Continuous Low-dose Therapy Research Articles

Feasibility and Determinants of Deprescription of Proton Pump Inhibitors in Patients with Typical Reflux Symptoms

Background and Aims: Proton pump inhibitors (PPIs) are commonly used drugs in the management of reflux symptoms. These drugs are frequently overused and have side effects on long term use. The present study was undertaken to determine the feasibility and determinants of deprescription of PPI in patients with typical reflux symptoms. Materials and Methods: This retrospective study recruited all patients, >18 years, with heartburn and/or regurgitation of more than 3-month duration. The severity of reflux was assessed with white light endoscopy and graded as per Los Angeles classification. All patients were advised lifestyle changes, aerobic exercises for >30 min/day, and dietary modifications. Follow-up details, including symptom resolution and drug requirement, were noted at 3 months after the initial visit. Results: A total of 106 patients formed the study cohort (males 60, median age 43 years [range 18–72 years]). Reflux esophagitis was noted in 32 cases (30%). Of these patients, 8 (25%) had Grade A esophagitis and the remaining had Grade B or beyond. Three-fourths of the patients were prescribed once a day PPI. On follow-up at 3 months, PPI therapy was stopped completely in 58 (54.7%) cases. Thirty-two (30.2%) and 16 (15.1%) patients were on on-demand PPI and continuous low dose therapy, respectively. A significantly higher proportion of patients with reflux esophagitis (30/32, 93.75%) could stop PPI at the end of 3 months. The need for on-demand PPI and continuous low dose therapy was higher in patients with nonerosive reflux disease (14 cases, 19%). In univariate analysis, use of alcohol (P = 0.04), smoking (P = 0.0006), presence of diabetes mellitus (P = 0.01), and presence of hiatus on endoscopy (P = 0.03) were the factors significantly associated with continued use of PPI at the end of 3 months. In multivariate analysis, smoking was the only factor independently associated with the continuation of PPI use after 3 months. Conclusion: Deprescription of PPI was achieved in 90 cases (84.9%) at 3 months. In univariate analysis, use of alcohol, smoking, presence of diabetes mellitus, and presence of hiatus are associated with continued PPI use at 3 months. In multivariate analysis, smoking was the only factor independently associated with the continuation of PPI use after 3 months.

