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PubMed1982

Active metabolites of neuroleptic drugs: possible contribution to therapeutic and toxic effects.

Recent studies demonstrating a relationship between plasma levels and effects of haloperidol, thioridazine, chlorpromazine, butaperazine, fluphenazine, and perphenazine suggest that therapeutic plasma level monitoring of neuroleptics may be clinically useful. Chlorpromazine, thioridazine, levomepromazine, and loxapine have active metabolites which attain plasma levels within the same range as that of the parent compound after therapeutic doses of the drug. The metabolites often have pharmacological profiles which are different from that of the parent drug, and some metabolites apparently contribute to the side effects of the drug but do not possess any neuroleptic potency. The ratios between the plasma levels of metabolites and the parent compound show large interpatient variations, and the metabolites should, therefore, be measured together with the parent drug by therapeutic plasma level monitoring. Accordingly, the assay method should be carefully selected in order to include metabolites which may contribute to the therapeutic or side effects of the drug.

Antipsychotic Agents↗
PubMed1994

Challenges in comparing treatment outcome from a prospective with that of a retrospective study: assessing the merit of gentamicin therapeutic drug monitoring in pediatric oncology.

The objectives of this study were: (a) to assess whether treatment outcome with gentamicin in pediatric oncology patients could be improved by a pharmacy based therapeutic drug monitoring (TDM) service that included pharmacokinetic interpretation; and (b) to describe the challenges in comparing treatment outcome from a prospective to a retrospective study when the merit of gentamicin therapeutic drug monitoring (TDM) was assessed in pediatric oncology patients. Two groups of pediatric oncology patients, aged 1-18 years, received empiric gentamicin therapy for fever and for confirmed or suspected infection, with the same inclusion and exclusion criteria. Group 1 consisted of patients from a prospective gentamicin pharmacokinetic study with a formalized pharmacy-based TDM service (n = 52). Group 2 consisted of patients admitted to the oncology units who had gentamicin levels analyzed in the TDM Laboratory without the formalized TDM Service (n = 25). Gentamicin dosage adjustments were recommended based on three blood samples (one pre- and two postdose concentrations) collected between the third and sixth doses from each patient in the TDM group, utilizing pharmacokinetic principles and the Sawchuk-Zaske method. In the non-TDM group, dosage adjustments based on two routine blood samples (one pre- and post-gentamicin dose) were performed by physicians without the help of the formalized TDM Service. Multiple regression analysis showed that time periods (TDM, non-TDM), duration of neutropenia, intravenous methotrexate, and types of cancer, e.g., hematologic malignancy vs. solid tumor, had significant effects on duration of fever. Initial absolute neutrophil count, insertion of central venous line, intravenous cloxacillin administration, bacteriologic cultures, and initial post gentamicin levels > or = 5 mg/ml had no significant effects on the duration of fever. Mean duration of fever in the TDM group (2.8 +/- 2.4 days) was significantly shorter than that in the non-TDM group (9.0 +/- 8.8 days) (p < 0.001). Therapeutic serum concentrations were achieved more promptly in the TDM group, with significantly fewer patients requiring dose changes and fewer sets of serum concentrations required. One patient from each group had a > 100% increase in serum creatinine on day 5 compared to baseline. No apparent nephrotoxicity was observed in other patients. Although there was an association of shorter duration of fever with prompt achievement of therapeutic gentamicin serum concentrations with the TDM Service, there were several unresolved factors that affected duration of fever. A randomized prospective and controlled study would be required to substantiate the merit of TDM in shortening the duration of fever in pediatric oncology patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Therapeutic drug monitoring of tacrolimus in clinical transplantation.

