The Role of Continuing Medical Education in Increasing Enrollment in Prescription Drug Monitoring Programs.

PURPOSE: Opioid diversion, misuse, and abuse are rapidly growing problems in the United States; >60% of all drug overdose deaths involve an opioid. At least 49 states now have fully operational prescription drug monitoring programs (PDMPs) to support legitimate medical use of controlled substances; however, there is considerable underutilization of such programs. METHODS: To increase awareness of PDMPs and their use, a continuing medical education program including 2 webcasts and a series of newsletters was offered to health care providers. FINDINGS: Four hundred and sixty-five clinicians participated in 1 of 2 webcasts. Of those, 207 clinicians responded to a pre-survey and 64 responded to a post-survey. Slightly more than half of clinicians were registered for their state's PDMP program before the educational intervention, and although significantly more clinicians reported increased likelihood to access their state PDMP after participation, the number that actually registered only trended toward a statistically significant increase to 74% after the education (P = 0.06). Immediate post-activity evaluation also indicated that the education significantly improved clinician knowledge of the characteristics of addiction, findings in a PDMP that would suggest diversion or abuse, and strategies to complement the use of a PDMP (P < 0.001). IMPLICATIONS: Continuing medical education is effective for improving clinician knowledge and confidence related to opioid misuse, abuse, and diversion and effective use of a PDMP; however, the education did not result in a significant increase in enrollment in state PDMPs.

Call to action on pneumococcal disease: review of vaccination evidence and outcomes of webcast programs.

In 2015, the Advisory Committee on Immunization Practices issued updated recommendations for the use of 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) to immunize adults aged 19 to 64 years with risk factors and all adults aged 65 years or older. Despite these recommendations, rates of vaccination among adults remain low. Federal and state initiatives have been launched to encourage health care providers to incorporate vaccination screening and recommendations in practice. Several resources are available to improve vaccination rates, including implementing electronic medical records; engaging non-physician staff in assessing vaccination history and administering immunizations; adopting standing order protocols; and implementing strong recommendations to patients regarding needed immunizations. However, even in the face of compelling evidence-based research, implementing changes in practice is challenging. The American Osteopathic Association implemented a 2-part Web program called the Call to Action on Pneumococcal Disease. Although some changes in attitudes and intent to change were demonstrated by this initiative, there were no statistically significant increases in self-reported actual adoption of standing order protocols or increases in adult pneumococcal immunization. Nonetheless, some lessons were learned, and these results support the need for ongoing efforts in this area of medicine.

Microclimate moderates plant responses to macroclimate warming.

Recent global warming is acting across marine, freshwater, and terrestrial ecosystems to favor species adapted to warmer conditions and/or reduce the abundance of cold-adapted organisms (i.e., "thermophilization" of communities). Lack of community responses to increased temperature, however, has also been reported for several taxa and regions, suggesting that "climatic lags" may be frequent. Here we show that microclimatic effects brought about by forest canopy closure can buffer biotic responses to macroclimate warming, thus explaining an apparent climatic lag. Using data from 1,409 vegetation plots in European and North American temperate forests, each surveyed at least twice over an interval of 12-67 y, we document significant thermophilization of ground-layer plant communities. These changes reflect concurrent declines in species adapted to cooler conditions and increases in species adapted to warmer conditions. However, thermophilization, particularly the increase of warm-adapted species, is attenuated in forests whose canopies have become denser, probably reflecting cooler growing-season ground temperatures via increased shading. As standing stocks of trees have increased in many temperate forests in recent decades, local microclimatic effects may commonly be moderating the impacts of macroclimate warming on forest understories. Conversely, increases in harvesting woody biomass--e.g., for bioenergy--may open forest canopies and accelerate thermophilization of temperate forest biodiversity.

Integration of fragment screening and library design.

