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PubMed2004

[The therapeutic index in asthma: how should it be defined?].

INTRODUCTION: The therapeutic index (efficacy/tolerance or benefit/risk ratio) is a major determinant of treatment decisions in asthma. METHODS: For the numerator, the therapeutic index depends on efficacy (maximal effect) and not potency (dose-response relationship). With regard to the denominator, several pharmacological factors influence the occurrence of side-effects, the acceptability of which also has to be considered. RESULTS: In asthma, some strategies have a more favourable therapeutic index than others;e.g additional treatment (long acting beta2 agonists, leukotriene receptor antagonists, theophylline) to inhaled corticosteroids instead of doubling the dose of the latter. Conversely, it is extremely difficult to compare the therapeutic indices of different molecules of inhaled corticosteroids. CONCLUSIONS: The potential risk of systemic side effects with long-term administration of high doses of inhaled corticosteroids suggests the need to seek the minimal effective dose.

Administration, Inhalation↗
PubMed1996

Development of a tool to measure therapeutic factors in group process.

A tool, the Therapeutic Group Interaction Factors Scale (TGIF), was developed for systematically and objectively measuring the extent to which therapeutic factors defined by Yalom are present or absent in group process. Preliminary findings suggest that the TGIF is relatively easy to learn and use by coders who are familiar with Yalom's work. Once this tool has been further developed and tested, it will permit nurses and other therapists who lead/facilitate therapeutic groups to study the relationship between Yalom's factors and therapeutic outcomes objectively, rather than by asking patients to evaluate the contribution of each factor subjectively.

Group Processes↗
PubMed2002

Inhibitors of the ras oncogene as therapeutic targets.

Advances in our understanding of the molecular pathways and genetic mutations that control tumor cell proliferation and metastasis present an opportunity to develop novel, mechanism-based therapeutic strategies. Ras mutations are the most frequently activated oncogenes in human tumors, with over 30% expressing ras mutations. Molecular dissection of the signaling pathway and the mechanisms of ras anchorage, post-translational modification, and downstream effector signaling of ras now under intensive investigation will help us to design additional methods for ras-directed therapy in an effort to reach an optimal treatment for human tumors that will most likely comprise a combination of modalities targeted at the different underlying genetic defects. The successes and limitations of ras-targeted therapies must be viewed in light of the increasing understanding of the complexity of the ras-signaling pathway. Only now are we beginning to discover the many functions of this integrated pathway, such as the differences between the actions of various ras isoforms that may affect our choice of therapeutic approach. Many of these Ras therapeutic targets have shown success in preclinical studies, and some have shown efficacy in clinical trials with minimal toxicities. Compounds that block ras-transforming activity without affecting normal ras function seem more attractive for the future development of ras-targeted therapy. FTIs may partially fulfill such requirements. Based on their specific, novel, and mechanism-based action; minimal toxicity; and encouraging responses in clinical trials, the development of Ras therapeutic targets as single agents or in combination with conventional chemotherapy and radiotherapy should be pursued.

Alkyl and Aryl Transferases↗
PubMed2002

Targeting intracellular signal transduction. A new paradigm for a brave new world of molecularly targeted therapeutics.

Significant advances in the field of molecular biology over the past decade have led to a new era in cancer therapeutics, with an explosion of rationally designed therapeutic strategies directed against selective molecular targets. The complex array of aberrant signal transduction proteins involved in carcinogenesis has been the focus of target-based anticancer agents. Inhibitors of intracellular signal transduction represent a unique approach in that they inhibit critical downstream regulatory proteins, which are vital to the process of cellular communication. Although these agents are in early-phase evaluations, the preliminary data suggest that they are well tolerated and capable of target inhibition in surrogate and tumor tissue. Although the primary therapeutic benefit of these agents is expected to be decreased tumor growth, evidence suggests that objective tumor responses may also be achieved. There are many unresolved questions pertaining to the development of this class of compounds, including selection of optimal dose and schedule, determination of relevant endpoints, methods for target validation, and strategies for combination with cytotoxic agents. However, despite the numerous unresolved issues, the emergence of this class of compounds has resulted in an undeniable impact on the present and future of cancer therapeutics.

