Histone deacetylase inhibitors represent a promising new class of compounds for the treatment of cancer. Inhibitors of this kind currently under clinical evaluation mainly target the classical (Rpd3/Hda1) family of histone deacetylases. Of particular note, the U.S. Food and Drug Administration recently approved the first histone deacetylase inhibitor (Zolinza: Merck and Co., Whitehouse Station, NJ, U.S.A.) for the treatment of cutaneous T-cell lymphoma. Dozens of such inhibitors are now in phase ii–iii clinical trials, sometimes in combination with other chemotherapy drugs, for diverse cancer types, including both hematologic and solid tumours. In this mini-review, we provide an overview of the histone deacetylase superfamily, highlight the positive results of deacetylase inhibitors in cancer clinical trials, and comment on the prospects for the next generation of such inhibitors.
Histone deacetylase; tubulin acetylation; Hsp90; vorinostat; trichostatin A; tubacin; chromatin; epigenetics
The Expressed Sequence Tag (EST) division of GenBank, dbEST, is a large repository of the data being generated by human genome sequencing centers. ESTs are short, single pass cDNA sequences generated from randomly selected library clones. The approximately 415 000 human ESTs represent a valuable, low priced, and easily accessible biological reagent. As many ESTs are derived from yet uncharacterized genes, dbEST is a prime starting point for the identification of novel mRNAs. Conversely, other genes are represented by hundreds of ESTs, a redundancy which may provide data about rare mRNA isoforms. Here we present an analysis of >1000 ESTs generated by the WashU-Merck EST project. These ESTs were collected by querying dbEST with the genomic sequences of 15 human genes. When we aligned the matching ESTs to the genomic sequences, we found that in one gene, 73% of the ESTs which derive from spliced or partially spliced transcripts either contain intron sequences or are spliced at previously unreported sites; other genes have lower percentages of such ESTs, and some have none. This finding suggests that ESTs could provide researchers with novel information about alternative splicing in certain genes. In a related analysis of pairs of ESTs which are reported to derive from a single gene, we found that as many as 26% of the pairs do not BOTH align with the sequence of the same gene. We suspect that some of these unusual ESTs result from artifacts in EST generation, and caution researchers that they may find such clones while analyzing sequences in dbEST.
To assess the effects of binge drinking on students’ next-day academic test-taking performance.
A placebo-controlled cross-over design with randomly assigned order of conditions. Participants were randomized to either alcoholic beverage (mean =.12 g% breath alcohol concentration [BrAC]) or placebo on the first night and then received the other beverage a week later. The next day, participants were assessed on test-taking, neurocognitive performance and mood state.
193 college students (≥ 21 years) recruited from greater Boston.
The trial was conducted at the General Clinical Research Center at the Boston Medical Center.
The Graduate Record Exams © (GREs) and a quiz on a lecture presented the previous day measured test-taking performance; the Neurobehavioral Evaluation System (NES3) and the Psychomotor Vigilance Test (PVT) measured neurocognitive performance; and, the Profile of Mood States (POMS) measured mood.
Test-taking performance was not affected the morning after alcohol administration, but mood state and attention/reaction time were.
Drinking to a level of .12 g% BrAC does not affect next-day test-taking performance, but does affect some neurocognitive measures and mood state.
