State Regulation of Community Paramedicine Programs: A National Analysis.

Background: Community Paramedicine (CP) is a rapidly evolving field within prehospital care where paramedics step outside of their traditional roles of treating acute conditions to provide elements of primary and preventive care. It is unclear if current state oversight regarding the scope of practice (SOP) for paramedics provides clear guidance on the novel functions provided and skills performed by CP programs.

Objective: To determine the process and authority, as currently defined by state laws and regulations in the United States, to expand paramedic SOP in order to perform CP roles and to assess state EMS agencies' interpretation of paramedic SOP as it applies to CP.

Orthopedic uses of stem cell therapy.

The treatment of musculoskeletal disorders is gaining importance as the population ages. In addition to the complications brought on by prolonged life expectancy, the growing epidemic of obesity is contributing to joint degradation. Cell-based tissue engineering has the potential to advance the current treatment for musculoskeletal disorders.

Characterization of a three-drug nonlinear mixture response model.

Our group recently developed a response-surface modeling paradigm (White et al: Curr Drug Metab 2, 399-409, 2003) and tested its application to both mixtures of anticancer agents and antifungals. This new model is a Hill-type equation, with the slope and potency parameters being functions of the normalized drug ratios, using polynomial expressions. Response surface methods allow one to model and interpret all of the information present in the full concentration-effect data set, to visualize local regions of synergy, additivity and antagonism, and even to quantify the degree of synergy or antagonism, both globally, and across local regions of the response surface.

D-optimal designs for parameter estimation for indirect pharmacodynamic response models.

This report generates efficient experimental designs (dose, sampling times) for parameter estimation for four basic physiologic indirect pharmacodynamic response (IDR) models. The principles underlying IDR models and their response patterns have been well described. Each IDR model explicitly contains four parameters, k (in) (production), k (out) (loss), I (max)/S (max) (capacity) and IC (50)/SC (50) (sensitivity).

Extrapolation concepts for dealing with multiple contamination in environmental risk assessment.

Mixture exposure against several stressors is what organisms in the environment typically experience, and combined effects resulting from this are well documented. Risk management often still focuses on the assessment of individual priority compounds. Because of the large number of possible mixtures and their variability in time, experimental investigation of every conceivable mixture for their adverse effects is not a viable option.

Simultaneous modeling of concentration-effect and time-course patterns in gene expression data from microarrays.

Background: Time-course and concentration-effect experiments with multiple time-points and drug concentrations provide far more valuable information than experiments with just two design-points (treated vs. control), as commonly performed in most microarray studies. Analysis of the data from such complex experiments, however, remains a challenge.

Modeling the combination of amphotericin B, micafungin, and nikkomycin Z against Aspergillus fumigatus in vitro using a novel response surface paradigm.

Response surface methods for the study of multiple-agent interaction allow one to model all of the information present in full concentration-effect data sets and to visualize and quantify local regions of synergy, additivity, and antagonism. In randomized wells of 96-well plates, Aspergillus fumigatus was exposed to various combinations of amphotericin B, micafungin, and nikkomycin Z. The experimental design was comprised of 91 different fixed-ratio mixtures, all performed in quintuplicate.

Expression of genes related to activity of oxaliplatin and 5-fluorouracil in endoscopic biopsies of primary esophageal cancer in patients receiving oxaliplatin, 5-flourouracil and radiation: characterization and exploratory analysis with survival.

With a goal of identifying relations between gene expression and response (mucosal or pathological) or survival in esophageal cancer patients (stages II to IV) receiving oxaliplatin, 5-fluorouracil (5FU) and radiation, we measured in endoscopic primary tumor biopsies from 38 patients, the expression of seven genes (gammaGCS, gammaGT, MRP-2, ERCC-1, XPA, TS and DPD) prior to treatment, 1 week following oxaliplatin alone and at the end of the combined radio-chemotherapy cycle using real time QRT-PCR. A higher pretreatment level of XPA was related to shorter survival with a hazard ratio of 2.43 (90% confidence interval 1.

On the mode of action of N-phenyl-2-naphthylamine in plants.

N-phenyl-2-naphthylamine, a sediment contaminant previously identified as a major toxicant of site-specific importance was investigated for its mode of toxic action. From short-term bioassays with daphnids, fish eggs, bacteria, and algae it appears that this compound has specific phytotoxic properties at concentrations below 100 microg/L, which cannot be explained assuming an unspecific narcosis type of action in plants. Also, hydroxy-, nitro-, and methylderivatives show clear excess toxicity as compared to baseline toxic effects.

