Risks and benefits of withdrawing cyclosporine from the long-term immunosuppression regimen of heart and heart-lung transplant recipients.
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Adult↗
Biomedical subjects
S Walker
Publications and source records attributed to S Walker.
Clinical use and bioavailability of tacrolimus in heart-lung and double lung transplant recipients with cystic fibrosis.
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Biological Availability↗
Analysis of 50 patients with atypical odontalgia. A preliminary report on pharmacological procedures for diagnosis and treatment.
Atypical odontalgia is a distressing and unusual chronic orofacial pain condition. It is often difficult to diagnose because it is associated with a lack of clinical and radiographic abnormalities. The condition is poorly understood on a pathophysiological basis, and patients often undergo repetitive and unnecessary dental procedures in attempts to alleviate pain. In this study, 50 patients diagnosed with odontalgia were evaluated by pharmacological procedures, including topical anesthetic application and phentolamine infusion. Results of these pharmacological procedures suggest that atypical odontalgia is a neuropathic pain of the oral cavity that may have a component of sympathetically maintained pain. Therapeutic trials of topical capsaicin were carried out to assess its efficacy for pain reduction. Topical capsaicin was effective in most patients.
Administration, Topical↗
Lack of evidence for systemic toxicity following topical chloramphenicol use.
There has been considerable controversy regarding the safety of topical chloramphenicol in ophthalmic practice. The evidence for associated haematopoietic toxicity in idiosyncratic and dose-dependent forms was reviewed. The 7 cases of idiosyncratic haematopoietic reactions associated with topical chloramphenicol reported in the literature are refutable evidence for the existence of such a response. In Scotland, despite extensive prescription of topical chloramphenicol, the incidence of acquired aplastic anaemia was found to be low, as were associated reports of blood dyscrasias throughout the UK. The epidemiology of acquired aplastic anaemia failed to make an association with topical chloramphenicol use. High-performance liquid chromatography (minimum detection limit 1 mg/l) was used to investigate whether serum accumulation of chloramphenicol occurred after topical therapy in 40 patients. The mean dose of chloramphenicol eye drops used after 1 week of treatment was 8.0 mg, and after 2 weeks, 15.3 mg. As expected, chloramphenicol failed to accumulate to detectable levels. This supported the view that topical chloramphenicol was not a risk factor for inducing dose-related bone marrow toxicity. Calls for the abolition of treatment with topical chloramphenicol based on current data are not supported.
Adult↗
A prospective randomized trial comparing 2 diuresis renography techniques for evaluation of suspected upper urinary tract obstruction in children.
PURPOSE: We compare the diagnostic impact of 2 diuresis renography techniques for evaluation of suspected upper urinary tract obstruction in children. MATERIALS AND METHODS: A total of 72 children were randomly assigned to 1 of 2 standardized diuresis renography protocols. The protocols were identical, except for the time of furosemide (F) injection. In the F+20 scans furosemide was given 20 minutes after the 99mtechnetium pentetic acid radiopharmaceutical. With the modified F-15 scans furosemide was injected 15 minutes before renography. Hydration, bladder catheterization, urine output determination, radiopharmaceutical injection and scan acquisition were identical. Renography outcomes (obstructed, nonobstructed or equivocal) were analyzed for the investigated side(s) and for the contralateral side, which was used as a control in children with suspected unilateral obstruction. Chi-square test was used to compare the percentage of obstructed and nonobstructed scans of both protocols. Fisher's exact test was used to compare the nonobstructed scans and equivocal results of both protocols. RESULTS: Of the 96 scans performed 8 were excluded because of technical problems. The remaining scans included 44 F+20 and 44 F-15. Of the 88 scans 10 were used to evaluate possible bilateral obstruction. A total of 48 boys and 24 girls were evaluated. Because 2 children had a solitary kidney each, the total number of renal units studied for outcome was 174. The F-15 scan showed 7 times more obstruction than the F+20 scan on the investigated side, and this difference was statistically significant. No obstruction was diagnosed on the contralateral side with either technique when used to investigate cases of suspected unilateral obstruction. CONCLUSIONS: The timing of the furosemide injection (F-15 scan versus F+20) has a significant impact on the obstructive versus nonobstructive renography results when evaluating children with suspected upper urinary tract obstruction.
Child, Preschool↗
The major trauma management study: an analysis of the efficacy of current trauma care.
