Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer.

Introduction: Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods: Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results: Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion: Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity.

Pharmacology at the beginning of the 21st century: implications of several new developments for dentistry and current status of the major 20th century dental drugs.

This review has highlighted some of the developments in pharmacology likely to impact dentistry as we enter the 21st century. While dentistry will naturally lag behind medicine in the introduction of new drugs, we must constantly explore all information resources available to keep abreast of developments in pharmacology that will affect our patients and our use of drugs in dental practice. This century will abound with new therapies, some of which will hopefully lead us out of our tradition of using rather non-selective, widely distributed chemicals with multiple actions and side effects into an age of highly-selective therapies, including the repair and replacement of defective genetic determinants of disease with healthy ones.

Management of the postoperative anesthetic period.

While anesthetic methods and drugs have undergone many changes in the last 100 years, the incidence of complications during the postanesthesia recovery period remains constant. Prompt recognition and treatment of the complications observed during the postoperative period decreases unexpected hospital admissions and the undesirable mortality or morbidity associated with surgery and anesthesia.

COX-2 inhibitors and dental pain control.

Celecoxib (CELEBREX) and rofecoxib (VIOXX) appear to offer the following advantages: reduced incidence of gastric ulceration during long-term administration; little or no effect on platelet aggregation; longer clinical duration of action than aspirin, acetaminophen and ibuprofen. However, in the context of the management of dental pain and inflammation, the following points and disadvantages should be considered: no greater effectiveness than conventional NSAIDs (e.g., ibuprofen) for dental pain; greater cost than conventional NSAIDs (especially those available in generic forms); not available over-the-counter; possible inadequate duration of action for postoperative dental pain (see references 6 and 7); similar contraindications and drug interactions to less expensive, equally effective conventional non-selective NSAIDs. At this time, celebrex and rofecoxib cannot be recommended over conventional, non-selective NSAIDs as first-choice drugs for pain and inflammation in dentistry. Practitioners are cautioned against selecting any new drug based on "clinical trials of one", in which both the dentist and the patient know the drug being prescribed, (as opposed to double-blind studies), usually in the context of considerable "hype" about the drug (based on comments about the fact that the agent being tried is "new") and strong placebo reinforcement based on the dentist's enthusiasm for the new product, which does not usually accompany the prescription of older, routinely prescribed drugs. Finally, such "clinical trials of one" invariably involve close follow-up about the outcome of the treatment, which is usually not done with more common, older drugs, and which only introduces further bias into the interpretation of the effectiveness of the drug by both the patient and the dentist. Anaglesic drugs should be selected on the basis of controlled, double-blind, randomized clinical trials which utilize a reasonable, dentally-related pain model. The older NSAIDs, such as ibuprofen, naproxen, diflunisal and others, remain first-choice drugs for the treatment of mild-to-moderate pain in dentistry in patients lacking the contraindications for such drugs. As proposed by this author several years ago, the major contraindications to NSAIDs can be remembered by the "SAAB Rule", an acronym which stands for "Stomach problems", Aspirin Allergy" and "Bleeding problems", in addition to pregnancy and hepatic/renal disease.

Xylocaine: 50 years of clinical service to dentistry.

In today's dental practice, local anesthesia is safe and effective, and injectable agents only rarely cause allergy. Ester-type agents, like procaine, which served the profession for over 50 years, have now been abandoned and are no longer available in dental cartridges in the U.S. Modern practitioners know of their disadvantages only through historical accounts of local anesthesia, and utilize daily the excellent chemical and pharmacologic characteristics of the amide local anesthetics, a tradition begun with the introduction of Xylocaine in the late 1940s and a tradition which will likely continue into the 21st century. The reader is referred to Table III for a comparison of quantities and dollar-value of sales of amide local anesthetics available in dental cartridges (17). In order to supplant Xylocaine (lidocaine) as a preferred local anesthetic in dentistry, any new agent will have to prove that it is superior in terms of short onset, appropriate duration, stability, excellent safety record, low allergenicity, and topical efficacy. As our understanding of the molecular structure of ion channels and the interactions of local anesthetics with neural sodium channels increase, new agents can be developed rationally. In the meantime, the amide local anesthetics will continue to serve dentists and their patients by providing safe and effective control of pain to facilitate ever-advancing surgical and restorative techniques.

Iontophoresis: applications in transdermal medication delivery.