Platinum drug effects on the expression of genes in the polyamine pathway: time-course and concentration-effect analysis based on Affymetrix gene expression profiling of A2780 ovarian carcinoma cells.

Purpose: As a follow-up to our previous findings that platinum drugs induce a key enzyme in polyamine catabolism, gene expression profiling and mathematical modeling were used to define the effects of cisplatin and oxaliplatin on the expression of polyamine metabolic pathway genes in A2780 human ovarian carcinoma cells.

Methods: Time-course and concentration-effect experiments were each carried out with cisplatin or oxaliplatin in two separate experiments and cells subjected to gene expression profiling using Affymetrix array technology. Time-course data were modeled using exponential increase and decrease models.

Clinical pharmacokinetics of the PDT photosensitizers porfimer sodium (Photofrin), 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (Photochlor) and 5-ALA-induced protoporphyrin IX.

Background And Objectives: Photodynamic therapy (PDT) uses a photosensitizer activated by light, in an oxygen-rich environment, to destroy malignant tumors. Clinical trials of PDT at Roswell Park Cancer Institute (RPCI) use the photosensitizers Photofrin, Photochlor, and 5-ALA-induced protoporphyrin IX (PpIX). In some studies the concentrations of photosensitizer in blood, and occasionally in tumor tissue, were obtained.

Effect of amphotericin B and micafungin combination on survival, histopathology, and fungal burden in experimental aspergillosis in the p47phox-/- mouse model of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase characterized by recurrent life-threatening bacterial and fungal infections. We characterized the effects of single and combination antifungal therapy on survival, histopathology, and laboratory markers of fungal burden in experimental aspergillosis in the p47phox-/- knockout mouse model of CGD. CGD mice were highly susceptible to intratracheal Aspergillus fumigatus challenge, whereas wild-type mice were resistant.

Efficacy of lidocaine or bupivacaine combined with ephedrine in rat sciatic nerve block.

Background And Objectives: The adrenergic drug ephedrine inhibits Na(+) current in cultured cells expressing Na(+) channels and provides dose-dependent reversible rat sciatic nerve blockade. The dosage required for peripheral nerve blockade in humans would cause unacceptable cardiovascular side effects. We therefore hypothesized that either lidocaine or bupivacaine would show synergy with ephedrine in a rat sciatic nerve block model, allowing a dose reduction and limiting side effects while improving efficacy.

Gene expression profiling of a clonal isolate of oxaliplatin-resistant ovarian carcinoma cell line A2780/C10.

The efficacy of platinum drugs in the treatment of cancer is often restricted by the acquisition of tumor cell resistance subsequent to treatment. To better understand mechanisms involved in this phenomenon, a clonal subline (A2780/C10B) isolated from an oxaliplatin-resistant human ovarian carcinoma cell line (A2780/C10) was developed, as reported previously. This cell line is 18-fold resistant to oxaliplatin and shows a 3-fold cross resistance to cisplatin.

Sequential administration of irinotecan and cytarabine in the treatment of relapsed and refractory acute myeloid leukemia.

Purpose: Based on reported synergy of the topoisomerase-I (topo-I) inhibitor irinotecan with antimetabolites, irinotecan and cytarabine (Ara-C) were administered sequentially to patients with acute myeloid leukemia (AML) refractory to or relapsed following high-dose Ara-C and anthracycline therapy. Pharmacokinetic and pharmacodynamic studies were performed with the first irinotecan dose.

Experimental Design: In vitro synergy of irinotecan followed by Ara-C was confirmed in a human AML cell line as a basis for the clinical trial.

Mild skin photosensitivity in cancer patients following injection of Photochlor (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a; HPPH) for photodynamic therapy.

Purpose: To measure skin photosensitivity in cancer patients infused with the new second-generation photodynamic sensitizer Photochlor (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a). A major disadvantage of using the clinically approved photosensitizer Photofrin is potentially prolonged and sometimes severe cutaneous phototoxicity.

Patients And Methods: Forty-eight patients enrolled in Phases 1 and 2 clinical trials underwent two or more exposures to four graded doses (44.

Antiangiogenic chimeric anti-endoglin (CD105) antibody: pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin.