Initial clinical trials of FK did not incorporate available FK levels, and difficulties were quickly experienced particularly with neurotoxicity and nephrotoxicity. The introduction of routine assay allowed broad parameters to be identified, which assisted in evaluating effective therapeutic parameters. Levels approximately 20 ng/ml were frequently associated with toxicity and the initial therapeutic range between 10-25 ng/ml was probably excessive. Reliable effective assay > 5 ng/ml using the Abbott IMx is not available, and many patients will have excellent hepatic or renal function with what are currently undetectable levels of FK. However, IncStar have an ELISA assay with a sensitivity of 0.5 mg/ml. Clinical practice does not, at this time, dictate elevation of FK, although careful monitoring continues. Education of oral administration from 0.15 mg/kg to 0.1 mg/kg in combination therapy with steroids and 0.05 mg/kg with azathioprine and steroids has led to revision of therapeutic parameters, e.g., 5-15 ng/ml is now widely used. Therapeutic drug monitoring is important to avoid unnecessary toxicity, but the lower limit has not been fully defined. Clearly, many patients with < 5 ng/ml have excellent hepatic function.

Drug Monitoring↗
PubMed2001

Effect of coadministered drugs and ethanol on the binding of therapeutic drugs to human serum in vitro.

The effects of coadministered drugs and ethanol on the binding of therapeutic drugs to human serum in vitro was investigated. Acetaminophen, lidocaine, phenobarbital, quinidine, theophylline, and valproic acid were added to pooled human serum at therapeutic concentrations. To each preparation was added one additional drug at three concentrations ranging from therapeutic to toxic. The following eight target drug/added drug combinations were studied: acetaminophen/phenobarbital. acetaminophen/theophylline, lidocaine/quinidine, phenobarbital/acetaminophen, phenobarbital/valproic acid, quinidine/lidocaine, theophylline/acetaminophen, and valproic acid/phenobarbital. Each serum without the other added drug as well as the serum supplemented with the other drug at the three concentrations was dialyzed against phosphate buffer. Similarly dialyzed were phenobarbital, quinidine, and theophylline, both alone at therapeutic concentrations in serum and with ethanol at three different concentrations in serum. The percentage of drug binding in each preparation was calculated. Acetaminophen diminished the binding of theophylline to human serum by a net change of 5.7% (percentage increase in free drug fraction [FDF], 11.0%) at 662 micromol/L and by a net change of 7.1% (percentage increase in FDF, 13.7%) at 1324 micromol/L. Theophylline decreased the binding of acetaminophen by a net change of 6.8% (percentage increase in FDF, 8.8%) at 277.5 micromol/L; phenobarbital reduced it by a net change of 6.6% (percentage increase in FDF, 8.5%) at 431 micromol/L. Valproic acid diminished binding of phenobarbital by a net change of 9.9% (percentage increase in FDF, 21.2%) at 1732 micromol/L. No significant effects were noted with other drug combinations or with the addition of ethanol. Coingestion of acetaminophen with theophylline, phenobarbital with acetaminophen, and valproic acid with phenobarbital at high to toxic concentrations decreases the binding of the target drug. The resulting increase in free drug concentration may lead to enhanced drug effect in vivo.

Blood Proteins↗
PubMed2001

Effect of mild therapeutic hypothermia on phenytoin pharmacokinetics.

The authors examined the effect of mild therapeutic hypothermia on phenytoin pharmacokinetics in 14 patients with brain damage. Each patient was given phenytoin during and after mild therapeutic hypothermia. Plasma concentrations of total phenytoin, unbound phenytoin, and 5-(p-hydroxyphenyl)-5-phenylhydantoin (5-p-HPPH), the major metabolite of phenytoin, were measured. Pharmacokinetic parameters during and after mild therapeutic hypothermia were compared. Plasma concentrations of total and unbound phenytoin were significantly higher during hypothermia than after hypothermia. The area under the plasma concentration-time curve (zero to infinity) was increased by 180% and mean residence time was prolonged by 180% during hypothermia compared with the corresponding values after hypothermia. Moreover, the elimination constant (ke) was decreased by 50% and elimination clearance of phenytoin was decreased by 67% during hypothermia compared with the corresponding values after hypothermia. The plasma concentration of 5-p-HPPH was significantly lower during hypothermia than after hypothermia. These findings suggest that phenytoin metabolism is inhibited by mild therapeutic hypothermia.

Adolescent↗
PubMed2004

Everolimus therapeutic concentration range defined from a prospective trial with reduced-exposure cyclosporine in de novo kidney transplantation.