binge drinking; academic performance; neurocognitive performance; mood state; students; intoxication
Isothermal nucleic acid sequence-based amplification (NASBA) was applied to the detection of Mycoplasma pneumoniae. M. pneumoniae RNA prepared from a plasmid construct was used to assess the sensitivity of the assay, and an internal control for the detection of inhibitors was constructed. The sensitivity of the NASBA assay was 10 molecules of wild-type M. pneumoniae RNA generated in vitro and 5 color-changing units (CCU) of M. pneumoniae. An appropriate specimen preparation procedure was developed: after protease treatment of the respiratory specimens, guanidine thiocyanate lysis solution (4.7 M guanidine thiocyanate [Sigma-Aldrich NV], 46 mM Tris-HCl [Merck, Darmstadt, Germany], 20 mM EDTA [Sigma-Aldrich NV], 1.2% [wt/vol] Triton X-100 [Sigma-Aldrich NV], pH 6.2.) was added. With spiked throats, nasopharyngeal aspirates, bronchoalveolar lavage specimens, and sputum specimens, the sensitivity of the NASBA assay in the presence of the internal control was 2 × 104 molecules of in vitro-generated RNA or 5 CCU of M. pneumoniae. The sensitivity of the NASBA assay was comparable to that of a PCR targeted to the P1 adhesin gene. Fifteen clinical specimens positive for M. pneumoniae by PCR were also positive by NASBA. These results indicate that the sensitivity of detection of M. pneumoniae in spiked respiratory samples by NASBA is high. Together with the use of the internal control, the assay merits evaluation as a diagnostic tool.
In 1933, for the second time in the history of the Hospital for the Ruptured and Crippled (R & C), a general surgeon, Eugene Hillhouse Pool, MD, was appointed Surgeon-in-Chief by the Board of Managers of the New York Society for the Relief of the Ruptured and Crippled. R & C (whose name was changed to the Hospital for Special Surgery in 1940), then the oldest orthopaedic hospital in the country, was losing ground as the leading orthopaedic center in the nation. The R & C Board charged Dr. Pool with the task of recruiting the nation’s best orthopaedic surgeon to become the next Surgeon-in-Chief. Phillip D. Wilson, MD, from the Massachusetts General Hospital in Boston and the Harvard Medical School was selected and agreed to accept this challenge. He joined the staff of the Hospital for the Ruptured and Crippled in the spring of 1934 as Director of Surgery and replaced Dr. Pool as Surgeon-in-Chief the next year. It was the time of the Great Depression, which added a heavy financial toll to the daily operations of the hospital. With a clear and courageous vision, Dr. Wilson reorganized the hospital, its staff responsibilities, professional education and care of patients. He established orthopaedic fellowships to support young orthopaedic surgeons interested in conducting research and assisted them with the initiation of their new practices. Recognizing that the treatment of crippling conditions and hernia were becoming separate specialties, one of his first decisions was to restructure the Hernia Department to become the General Surgery Department. His World War I experiences in Europe helped develop his expertise in the fields of fractures, war trauma and amputations, providing a broad foundation in musculoskeletal diseases that was to be beneficial to him in his future role as the leader of R & C.
Eugene H. Pool; Virgil P. Gibney; William Bradley Coley; Hospital for the Ruptured and Crippled (R & C); New York Hospital; Hospital for Special Surgery (HSS); Philip D. Wilson; Franklin D. Roosevelt; Fiorella H. LaGuardia; Robert Moses; Robert B. Osgood; Memorial Hospital; Philip D. Wilson, Jr; Bradley L. Coley; Bradley L. Coley, Jr; Helen Coley Nauts; Fenwick Beekman
Four different pancreatin products, Pancrease, Creon, Pancrex V Forte, and Pancreatin Merck, were compared in a random crossover trial in children with cystic fibrosis. The results of our study showed that patients who received Creon and Pancrease had fewer gastrointestinal symptoms than patients who received Pancrex V Forte and Pancreatin Merck. Fat absorption was significantly improved with Pancrease when compared with Pancrex V forte and Pancreatin Merck. Also the fat absorption with Creon was superior to that with Pancrex V Forte. There was no significant difference in fat absorption between Pancrease and Creon. Pancrex V Forte and Pancreatin Merck, or Pancreatin Merck and Creon. Faecal nitrogen content was less with both Creon and Pancrease compared with Pancreatin Merck. Creon and Pancrease allow the patient with cystic fibrosis to take a high energy diet without any dietary restrictions.
To determine the extent of fluctuation in circadian intraocular pressure (IOP) and the efficacy of topical dorzolamide 2% q 8h in lowering IOP and blunting circadian fluctuation in IOP in glaucomatous cats.