Adult↗
PubMed2000

Therapeutic video-assisted thoracoscopic surgical resection of colorectal pulmonary metastases.

OBJECTIVE: Careful patient selection is vital when video-assisted thoracoscopic surgical (VATS) therapeutic pulmonary metastasectomy of colorectal carcinoma is considered. Complete resection of all metastatic disease remains a vital concept. We reviewed our VATS experience for therapeutic metastasectomy of peripheral colorectal pulmonary metastases. METHODS: Over 90 months, therapeutic VATS metastasectomy was accomplished upon 80 patients with colorectal metastases. Thin cut computed tomography (CT) was central in identifying lesions. The mean interval from primary carcinoma to VATS resection was 41 months (1-156 months; median, 33). A solitary lesion was resected in 60 patients and multiple (2-7) lesions resected in 20 patients. Statistics were obtained using the Student's t-test. RESULTS: No operative mortality or major postoperative complications occurred. The hospital stay was 4.5+/-2. 2 days (range, 1-13). All lesions were resected by VATS, with four conversions to thoracotomy to improve the margins. The mean survival of patients with one lesion was 34.8 months compared with 26.5 months for patients with multiple lesions (P=0.37). The mean survival was 20.5 months when metastases occurred <3 years vs. 28.1 months for >3 years from primary carcinoma resection (P=0.20). Twenty-five (31%) patients are disease free; with a mean interval of 38.7 (3-84; median, 35) months. Sixty-nine percent (55/80) of patients developed a recurrence: 6/80 (8%) local; 19/80 (24%) regional (same hemithorax away from resection); and 30/80 (38%) distant. The overall survival at 1 year was 81.2%, 48.4% at 3 years and 30.8% at 5 years. CONCLUSIONS: Therapeutic VATS resection of colorectal metastases appears efficacious. Preoperative CT can identify peripheral colorectal metastases amenable to VATS. Conversion to thoracotomy is indicated when none of the lesions identified by CT are found or when clear surgical margins are jeopardized.

Adult↗
PubMed2003

Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure.

We evaluated exposure, safety, and efficacy data from an international Phase 3 trial of everolimus in de novo heart transplantation to characterize the longitudinal pharmacokinetics of everolimus and cyclosporine and to identify a therapeutic concentration range for everolimus. We randomized 634 patients to receive either 0.75 mg everolimus twice daily, 1.5 mg everolimus twice daily, or azathioprine in addition to corticosteroids and cyclosporine. At 8 visits during the first 6 months after transplantation, we obtained 2,328 everolimus trough levels (Cmin) and 129 area-under-the-curve (AUC) profiles over the dosing interval in patients treated with everolimus; we collected 3,258 cyclosporine trough concentrations and 174 profiles in all 3 treatment arms. We used median-effect analysis to characterize exposure-response associations between everolimus average Cmin vs freedom from biopsy-confirmed acute rejection; maximum cholesterol, low density lipoprotein, triglyceride, and creatinine levels; and minimum leukocyte and platelet counts. Everolimus Cmins averaged 5.2 +/- 3.8 ng/ml and 9.4 +/- 6.3 ng/ml at the lower and upper dose levels. A 17% underproportionality was noted in Cmins; however, peak exposure and AUC were consistent with dose proportionality. Everolimus exposure was stable during the 6-month period. Interindividual variability was 37% for AUC and 40% for Cmin. The latter parameter was not influenced to a clinically relevant extent by sex, age, or weight. The Cmin was well correlated with AUC (r2 = 0.81). Everolimus Cmin was significantly related to freedom from rejection (p = 0.02) with 3 ng/ml being an informative lower threshold for efficacy. Thrombocytopenia, defined as <75 x 10(9)/liter, was related significantly to Cmin (p = 0.03); however, the incidence in this study was too low to establish an upper end for the therapeutic range. Lower doses of cyclosporine (by 15% to 19%) were used in patients treated with everolimus to achieve cyclosporine Cmins and AUCs similar to those in patients treated with azathioprine. Everolimus exposure was dose proportional and stable during the first 6 months after transplantation. Interindividual pharmacokinetic variability was high but not influenced by common demographic covariates. We observed a significantly increased risk of acute rejection at everolimus trough levels <3 ng/ml, which constitutes the lower therapeutic concentration limit when everolimus is used with conventionally dosed cyclosporine. Everolimus-related adverse events were manageable up to the highest troughs (22 ng/ml) observed in this population. We could not derive a precise upper therapeutic concentration limit from these data.