BACKGROUND: An audit of the management and outcome of major trauma patients was carried out to determine ways in which the system of care may be improved. METHODS: The Major Trauma Management Study (MTMS) collected data prospectively on all consecutively admitted major trauma patients at eight major hospitals during a 12-month period. Outcome was studied using trauma and injury severity score (TRISS) and a severity characterization of trauma (ASCOT) analyses, as well as a preventable outcome analysis, which looked at survivors with complications or with a Glasgow Coma Score < 15 on discharge from hospital, as well as studying deaths. RESULTS: The group of 859 patients was more severely injured than most described previously, with a mortality of 14.8% and a mean injury severity score of 19.8. Formal ASCOT analysis indicated 2.25% fewer survivors than would be predicted by Major Trauma Outcome Study norms. Extrapolating the TRISS and ASCOT process to include those patients with missing data, and then comparing groups of matched severity with the norms, gave no statistically different outcome in the MTMS group of patients. Preventable outcome analysis revealed rates of preventable and potentially preventable (P/PP) outcomes of 32% among deaths and 8% among survivors. The types of management deficiencies responsible for P/PP outcomes are identified. CONCLUSIONS: The points of deficiency in a system of care have been identified, and the development of an integrated trauma system in Victoria, based upon these facts, is recommended. Children, the elderly, patients with head injuries and patients being transferred between hospitals would benefit from improvements to the system of care. The calculation of efficacy rate (0.95 for the MTMS patients) is recommended to accurately assess the system of care. Preventable Outcome Analysis is more relevant to auditing a system of trauma care in detail, than is ASCOT or TRISS. The MTMS has refined and defined the process so that it is reproducible in further comparative studies.
Critical Pathways↗
Electron dose calculation using multiple-scattering theory: a hybrid electron pencil-beam model.
We have embedded the bipartition model into Fermi-Eyges multiple-scattering theory to produce a more accurate hybrid electron pencil-beam model, by using the fact that away from the edges of a large field, the electron distribution function exactly equals that for an infinitely wide electron beam. The bipartition model calculates various electron transport quantities in a homogeneous or horizontally layered medium with very high accuracy, for an infinitely broad beam. In our hybrid model, we use the bipartition model to calculate the longitudinal part of the pencil-beam distribution function, and the Fermi-Eyges theory to calculate its transverse part. Doing this allows calculation not only of dose distribution, but also of such quantities as electron fluence distribution, energy spectrum, angular distribution, and electron-charge distribution. Using the hybrid electron pencil-beam model, we have calculated the dose distribution for collimated electron beams and compared them with experimental data, for rectangular fields.
Biophysical Phenomena↗
Amphotericin B in lipid emulsion: stability, compatibility, and in vitro antifungal activity.
Newer formulations of amphotericin B (AmB) complexed with liposomes or lipid suspensions have been developed. Preliminary studies have suggested that AmB in Intralipid (IL) may be as effective as, but less toxic than, conventional formulations of AmB, but few data are available regarding its stability, compatibility, or in vitro antifungal activity. A compatibility study was done to evaluate the effects of AmB concentrations in IL containing either 10 or 20% soybean oil. The effects of temperature, shaking, and AmB and IL concentrations on the stability of AmB-IL suspensions were analyzed by visual inspection and liquid chromatography. The in vitro antifungal activity of AmB-IL, compared to that of AmB alone against reference strains of Candida species was determined by using a broth macrodilution method in accordance with National Committee for Clinical Laboratory Standards guidelines (M27-T). Samples of AmB-IL which were lightly shaken retained more than 90% of the AmB concentration over 21 days when stored at either 4 or 23 degrees C. Varying the AmB concentration did not appear to affect the stability of AmB-IL. However, a precipitate was formed when mixtures with more than 30% lipid as a proportion of the total volume were centrifuged. AmB-IL and AmB alone had similar in vitro antifungal activities against reference strains of yeasts. Further pharmacologic and clinical studies with AmB-IL are warranted, although AmB should not be combined with IL in concentrations capable of producing a precipitate.
Amphotericin B↗
Medium term results of lung transplantation for end stage pulmonary sarcoidosis.
BACKGROUND: Lung transplantation is an accepted therapeutic option for patients with end stage pulmonary sarcoidosis. However, the medium term outcome of transplantation in this patient group is unknown. METHODS: This study was performed to evaluate our experience with lung transplantation for end stage pulmonary sarcoidosis. Between July 1988 and July 1997 12 patients (nine men) underwent lung transplantation for sarcoidosis at our institution. Ten underwent single lung transplantation and two double lung transplantation. RESULTS: Survival at three and five years was 70% and 56%, respectively. Three patients developed obliterative bronchiolitis at six, 18, and 45 months. One died at the time of retransplantation. Sarcoid granulomas have recurred in the donor organ in three patients. In one the development of granulomas has been associated with clinical deterioration, necessitating retransplantation. Mean (SD) forced expiratory volumes in one second at three and five years were 1.37 (0.67) 1 and 1.34 (0.13) 1, respectively. CONCLUSIONS: Lung transplantation is a viable option for patients with end stage pulmonary sarcoidosis. The medium term results are comparable with patients undergoing lung transplantation for other indications. Despite histological recurrence of sarcoidosis, the risk of clinically important recurrence is low.