7 adult cats with primary congenital glaucoma (PCG).
Measurements of IOP and pupil diameter were obtained for both eyes (OU) of each cat q 4h for 12 days. Cats were housed in a laboratory animal facility with a 12 hour light:dark cycle. Baseline values were established for 2 days. For the next 5 days, placebo (1.4% polyvinyl alcohol) was administered OU q 8h. Dorzolamide 2% (Trusopt, Merck and Co., Inc., West Point, PA) was then administered OU q 8h for a further 5 days. A multivariate mixed linear model was fitted to the data, with parameters estimated from a Bayesian perspective. The 4am time point was selected as the reference for the purposes of comparisons.
Estimated mean IOP for the reference time point pre-treatment was symmetric (about 33mmHg OU). In all cats, IOP was significantly lower during the diurnal phase, relative to the 4 am measurements, with highest IOP observed 2-6h after the onset of the dark-phase. Circadian fluctuations in IOP were dampened during the treatment period. There was a significant decrease in IOP in all cats during the dorzolamide treatment period (estimated mean for the treatment period reference =17.9 mmHg OU).
Topical dorzolamide 2% q 8 h is effective in reducing IOP and IOP fluctuation in cats with PCG.
glaucoma; feline; intraocular pressure; pupil diameter; carbonic-anhydrase; inhibitor; circadian
Cancer survivors are a rapidly growing and aging population in the U.S., but there are many challenges associated with the survivorship experience such as functional disabilities and psychosocial distress. When viewed next to the general population, Veterans are especially at risk for these challenges as they are older and have a high incidence of co-morbid conditions. While the Institute of Medicine (IOM) has called for further cancer survivorship research to address these challenges, we still know little about this experience from the perspective of aging Veterans.
We conducted a longitudinal, mixed-methods study over the course of three and a half years at the Boston and Houston VA Medical Centers. We recruited 170 Veterans diagnosed with head and neck, colorectal and esophageal/gastric cancers that were identified from the VA tumor registry. Veterans completed three in-depth interviews, conducted at 6, 12 and 18 months after pathology confirmation, measuring the physical, social and psychological factors related to cancer survivorship. The longitudinal design allowed us to assess any changes in cancer related disability and distress over time.
Weekly teleconference study team meetings were a key aspect to the research process. Issues related to recruitment, data management and analysis, and the dissemination of research results was discussed. Interviewers presented detailed case reports of completed interviews that allowed us to refine our interview protocols. We also discussed issues relevant to the Veteran population of which we were previously unaware and some of the challenges of the research process itself. This novel study produced a robust data set that documents the functional and psychosocial cancer survivorship experiences of aging Veterans. The longitudinal design will help us more fully understand the recovery patterns for this specific population, and identify the unique needs and gaps in health services.
Cancer care; Cancer survivorship; Veterans; Aging; Psychosocial; Functional assessment; Quality of life
In a general practice population of 57 000, 32 patients suffering from Parkinson's disease were identified from repeat prescription indexes and direct questioning of all members of the primary health care team. Of these patients 26 were receiving an L-dopa preparation and 10 an anticholinergic drug. The only newer drug found to be in use was bromocriptine and three patients were receiving this treatment.
Of the 26 patients receiving an L-dopa preparation one received L-dopa alone, six L-dopa with benserazide (Madopar, Roche) and 19 L-dopa with carbidopa (Sinemet, Merck, Sharp and Dohme). The patients treated with Sinemet were receiving inadequate doses of carbidopa - three quarters received less than 75 mg per day which was in part a reflection of the low doses of L-dopa the patients received, the average dose being 468 mg per day. The L-dopa preparations were given in adequately spaced doses.
The general practitioner made the diagnosis in 20 of the 32 cases and was in control of the drug therapy in 15 cases, however 25 cases were referred for specialist advice.