With more than 10 years of practical experience and theoretical analysis, fragment-based drug discovery (FBDD) has entered the mainstream of the pharmaceutical and biotech industries. An array of biophysical techniques has been used to detect the weak interaction between a fragment and the target. Each technique presents its own requirements regarding the fragment collection and the target; therefore, in order to optimize the potential of FBDD, the nature of the target should be a driving factor for simultaneous development of both the library and the screening technology. A roadmap is now available to guide fragment-to-lead evolution when structural information is available. The next challenge is to apply FBDD to targets for which high-resolution structural information is not available.

Intratumoral injection of DNA encoding human interleukin 12 into patients with metastatic melanoma: clinical efficacy.

Plasmid DNA encoding human interleukin 12 (IL-12) was produced under GMP conditions and injected into lesions of nine patients with malignant melanoma (stage IV) previously treated with both standard and nonstandard therapies. The treatment was based on efficacy in preclinical studies with melanoma in mice and gray horses. The DNA was applied in cycles, three injections per cycle, for up to seven cycles. Three therapy arms comprised low (2 mg), medium (4 mg), and high (10 to 20 mg) amounts of total DNA. The therapy was well tolerated. Three of nine patients experienced a clinical response: two stable disease and one complete remission. One patient receiving a low dose of DNA experienced a long-lasting stabilization of the disease for more than 3 years, whereas the other two responders received high doses of DNA. All patients but one (patient 9) experienced a transient response at the intratumoral injection site. Immunohistochemical staining of responder sections showed local reduction of angiogenesis and lymphocyte infiltrations. All patients, in particular the clinical and local responders (patients 3, 7, and 8), exhibited an antigen-specific immune response against MAGE-1 and MART-1, which in some cases preexisted. Biopsies of responders showed some increase in IL-12, IP-10, and IFN-(). Serum levels revealed fluctuations. The results show that intratumoral injection of DNA produced some beneficial clinical effect. DNA encoding a cytokine may be useful as a therapeutic or adjuvant against various human cancers.

The profound augmentation of the oculocardiac reflex by fast acting opioids.

BACKGROUND: Trigemino-vagal bradycardia elicited by tension on an extraocular muscles (oculocardiac reflex; OCR) is a hazard for strabismus surgery patients. OCR can be reduced by anticholinergic medications and regulating the depth of anesthesia. We investigated the influence of narcotic agents as a routine part of general anesthesia for strabismus surgery in adults and children. METHOD: From August, 1992 through September, 2000, 1275 patients undergoing extraocular muscle surgery were prospectively studied during 10 second, 200 gram square wave tension on gently isolated rectus muscles. The anesthetic agents, gas concentrations, and patient age were recorded. Patients receiving an anticholinergic agent and reoperated cases were excluded, yielding 1029 study cases. 849 received no narcotic as a part of induction. Two groups of patients were given no opiate before the first inferior rectus muscle was pulled. A narcotic was administered IV 5 minutes before the second inferior rectus was pulled. One group of 49 received fentanyl 0.15 uL/Kg and the second group of 12 received meperidine 1 mg/kg. RESULTS: Faster acting intravenous induction opioids had a profound augmenting effect on the degree of oculocardiac reflex. Compared to no narcotic, the OCR was increased most by remifentanyl (p less than .0001), then sufenta (p=.02), and fentanyl (p less than .0001). Induction morphine had no appreciable effect on the OCR (p=.9). For the 49 patients with IV fentanyl delivered between the first OCR and second OCR, a significant increase occurred (p=.003). This increase in %OCR was not correlated with a change in inhalational gas concentration (p=.9), CO2 concentration (p=.6) or age (p=.12). For the 12 patients given demerol between the first and second rectus tension, no significant OCR change occurred (p=.7). The OCR was greatest for inferior rectus, then superior rectus, then medial rectus, and least for lateral rectus. (See text for details.) CONCLUSION: In the absence of anticholinergic blockade, rapidly acting narcotics enhance the degree of bradycardia due to the OCR elicited by controlled extraocular muscle tension during strabismus surgery. Some opioids had the same augmenting magnitude as the blocking effect of IV anticholinergic medication. Meperidine, which has some anticholinergic characteristics, neither blocked nor augmented the OCR.

