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Vascular integrins in tumor angiogenesis: mediators and therapeutic targets.

The notion that tumor angiogenesis may have therapeutic implications in the control of tumor growth was introduced by Dr. Judah Folkman in 1971. The approval of Avastin in 2004 as the first antiangiogenic systemic drug to treat cancer patients came as a validation of this visionary concept and opened new perspectives to the treatment of cancer. In addition, this success boosted the field to the quest for new therapeutic targets and antiangiogenic drugs. Preclinical and clinical evidence indicate that vascular integrins may be valid therapeutic targets. In preclinical studies, pharmacological inhibition of integrin function efficiently suppressed angiogenesis and inhibited tumor progression. alphaVbeta3 and alphaVbeta5 were the first vascular integrins targeted to suppress tumor angiogenesis. Subsequent experiments revealed that at least four additional integrins (i.e., alpha1beta1, alpha2beta1, alpha5beta1, and alpha6beta4) might be potential therapeutic targets. In clinical studies low-molecular-weight integrin inhibitors and anti-integrin function-blocking antibodies demonstrated low toxicity and good tolerability and are now being tested in combination with radiotherapy and chemotherapy for anticancer activity in patients. In this article the authors review the role of integrins in angiogenesis, present recent development in the use of alphaVbeta3 and alpha5beta1 integrin antagonists as potential therapeutics in cancer, and discuss future perspectives.

Animals↗

Torticollis and plagiocephaly in infancy: therapeutic strategies.

BACKGROUND: Asymmetry in infancy is a diagnosis with a large spectrum of features, expressing an abnormal shape of parts of the body or unequal postures and movements, which might be structural and/or functional, with localized or generalized expression. PURPOSE: The purpose of the present study is to highlight different therapeutic aspects of the most occurring asymmetries in infancy: congenital muscular torticollis, positional torticollis and plagiocephaly, based on best evidence in current literature. RESULTS: A flow chart is presented showing different pathways in therapeutic strategies, such as physical therapy, orthotic devices (helmet treatment and Dynamic Orthotic Cranioplasty) and surgery. CONCLUSION: It is concluded that there are different views towards management on torticollis and plagiocephaly. A systematic therapeutic management to evaluate these asymmetries is indicated. The presented therapeutic flow chart might serve as a basis in order to achieve uniformity in therapeutic thinking and performance.

Craniosynostoses↗

A virtual therapeutic environment with user projective agents.

Today, we see the Internet as more than just an information infrastructure, but a socializing place and a safe outlet of inner feelings. Many personalities develop aside from real world life due to its anonymous environment. Virtual world interactions are bringing about new psychological illnesses ranging from netaddiction to technostress, as well as online personality disorders and conflicts in multiple identities that exist in the virtual world. Presently, there are no standard therapy models for the virtual environment. There are very few therapeutic environments, or tools especially made for virtual therapeutic environments. The goal of our research is to provide the therapy model and middleware tools for psychologists to use in virtual therapeutic environments. We propose the Cyber Therapy Model, and Projective Agents, a tool used in the therapeutic environment. To evaluate the effectiveness of the tool, we created a prototype system, called the Virtual Group Counseling System, which is a therapeutic environment that allows the user to participate in group counseling through the eyes of their Projective Agent. Projective Agents inherit the user's personality traits. During the virtual group counseling, the user's Projective Agent interacts and collaborates to recover and increase their psychological growth. The prototype system provides a simulation environment where psychologists can adjust the parameters and customize their own simulation environment. The model and tool is a first attempt toward simulating online personalities that may exist only online, and provide data for observation.

Behavior, Addictive↗

Beyond needling--therapeutic processes in acupuncture care: a qualitative study nested within a low-back pain trial.