It is commonly agreed that people with a high blood LDL-cholesterol will have a higher risk of coronary artery disease (CAD) than people with low blood LDL-cholesterol. Due to the increasingly high costs of medication in Thailand, the government has set up several measures to combat the problem. One of such strategies is to promote the utilization of locally manufactured drug products, especially those contained in the National Drug List. Simvastatin, an HMG-CoA reductase inhibitor, is listed as an essential drug for the treatment of hypercholesterolemia. Here, we reported the study on the LDL-cholesterol-lowering effect of a generic simvastatin product in comparison with the Zocor©, in 43 healthy thai volunteers.
The generic product tested was Eucor©, locally manufactured by Greater Pharma Ltd., Part, Thailand, and the reference product was Zocor© (Merck Sharp & Dohme, USA). The two products were administered as 10-mg single oral doses in a two-period crossover design. After drug administration, serial blood samples were collected every 4 weeks for 16 weeks. The major parameter monitored in this study was blood LDL-cholesterol.
After taking the drugs for the first 8 weeks, no statistically significant difference was dedected in blood LDL-cholesterol between the first (Zocor©-treated) and the second (Eucor©-treated) groups. After crossover and taking drugs for further 8 weeks, a similar result was obtained, i.e., no significant difference in blood LDL-cholesterol between the first (Eucor©-treated) and the second (Zocor©-treated) groups was observed. Upon completion of the 16-week study, there was also no statisticaly significant difference in the changes of all tested blood parameters between the two products (randomized block ANOVA, N = 37). Only minor side effects, mainly dizziness and nausea, were observed in both products.
Our study demonstrated no significant differences in the therapeutic effect and safety between the generic and original simvastatin products.
Rotavirus (RV) vaccination programs have been established in several countries using the human-attenuated G1P monovalent vaccine Rotarix™ (GlaxoSmithKline) and/or the human-bovine reassortant G1, G2, G3, G4, P pentavalent vaccine RotaTeq™ (Merck). The efficacy of both vaccines is high (~90%) in developed countries, but can be remarkably lower in developing countries. For example, a vaccine efficacy against severe diarrhea of only 58% was observed in a 2007–2009 Nicaraguan study using RotaTeq. To gain insight into the significant level of vaccine failure in this country, we sequenced the genomes of RVs recovered from vaccinated Nicaraguan children with gastroenteritis. The results revealed that all had genotype specificities typical for human RVs (11 G1P, 1 G3P) and that the sequences and antigenic epitopes of the outer capsid proteins (VP4 and VP7) of these viruses were similar to those reported for RVs isolated elsewhere in the world. As expected, nine of the G1P viruses and the single G3P virus had genome constellations typical of human G1P and G3P RVs: G1/3-P-I1-R1-C1-M1-A1-N1-T1-E1-H1. However, two of the G1P viruses had atypical constellations, G1-P-I1-R1-C1-M1-A1-N2-T1-E1-H1, due to the presence of a genotype-2 NSP2 (N2) gene. The sequence of the N2 NSP2 gene was identical to the bovine N2 NSP2 gene of RotaTeq, indicating that the two atypical viruses originated via reassortment of human G1P RVs with RotaTeq viruses. Together, our data suggest that the high level of vaccine failure in Nicaraguan is probably not due to antigenic drift of commonly circulating virus strains nor the emergence of new antigenetically distinct virus strains. Furthermore, our data suggests that the widespread use of the RotaTeq vaccine has led to the introduction of vaccine genes into circulating human RVs.
rotavirus; genomics; vaccine; RotaTeq
Varicella-zoster virus (VZV) is a herpesvirus and is the causative agent of chicken pox (varicella) and shingles (herpes zoster). Active immunization against varicella became possible with the development of live attenuated varicella vaccine. The Oka vaccine strain was isolated in Japan from a child who had typical varicella, and it was then attenuated by serial passages in cell culture. Several manufacturers have obtained this attenuated Oka strain and, following additional passages, have developed their own vaccine strains. Notably, the vaccines Varilrix and Varivax are produced by GlaxoSmithKline Biologicals and Merck & Co., Inc., respectively. Both vaccines have been well studied in terms of safety and immunogenicity. In this study, we report the complete nucleotide sequence of the Varilrix (Oka-VGSK) and Varivax (Oka-VMerck) vaccine strain genomes. Their genomes are composed of 124,821 and 124,815 bp, respectively. Full genome annotations covering the features of Oka-derived vaccine genomes have been established for the first time. Sequence analysis indicates 36 nucleotide differences between the two vaccine strains throughout the entire genome, among which only 14 are involved in unique amino acid substitutions. These results demonstrate that, although Oka-VGSK and Oka-VMerck vaccine strains are not identical, they are very similar, which supports the clinical data showing that both vaccines are well tolerated and elicit strong immune responses against varicella.