Adult↗
Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model.
PURPOSE: To attempt to safely escalate the dose of radiation for patients with intrahepatic cancer, we designed a protocol in which each patient received the maximum possible dose while being subjected to a 10% risk of radiation-induced liver disease (RILD, or radiation hepatitis) based on a normal tissue complication probability (NTCP) model. We had two hypotheses: H1; with this approach, we could safely deliver higher doses of radiation than we would have prescribed based on our previous protocol, and H2; the model would predict the observed complication probability (10%). PATIENTS AND METHODS: Patients with either primary hepatobiliary cancer or colorectal cancer metastatic to the liver and normal liver function were eligible. We used an NTCP model with parameters calculated from our previous patient data to prescribe a dose that subjected each patient to a 10% complication risk within the model. Treatment was delivered with concurrent hepatic arterial fluorodeoxyuridine (HA FUdR). Patients were evaluated for RILD 2 and 4 months after the completion of treatment. RESULTS: Twenty-one patients completed treatment and were followed up for at least 3 months. The mean dose delivered by the current protocol was 56.6 +/- 2.31 Gy (range, 40.5 to 81 Gy). This dose was significantly greater than the dose that would have been prescribed by the previous protocol (46.0 +/- 1.65 Gy; range, 33 to 66 Gy; P < .01). These data are consistent with H1. One of 21 patients developed RILD. The complication rate of 4.8% (95% confidence interval, 0% to 23.8%) did not differ significantly from the predicted 8.8% NTCP (based on dose delivered) and excluded a 25% true incidence rate (P < .05). This finding supports H2. CONCLUSION: Our results suggest that an NTCP model can be used prospectively to safely deliver far greater doses of radiation for patients with intrahepatic cancer than with previous approaches. Although the observed complication probability is within the confidence intervals of our model, it is possible that this model overestimates the risk of complication and that further dose escalation will be possible. Additional follow-up and accrual will be required to determine if these higher doses produce further improvements in response and survival.
Antimetabolites, Antineoplastic↗
Site-specific data confirm arsenic exposure predicted by the U.S. Environmental Protection Agency.
The EPA uses an exposure assessment model to estimate daily intake to chemicals of potential concern. At the Anaconda Superfund site in Montana, the EPA exposure assessment model was used to predict total and speciated urinary arsenic concentrations. Predicted concentrations were then compared to concentrations measured in children living near the site. When site-specific information on concentrations of arsenic in soil, interior dust, and diet, site-specific ingestion rates, and arsenic absorption rates were used, measured and predicted urinary arsenic concentrations were in reasonable agreement. The central tendency exposure assessment model successfully described the measured urinary arsenic concentration for the majority of children at the site. The reasonable maximum exposure assessment model successfully identified the uppermost exposed population. While the agreement between measured and predicted urinary arsenic is good, it is not exact. The variables that were identified which influenced agreement included soil and dust sample collection methodology, daily urinary volume, soil ingestion rate, and the ability to define the exposure unit. The concentration of arsenic in food affected agreement between measured and predicted total urinary arsenic, but was not considered when comparing measured and predicted speciated urinary arsenic. Speciated urinary arsenic is the recommended biomarker for recent inorganic arsenic exposure. By using site-specific data in the exposure assessment model, predicted risks from exposure to arsenic were less than predicted risks would have been if the EPA's default values had been used in the exposure assessment model. This difference resulted in reduced magnitude and cost of remediation while still protecting human health.
Algorithms↗
[Collagen colitis, adenomatous polyp and colon carcinoma].
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Adenocarcinoma↗
A nonparametric approach to a survival study with surrogate endpoints.
A nonparametric estimator for the joint distribution of a survival time and surrogate response time, which may occur earlier during follow-up, is presented. In the absence of the surrogate response variable, the estimator reduces to the Kaplan Meier nonparametric estimator for the survival time alone. The estimator derived in this paper is done so in a particular novel way using an exchangeable process (reinforced random walks) to model individual observations. The methodology introduced in the paper is readily extended to modelling multiple state processes.
Humans↗
A phase I trial of hepatic arterial bromodeoxyuridine and conformal radiation therapy for patients with primary hepatobiliary cancers or colorectal liver metastases.