IP-10-encoding plasmid DNA therapy exhibits anti-tumor and anti-metastatic efficiency.

We report here that the interferon-induced protein of 10 kDa (IP-10 or CXCL10) elicits strong anti-tumor and anti-metastatic responses in mice when administered by plasmid DNA. Intratumoral but not intramuscular IP-10 DNA inoculation resulted in reduced tumor formation of malignant melanoma (B16F10) and Lewis lung carcinoma (LL/2) in C57BL/6 mice. In addition, plasmid DNA-encoding IP-10 substantially reduced the establishment of metastases when injected systemically by the intramuscular route. In contrast to the primary tumor model, the anti-metastatic effect of DNA-encoding IP-10 was primarily mediated by NK cells. Compared to DNA-encoding interleukin-12 (IL-12), therapy with DNA-encoding IP-10 exhibits lower efficacy against primary melanoma tumors but equivalent efficacy against primary Lewis lung tumors and against B16F10 lung metastasis formation. Co-administration of DNA-encoding IP-10 and IL-12 enhanced the anti-tumor activity of IL-12 in the lung metastasis model but had little effect in the local treatment of established subcutaneous tumors. Interestingly, treatment of nude mice lacking T lymphocytes with DNA-encoding IP-10 or IL-12 still resulted in a pronounced reduction of tumor growth or metastasis formation.

Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium.

BACKGROUND: No replacement for succinylcholine is yet available. GW280430A (AV430A) is a representative of a new class of nondepolarizing neuromuscular blocking drugs called asymmetric mixed-onium chlorofumarates. It undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction, resulting in a very short duration of effect. The neuromuscular, cardiovascular, and autonomic pharmacology of GW280430A is compared herein with that of mivacurium. METHODS: Adult male rhesus monkeys and adult male cats were anesthetized with nitrous oxide-oxygen-halothane and chloralose-pentobarbital, respectively. The neuromuscular blocking properties of GW280430A and mivacurium were compared at a stimulation rate of 0.15 Hz in the extensor digitorum of the foot (monkey) and the tibialis anterior (cat). Sympathetic responses were assayed in the cat in the nictitating membrane preparation, and vagal effects were evaluated in the cat via observation of bradycardic responses after stimulation of the cervical right vagus nerve. RESULTS: GW280430A and mivacurium were equipotent in the monkey (ED95 was 0.06 mg/kg in each case). GW280430A was half as potent as mivacurium in the cat. The total duration of action of GW280430A was less than half that of mivacurium in the monkey; recovery slopes were more than twice as rapid. The 25-75% recovery index of GW280430A did not vary significantly after various bolus doses or infusions, averaging 1.4-1.8 min in the monkey, significantly shorter than the same time interval (4.8-5.7 min) for mivacurium. Dose ratios for autonomic versus neuromuscular blocking properties in the cat were greater than 25 for both GW280430A and mivacurium. The ratio ED Hist:ED95 Neuromuscular Block in the monkey was significantly greater (approximately 53 vs. 13) for GW280430A, indicating approximately four times less relative prominence of the side effects of skin flushing and decrease of blood pressure, which are associated with release of histamine. CONCLUSIONS: These experiments show a much shorter neuromuscular blocking effect and much-reduced side effects in the case of GW280430A vis-à-vis mivacurium. These results, together with the novel chemical degradation of GW280430A, suggest further evaluation in human subjects.

Linear closed mini DNA generated by the prokaryotic cleaving-joining enzyme TelN is functional in mammalian cells.