Barton Kamen: In Memoriam

Barton Kamen, M.D., Ph.D., passed away on September 27, 2012, at age 63 after his own courageous battle with cancer. Bart was a clinical professor of pediatrics and pharmacology, and former chief of the Division of Pediatric Hematology/Oncology at the Cancer Institute of New Jersey/Robert Wood Johnson Medical School. He graduated from Case Western University and then was accepted in the M.D./Ph.D. program at Case Western University Medical School. Figure 1. Barton Kamen, 1948–2012 After graduating from Case Western Reserve University Medical School, Dr. Kamen came to Yale for his pediatric residency. I first met Bart when he came to my office in the Yale Pharmacology Department one day in 1978 and asked about joining the laboratory. After a few minutes, I realized that he was terribly bright and passionate about science, so I quickly offered him a position. His previous Ph.D. work had centered on folate-binding proteins, and his work in my laboratory at Yale broadened his interest in folate biochemistry. He made significant contributions over the years in both fields, and he has been widely sought after as a lecturer and consultant for his expertise in both areas. It was during this fellowship year that golf became another lifetime passion for him, and we often played nine holes at Yale early in the mornings before work. After his fellowship, Bart accepted an assistant professor position with Bruce Camitta in Wisconsin. Three years later, he joined the faculty at the University of Texas Southwestern Medical Center where he was the Carl B. and Florence E. King Distinguished Professor of Professor of Pediatrics and Pharmacology. At Southwestern, Bart and his colleagues demonstrated the functions and tissue and tumor distribution of the folate binding protein now known as FBPα. These studies have led to the trials of antibodies to this protein to treat ovarian cancer, as well as the use of folic acid linked to toxins to target and treat ovarian cancer. After 18 years in Texas, Bart was recruited by William Hait, the director of the newly formed Cancer Institute of New Jersey and the Robert Wood Johnson Medical School, in 1999 to build the pediatric hematology and oncology program. During the next 8 years, under his leadership, the faculty increased from three to nine members and the program became one of the premier pediatric hematology/oncology programs in the country. Dr. Kamen and Dr. Peter Cole, one of his recruits, studied neurotoxicity from methotrexate. They showed that dextromethorphan, found in some cough medicines, and caffeine could reverse some types of methotrexate toxicity. This work in part led him to reinvestigate aminopterin as a more potent drug than methotrexate with less neurotoxicity. During this time, he also developed an interest in metronomic therapy and became one of the experts and proponents of this low-dose continuous therapy concept. Bart received many awards for his research, including a Damon Runyon Walter Winchell Fellowship, a Scholar Award from the Leukemia and Lymphoma Society, and a Burroughs Wellcome Clinical Pharmacology Award. Bart also was an American Cancer Society Clinical Research Professor, the first pediatrician to be honored with this award. His incredible energy and passion for science is reflected in more than 200 publications. He was the editor for the Journal of Pediatric Hematology Oncology, for which he often contributed thoughtful editorials—the last one dealing with his own disease [J Pediatr Hematol Oncol 2012;34:1]. From the time of his diagnosis in May 2011 until he required hospitalization in September, he continued working, playing golf, and dealt amazingly well with the side effects of treatments that unfortunately did not stop the progress of his disease. An important colleague was his famous engineer brother Dean, with whom Bart worked on the development of the insulin pump. On other projects with Dean, he provided key biological insights. His other brother Mitchell is a talented musician, and his sister, Terri Kamen Schuler, is a successful businesswoman. His mother, Evelyn Kamen, lives in Boca Raton, Florida. His father, Jack, who died in 2008, was a well-known artist and illustrator for comics. Bart's motivation as a physician scientist was focused on finding better treatment for his patients. He used magic tricks to break down their fears, and he became their friend for life. Nothing pleased him more than to see a patient he treated years ago return, cured of his or her disease. We miss Bart's bad jokes, his “out-of-the-box thinking,” and his passion for science, which was second only to his love and caring for his wife, Ruth, and his daughter, Libby.

Clinical trial: interferon alpha‐2b continuous long‐term therapy vs. repeated 24‐week cycles for re‐treating chronic hepatitis C

Treatment options are limited for patients with hepatitis C virus who do not experience sustained viral eradication with pegylated interferon and ribavirin therapy. To compare, in an open-label, randomized study, long-term continuous interferon alpha-2b treatment with repeated 24-week courses in patients with chronic hepatitis C virus that relapsed after prior interferon monotherapy. A total of 499 patients received 24 weeks of interferon alpha-2b, 3 MIU administered 3 TIW. Responders (normal alanine aminotransferase and negative hepatitis C virus -RNA, n = 244) were then randomized to continuous interferon therapy (1, 2 or 3 MIU TIW depending on response) or cyclical therapy (3 MIU TIW for 24 weeks per relapse). Mean Knodell inflammation (I + II + III) and necrosis (IV) scores at baseline vs. year 2 were compared. Patients receiving continuous low-dose therapy vs. cycled therapy had larger reductions in inflammation (-3.9 vs. -3.1) and fibrosis (-0.49 vs. -0.24). Among both groups, the mean change was -3.4 for inflammation and -0.36 for fibrosis. Overall, 73% (95% CI: 67-79) of patients experienced reduced inflammation and 28% (95% CI: 22-34) had reduced fibrosis. Our results suggest hepatitis C virus patients experiencing viral suppression during long-term maintenance therapy with interferon demonstrate histological improvement. Further prospective trials testing this hypothesis are in progress.

Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity

Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity

Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity

Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity

Hypersensitivity pneumonitis associated with the use of trofosfamide

Trofosfamide (Ixoten; Baxter Oncology, Germany) is an alkylating agent that, as with other oxazaphosphorine derivatives, has to be activated by hepatic cytochrome P450 oxidases. The bioavailability is nearly 100% after oral application, and the main metabolites are 4-hydroxytrofosfamide, and 4-hydroxyifosfamide. The main side-chain metabolites ifosfamide and cyclophosphamide can be further activated by oxidation and formation of their respective phosphoramide mustards. Oral continuous low-dose therapy has been the most widely used schedule. The toxicity profile consists mainly of dose-dependent hematotoxicity and, rarely, hemorrhagic cystitis. Nausea and vomiting are infrequently seen. Higher grades of nephrotoxicity or neurotoxicity--side-effects that typically limit the use of ifosfamide-have not been reported with low-dose continuous trofosfamide treatment. We report herein a case of a 83-year-old female patient with a disseminated malignant peripheral nerve sheath tumor treated with trofosfamide developing pulmonal toxicity. To our knowledge, this is the first reported case of exogenous allergic alveolitis after exposure to this drug.

Monitoring dose response of enzyme replacement therapy in feline mucopolysaccharidosis type VI by tandem mass spectrometry.

Mucopolysaccharidosis type VI is an inherited disorder of glycosaminoglycan metabolism characterized by organomegaly, corneal clouding, and skeletal dysplasia. Recent developments in the use of tandem mass spectrometry to measure sulfated mono- and disaccharides have enabled us to perform noninvasive, biochemical monitoring during therapy regimes in mucopolysaccharidosis type VI cats in addition to established methods of disease evaluation. In this study, mucopolysaccharidosis type VI animals were given high-dose (20 mg/kg) enzyme replacement therapy for the first month after birth followed by low doses (1 mg/kg) for a further 2 mo and were compared with animals maintained on 1 mg/kg enzyme replacement therapy for 3 mo. A sulfated monosaccharide (N-acetylhexosamine) and a sulfated disaccharide (N-acetylhexosamine-uronic acid) were elevated in MPS VI cat urine and blood. These markers showed a clear discrimination between the treatment groups during the first 4 wk of therapy: values in the high-dose group were close to normal whereas those in the low-dose group were only slightly lower than the untreated mucopolysaccharidosis type VI cats. However, within 2 mo of cessation of the high-dose therapy there was minimal difference in the oligosaccharide levels, with both groups lying between the untreated and unaffected cats. At the completion of the trial, subjective minor improvement was noted in overall physical disease features and also in lysosomal vacuolation in tissues from animals on the initial high-dose enzyme replacement therapy compared to the low-dose therapy animals. Initial high-dose therapy reduced storage load in the animals but had no lasting clinical benefit over continuous low-dose therapy.

In vivo chamber angiogenesis assay: An optimized Matrigel plug assay for fast assessment of anti-angiogenic activity

Efficient in vitro and in vivo angiogenesis assays, to assess and compare anti-angiogenic activity are a prerequisite for the discovery and characterization of anti-angiogenic targets. Here we describe an optimized Matrigel plug assay based on subcutaneously implanted chambers and two fast and reproducible measuring techniques. Plexiglas ring/nylon net filter-chambers (0.2 ml) containing growth factor-reduced Matrigel and 300 ng basic fibroblast growth factor (bFGF) were subcutaneously implanted into the right flank of rats. Chamber angiogenesis was scored on day 5 and day 10 post-implantation by computer image analysis of the chamber, and by optical density reading at 415 nm of a PBS solution of the chamber content. bFGF significantly induced chamber angiogenesis and histological examination confirmed that numerous blood vessels were present in the bFGF-induced chambers. The anti-angiogenic control compound TNP-470 (10 mg/kg/d s.c.) completely inhibited the bFGF-induced angiogenesis. In contrast, the anti-inflammatory or immuno-suppressive compounds cyclosporin A (15 mg/kg/d p.o.), indomethacin (1 mg/kg/d p.o.), and prednisolone (5 mg/kg/d p.o.) showed no anti-angiogenic activity, indicating that the bFGF-induced angiogenesis was not driven by an inflammatory response or by a foreign body reaction. Finally, two candidate anti-angiogenic compounds were tested in the assay. Continuous low-dose therapy with cyclophosphamide (25 mg/kg/d p.o.) significantly inhibited bFGF-induced angiogenesis, whereas 1alpha,25-dihydroxyvitamin D3 (0.5 micro g/kg/d p.o.) showed no significant anti-angiogenic activity. In conclusion, this in vivo chamber angiogenesis assay is a useful new tool for drug evaluation as well as research into anti-angiogenesis.

Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity.

Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a treatment regimen that augments the potential antivascular effects of chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the low-dose chemotherapy would be selectively enhanced in cells of newly formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant but transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Mathematical model for human myeloma relating growth kinetics and drug resistance.

We present a computer-based mathematical model that can simulate characteristic features of the clinical time course of human myeloma. It asserts that therapy resistance in myeloma cells is an inherited trait associated with the longer inter-mitotic times of some cells and that the strength of this trait affects tumour growth characteristics. These kinetic differences within the malignant cell clone may also influence therapeutic efficacy. In the model, the same total therapy, administered in different time-dose fractions, could be 'curative' or 'minimally effective' depending on kinetic properties. For example, as others have shown, in myeloma pulsed intermittent therapy is often more effective than low dose continuous therapy. According to our model this finding is compatible with a high coefficient of inheritability of resistance from one cell generation to the next. The model also suggests that if there are subclones of varying resistance, a therapy must have some effect on each of them if it is to be employed in a curative fashion. While many aspects of the model are not yet clinically testable, exploration of its concepts might increase knowledge about fundamental neoplastic mechanisms.

CONTRASTING EFFECTS OF COMBINED AND SEQUENTIAL ORAL CONTRACEPTIVES ON LH-RH-STIMULATED RELEASE OF LH AND FSH AS COMPARED TO MINIPILLS

The stimulation of luteinizing hormone (LH) and follicle stimulating hormone (FSH) release from the pitutiary by LH-RH has recently been show n to be impeded in women using oral contraceptives (OCs). It remained to be shown however whether or not the steroid-induced inhibition of gonadotropin release would be influenced by type dosage and duration of application of OCs. We therefore studied the pituitary reaction to stimulation with LH-RH in 42 volunteers taking different types of OCs and in 10 women during the luteal phase of the normal cycle. The tests were performed during the last 3 days of taking the OCs. In some cases the test was repeated during the pill-free interval. In women using a normophasic sequential OC the test was carried out during the 1st and 2nd phase. The standard test dose of 100 mcg synthetic LH-RH (HOE 471) was given as rapid iv injection. In some women 100 and 500 mcg LH-RH respectively were also given as iv infusion over a 3-hour period or as iterative injection. Serum LH and FSH were measured by radioimmunoassay using a double-antibody solid-phase method. In normally cyclic women LH rose in response to the injection from a mean serum level of 1.9 + or - .9 ng/ml to a peak value of 12.9 + or -5.3 ng/ml and FSH from 2.2 + or - 1.6 ng/ml to 5.1 + or -3.8 ng/ml. In 15/18 women using combined OCs the response to LH-RH was found to be severely impeded or completely suppressed. In the remaining 3 cases normal reactions were obtained. Similar results were seen in women using a normophasic preparation. A release of LH and FSH was seen 4-6 days after taking the pill in 3/7 women but in those 3 cases normal reactions had also been obtained while taking the OC. The suppressive effect of OCs could not be overcome to an appreciable degree by iv infusion or iterative injection. In 2/5 women a slight increase in serum LH was found after 3 hours of infusion. Contrary to this a normal reaction to LH-RH was found in 8/12 volunteers using various minipills. In the remaining 4 cases the reaction was somewhat impeded. These results are interpreted as meaning that there is no difference in the suppressive effect of combined and sequential OCs and gonadotropin release seems to be affected by continuous low-dose therapy with progestagens only to a very slight degree. (FULL TEXT)