Adrenal Cortex Hormones↗
PubMed1996

Influence of magnetic resonance imaging on diagnosis and therapeutic intention.

RATIONALE AND OBJECTIVES: We assessed the contribution of magnetic resonance (MR) imaging to diagnostic and therapeutic decision making. METHODS: In a before-after observational study, we collected information from clinicians before and after patients were given MR examinations. We studied 406 cases selected from consecutive referrals to a single MR imaging facility in Manitoba between November 1, 1991, and October 30, 1992, for diagnosis of suspected brain, spinal column, or large-joint disorder. We examined changes in diagnoses, changes in clinician diagnostic confidence, and changes in therapeutic intentions after MR examinations. RESULTS: Overall, MR imaging findings contributed to a change in referring physicians' diagnoses or diagnostic confidence in 76% of the cases. Referring physicians reported a change in provisional diagnosis in 42% of the cases. In 67% of these cases, the referring physician's provisional diagnosis was ruled out by normal examination findings; in the remaining 33% of the cases, an alternate diagnosis was offered by the consulting radiologist. In the 58% of the cases in which the provisional diagnosis was not altered by MR imaging findings, clinical confidence in the provisional diagnosis increased in 46% of the cases and decreased in 12% of the cases. Management plans were reported to be altered in 54% of the cases; in 24% of the cases, therapeutic intentions changed from lower to higher levels of intervention. CONCLUSION: Although MR imaging had a substantial influence on clinicians' decisions concerning diagnoses, the influence of MR imaging findings on therapeutic decision making, and therefore on patients' health status, was more moderate.

Brain Diseases↗
PubMed1998

The role of panoramic radiography in determining an increased risk of cervical atheromas in patients treated with therapeutic irradiation.

PURPOSE: Therapeutic irradiation of the neck is a common component of treatment for those with carcinoma of the oral cavity, pharynx, and larynx. Such irradiation, however, has been implicated as the cause of accelerated atherosclerosis of the cervical carotid artery and subsequent stroke. Panoramic radiography, previously shown to be capable of identifying carotid artery atherosclerosis in non-irradiated individuals, was used to assess the carotid vasculature of patients who had been treated for cancer with therapeutic irradiation. METHODS: The panoramic radiographs of 33 male subjects who had received therapeutic irradiation (> or = 50 Gy) to the neck 30 or more months previously were assessed for the presence of calcified carotid artery atherosclerotic lesions. Age-matched controls, similarly liable for oropharyngeal malignancy and atherosclerosis by virtue of their medical and habitual risk factors (hypertension, smoking, obesity) were assessed in a like manner. RESULTS: The panoramic radiographs of the irradiation-treated subjects (age range, 32 to 84 years; mean age, 66.1 years) showed that 21% (7 of 33 subjects) had calcified atherosclerotic lesions. The mean age of these seven subjects was 64.6 years; four had unilateral lesions and three had bilateral lesions. The radiographs of the control subjects showed that 4.7% (5 of 107 subjects) had calcified atherosclerotic lesions. The mean age of these five subjects was 67; three had unilateral lesions and two had bilateral lesions. The lesions seen in the two populations had similar morphologic appearances. The discrete radiopaque calcifications were located within the soft tissues of the neck, approximately 2.5 cm inferior-posterior to the angle of the mandible. CONCLUSIONS: Subjects who had received therapeutic irradiation of the neck had a statistically higher risk (p = 0.007, according to Fisher's Exact Test) of the development of calcified carotid artery atherosclerotic lesions than age-matched, risk-matched, non-irradiated control subjects. These lesions can be detected on routine panoramic radiographs.