Next-generation sequencing technologies are revolutionizing biology by allowing for genome-wide transcription factor binding-site profiling, transcriptome sequencing, and more recently, whole-genome resequencing. While it is currently not possible to generate complete de novo assemblies of higher-vertebrate genomes using next-generation sequencing, improvements in sequence read lengths and throughput, coupled with new assembly algorithms for large data sets, will soon make this a reality. These developments will in turn spawn a revolution in how genomic data are used to understand genetics and how model organisms are used for disease gene discovery. This review provides an overview of the current next-generation sequencing platforms and the newest computational tools for the analysis of next-generation sequencing data. We also describe how next-generation sequencing may be applied in the context of vertebrate model organism genetics.
In the last few years the HIV vaccine field has moved forward a number of promising vaccine candidates into human clinical trials.
In this review we briefly discuss the advances made in vaccine development and HIV pathogenesis and give an overview of the body of work our lab has generated in multiple animal models on replication-competent Ad recombinant vaccines.
Emphasis is placed on comparative examination of vaccine components, routes of immunization and challenge models using replicating Ad vectors.
The overall findings make the case that replicating Ad vectors are superior in priming multiple arms of the immune system, and in conjunction with protein boosting, have resulted in dramatic protective efficacy leading to their advancement to phase 1 trials. Implications of the recent halting of the Merck Ad5-HIV phase 2b clinical trial for our vaccine approach and other vectored vaccines are discussed.
HIV vaccine; replication competent adenovirus vectors; mucosal immunity; protein boost; multigenic priming; animal models
The immunogenicity and reactogenicity of two preparations of yeast-derived hepatitis B vaccines were compared in healthy adult populations. The two groups were vaccinated in parallel, but they were not matched for age and sex. All subjects seroconverted, and 9 months after the first vaccine dose, all had anti HBs titres of at least 10 IU/l. The anti-HBs titres were higher in the group of subjects given 20 micrograms vaccine antigen made by Smith Kline & RIT (GMT 2943 at 9 months) compared to those who received 10 micrograms of vaccine made by Merck, Sharp & Dohme (GMT 729 at 9 months). Adverse effects were recorded in 32.0 and 44.7% of the participants, but these were limited to minor local and general reactions. In the present study both preparations were safe and efficient.
As one viewpoint of three in the PLoS Medicine Debate on whether drug companies are living up to their human rights responsibilities, Geralyn Ritter, Vice President of Global Health Policy and Corporate Social Responsibility at Merck & Co., argues that that multiple stakeholders could do more to help States deliver the right to health.
Background to the debate
The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The “Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines” include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.
HIV infection, once established, is never cleared. Rare individuals do, however, control viral replication to low levels. These successful immune responses are primarily linked to certain class I MHC alleles (MHC-I). Because of this association, many AIDS vaccines in development are designed to generate virus-specific CD8+ T cells. The Merck STEP phase 2b efficacy trial of one such vaccine was recently halted, and declared a failure. Thus, basic questions regarding what constitutes an effective T cell response and how such responses could be elicited by vaccination remain open. The best animal model available to explore such issues is simian immunodeficiency virus infection of rhesus macaques, which serves as the primary proving ground for AIDS vaccines.
The development of new anticoagulants is an important goal for the improvement of thromboses treatments.
The design, synthesis and experimental testing of new safe and effective small molecule direct thrombin inhibitors for intravenous administration.