BACKGROUND: In the medical and scientific literature, there is a dearth of reports about how acupuncturists work and deliver care in practice. An informed characterization of the treatment process is needed to support the appropriate design of evaluative studies in acupuncture. METHODS: The design was that of a nested qualitative study within a pragmatic clinical trial. Six acupuncturists who treated up to 25 patients each were interviewed after the treatment phase of the trial to obtain an account of their experiences of providing acupuncture care to patients with low back pain referred by their GP. Using semistructured interviews and a topic guide, data were collected and analyzed for both a priori and emergent themes. This paper focuses on practitioners' accounts of the goals and processes of care, and describes the strategies employed in addition to needling and other hands-on treatments. RESULTS: From the interview data, it is clear that a coherent body of theoretical knowledge informed clinical decisions and practice, and that the goals of treatment went beyond the alleviation of immediate pain-related symptoms. Acupuncturists in this study all described a pattern of patient-centered care based on a therapeutic partnership. Study participants confirmed the importance of three processes that characterized acupuncture care in this trial, each contributing to the goal of a positive long-term outcome; building a therapeutic relationship; individualizing care; and facilitating the active engagement of patients in their own recovery. Acupuncturists described elements of care that characterized these processes including establishing rapport, facilitating communication throughout the period of care, using an interactive diagnostic process, matching treatment to the individual patient, and the use of explanatory models from Chinese medicine to aid the development of a shared understanding of the patient's condition and to motivate lifestyle changes that reinforce the potential for a recovery of health. Acupuncturists did not view these therapeutic goals, processes, and strategies as a departure from their usual practice. CONCLUSIONS: This study suggests that acupuncture care for patients with chronic conditions such as low back pain is likely to be a complex intervention that utilizes a number of patient-centered strategies to elicit longterm therapeutic benefits. Research designed to evaluate the effectiveness of acupuncture as it is practiced in the UK needs to accommodate the full range of therapeutic goals and related treatment processes.

Acupuncture↗

Three-dimensional fibroblast culture implant for the treatment of diabetic foot ulcers: metabolic activity and therapeutic range.

Dermagraft is three-dimensional, allogeneic, human neonatal dermal fibroblast culture grown on a degradable scaffold and cryopreserved. Clinical trials for treatment of diabetic foot ulcers showed optimal healing within a therapeutic range of metabolic activity, determined by 3[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide (MTT) reduction. Actions of Dermagraft in wound repair include colonization by cells and provision of growth factors and cytokines, both activities dependent on living cells. Cells in the cryopreserved culture showed 60% viability by dye exclusion and, when isolated, were able to proliferate in monolayer culture. Protein synthesis by Dermagraft was inhibited 70-98% by cryopreservation, but, if within the therapeutic range, recovered to 45-85% of the prefreeze value over 48 h. Subtherapeutic Dermagraft showed variable, low recovery. Expression of mRNA for vascular endothelial growth factor (VEGF), platelet-derived growth factor A chain, and insulin-like growth factor-1 was reduced >83% in subtherapeutic compared with therapeutic Dermagraft. Granulocyte colony-stimulating factor and VEGF protein secretion, determined by enzyme-linked immunosorbent assay (ELISA), and angiogenic activity also depended on therapeutic range. VEGF secretion dropped sharply with MTT reductase in subtherapeutic tissue. The data demonstrate the critical dependence of the therapeutic properties of this living dermal implant on recovery of protein synthesis, growth factor expression, and angiogenesis, determined by metabolic activity.

Animals↗

Influence of age on clinical presentation, therapeutic options, and prognosis in anti-HCV positive cirrhotic patients with hepatocellular carcinoma.