Prospective therapeutic drug monitoring of everolimus was performed in a 1-year multicenter trial in 237 de novo kidney transplant patients. Trough blood levels, rejection episodes, and safety parameters were evaluated to define an appropriate therapeutic concentration range for everolimus in this setting. Patients were randomized to everolimus starting doses of 0.75 mg bid (n = 112) or 1.5 mg bid (n = 125). Doses were then individualized based on everolimus trough blood levels (C0) in an attempt to maintain troughs > or = 3 ng/mL; no upper limit was specified. The regimen also contained corticosteroids and cyclosporine with an early dose reduction in months 2-3 posttransplant based on concentrations 2 hours postdose (C2). Cyclosporine C0 levels were also collected. Prospective therapeutic drug monitoring of everolimus C0 in patients starting at 0.75 mg bid led to dose adjustments in 52% of patients to an average long-term dose of 0.93 +/- 0.36 mg bid. This gave median (10th to 90th percentile) C0 levels of 5.3 (3.4-7.9) ng/mL. In patients starting at 1.5 mg bid, 55% had dose adjustments leading to an average long-term dose of 1.24 +/- 0.35 mg bid. This yielded C0 levels of 7.2 (4.4-11.6) ng/mL. Cyclosporine dosing began on average at 274 +/- 78 mg bid, was down-titrated in months 2-3 from 181 +/- 80 mg to 81 +/- 33 mg bid, and stabilized at 70 +/- 26 mg bid thereafter. This yielded median C2 levels of 1165 ng/mL in month 1, a down-titration with levels of 853 and 630 ng/mL in months 2 and 3, and a posttitration level of 472 ng/mL. The corresponding median cyclosporine C0 was 242 ng/mL initially and 70 ng/mL in the posttitration phase. In patients starting at 0.75 mg bid everolimus and an early down-titration of cyclosporine, everolimus C0 between 3 and 8 ng/mL was an effective and safe concentration range. Concentrations up to 12 ng/mL were tolerated over the first year posttransplant. This trial demonstrated that therapeutic monitoring of everolimus can be prospectively performed for dose individualization. Maintaining everolimus troughs in the range 3 to 8 ng/mL in the first posttransplant year with reduced-exposure cyclosporine is associated with good efficacy and safety profiles.

Adrenal Cortex Hormones↗
PubMed2002

Radiation exposure from diagnostic and therapeutic treatments and risk of breast cancer.

An association between low-dose diagnostic X-ray exposure or therapeutic radiation treatment and breast cancer risk has not been established. To further investigate the issue, we analysed data from a case-control study of breast cancer in Connecticut in 1994-1997. A total of 1217 subjects (608 breast cancer cases and 609 controls), 30-80 years old, participated in the study. A standardized, structured questionnaire was used to collect information through in-person interviews on diagnostic or therapeutic radiation and other breast cancer risk factors. An odds ratio (OR) of 1.7 (95% confidence interval (CI) 0.8-3.6) was observed for postmenopausal women with therapeutic radiation treatment for skin problems such as ringworm and acne, and an OR of 2.5 (95% CI 1.0-6.8) for those who reported having been treated six or more times. Radiation treatment received at younger ages seems to carry a higher risk. In earlier studies therapeutic radiation for skin problems has been associated with an increased risk of breast cancer. Therefore, it is possible that scattered radiation from these treatments could increase the risk of breast cancer. Radiation exposure from diagnostic X-rays was not associated with a significantly increased risk of breast cancer in this study.

Adult↗
PubMed2006

The brain erythropoietin system and its potential for therapeutic exploitation in brain disease.

The discovery of the broad neuroprotective potential of erythropoietin (EPO), an endogenous hematopoietic growth factor, has opened new therapeutic avenues in the treatment of brain diseases. EPO expression in the brain is induced by hypoxia. Practically all brain cells are capable of production and release of EPO and expression of its receptor. EPO exerts multifaceted protective effects on brain cells. It protects neuronal cells from noxious stimuli such as hypoxia, excess glutamate, serum deprivation or kainic acid exposure in vitro by targeting a variety of mechanisms and involves neuronal, glial and endothelial cell functions. In rodent models of ischemic stroke, EPO reduces infarct volume and improves functional outcome, but beneficial effects have also been observed in animal models of subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, and spinal cord injury. EPO has a convenient therapeutic window upon ischemic stroke and favorable pharmacokinetics. Results from first therapeutic trials in humans are promising, but will need to be validated in larger trials. The safety profile and effectiveness of EPO in a wide variety of neurologic disease models make EPO a candidate compound for a potential first-line therapeutic for neurologic emergencies.