Adult↗
PubMed2004

Gliclazide at a lower concentration than therapeutic dose increases the sensitivity of insulin secretion to glucose in perfused rat pancreas.

OBJECTIVES: We studied the difference between effects of therapeutic dose and sub-therapeutic dose of gliclazide on the glucose-induced insulin secretion. METHODS: The normal rat pancreas was isolated and perfused with Krebs-Ringer buffer containing 1-14 mmol/l glucose. Influcences of 0.25 and 2.5 microg/ml gliclazide on the glucose concentration-insulin secretion curve was examined. RESULTS: Gliclazide at 0.25 microg/ml significantly potentiated 5-8 mmol/l glucose-induced insulin secretion (2.5 +/- 0.5 vs 1.0 +/- 0.3 mU for 15 min at 6.5 mmol/l glucose, P<0.01), but did not give influence on either 1-3 or 10-14 mmol/l glucose-induced insulin secretion. The glucose concentration, at which half-maximal insulin secretion was observed, was lower with gliclazide (5.9 mmol/l) than in the control (7.5 mmol/l). Gliclazide at 2.5 microg/ml markedly increased the maximally glucose-stimulated insulin secretion from 3.9 +/- 0.5 mU for 15 min in the control to 6.6 +/- 0.7 mU for 15 min (P<0.01). The half-maximal insulin secretion was observed at a lower glucose concentration (5.0 mmol/l) than in the absence of gliclazide. CONCLUSION: Gliclazide in sub-therapeutically low dose has different effects on insulin secretion from in therapeutic dose, namely sharpens the insulin secretion sensitivity to glucose with no influence on the maximal insulin secretion. It is possible that low doses of gliclazide might be of interest in some type 2 diabetics whose main pathophysiology is the blunting of insulin secretion response to hyperglycemia.

Animals↗
PubMed2003

Rational design and engineering of therapeutic proteins.

An increasing number of engineered protein therapeutics are currently being developed, tested in clinical trials and marketed for use. Many of these proteins arose out of hit-and-miss efforts to discover specific mutations, fusion partners or chemical modifications that confer desired properties. Through these efforts, several useful strategies have emerged for rational optimization of therapeutic candidates. The controlled manipulation of the physical, chemical and biological properties of proteins enabled by structure-based simulation is now being used to refine established rational engineering approaches and to advance new strategies. These methods provide clear, hypothesis-driven routes to solve problems that plague many proteins and to create novel mechanisms of action. We anticipate that rational protein engineering will shape the field of protein therapeutics dramatically by improving existing products and enabling the development of novel therapeutic agents.

Animals↗
PubMed1995

The rational use of therapeutic drugs in the 21st century. Important lessons from cumulative meta-analyses of randomized control trials.

The use of randomized control trials to assess the usefulness of therapeutic drugs over the last half century has brought significant benefits to patient care. The full potential benefits, however, have been only partially fulfilled because available data are frequently poorly used. Meta-analysis has emerged as an important tool for combining clinical evidence. Several examples are presented that compared the results of cumulative meta-analysis of randomized control trials with clinical expert recommendations. These comparisons demonstrated that clinical expert recommendations are often not synchronized with accumulating evidence, and this lack of recognition often resulted in delays in the acceptance of effective drugs and the slow abandonment of possibly harmful therapeutic practices. The problems of inappropriate therapeutic drug use will only intensify as new drugs are introduced and new uses for established drugs are proposed. The rational use of therapeutic drugs can be achieved only through the routine use of meta-analysis on high-quality clinical data. Some suggestions are made to improve the quality of the original research and the ways of assembling meta-analyses and disseminating their results.

Diffusion of Innovation↗
PubMed1999

Acute complications in the current era of therapeutic cardiac catheterization for congenital heart disease.