For application of DNA in gene medicine plasmid or viral DNA is usually used as a vector for the gene of interest. To generate DNA with a minimum of foreign DNA sequences, we used the prokaryotic telomerase, protelomerase TelN, of bacteriophage N15. This is a novel enzyme with cleaving-joining activity, which is required for the formation of linear prophage DNA with closed ends in lysogenic bacteria. Acting on a telomere resolution site telRL, the protelomerase converts circular plasmid DNA into linear covalently closed dumbbell-shaped molecules ("doggybones") in a single-step enzyme reaction. Two such sites were inserted into an expression plasmid flanking a gene of interest. This is cleaved and joined by means of the protelomerase, yielding linear closed mini DNA coding for green fluorescent protein (EGFP) or interleukin-12 (IL-12). Upon transient transfection of human embryonal kidney cells, EGFP was expressed at higher levels from linear closed molecules than from linear open molecules generated by restriction endonucleases for comparison. The level of transcription was comparable to that observed for the parental plasmid DNA. To test whether the linear closed mini DNA molecules are functional in vivo the B16F10/C57BL/6 melanoma metastasis model was applied, where injection of IL-12-expressing DNA inhibits metastasis formation in the lung. The anti-metastatic effect of the IL-12-expressing linear closed DNA was equal or higher than that of the parental plasmid DNA. Therefore, the TelN/ telRL system is well suited to generate linear closed mini DNA with high stability and a minimum of foreign nucleotide sequences.

Tumor regression of human and murine melanoma after intratumoral injection of IL-12-encoding plasmid DNA in mice.

DNA coding for murine interleukin 12 (IL-12) prevents the formation of B16-melanoma metastasis when administered intramuscularly. Here, the antitumor effect of IL-12-encoding DNA on established mouse B16 melanoma and human melanoma tumors was investigated in vivo using two animal models: B16 melanoma in C57B/6 mice and human melanoma in nude mice. In B16 melanoma, intratumoral injections of IL-12-encoding DNA resulted in highly significant growth retardation when compared with mice injected with control vector. In the case of the human melanoma model, treatment with DNA coding for IL-12 induced regression of tumors in all cases, with complete disappearance of the tumor in two out of five animals. DNA treatment did not induce systemic side-effects. In the animals injected with control vector the human melanoma tumors grew expansively. The therapeutic effect of the DNA injection was mediated in part by natural killer (NK) cells as shown by NK-depletion experiments. An antivascular effect of IL-12 treatment was evident in histological examination with endothelial thickening and abrupt changes in vessel diameters. These results suggest that intratumoral plasmid DNA coding for IL-12 holds some promise as a new therapeutic tool for accessible melanoma lesions and should be tested in clinical trial.

Passive immunization against beta-amyloid peptide protects central nervous system (CNS) neurons from increased vulnerability associated with an Alzheimer's disease-causing mutation.

To characterize the effects of the familial Alzheimer's disease-causing Swedish mutations of amyloid precursor protein (SwAPP) on the vulnerability of central nervous system neurons, we induced epileptic seizures in transgenic mice expressing SwAPP. The transgene expression did not change the seizure threshold, but consistently more neurons degenerated in brains of SwAPP mice as compared with wild-type littermates. The degenerating neurons were stained both by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and by Gallyas silver impregnation. A susceptible population of neurons accumulated intracellular Abeta and immunoreacted with antibodies against activated caspase-3. To demonstrate that increased Abeta levels mediated the increased vulnerability, we infused antibodies against Abeta and found a significant reduction in neuronal loss that was paralleled by decreased brain levels of Abeta. Because the SwAPP mice exhibited no amyloid plaques at the age of these experiments, transgenic overproduction of Abeta in brain rendered neurons susceptible to damage much earlier than the onset of amyloid plaque formation. Our data underscore the possibility that Abeta is toxic, that it increases the vulnerability of neurons to excitotoxic events produced by seizures, and that lowering Abeta by passive immunization can protect neurons from Abeta-related toxicity.