Computer-aided molecular design of new thrombin inhibitors was performed using our original docking program SOL, which is based on the genetic algorithm of global energy minimization in the framework of a Merck Molecular Force Field. This program takes into account the effects of solvent. The designed molecules with the best scoring functions (calculated binding energies) were synthesized and their thrombin inhibitory activity evaluated experimentally in vitro using a chromogenic substrate in a buffer system and using a thrombin generation test in isolated plasma and in vivo using the newly developed model of hemodilution-induced hypercoagulation in rats. The acute toxicities of the most promising new thrombin inhibitors were evaluated in mice, and their stabilities in aqueous solutions were measured.
New compounds that are both effective direct thrombin inhibitors (the best KI was <1 nM) and strong anticoagulants in plasma (an IC50 in the thrombin generation assay of approximately 100 nM) were discovered. These compounds contain one of the following new residues as the basic fragment: isothiuronium, 4-aminopyridinium, or 2-aminothiazolinium. LD50 values for the best new inhibitors ranged from 166.7 to >1111.1 mg/kg. A plasma-substituting solution supplemented with one of the new inhibitors prevented hypercoagulation in the rat model of hemodilution-induced hypercoagulation. Activities of the best new inhibitors in physiological saline (1 µM solutions) were stable after sterilization by autoclaving, and the inhibitors remained stable at long-term storage over more than 1.5 years at room temperature and at 4°C.
The high efficacy, stability and low acute toxicity reveal that the inhibitors that were developed may be promising for potential medical applications.
The World Health Organization estimates that rotavirus diarrhea results in approximately half a million deaths and approximately 2.4 million hospitalizations in developing countries each year. Two live oral rotavirus vaccines, RotaTeq® (RV 5; Merck) and Rotarix® (RV 1; GlaxoSmithKline) with good efficacy against severe rotavirus disease and a reassuring safety profile could substantially impact the burden of rotavirus disease. In April 2009, WHO provided a recommendation for global introduction of these vaccines in national immunization programs of developing countries worldwide. In this article, we review published data on previous candidate rotavirus vaccines and vaccines in current use, with emphasis on their performance in developed versus developing countries. In developed countries, both first and second generation rotavirus vaccines have demonstrated high efficacy against severe rotavirus disease (pooled efficacy = 73% and 85%, respectively). In developing countries, small early trials for the first generation vaccines failed to provide protection against rotavirus disease (pooled efficacy = 20%), however, trials of the second generation vaccines yielded substantial improvements in efficacy in developing countries (pooled efficacy of 51%), leading to a global recommendation for rotavirus vaccine introduction by WHO. Future efforts for these vaccines should focus on optimizing the efficacy and delivery of these vaccines in challenging target populations of Asia and Africa with the greatest burden of severe rotavirus disease.
rotavirus; vaccines; immunization; vaccination; diarrhea; gastroenteritis
In a previous pooled analysis of 19 double-blind clinical studies conducted by Merck, which included data available as of July 2009 on 10,246 patients with type 2 diabetes (T2DM), treatment with sitagliptin was shown to be generally well tolerated compared with treatment with control agents. As the sitagliptin clinical development program continues, additional studies with sitagliptin have been completed. The present analysis updates the safety and tolerability assessment of sitagliptin by examining pooled data from 25 double-blind clinical studies.
The present analysis included data from 14,611 patients in 25 studies with T2DM who received either sitagliptin 100 mg/day (n = 7,726; sitagliptin group) or a comparator agent (n = 6,885; non-exposed group). These studies represent all randomized, double-blind trials conducted by Merck that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years, and for which results were available as of December 2011. These studies assessed sitagliptin, versus comparator agents, taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or metformin + pioglitazone or rosiglitazone). Patient-level data from each study were used to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events (AEs).
Overall incidence rates of AEs and drug-related AEs were higher in the non-exposed group compared with the sitagliptin group. Incidence rates of specific AEs were generally similar between the two groups, except for higher incidence rates of hypoglycemia related to the greater use of a sulfonylurea and diarrhea related to the greater use of metformin in the non-exposed group, and of constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events, malignancy, or pancreatitis.
