The application of a haemorrhage assessment tool in evaluating control of bleeding in a pilot trauma haemorrhage trial.

OBJECTIVES: To determine whether it was feasible to use a haemorrhage assessment tool (HAT) within a trauma trial and whether the data obtained could differentiate patients who had achieved haemostasis. BACKGROUND: Major haemorrhage is one of the leading causes of death worldwide, affecting 40% of trauma patients. Clinical trials evaluating haemostatic interventions often use transfusion outcomes as a primary endpoint. Transfusion is highly dependent on local practice, limiting its reliability as a robust, transferable endpoint. METHODS: A five-point HAT questionnaire was applied to participants enrolled into the EFIT-1 trial. This RCT evaluated the feasibility of administering a 6 g fibrinogen concentrate to patients with severe trauma haemorrhage. RESULTS: Of participants, 98% completed a HAT; 75% participants had 'achieved haemostasis' at the time of tool completion, as determined by clinical acumen alone. HAT scores were able to differentiate which participants required transfusion after 3 h. Of participants, 56% were transfused red blood cells when they scored 0-2, compared to 17% with HAT scores between 3 and 5. CONCLUSION: This study has confirmed the feasibility of using a HAT during the emergency care of patients suffering trauma haemorrhage, and future studies should be conducted to determine its value as an endpoint in haemostasis studies.

CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.

Background: Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methods: Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg od (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). Results: Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39-68] and 92% (46/50; 95% CI 81-98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1-15 months); at 9 months, 75% (95% CI 53-88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Conclusions: Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. ClinicalTrials.gov number: NCT01802632; NCT02094261.

Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype?

The gastrointestinal tract regulates glucose and energy metabolism, and there is increasing recognition that bile acids function as key signalling molecules in these processes. For example, bile acid changes that occur after bariatric surgery have been implicated in the effects on satiety, lipid and cholesterol regulation, glucose and energy metabolism, and the gut microbiome. In recent years, Takeda-G-protein-receptor-5 (TGR5), a bile acid receptor found in widely dispersed tissues, has been the target of significant drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including type 2 diabetes, obesity, atherosclerosis, fatty liver disease and cancer. Although the benefits of targeting the TGR5 receptor are potentially great, drug development work to date has identified risks that include histopathological changes, tumorigenesis, gender differences, and questions about the translation of animal data to humans. The present article reviews the noteworthy challenges that must be addressed along the path of development of a safe and effective TGR5 agonist therapy.

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing.

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

GSK2374697, a long duration glucagon-like peptide-1 (GLP-1) receptor agonist, reduces postprandial circulating endogenous total GLP-1 and peptide YY in healthy subjects.

We investigated the effects of a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist, GSK2374697, on postprandial endogenous total GLP-1 and peptide YY (PYY). Two cohorts of healthy subjects, one normal/overweight and one obese, were randomized to receive GSK2374697 2 mg (n = 8 each) or placebo (n = 4 and n = 2) subcutaneously on days 1, 4 and 7. Samples for plasma endogenous GLP-1 and PYY were collected after breakfast on days -1 and 12. Weighted mean area under the curve (0-4 h) of total GLP-1 and PYY in treated subjects was reduced compared with placebo. The least squares mean difference for change from baseline was -1.24 pmol/l [95% confidence interval (CI) -2.33, -0.16] and -4.47 pmol/l (95% CI -8.74, -0.20) for total GLP-1 and PYY, respectively, in normal/overweight subjects (p < 0.05 for both), and -1.56 (95% CI -2.95, -0.16) and -3.02 (95% CI -8.58, 2.55), respectively, in obese subjects (p < 0.05 for GLP-1). In healthy subjects, GSK2374697 reduced postprandial total GLP-1 and PYY levels, suggesting feedback suppression of enteroendocrine L-cell secretion of these peptides.

Long-term responders and survivors on pazopanib for advanced soft tissue sarcomas: subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072.