BACKGROUND: Hepatitis C virus infection-related cirrhosis is a major risk factor for the development of hepatocellular carcinoma. Hepatocellular carcinoma in anti-hepatitis C virus positive cirrhotics shows an increasing prevalence with ageing, although it is not clear whether the age of the patients can be considered a critical factor in the overall assessment of severity of disease or in the choice of therapeutic procedures and prognosis. OBJECTIVE: To evaluate the influence of older age on modality of presentation, therapeutic choices, outcome, and survival in anti-hepatitis C virus patients with hepatocellular carcinoma. METHODS: We retrospectively evaluated 75 anti-hepatitis C virus positive cirrhotic patients with hepatocellular carcinoma consecutively referred to our unit. Patients were sub-divided into two sub-groups according to their age (<65 or >or=65 years) at tumor diagnosis. The characteristics of the patients and of hepatocellular carcinoma, therapeutic procedures, and survival were then analyzed. RESULTS: Median age of the patients was 68 years and mean duration of infection was 24 years. Clinical characteristics of older hepatocellular carcinoma patients were no different from those of younger ones. Hepatocellular carcinoma was more frequently of diffuse type in patients aged <65 years. However, therapeutic options were no different between the two sub-groups of patients, and a similar proportion of patients did not undergo therapy in either group. Overall, 1- and 2-year survival rates were 73% and 51%, respectively. After a mean follow-up of 21 months a higher number of patients aged <65 years died (p=0.002). Moreover, Kaplan-Meier curves showed longer survival in patients aged >or=65 years (p=0.002). Lastly, diffuse type of hepatocellular carcinoma and tumor staging were the variables independently associated with worse survival in multivariate regression analysis. CONCLUSIONS: Hepatocellular carcinoma appears in older anti-hepatitis C virus positive cirrhotic patients showing long duration of infection. Older age of the patients does not seem to influence therapeutic options, and more importantly does not exclude patients from treatment. Lastly, older patients seem to have better prognosis most likely due to hepatocellular carcinoma characteristics, since hepatocellular carcinoma seems to present with more unfavourable characteristics in younger cirrhotic patients.

Age Factors↗

Therapeutic selection during an emergency response.

Therapeutic selection in a postdisaster setting is described. Therapeutic selection is the process of assessing a patient's pharmaceutical requirements and selecting the appropriate therapy. Although the primary criteria for drug selection during a disaster response are the same as in usual pharmacy practice, there is a shift in emphasis created by communication and transportation limitations and by changes in the patient's general living environment. The cost of agents is no longer viewed in terms of dollars but in the context of limited inventories. A disaster may exacerbate health problems or make adverse drug effects more common and problematic. Drug administration and patient compliance will be hampered. Pre-established guidelines for appropriate patient care should be reviewed and approved by a group of representative health care providers. General policies for pharmaceutical care should include guidelines for a formulary, prescription refills, dispensing limitations, and prescriber approval. Therapeutic selection should involve obtaining a medical history, selecting a drug regimen, educating and counseling the patient, and documenting the process. Pharmacists should use familiar procedures that they are comfortable with to minimize stress and optimize outcomes. Procedures should be flexible to adjust to circumstances and individual patient needs. Therapeutic selection during a disaster response, although based on the same principles as traditional therapeutic selection, is more complex. Pharmacists will need to tailor their approach to the circumstances and to individual patient needs.

Decision Making↗

Therapeutic opportunities involving cellular oncogenes: novel approaches fostered by biotechnology.

Biotechnological processes are having a major impact on many industrial sectors, including the pharmaceutical industry. The contributions of recombinant DNA and hybridoma technologies to modern therapeutics include production of natural and unnatural peptides, subunit vaccines, monoclonal antibodies and nucleic acid hybridization probes for in vitro and in vivo diagnostics and biological imaging, therapeutic monoclonal antibodies as tissue-specific delivery systems or as agents to confer passive immunity, production of therapeutic targets for rational drug design, and the use of cloned enzymes as stereospecific catalysts in large-scale production of small medicinal molecules. Biotechnological advances have led to the identification of a discrete set of genes, oncogenes, which may be essential contributing factors for a great variety and number of human cancers. In addition, biotechnological innovations are fostering the exploitation of oncogenes as novel therapeutic targets for cancer diagnosis, prognosis, and treatment. Because oncogenes are activated in transformation by either qualitative or quantitative mechanisms, however, different biotechnology-based therapeutic approaches are required for each class.

Biotechnology↗

Efficacy of therapeutic suggestions for improved postoperative recovery presented during general anesthesia.