PURPOSE: We have previously found that conformal radiation therapy (RT) and hepatic arterial fluorodeoxyuridine was associated with durable responses and long-term survival for patients treated for nondiffuse primary hepatobiliary tumors and colorectal liver metastases. Further improvements in hepatic control may result from the addition of selective radiosensitization using bromodeoxyuridine (BrdU) infused through the hepatic artery (HA) concurrently with RT. This is a Phase I study of escalating doses of HA BrdU combined with our standard hepatic RT. METHODS AND MATERIALS: Patients with unresectable primary hepatobiliary cancer or colorectal liver metastases were treated with concurrent HA BrdU and conformal RT (1.5 Gy per fraction, twice a day). Three-dimensional treatment planning was used to define both the target and normal liver volumes. The total dose of RT (24, 48, or 66 Gy) was determined by the fractional volume of normal liver excluded from the high dose volume. HA BrdU was escalated in standard Phase I fashion with at least three patients receiving each combination of RT dose and BrdU dose. The starting dose of HA BrdU was 10 mg/kg/day, with two potential escalations to a maximum of 25 mg/kg/day (the maximum tolerable dose of HA BrdU when given alone on this same schedule). Grade > or = 3 toxicity was considered dose limiting. Patients receiving 24 Gy had one cycle of HA BrdU, while those receiving either 48 or 66 Gy had two cycles. Patients were followed for toxicity, complications, and response (when evaluable). RESULTS: A total of 41 patients (18 with colorectal liver metastases, 16 with cholangiocarcinoma and 7 with hepatoma) were treated. Five patients were removed from the protocol (three had HA catheter complications, one developed atrial fibrillation, and one was removed due to recurrent Grade 4 toxicity), although all five are included for toxicity purposes. Dose-limiting toxicity was primarily thrombocytopenia and there was no obvious relationship with the RT dose. Only 2 of 17 cycles given at 25 mg/kg/day had Grade > or = 3 toxicity. Complications developed in four patients, including one patient with radiation-induced liver disease. Response rates were not improved compared to our previous experience. CONCLUSIONS: The appropriate dose of HA BrdU for Phase II evaluation is 25 mg/kg/day. Neither the hepatic parenchyma nor the gastrointestinal mucosa appeared to be sensitized by this method of BrdU administration. It is anticipated that these, or still newer methods of therapy, can improve treatment results in the near future.
Adult↗
Death of Diana, Princess of Wales. Her death and funeral rate as traumatic stressors.
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Adolescent↗
Design of compounds that increase the absorption of polar molecules.
Hydrophilic drugs are often poorly absorbed when administered orally. There has been considerable interest in the possibility of using absorption enhancers to promote absorption of polar molecules across membrane surfaces. The bile acids are one of the most widely investigated classes of absorption enhancers, but there is disagreement about what features of bile acid enhancers are responsible for their efficacy. We have designed a class of glycosylated bile acid derivatives to evaluate how increasing the hydrophilicity of the steroid nucleus affects the ability to transport polar molecules across membranes. Some of the glycosylated molecules are significantly more effective than taurocholate in promoting the intestinal absorption of a range of drugs, showing that hydrophobicity is not a critical parameter in transport efficacy, as previously suggested. Furthermore, the most effective glycosylated compound is also far less damaging to membranes than the best bile acid absorption promoters, presumably because it is more hydrophilic. The results reported here show that it is possible to decouple absorption-promoting activity from membrane damage, a finding that should spark interest in the design of new compounds to facilitate the delivery of polar drugs.
Animals↗
Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection.
BACKGROUND: Reports suggest that antituberculosis drugs are malabsorbed in patients with advanced HIV disease. OBJECTIVE: To evaluate the pharmacokinetics of antituberculosis agents in HIV-seropositive patients at different stages of disease. DESIGN: Parallel study. SETTING: Two hospital outpatient clinics. PARTICIPANTS: 12 healthy volunteers, 12 patients with asymptomatic HIV disease, 12 patients with symptomatic HIV disease, and 12 patients with symptomatic HIV disease and diarrhea. MEASUREMENTS: Drug plasma concentrations were measured over 24 hours on day 4 of concurrent therapy. INTERVENTION: Oral isoniazid (300 mg/d), rifampin (600 mg/d), pyrazinamide (1000 mg/d), and ethambutol (1000 mg/d). RESULTS: Reduced total drug exposure to rifampin and pyrazinamide was associated with D-xylose malabsorption in persons with HIV infection or AIDS. Peak drug exposure to isoniazid was lower in patients with diarrhea. CONCLUSIONS: Reduced total drug exposure may be related to malabsorption in persons with HIV infection or AIDS.
Adult↗
A population approach to initial dose selection.
Before a drug can be marketed, an initial dose must be established. Sheiner et al. argue that a population approach leads to the most informed and rational decision making. We discuss the choice of an initial dose from both a predictive and estimative viewpoint. Our criteria are based upon evaluating the probabilities that a patient from the specified population obtains a response that is at least of a specified size. We demonstrate the approach using a simulation study and compare estimation of population parameters and initial dose using Bayesian and likelihood-based methods.
Bayes Theorem↗