In this updated pooled safety analysis of data from 14,611 patients with T2DM, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.
Adverse events; Dipeptidyl peptidase-4 inhibitor; Safety; Sitagliptin; Tolerability; Type 2 diabetes
Growth hormone (GH) is used to treat growth hormone deficiency (GHD, adult and paediatric), short bowel syndrome in patients on a specialized diet, HIV-associated wasting and, in children, growth failure due to a number of disorders including Turner's syndrome and chronic renal failure, and in children born small for gestational age. Different brands and generic forms of recombinant human growth hormone (r-hGH) are approved for varying indications in different countries. New ways of administering GH are required because the use of a needle and syringe or a device where a patient still has to insert the needle manually into the skin on a daily basis can lead to low adherence and sub-optimal treatment outcomes. The objective of this study was to assess the relative bioavailability of r-hGH (Saizen®, Merck Serono) administered by a new needle-free device, cool.click™ 2, and a standard needle and syringe.
The study was performed with 38 healthy volunteers who underwent pituitary somatotrope cell down-regulation using somatostatin, according to a randomized, two-period, two-sequence crossover design. Following subcutaneous administration of r-hGH using cool.click™ 2 or needle and syringe, pharmacokinetic parameters were analysed by non-compartmental methods. Bioequivalence was assessed based on log-transformed AUC and Cmax values.
The 90% confidence intervals for test/reference mean ratio of the plasma pharmacokinetic variables Cmax and AUC0-inf were 103.7–118.3 and 97.1–110.0, respectively, which is within the accepted bioequivalence range of 80–125%. r-hGH administered by cool.click™ 2 is, therefore, bioequivalent to administration by needle and syringe with respect to the rate and extent of GH exposure. Treatment using cool.click™ 2 was found to be well tolerated. With cool.click™ 2 the tmax was less (3.0 hours) than for needle and syringe delivery (4.5 hours), p = 0.002 (Friedman test), although this is unlikely to have any clinical implications.
These results demonstrate that cool.click™ 2 delivers subcutaneous r-hGH exposure that is bioequivalent to the conventional mode of injection. The new device has the additional advantage of being needle-free, and should help to increase patient adherence and achieve good therapeutic outcomes from r-hGH treatment.
Between 2001 and 2005, 21,155 of 445,638 wells in 20,517 villages in 292 counties in 16 provinces from China, or 5% of wells, were found to contain > 50 μg/L arsenic (As) by field testing with the Merck As kit. We achieved quality assurance of analysis of at least 10% of the wells containing > 50 μg/L As using hydride generation atomic fluorescence spectrometry and silver dithiodicarbomate spectrometry. Our best estimate of the population exposed to > 50 μg/L As in drinking water was 582,769. This is probably an underestimate for China because of the limited area surveyed. In a survey of 135,492 individuals in eight provinces, we used the National Diagnosis Standard for Endemic Arsenicosis and identified 10,096 cases of arsenicosis with various degrees of skin lesions. The arsenicosis occurrence rate of 7.5% is likely an overestimate, because the survey focused more on known and suspected endemic areas of arsenicosis. The occurrence of arsenicosis correlates positively with the percentage of wells containing > 50 μg/L As, or at a ratio of 1 to 5%. Based on both the amount of As in well water and the rate of occurrence of arsenicosis, Shanxi province, Inner Mongolia autonomous region, and Jilin province are the top three areas in China as of 2005 for exposure to endemic As from drinking water. Our survey also identified exposure to high levels of As from wells in several provinces and from the indoor burning of coal containing high levels of As in Shaanxi province. These areas, however, have not had any reports of previous arsenicosis endemics. In the endemic areas, the average rate of occurrence of arsenicosis at advanced stages was 1.2%, possibly because of a long exposure time of > 20 years; the rate of occurrence increased to 2.7% when we included a high dose of As exposure from the indoor burning of coal. Mitigation to reduce As exposure remains a challenge in rural China.