Animals↗
PubMed2004

Novel therapeutics in the treatment of bladder cancer.

PURPOSE OF REVIEW: The successful treatment of bladder cancer remains a challenge for urologists and oncologists. There have been substantial changes in the therapeutic options for the management of both superficial and muscle-invasive bladder cancer in the last 5 years. Here we review the preclinical and clinical developments over the last year in bladder cancer therapeutics. RECENT FINDINGS: There is a growing trend toward the use of multimodal treatments for all bladder cancers. For superficial disease, intravesical instillation of chemotherapeutic agents after transurethral resection is quickly becoming the standard of care. Novel therapeutic modalities under investigation include DNA vaccines, magnetically targeted carriers, bio-adhesive microspheres and antisense oligodeoxynucleotides. For muscle-invasive bladder cancer, systemic perioperative chemotherapy is being used with increasing frequency and the latest preclinical research efforts are focused on the inhibition of angiogenesis and other processes predisposing to metastatic disease. SUMMARY: Treatment goals for bladder cancer of any stage are complete removal of the initial tumor, prevention of disease recurrence and effective inhibition of progression to advanced disease with the ultimate aim of reducing mortality. The myriad novel therapeutic modalities currently being explored suggest that these goals may perhaps be achievable within our lifetime.

Humans↗
PubMed2003

Therapeutic exercise and orthopedic manual therapy for impingement syndrome: a systematic review.

OBJECTIVE: To review randomized controlled trials evaluating the effectiveness of therapeutic exercise and orthopedic manual therapy for the treatment of impingement syndrome. DATA SOURCE: Reports up to October 2002 were located from MEDLINE, the Cochrane Database of Systematic Reviews, the Physiotherapy Evidence Database (PEDro), the TRIP database, and the Cumulative Index to Nursing & Allied Health Literature (CINAHL) using "shoulder" and "clinical trial"/"randomized controlled trial" as search terms. STUDY SELECTION: Studies were included if (1) they were a randomized controlled trial; (2) they were related to impingement syndrome, rotator cuff tendinitis, or bursitis; (3) one of the treatments included therapeutic exercise or manual therapy. DATA EXTRACTION: Two independent observers reviewed the methodological quality of the studies using an assessment tool developed by the Cochrane Musculoskeletal Injuries Group. Differences were resolved by consensus. DATA SYNTHESIS: Seven trials met our inclusion criteria. After consensus, the mean methodological score for all studies was 13.9 +/- 2.4 (of 24). Four studies of 7, including the 3 trials with the best methodological score (67%), suggested some benefit of therapeutic exercise or manual therapy compared with other treatments such as acromioplasty, placebo, or no intervention. CONCLUSIONS: There is limited evidence to support the efficacy of therapeutic exercise and manual therapy to treat impingement syndrome. More methodologically sound studies are needed to further evaluate these interventions.

Exercise Therapy↗
PubMed2005

Therapeutic hypothermia after cardiac arrest.

PURPOSE OF REVIEW: Most patients who suffer a cardiac arrest die after the event. Full neurological recovery occurs in only 6-23%. Until recently no specific post-arrest therapy was available to improve outcome. Application of therapeutic hypothermia (32-34 degrees C for 12-24 h) applied after cardiac arrest could help to improve this dreadful situation. This review covers the background of and recent clinical studies into hypothermia after cardiac arrest, and gives some insights into the future of resuscitation, namely suspended animation. RECENT FINDINGS: Two randomized clinical trials of mild therapeutic hypothermia applied after successful resuscitation from cardiac arrest showed that hypothermia after cardiac arrest improves neurological outcome as well as overall mortality. SUMMARY: The introduction of therapeutic hypothermia after cardiac arrest into routine intensive care practice could save thousands of lives worldwide, because only six patients must be treated to yield one additional patient with favourable neurological recovery. New developments in cooling techniques will make early induction of therapeutic hypothermia simple and convenient. The optimal duration and depth of hypothermia will be determined by future trials. Suspended animation is cooling during cardiac arrest to preserve the organism under conditions of prolonged controlled clinical death, followed by delayed resuscitation, resulting in survival without brain damage. This concept was initially introduced for trauma victims who rapidly bleed to death, and proved to be feasible in studies evaluating outcomes following exsanguination cardiac arrest in large animals. Whether the concept of suspended animation is applicable to normovolemic cardiac arrest is under investigation.