There have been claims that the postoperative course of patients may be improved by presentation during general anesthesia of therapeutic suggestions which predict a rapid and comfortable postoperative recovery. This study evaluated the effectiveness of such therapeutic suggestions under double-blind and randomized conditions. A tape recording predicting a smooth recovery during a short postoperative stay without pain, nausea, or vomiting was played during anesthesia to about half the patients (N = 109), while the remaining, control patients were played a blank tape instead (N = 100). The patients were primarily undergoing operations on the fallopian tubes, total abdominal hysterectomy, vertical banding gastroplasty, cholecystectomy, and ovarian cystectomy or myomectomy. The anesthesia methods consisted of either isoflurane with 70% nitrous oxide in oxygen to produce end-tidal concentrations of 1.0, 1.3, or 1.5 MAC; or 70% nitrous oxide in oxygen combined with high or low doses of opioids. Assessments of the efficacy of the therapeutic suggestions in the recovery room and throughout the postoperative hospital stay included: the frequency of administration of analgesic and antiemetic drugs; opioid doses; the incidence of fever; nausea, retching, and vomiting; other gastrointestinal and urinary symptoms; ratings of pain; ratings of anxiety; global ratings of the patients' physical and psychological recoveries by the patients and their nurses; and length of postoperative hospital stay. There were no meaningful, significant differences in postoperative recovery of patients receiving therapeutic suggestions and controls. These negative results were not likely to be due to insensitivity of the assessments of recovery, as they showed meaningful interrelations among themselves and numerous differences in recovery following different types of surgery. Widespread utilization of therapeutic suggestions as a routine operating room procedure seems premature in the absence of adequate replication of previously published positive studies.

Adult↗

Therapeutic drug monitoring.

PURPOSE OF REVIEW: Traditionally, therapeutic drug monitoring has been used for the management of epilepsy, cardiac arrhythmias, asthma and depression. This review provides an update, particularly for the newer clinical applications, and how therapeutic drug monitoring (including use of analytical and interpretation tools) can improve clinical outcomes. RECENT FINDINGS: Improved drug assay methodologies and a greater understanding of pharmacokinetic and pharmacodynamic mechanisms has allowed the use of therapeutic drug monitoring for immunosuppressant drugs in organ transplant recipients, antiretroviral agents for HIV/AIDS and antimetabolite drugs for leukaemia. In addition, new computer software to analyse drug concentrations in complex populations is being developed and introduced into routine clinical applications to allow increasingly patient-specific assay interpretation. SUMMARY: Therapeutic drug monitoring assists in improving clinical success rates and minimizing toxicity. The use of therapeutic drug monitoring is therefore likely to become more widespread as new modalities are adopted.

Journal Article↗

Fluoroscopically guided therapeutic sacroiliac joint injections for sacroiliac joint syndrome.

OBJECTIVE: To investigate the outcomes resulting from the use of fluoroscopically guided therapeutic sacroiliac joint injections in patients with sacroiliac joint syndrome. DESIGN: A retrospective study design with independent clinical review was utilized. Thirty-one patients were included; each patient met specific physical examination criteria and failed to improve clinically after at least 4 wk of physical therapy. Each patient demonstrated a positive response to a fluoroscopically guided diagnostic sacroiliac joint injection. Therapeutic sacroiliac joint injections were administered in conjunction with physical therapy. Outcome measures included Oswestry scores, Visual Analog Scale pain scores, work status, and medication usage. RESULTS: Patients' symptom duration before diagnostic injection averaged 20.6 mo. An average of 2.1 therapeutic injections was administered. Follow-up data collection was obtained at an average of 94.4 wk. A significant reduction (P = 0.0014) in Oswestry disability score was observed at the time of follow-up. Visual Analog Scale pain scores were reduced (P < 0.0001) at the time of discharge and at follow-up. Work status was also significantly improved at the time of discharge (P = 0.0313) and at follow-up (P = 0.0010). A trend (P = 0.0645) toward less drug usage was observed. CONCLUSIONS: These initial findings suggest that fluoroscopically guided therapeutic sacroiliac joint injections are a clinically effective intervention in the treatment of patients with sacroiliac joint syndrome. Controlled, prospective studies are necessary to further clarify the role of therapeutic injections in this patient population.