This article presents a review of the literature relating to iontophoresis. This technique has been used in physical therapy to introduce ionic medications through the skin, primarily for a local effect. Recently, there has been increased interest in using this technique for the transdermal delivery of medications, both ionic and nonionic. This article includes an overview of the history of iontophoresis and a discussion of the physico-chemical and biological factors affecting iontophoretic drug transfer for both local and systemic effects. Factors affecting skin injury and techniques for optimizing iontophoretic drug delivery through the use of current modulation, electrode construction, and skin permeation enhancers are also discussed. Clinical applications of iontophoresis in physical therapy and the pharmacology of selected medications are presented. Thoughts for future potential uses of this technique and needs for further research are also discussed.

Cellular distribution in the rat telencephalon of mRNAs encoding for the alpha 3 and alpha 4 subunits of the nicotinic acetylcholine receptor.

Pharmacological and electrophysiological studies provide evidence for the involvement of different nicotinic acetylcholine receptor isoforms in rat neocortical and hippocampal signal transduction. Yet, rather little is known on the cellular localization of these isoforms. With the availability of isoform specific nucleic acid probes and sensitive non-isotopic detection systems, nicotinic receptors can be studied on the mRNA level in individual neurons. In this way, we have paradigmatically studied the distribution of the alpha 3 and alpha 4 isoform mRNAs of the nicotinic receptor in the rat telencephalon. In the cerebral cortex, alpha 3 transcripts were mainly located in pyramidal neurons of layers V and VI and in some non-pyramidal cells in layer IV, while alpha 4 mRNA was detected in different types of neurons located in almost all layers. In the hippocampus, local distribution of both transcripts was comparable. Only very few labeled neurons were observed in the dentate gyrus. In the CA region, the specific mRNAs were detected in pyramidal perikarya and individual neurons in the strata oriens and lacunosum-moleculare. Our data show that the applied method is sufficiently sensitive and isoform-selective in order to study the differential expression of nicotinic receptors on the cellular level in the mammalian brain.

Cellular distribution of nicotinic acetylcholine receptor subunit mRNAs in the human cerebral cortex as revealed by non-isotopic in situ hybridization.

The pharmacology of telencephalic nicotinic acetylcholine receptors (nAChRs) has become an important issue in recent years. While in the human brain a direct pharmacological assessment is difficult to achieve the visualization of nAChRs has been enabled by histochemical techniques providing an ever increasing and improving resolution. Receptor autoradiography was used to visualize binding sites on the level of cortical layers whereas immunohistochemistry has allowed for the cell type-specific and ultrastructural localization of receptor protein. Further investigations have to elucidate the cellular sites of NAChR biosynthesis by visualizing subunit-specific transcripts. Using autopsy samples of the human precentral cortex (Area 4) as a paradigm we have applied digoxigenin-labeled cRNA probes to localize transcripts for the alpha 3- and alpha 4-1-subunits of the nAChR. In accordance with findings in the monkey cortex, the alpha 3-subunit seems to be expressed mainly in pyramidal neurons of layers III-VI of the human cerebral cortex. Transcripts for the alpha 4-1-subunit, by contrast, appear to be present in a large number of neurons throughout all layers of the cerebral cortex, consonant with its ubiquitous distribution in the rodent brain. The present findings show that also in human autopsy brains the cell type-specific detection of nAChR transcripts is possible. For the future, this technique will enable to investigate the expression of receptor transcripts in diseased human brains as compared to controls.

Influence of vitamins and iron on plasma fluoride levels in rats.

Thirty female Sprague-Dawley rats (250 +/- 10 g) were divided randomly into five equal groups. After overnight fasting, a silastic catheter was placed in the jugular vein of each rat. Each group was intragastrically administered 0.25 mg F/250 g rat weight in 1 ml of one of the following forms of fluoride supplements: Pediaflor (Abbott/Ross, Columbus, OH), Tri-Vi-Flor, Tri-Vi-Flor + iron; Poly-Vi-Flor or Poly-Vi-Flor + iron (Mead Johnson Nutritionals, Bristol-Myers Squibb Co., Evansville, IN). Timed blood samples were collected and plasma fluoride concentration was determined using the microdiffusion method. The presence of iron and vitamins affect the bioavailability of fluoride as measured by the area under the time-plasma fluoride concentration curve.