Journal Article↗
PubMed2005

A novel back school using a multidisciplinary team approach featuring quantitative functional evaluation and therapeutic exercises for patients with chronic low back pain: the Japanese experience in the general setting.

STUDY DESIGN: A prospective cohort study. OBJECTIVES: To introduce a novel back school for the treatment of patients with chronic low back pain (CLBP), and to report its clinical results. SUMMARY OF BACKGROUND DATA: Although back school is one of the treatment methods for patients with CLBP, its efficacy and appropriate style remain controversial. No studies have been published regarding the combined program of back school with a multidisciplinary team approach. METHODS: A total of 182 patients with CLBP (74 men and 108 women; average age, 43.8 years) participated in this study. All patients were enrolled in the back school using a multidisciplinary team approach featuring quantitative functional evaluation and therapeutic exercises. The following outcome measures were evaluated at the baseline, and 6 and 12 months after the enrollment: the level of pain evaluated with a Visual Analog Scale (VAS), flexibility of trunk and hamstrings (finger-floor distance, straight leg raising), trunk muscle strength and endurance, frequency of therapeutic exercises, and self-reported patient satisfaction. RESULTS: An averaged VAS score was 6.2 before enrollment in the program and 2.8 at follow-up. The pain improved in 141 patients (80.8%), did not change in 27 (15.4%), and was aggravated in 7 (3.8%). There was statistically significant improvement of finger-floor distance, trunk muscle strength, and endurance in the patients whose pain was relieved after enrollment in the program (P < 0.05). The compliance with the exercise program was significantly correlated with the clinical results (P < 0.05). CONCLUSIONS: We developed a novel back school using a multidisciplinary team approach, featuring quantitative functional evaluation and therapeutic exercises. The current study demonstrated that our program could provide a satisfactory result for the treatment of patients with CLBP. The quantitative functional evaluation was a worthwhile outcome measure when evaluating the efficacy of the treatment program. Teaching body mechanics and performing the therapeutic exercises through the multidisciplinary team approach are essential to managing CLBP in a general setting.

Adult↗
PubMed2006

Effects of therapeutic bronchoalveolar lavage and partial liquid ventilation on meconium-aspirated newborn piglets.

OBJECTIVE: To investigate the therapeutic effects of bronchoalveolar lavage (BAL) with either diluted surfactant (SBAL) or perfluorochemical liquid (PBAL), followed by either conventional mechanical ventilation (CMV) or partial liquid ventilation (PLV), on lung injury and proinflammatory cytokine production induced by meconium aspiration in newborn piglets. DESIGN: A prospective, randomized, experimental study. SETTING: An animal research laboratory at a medical center. SUBJECTS: Anesthetized and mechanically ventilated newborn piglets (n = 27). INTERVENTIONS: The animals were instilled with 3-5 mL/kg 25% human meconium via an endotracheal tube to induce meconium aspiration syndrome (MAS). After stabilization, animals were randomly assigned to either CMV group (no BAL) or one of the treatment groups (SBAL-CMV, SBAL-PLV, PBAL-CMV, and PBAL-PLV). MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary variables were monitored, and interleukin-1beta and interleukin-6 content of the serum and lung tissue was measured. The animals without any treatment (CMV group) displayed the worst outcome; the animals in the PBAL-PLV group had the best gas exchange, lung compliance, and least pulmonary damage; and the SBAL-CMV, PBAL-CMV, and SBAL-PLV groups had intermediate effects. The serum interleukin-1beta concentration of the CMV group was significantly higher than all other groups over time (p < .05), and interleukin-6 concentration was significantly higher than the PBAL-PLV group (p < .05). The tissue interleukin-1beta and interleukin-6 contents were also highest in the CMV group and lowest in the PBAL-PLV group. CONCLUSIONS: Initial therapeutic BAL and therapeutic BAL followed by PLV with the same perfluorochemical liquid provided significant therapeutic effects in treating an animal model with severe MAS and therefore warrant consideration in cases that are intractable to other therapies.