arsenic; arsenicosis; China; coal; groundwater; health effect
Six New Zealand white rabbits were given gas induction anaesthetics and maintained on glucochloralose (Merck) 60 mg/kg given intravenously. Intracolonic pressures were measured after a standard dose of prostigmine, 0·05 mg/kg, using fluid-filled, open-tipped, narrow-bore polythene tubes. Then the rabbits were put on a diet of white bread, butter, milk, and sugar supplemented by vitamins for four months. All six rabbits had put on weight but their general condition deteriorated; they had become constipated and the colon contracted. After stimulation with prostigmine 0·05 mg/kg scattered intertaenial wide-necked diverticula appeared which were thinner than the normal haustra and looked like a blackcurrant in colour, size, and shape. Repeat pressure measurements showed that the colonic motility index was increased up to 10 times from predietary levels with a highly significant mean increase from 5299 to 33151 (p < 0·0005).
Results from Merck's phase II adenovirus type 5 (Ad5) gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against human immunodeficiency virus (HIV) infection in a high-risk population. Among the many questions to be explored following this outcome are whether (i) the Ad5 vaccine induced the quality of T-cell responses necessary for efficacy and (ii) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV type 1 (HIV-1)-specific T-cell responses. Here we present a comprehensive evaluation of the T-cell response profiles from cohorts of clinical trial subjects who received the HIV CAM-1 gag insert delivered by either a regimen with DNA priming followed by Ad5 boosting (n = 50) or a homologous Ad5/Ad5 prime-boost regimen (n = 70). The samples were tested using a statistically qualified nine-color intracellular cytokine staining assay measuring interleukin-2 (IL-2), tumor necrosis factor alpha, macrophage inflammatory protein 1β, and gamma interferon production and expression of CD107a. Both vaccine regimens induced CD4+ and CD8+ HIV gag-specific T-cell responses which variably expressed several intracellular markers. Several trends were observed in which the frequencies of HIV-1-specific CD4+ T cells and IL-2 production from antigen-specific CD8+ T cells in the DNA/Ad5 cohort were more pronounced than in the Ad5/Ad5 cohort. Implications of these results for future vaccine development will be discussed.
In this study, we evaluated the potency of a human papillomavirus (HPV) virus-like particle (VLP)-based vaccine at generating HPV type 11 (HPV-11)-specific cellular and humoral immune responses in seronegative women. The vaccine was administered by intramuscular immunizations at months 0, 2, and 6. A fourth immunization was administered to approximately half of the women at month 12. All vaccine recipients had positive HPV-11 VLP-specific lymphoproliferative responses at month 3 following the second immunization (geometric mean lymphoproliferative stimulation index [SI] = 28.4; 95% confidence interval [CI] = 16.9 to 48.0) and HPV-11 VLP-specific antibody titers following the first immunization at month 1 (geometric mean antibody titer = 53.9 milli-Merck units/ml, 95% CI, 34.8 to 83.7). In contrast, lymphoproliferative and antibody titer responses were never detected in the participants who received placebo. Relatively homogeneous lymphoproliferative responses were observed in all vaccinated women. The mean lymphoproliferative SI of the vaccinated group over the first 12 months of the study was 7.6-fold greater than that of the placebo group following the initial immunization. The cellular immune responses generated by VLP immunization were both Th1 and Th2, since peripheral blood mononuclear cells from vaccinees, but not placebo recipients, secreted interleukin 2 (IL-2), IL-5, and gamma interferon (IFN-γ) in response to in vitro stimulation with HPV-11 VLP. The proliferation-based SI was moderately correlated with IFN-γ production and significantly correlated with IL-2 production after the third immunization (P = 0.078 and 0.002, respectively). The robust lymphoproliferative responses were specific for HPV-11, since SIs generated against bovine papillomavirus and HPV-16 VLPs were not generally observed and when detected were similar pre- and postimmunization.