We generated a human/mouse chimeric antibody c-SN6j of human IgG1 isotype from a murine anti-human endoglin (EDG) monoclonal antibody (mAb) SN6j that suppressed angiogenesis, tumor growth and metastasis in mice. We determined pharmacokinetics (PKs) and immunogenicity of c-SN6j in monkeys after multiple i.v.

Cyclosporin A is a broad-spectrum multidrug resistance modulator.

Purpose: Overexpression of the multidrug resistance proteins P-glycoprotein (Pgp), multidrug resistance protein (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) is associated with treatment failure in acute myeloid leukemia (AML) and other malignancies. The Pgp modulator cyclosporin A has shown clinical efficacy in AML, whereas its analogue PSC-833 has not. Cyclosporin A is known to also modulate MRP-1, and we hypothesized that broad-spectrum multidrug resistance modulation might contribute to its clinical efficacy.

Breast cancer resistance protein (BCRP/MXR/ABCG2) in adult acute lymphoblastic leukaemia: frequent expression and possible correlation with shorter disease-free survival.

Drugs used in treatment of adult acute lymphoblastic leukaemia (ALL) are substrates for breast cancer resistance protein (BCRP, MXR, ABCG2), which may thus play a role in resistance in this disease. Pretreatment blasts from 30 adult ALL patients were studied for BCRP mRNA by quantitative reverse transcription polymerase chain reaction analysis, BCRP protein by immunophenotyping with three antibodies and BCRP function by fumitremorgin C modulation of intracellular mitoxantrone retention, measured by flow cytometry. BCRP mRNA in all cases encoded wild type protein (BCRP(R482)), which mediates mitoxantrone and methotrexate resistance, but only low-level anthracycline resistance.

Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function.

Data on breast cancer resistance protein (BCRP, MXR, ABCG2) expression in acute myeloid leukemia (AML) have been inconsistent, possibly due to use of different assays in different studies. BCRP mRNA was studied by the reverse-transcription polymerase chain reaction and BCRP protein expression (BXP-21, BXP-34 or anti-ABCG2 antibody, with anti-CD34 and anti-CD33) and function (fumitremorgin C modulation of mitoxantrone retention) by flow cytometry in eight cell lines and in pretreatment blasts from 31 AML patients. BCRP mRNA levels, antibody staining and function correlated strongly in cell lines (Pearson r values, 0.

Expression of the neural cell adhesion molecule CD56 is not associated with P-glycoprotein overexpression in core-binding factor acute myeloid leukemia.

Acute myeloid leukemia (AML) with rearrangement of the core-binding factor (CBF) alpha or beta subunit gene has a favorable prognosis, but CD56 expression in CBFalpha-AML is associated with short disease-free survival. A proposed mechanism is overexpression of the multidrug resistance (MDR) protein P-glycoprotein (Pgp). CD56 expression, Pgp expression and function, and expression of the additional MDR proteins multidrug resistance protein-1 (MRP-1), lung resistance protein (LRP) and breast cancer resistance protein (BCRP) were studied in pretreatment blasts from 25 CBF-AML patients.

Prostate derived Ets transcription factor shows better tumor-association than other cancer-associated molecules.

We previously reported that prostate derived Ets transcription factor (PDEF) is a breast tumor-associated molecule. To obtain further insights into PDEF expression in other human tumor types, a cDNA library database from human adult normal and tumor tissues was compiled and searched for PDEF distribution. The results showed that PDEF is present at relative higher frequencies in the cDNA libraries from brain, breast, lung and ovarian tumors in comparison to those from the corresponding normal tissues.

Photodynamic therapy: a means to enhanced drug delivery to tumors.

Using the photosensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a, we have determined that photodynamic therapy (PDT) can be used to facilitate the delivery of macromolecular agents. PDT regimens that use low fluences and fluence rates were the most successful. This effect was demonstrated for fluorescent microspheres with diameters ranging from 0.

Treatment with the tumor necrosis factor-alpha-inducing drug 5,6-dimethylxanthenone-4-acetic acid enhances the antitumor activity of the photodynamic therapy of RIF-1 mouse tumors.

DMXAA (5,6-dimethylxanthenone-4-acetic acid) is an antivascular agent that exerts its antitumor effect at least partly through the induction of tumor necrosis factor (TNF)-alpha. Photodynamic therapy (PDT), the activation of a photoreactive drug in tumor tissue with visible light, is used clinically to control solid malignancies. PDT has been shown previously to be potentiated, in mice, by the i.