Animals↗
PubMed2006

Therapeutic hypothermia utilization among physicians after resuscitation from cardiac arrest.

OBJECTIVE: We sought to evaluate current physician use of therapeutic hypothermia after cardiac arrest, to ascertain reasons for nonadoption of this treatment, and to determine current cooling techniques employed. DESIGN: Web-based survey. SETTING: International physician cohort in the United States, UK, and Finland. SUBJECTS: Physicians (MD or DO) caring for resuscitated cardiac arrest patients. INTERVENTIONS: An anonymous Web-based survey was distributed to physicians identified through United States-based critical care, cardiology, and emergency medicine directories and critical care networks in the UK and Finland. Recipients were queried regarding use of postresuscitation therapeutic hypothermia. MEASUREMENTS AND MAIN RESULTS: Of the final 13,272 surveys actually distributed to physicians, 2,248 (17%) were completed. Most respondents were attending physicians (82%) at teaching hospitals (76%) who practiced critical care (35%), cardiology (20%), or emergency medicine (22%). Of all replies, 74% of United States respondents and 64% of non-United States respondents had never used therapeutic hypothermia. United States emergency medicine physician adoption of cooling was significantly less than that of United States intensivists (16% vs. 34%, p < .05). The most often cited reasons for nonuse by respondents were "not enough data," "not part of Advanced Cardiac Life Support guidelines," and "too technically difficult to use." Factors associated with increased use included non-United States residence, critical care specialty, and larger hospital size. CONCLUSIONS: Physician utilization of cooling after cardiac arrest remains low. For improved adoption of therapeutic hypothermia, our data suggest that development of better cooling methodology and recent incorporation into resuscitation guidelines may improve use.

Attitude of Health Personnel↗
PubMed2006

Growth factor-induced therapeutic neovascularization for ischaemic vascular disease: time for a re-evaluation?

PURPOSE OF REVIEW: Therapeutic angiogenesis and arteriogenesis represent an alternative treatment modality for patients with advanced ischaemic coronary or peripheral artery occlusive disease, who are unsuitable for standard revascularization procedures. RECENT DEVELOPMENTS: Proof-of-concept evidence for therapeutic growth factor, both gene and protein-mediated neovascularization was provided in animal models of chronic myocardial and hindlimb ischaemia. Early human, phase I, trials utilizing the prototypical growth factor families, vascular endothelial growth factor and fibroblast growth factor, documented safety and suggested improvements in anginal symptoms and functional status. Large, randomized, placebo-controlled phase II/III clinical trials have, however, yielded variable results as such studies have suffered from significant limitations in therapeutic approach or design, which limits the ability to draw firm conclusions. SUMMARY: Future trials must incorporate robust delivery strategies and address issues of study design including proper patient selection. Laboratory-based refinements in therapy, including a focus on the promotion of arteriogenesis and the modification of patient 'endotheliopathy', will all further enhance the potential of therapeutic neovascularization strategies.

Angiogenesis Inducing Agents↗
PubMed2006

Therapeutic use of silicone hydrogel contact lenses in children.

PURPOSE: To evaluate the safety and efficacy of silicone hydrogel extended-wear contact lenses when used for therapeutic purposes for children. METHODS: This was a prospective open-ended nonrandomized study. Twenty-nine consecutive pediatric patients at the Eye Clinic of Kaunas University of Medicine in Lithuania requiring therapeutic contact lens wear for anterior segment disorders were enrolled. In all cases, Focus NIGHT & DAY (CIBA Vision, Duluth, GA) contact lenses were used. Success or failure of specific treatment and the presence of ocular or lens-related complications were noted in each case. RESULTS: Twenty-nine eyes were fitted with Focus NIGHT & DAY contact lenses. The average age at the time of presentation was 9 years (range, 2 months to 17 years). The conditions treated were burn (seven eyes), corneal erosion (three eyes), neurotrophic keratitis (four eyes), descemetocele (one eye), corneal ulcer (one eye), keratouveitis (one eye), exposure keratitis (one eye), vernal keratoconjunctivitis (one eye), herpetic keratitis (one eye), corneal perforation (two eyes), and corneal injury (seven eyes). The mean duration of continuous contact lens wear was 17.8 days (range, 1-131 days). Dry eye was the cause of contact lens loss in one eye. Total bandage contact lens wear was effective in 27 (93%) eyes. Complications related to contact lens wear were limited to one case (increased signs of inflammation in the case of herpetic keratitis) requiring cessation of therapeutic lens wear after 24 hours. CONCLUSIONS: Focus NIGHT & DAY silicone hydrogel contact lenses were found to be safe and efficacious for continuous-wear therapeutic use for children.