The acute complications of therapeutic cardiac catheterization for congenital heart disease as performed currently in a small unit were reviewed. In recent years, there has been a significant increase in the number of lesions thought amenable to catheter therapy. Only a few reports, however, have addressed the overall incidence of acute complications of therapeutic cardiac catheterization, all representing the experience of centres performing moderate-to-large numbers of procedures. A retrospective review was performed of 425 therapeutic catheter procedures performed at our institution between May 1993 and November 1997. Acute complications were retrieved from the database. This included all adverse events that were clinically recognized at the time of or within 2 weeks after the procedure and which, to the best of the authors' clinical judgement, were related to the catheterization and not part of the natural history of the child's illness. All patients were observed overnight following the procedure, and stayed in hospital if a complication developed. There were 49 acute complications (11.5%), of which 43 (10.1%) were deemed minor and 6 (1.4%) were considered major. The rate was low in patients with valvar pulmonary stenosis, including three neonates (3/45, 6.7%), for those undergoing angioplasty of native co-arctation (1/15, 6.7%) and pulmonary arteries (2/27, 7.4%); and for coil embolization of systemic to pulmonary collateral arteries (1/16, 6.3%). The rate was high in patients with valvar aortic stenosis, including 12 neonates (9/37, 24.3%), and for angioplasty of re-coarctation (4/23, 21.7%). There were more overall complications in neonates (25.6%) than in older patients (10.1%) (p < 0.01). Two patients died (0.5%), but no patient required emergency surgical intervention. In spite of the introduction of many new therapeutic modalities with greater intrinsic risk, and the fact that patients with more complex lesions and who are more acutely ill are being treated, the overall rate of complications remains relatively low. This probably reflects improvements in pericatheterization medical management, in selection of patients, in procedural techniques, and in the experience of operators.

Adolescent↗
PubMed2001

Glycoengineering of therapeutic glycoproteins: in vitro galactosylation and sialylation of glycoproteins with terminal N-acetylglucosamine and galactose residues.

Therapeutic glycoproteins produced in different host cells by recombinant DNA technology often contain terminal GlcNAc and Gal residues. Such glycoproteins clear rapidly from the serum as a consequence of binding to the mannose receptor and/or the asialoglycoprotein receptor in the liver. To increase the serum half-life of these glycoproteins, we carried out in vitro glycosylation experiments using TNFR-IgG, an immunoadhesin molecule, as a model therapeutic glycoprotein. TNFR-IgG is a disulfide-linked dimer of a polypeptide composed of the extracellular portion of the human type 1 (p55) tumor necrosis factor receptor (TNFR) fused to the hinge and Fc regions of the human IgG(1) heavy chain. This bivalent antibody-like molecule contains four N-glycosylation sites per polypeptide, three in the receptor portion and one in the Fc. The heterogeneous N-linked oligosaccharides of TNFR-IgG contain sialic acid (Sia), Gal, and GlcNAc as terminal sugar residues. To increase the level of terminal sialylation, we regalactosylated and/or resialylated TNFR-IgG using beta-1,4-galactosyltransferase (beta1,4GT) and/or alpha-2,3-sialyltransferase (alpha2,3ST). Treatment of TNFR-IgG with beta1,4GT and UDP-Gal, in the presence of MnCl(2), followed by MALDI-TOF-MS analysis of PNGase F-released N-glycans showed that the number of oligosaccharides with terminal GlcNAc residues was significantly decreased with a concomitant increase in the number of terminal Gal residues. Similar treatment of TNFR-IgG with alpha2,3ST and CMP-sialic acid (CMP-Sia), in the presence of MnCl(2), produced a molecule with an approximately 11% increase in the level of terminal sialylation but still contained oligosaccharides with terminal GlcNAc residues. When TNFR-IgG was treated with a combination of beta1,4GT and alpha2,3ST (either in a single step or in a stepwise fashion), the level of terminal sialylation was increased by approximately 20-23%. These results suggest that in vitro galactosylation and sialylation of therapeutic glycoproteins with terminal GlcNAc and Gal residues can be achieved in a single step, and the results are similar to those for the stepwise reaction. This type of in vitro glycosylation is applicable to other glycoproteins containing terminal GlcNAc and Gal residues and could prove to be useful in increasing the serum half-life of therapeutic glycoproteins.

Acetylglucosamine↗
PubMedDate not supplied

Glycosylation of recombinant antibody therapeutics.

