studies in Sudanese children.

Aflatoxin analysis of blood and urine by high performance liquid chromatography in 584 Sudanese children is reported. The results in 404 malnourished children comprising 141 kwashiorkor, 111 marasmic kwashiorkor and 152 with marasmus are compared with 180 age-matched controls and correlated with clinical findings. The aflatoxin detection rate and mean concentration were higher in serum of children with kwashiorkor than the other groups. The difference between the detection rate in kwashiorkor and controls was significant (p less than 0.05). The aflatoxin detection rate in urine was highest in the marasmic kwashiorkor group and the mean concentration was higher in the marasmic kwashiorkor and marasmic groups than in the kwashiorkor and control groups. There were important differences in the detection of certain aflatoxins between the groups. Aflatoxicol was detected in the sera of 16 (11.6%) kwashiorkor, in six (6.1%) marasmic kwashiorkor, but in none of the controls and only once in marasmus. These differences are highly significant (p less than 0.0001). The ratio of AFB1 to AFM1 was higher in the sera and urines of kwashiorkors than in controls, suggesting that the normal transformation of AFB1 to AFM1 may be impaired in kwashiorkor with consequent increase in transformation of AFB1 to aflatoxicol. The study therefore provides evidence of differences in the metabolism of aflatoxins in children with kwashiorkor compared with children with other forms of malnutrition and normally nourished children and confirms the association between aflatoxins and kwashiorkor contained in a preliminary report on this work.

Aflatoxin B1↗
PubMed1985

Palliation of esophageal malignancy with photodynamic therapy.

Sixteen patients with esophageal malignancies received photodynamic therapy after 3 mg of hematoporphyrin derivative (Photofrin I) or 2 mg of Photofrin II per kilogram of body weight was injected intravenously two to six days prior to treatment. A tunable dye argon laser system delivered 630 nm light through quartz fibers passed through the biopsy channel of a gastroscope. All patients obtained improvement in swallowing, usually from total obstruction or clear liquids only to a regular diet within three weeks and with new techniques, at least liquids within three days of treatment. Karnofsky Performance Status (KPS) and esophageal grades were measured before treatment, 1 month following treatment, and periodically until death. Ten patients died an average of 3.7 months after initial treatment (range, 0.6 to 19 months). Six patients are alive at 11, 10, 5, 2.5, 2 months, and 1 month after treatment. The median survival of 12 patients treated more than 6 months ago was 6.5 months and of 9 patients with an initial KPS higher than 30, 8.1 months.

Adenocarcinoma↗