Adult↗

Use of therapeutic radionuclides in medicine.

The purpose of this paper is to follow the course of historical development in the use of radiopharmaceuticals as a therapeutic tool in nuclear medicine. This chapter is designed to point out the different phases of the development of therapeutic nuclear medicine, pointing out the events which most shaped its history along the way. Those events included the discovery of radioactivity, the development of the cyclotron and nuclear reactor as a method of delivering high specific activity radioactive sources, and a few significant therapeutic radionuclides such as 131I and 32P. The most significant therapeutic radionuclide was radium, which is treated very extensively in this paper from an historical viewpoint. It is only recently that attention of the nuclear medicine community turned to new therapeutic agents, such as bone pain palliation agents, monoclonal antibodies, and others. It may be that the next growth phase of nuclear medicine will revolve around therapy with these radionuclides.

Brachytherapy↗

Antipsychotic-induced weight gain and therapeutic response: a differential association.

This study investigated the association between antipsychotic-induced weight gain and therapeutic response to haloperidol and three commonly used atypical neuroleptic medications in schizophrenia and schizoaffective disorder. The subjects were 151 patients enrolled in a double-blind experiment with a duration of 14 weeks comparing the therapeutic efficacy of haloperidol (n = 36), clozapine (n = 38), olanzapine (n = 38), and risperidone (n = 39). Absolute and relative (%) gain in body weight and body mass index (BMI) was determined for the entire duration of the double-blind treatment period; therapeutic response was assessed by the total score and the individual subscales of the Positive and Negative Symptom Scale. Compared with the pretreatment baseline, results indicated that for olanzapine and clozapine, therapeutic response was closely related to an absolute and relative gain in weight and to a gain in BMI. No association between weight gain and therapeutic response was found for risperidone and haloperidol. These findings suggest that patients who are likely to have the maximal benefits of olanzapine or clozapine treatment for symptom alleviation are at the highest risk of a clinically significant increase in weight gain.

Adult↗

Hemoperitoneum score helps determine need for therapeutic laparotomy.

PURPOSE: Sonography provides a fast, portable, and noninvasive method for patient assessment. However, the benefit of providing real-time ultrasound (US) imaging and fluid quantification shortly after patient arrival has not been explored. The objective of this study was to prospectively validate a US hemoperitoneum scoring system developed at our institution and determine whether sonography can predict a therapeutic operation. METHODS: For 12 months, prospective data on all patients undergoing a trauma sonogram were recorded. All sonograms positive for free fluid were given a hemoperitoneum score. The US score was compared with initial systolic blood pressure and base deficit to assess the ability of sonography to predict a therapeutic laparotomy. RESULTS: Forty of 46 patients (87%) with a US score > or = 3 required a therapeutic laparotomy. Forty-six of 54 patients with a US score < 3 (85%) did not need operative intervention. The sensitivity of sonography was 83% compared with 28% and 49% for systolic blood pressure and base deficit, respectively, in determining the need for therapeutic operation. CONCLUSION: We conclude that the majority of patients with a score > or = 3 will need surgery. The US hemoperitoneum scoring system was a better predictor of a therapeutic laparotomy than initial blood pressure and/or base deficit.

Abdominal Injuries↗

Who is ordering all those cyclosporin concentrations and how do they use them? An audit of cyclosporin therapeutic drug monitoring.

Therapeutic drug monitoring is used for the immunosuppressant drug, cyclosporin, even though it is often unclear what concentration should be targetted. At St. Vincent's Hospital, Sydney, a polyclonal, whole blood immunoassay is used to measure cyclosporin and metabolites. The objective of the present study was to audit how the concentration results produced by the laboratory were actually used to adjust dosage. Each transplantation unit was asked about their policy for dosage adjustment and which therapeutic range was used. The audit criteria were considered to be passed if the action taken based on a concentration result was (a) predictable based solely on the concentration and its relationship to the stated therapeutic range (e.g., dosage increased if concentration was below therapeutic range) or (b) based on clinical considerations (e.g., dosage decreased because of increased serum creatinine). Data were collected for the actions taken following 347 concentration results over a 6-week period. Audit criteria were fulfilled for 246 (71%) of the results. The majority of the cyclosporin concentrations (75%) were determined for the cardiopulmonary unit; 66% of these fulfilled audit criteria. Approximately two-thirds of all the cyclosporin concentrations requested were followed up by appropriate action based on stated therapeutic ranges or documented clinical reasons.