The adaptive immune system has the capacity to produce antibodies with a virtually infinite repertoire of specificities. Recombinant antibodies specific for human targets are established in the clinic as therapeutics and represent a major new class of drug. Therapeutic efficacy depends on the formation of complexes with target molecules and subsequent activation of downstream biologic effector mechanisms that result in elimination of the target. The activation of effector mechanisms is dependent on structural characteristics of the antibody molecule that result from posttranslational modifications, in particular, glycosylation. The production of therapeutic antibody with a consistent human glycoform profile has been and remains a considerable challenge to the biopharmaceutical industry. Recent research has shown that individual glycoforms of antibody may provide optimal efficacy for selected outcomes. Thus a further challenge will be the production of a second generation of antibody therapeutics customized for their clinical indication.

Antibodies↗
PubMedDate not supplied

Radiopaque alginate microcapsules for X-ray visualization and immunoprotection of cellular therapeutics.

Alginate-poly-L-lysine-alginate (APA) microcapsules have been explored as vehicles for therapeutic drug and cell delivery. The permselectivity of these capsules provides a unique means of controlled drug release and immunoisolation of encapsulated cells. Immunoisolation is especially attractive as it abrogates the need for chronic immunosuppressive therapy and opens up the possibility for the delivery of numerous cell sources including xenogeneic grafts. APA microcapsules containing cellular therapeutics have proven effective in the short-term treatment of a wide range of diseases requiring enzyme or endocrine replacement therapy, including type I diabetes. If these microcapsules could be noninvasively monitored with X-ray imaging modalities (i.e., fluoroscopy, CT, and digital subtraction angiography), questions such as the ideal transplantation site, the best means of delivery, and the long-term survival of grafts could be better addressed. We have developed two novel alginate-based radiopaque microcapsule formulations containing either barium sulfate (Ba X-Caps) or bismuth sulfate (Bi X-Caps). As compared to conventional, nonradiopaque APA capsules, Ba X-Caps and Bi X-Caps containing human cadaveric islets resulted in a decrease in cellular viability of less than 5% up to 14 days after encapsulation. Both radiopaque capsules were found to be permeable to lectins < or =75 kDa, but were impermeable to lectins > or =120 kDa, thus ensuring the blockage of the penetration of antibodies while allowing free diffusion of insulin and nutrients. The glucose-responsive insulin secretion of the radiopaque encapsulated human islets was found to be unaltered compared to that of unlabeled controls, with human C-peptide levels ranging from 3.21 to 2.87 (Ba X-Caps) and 3.23 to 2.87 (Bi X-Caps) ng/islet at 7 and 14 days postencapsulation, respectively. Using fluoroscopy, both Ba X-Caps and Bi X-Caps could be readily visualized as single radiopaque entities in vitro. Furthermore, following transplantation in vivo in mice and rabbits, single capsules could be identified with no significant change in contrast for at least 2 weeks. This study represents the first attempt at making radiopaque microcapsules for X-ray guided delivery and imaging of cellular therapeutics. While human cadaveric islets were used as a proof-of-principle, these radiopaque capsules may have wide ranging therapeutic applications for a variety of cell types.

Alginates↗
PubMed2000

Pharmacokinetic variability and therapeutic drug monitoring actions at steady state.

PURPOSE: To develop a mathematical model for therapeutic drug monitoring and to assess the kinetic relationships between the intensity of corrective action and the approach of drug concentrations to target values. METHODS: A mathematical model that succinctly accounts for the corrective actions and the variability inherent in the pharmacokinetics was used. RESULTS: The validity of the variability term was tested using experimental data for steady state concentrations of the drug procainamide. The approach of the monitored process to the target value followed exponential kinetics and an analytical expression for dependence the variance with time and various dosing parameters was derived. The variance of the drug concentration depends critically on a single non-dimensional parameter containing the rate constant for the therapeutic corrective actions and a coefficient describing the variance rate. When the rate constant for the therapeutic corrective actions was less than this critical value, the variance increased indefinitely. CONCLUSIONS: From a dosing standpoint, large variances in drug concentrations are undesirable because some patients will be overdosed or underdosed. Since deterministic models cannot provide analytical solutions for the moments of drug concentration distribution functions, stochastic models can be used to provide useful insights into the design of therapeutic regimens.