Adolescent↗
PubMed2004

Genetically modified mice and their use in developing therapeutic strategies for prostate cancer.

PURPOSE: At the National Cancer Institute a comprehensive program has been developed for accelerating prostate cancer research, especially in the area of mouse models for human cancers. This review focuses on transgenic mouse models for elucidating the molecular and cellular processes that lead to prostate cancer initiation, progression and metastasis, and on their suitability for therapeutic and chemopreventive trials. MATERIALS AND METHODS: Published data from MEDLINE, http://emice.nci.nih.gov/, our laboratory and other investigators are reviewed. RESULTS: Currently no 1 mouse model displays the entire continuum of human prostate cancer initiation, development and metastasis. The loss or over expression of a single gene results primarily in epithelial hyperplasia, prostatic intraepithelial neoplasia or more aggressive localized adenocarcinoma. To date the only models that develop lung, liver and occasionally bone metastasis are those that express SV40 large T antigen. A number of models have been used to investigate the efficacy of androgen deprivation, lovastatin, vitamin D, the anti-inflammatory drug E-7869, genistein and (-)-epigallocatechin-3-gallate as therapeutic or chemopreventive agents. Noninvasive optical imaging technologies facilitate the detection of metastatic lesions and the effects of therapeutic agents on tumor regression. CONCLUSIONS: Integrating mouse studies with human clinical trials would ensure that mechanisms that promote prostate cancer are identified and potential therapeutic targets are validated.

Adenocarcinoma↗
PubMed2004

ErbB2 is a tumor associated antigen and a suitable therapeutic target in Wilms tumor.

PURPOSE: The modern multimodality therapeutic approach to Wilms tumor (WT), combining surgery with radiotherapy and chemotherapy results in high cure rates even for high stage disease. However, the combination of radiotherapy and chemotherapy is associated with severe early and late complications such as neutropenic sepsis, growth retardation and secondary malignancies. Therefore, novel therapeutic strategies, which would decrease the treatment burden, are required. We studied the expression of erbB2 growth factor receptor in WT cells as well as its role as a tumor therapeutic target in an in vivo xenograft model of Wilms tumor. MATERIALS AND METHODS: Paraffin embedded pathological samples from 14 different WT cases as well as xenografts derived thereof were immunostained with anti-erbB2 monoclonal antibody. The immunostaining was graded in comparison to a known positive control (breast cancer) and was scored by the intensity of staining (0 to +3) multiplied by the percentage of cells expressing the antigen. The expression of erbB2 in the human WT xenograft was verified also by fluorescence activated cell sorter analysis. In addition, nude mice bearing established subcutaneous human WT xenografts were treated with either 3 intraperitoneal injections of N29 anti-erbB2 monoclonal antibody or irrelevant antibody. RESULTS: All of the authentic human pathological samples, except 1 anaplastic WT as well the WT xenografts (at different stages), expressed erbB2. Expression was also observed in WT metastasis and in tumors which out grew chemotherapy. Systemic administration of anti-erbB2 monoclonal antibody inhibited and even prevented the growth of WT xenograft in vivo. CONCLUSIONS: ErbB2 is a tumor associated antigen in WT. Being expressed in almost all tumor stages, our in vivo model suggests that erbB2 may serve as a WT therapeutic target. Further work is needed to establish the role of erbB2 in the disease and its potential use in decreasing current treatment burden.

Adolescent↗