Cyclosporine↗

A comparison of high-performance liquid chromatography and fluorescence polarization immunoassay for therapeutic drug monitoring of tricyclic antidepressants.

Although the manufacturer of the polyclonal fluorescence polarization immunoassay (FPIA) for tricyclic antidepressants (TCA) only recommends its use in the diagnosis of overdose, the assay is nevertheless widely used in therapeutic drug monitoring. Using plasma samples from 337 patients taking one of eight different tricyclic antidepressants, the authors investigated the performance of the TDx assay procedure for eight different TCAs by comparison to specific high-performance liquid chromatography (HPLC) assay methods. The regression correlation between the TDx assay value and that for active tricyclic measured by HPLC was poor (r2 < 0.9) for amitriptyline, clomipramine, dothiepin, and doxepin. The regression line for amitriptyline also had a significant positive y-axis intercept. Moreover, the TDx method overestimated the concentration of active drug to an extent that varied considerably between different TCAs and within the usual therapeutic range for a single TCA. The authors conclude that the TDx assay is probably satisfactory for routine TDM of desipramine, imipramine, nortriptyline, and trimipramine. However, it significantly overestimates therapeutic concentrations of amitriptyline, clomipramine, dothiepin, and doxepin. The use of TDx and HPLC assay methods by different laboratories for sequential therapeutic drug monitoring of TCAs in the same patient may confuse physicians and confound dose adjustment and patient management. Although their study shows that the TDx assay can give satisfactory therapeutic drug monitoring results for some drugs, the authors conclude that its use should be restricted to the evaluation of overdose as recommended by the manufacturer.

Antidepressive Agents, Tricyclic↗

Does carbamazepine have a narrow therapeutic plasma concentration range?

Recently, there has been considerable discussion regarding the classification of drugs as a function of their therapeutic index, defined as the ratio between the upper and lower limits of the therapeutic range. Pharmacologic agents with a therapeutic index < 2 are classified as "narrow therapeutic index" (NTI) drugs. One of the agents classified as an NTI drug is carbamazepine. These recent developments led us to evaluate critically the evidence supporting the classification of carbamazepine as an NTI drug to address an old question: "Does carbamazepine have a narrow therapeutic plasma concentration range?"

Anticonvulsants↗

Therapeutic monitoring of new antipsychotic drugs.

Typical antipsychotic drugs qualify for therapeutic drug monitoring (TDM) primarily for the following reasons: control of compliance and avoidance of extrapyramidal side effects by keeping chronic exposure to minimal effective blood levels. For the atypical antipsychotic clozapine, drug safety is another reason to use TDM. With regard to the new antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole, which have been introduced in the clinic during the last few years, the rationale to use TDM is a matter of debate. Positron emission tomography (PET), which enables measurement of the occupancy of dopamine D2 receptors, revealed that receptor occupancy correlated better with plasma concentrations than with doses of the antipsychotics. Regarding plasma levels related to therapeutic effects, optimal concentrations have been established for clozapine (350-600 ng/mL), risperidone (20-60 ng/mL), and olanzapine (20-80 ng/mL) but not for the other new antipsychotics. Studies that included analyses of drug levels in blood reported mean concentrations of 68 ng/mL for quetiapine and 317 ng/mL for amisulpride under therapeutic doses of the antipsychotic drugs. For ziprasidone or aripriprazole, data on therapeutic drug concentrations are so far lacking. In conclusion, evidence is growing that TDM may improve efficacy and safety in patients treated with the new antipsychotic drugs, especially when patients do not respond or develop side effects under therapeutic doses. The few reported investigations, however, need to be confirmed and extended.

Antipsychotic Agents↗