Algorithms↗
PubMed2001

Magnetic resonance imaging of ethyl-nitrosourea-induced rat gliomas: a model for experimental therapeutics of low-grade gliomas.

Human low-grade gliomas represent a population of brain tumors that remain a therapeutic challenge. Preclinical evaluation of agents, to test their preventive or therapeutic efficacy in these tumors, requires the use of animal models. Spontaneous gliomas develop in models of chemically induced carcinogenesis, such as in the transplacental N-ethyl-N-nitrosourea (ENU) rat model. However, without the ability to detect initial tumor formation, multiplicity or to measure growth rates, it is difficult to test compounds for their interventional or preventional capabilities. In this study Fisher-334 rats, treated transplacentally with ENU, underwent magnetic resonance imaging (MRI) examination in order to evaluate this approach for detection of tumor formation and growth. ENU-induced intracranial cerebral tumors were first observable in T2-weighted images beginning at 4 months of age and grew with a mean doubling time of 0.487 +/- 0.112 months. These tumors were found histologically to be predominately mixed gliomas. Two therapeutic interventions were evaluated using MRI, vitamin A (all-trans retinol palmitate, RP), as a chemopreventative agent and the anti-angiogenic drug SU-5416. RP was found to significantly delay the time to first tumor observation by one month (P = 0.05). No differences in rates of tumor formation or growth rates were observed between control and RP-treated groups. MRI studies of rats treated with SU-5416 resulted in reduction in tumor growth rates compared to matched controls. These results show that MRI can be used to provide novel information relating to the therapeutic efficacy of agents against the ENU-induced tumor model.

Angiogenesis Inhibitors↗
PubMed2003

Therapeutic clenbuterol treatment does not alter Ca2+ sensitivity of permeabilized fast muscle fibres from exercise trained or untrained horses.

Clenbuterol is a beta2-adrenoceptor agonist primarily used for treating bronchospasm and alleviating the symptoms of chronic obstructive pulmonary disease (COPD) in the horse. In other species (rats, mice, sheep, and cattle), chronic high doses of clenbuterol (typically in the milligram per kilogram body weight range) has been shown to cause a muscle directed protein anabolic response. Clenbuterol can also modify muscle fibre composition and therefore potentially affect muscle function. This has implications for the performance of exercising horses being treated with therapeutic doses of clenbuterol (typically in the microgram per kilogram body weight range) for bronchospasm or COPD. It is not known whether clenbuterol treatment affects muscle fibre function in horses. The purpose of this study was to examine the effects of a therapeutic dose of clenbuterol, with and without exercise, on the contractile activation characteristics of single membrane permeabilized fibres prepared from muscle biopsies. We tested the hypothesis that therapeutic treatment with clenbuterol would not affect muscle fibre function. Unfit Standardbred mares were treated for 8 weeks with; clenbuterol (2.4 microg/kg twice/day, 5 days/week) plus exercise (20 min at 50% VO2(max) 3 d/wk; CLENEX), clenbuterol only (CLEN), or exercise only (EX). Muscle biopsies were taken from the gluteus medius muscle before and after treatment and stored in a glycerol-based solution to prepare permeabilized muscle fibres. The force-pCa relationship for fibres from CLEN horses was steeper (P < 0.05) indicative of greater cooperative interactions within the thin filament, however, fibre sensitivity to Ca2+ was unchanged. In contrast, the steepness of the force-pCa relationship was not changed in fibres from EX and CLENEX horses and Ca2+ sensitivity was also unaffected. Rigor force, activation in the absence of ATP, was not affected by any treatment indicating an approximately equivalent number of participating cross-bridges during activation. The results indicate that a therapeutic dose of clenbuterol to Standardbred horses does not affect the Ca(2+)-activated contractile characteristics of isolated muscle fibres.

Adrenergic beta-Agonists↗