BACKGROUND: Pazopanib recently received approval for the treatment of certain soft tissue sarcoma (STS) subtypes. We conducted a retrospective analysis on pooled data from two EORTC trials on pazopanib in STS in order to characterize long-term responders and survivors. PATIENTS AND METHODS: Selected patients were treated with pazopanib in phase II (n = 118) and phase III study (PALETTE) (n = 226). Combined median progression-free survival (PFS) was 4.4 months; the median overall survival (OS) was 11.7 months. Thirty-six percent of patients had a PFS ≥ 6 months and were defined as long-term responders; 34% of patients survived ≥18 months, defined as long-term survivors. Patient characteristics were studied for their association with long-term outcomes. RESULTS: The median follow-up was 2.3 years. Patient characteristics were compared among four subgroups based on short-/long-term PFS and OS, respectively. Seventy-six patients (22.1%) were both long-term responders and long-term survivors. The analysis confirmed the importance of known prognostic factors in metastatic STS patients treated with systemic treatment, such as performance status and tumor grading, and additionally hemoglobin at baseline as new prognostic factor. We identified 12 patients (3.5%) remaining on pazopanib for more than 2 years: nine aged younger than 50 years, nine females, four with smooth muscle tumors and nine with low or intermediate grade tumors at initial diagnosis. The median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years. CONCLUSIONS: Thirty-six percent and 34% of all STS patients who received pazopanib in these studies had a long PFS and/or OS, respectively. For more than 2 years, 3.5% of patients remained progression free under pazopanib. Good performance status, low/intermediate grade of the primary tumor and a normal hemoglobin level at baseline were advantageous for long-term outcome. NCT00297258 (phase II) and NCT00753688 (phase III, PALETTE).

Recent developments in anti-herpesvirus drugs.

Background Herpesviruses notably establish lifelong infections, with latency and reactivation. Many of the known human herpesviruses infect large proportions of the population worldwide. Treatment or prevention of herpes infections and recurrent disease still pose a challenge in the 21st century. Sources of data Original papers and review articles, meeting abstracts, a book (Clinical Virology; DD Richman, RJ Whitley & FG Hayden eds) and company web sites. Areas of agreement For herpes simplex types 1 and 2 and for varicella zoster, acyclovir (ACV; now increasingly replaced by its prodrug valacyclovir, VACV) and famciclovir (FCV) have greatly reduced the burden of disease and have established a remarkable safety record. Drug-resistance, in the otherwise healthy population, has remained below 0.5% after more that 20 years of antiviral use. In immunocompromised patients, drug resistance is more common and alternative drugs with good safety profiles are desirable. For human cytomegalovirus disease, which occurs in immunocompromised patients, ganciclovir and increasingly its prodrug valganciclovir are the drugs of choice. However, alternative drugs, with better safety, are much needed. Areas of controversy Various questions are highlighted. Should the new 1-day therapies for recurrent herpes labialis and genital herpes replace the current standard multi-day therapies? The marked differences between VACV and FCV (e.g. triphosphate stability, effect on latency) may not yet be fully exploited? Do current antivirals reduce post-herpetic neuralgia (PHN)? For immunocompromised patients with varicella zoster virus (VZV) disease, should the first-line treatment be FCV, not ACV or VACV? Should there be more support to explore new avenues for current antivirals, for example in possibly reducing herpes latency or Alzheimer's disease (AD)? Should primary Epstein-Barr virus (EBV) disease in adolescents be treated with antivirals? How can new compounds be progressed when the perceived market need is small but the medical need is great. FCV was reclassified from prescription-only to pharmacist-controlled for herpes labialis in New Zealand in 2010; should this be repeated more widely? This article reviews new drugs in clinical trials and highlights some of the problems hindering their progress.

Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects.

AIMS: Albiglutide is a glucagon-like peptide-1 (GLP-1) mimetic generated by genetic fusion of a dipeptidyl peptidase-IV-resistant GLP-1 dimer to human albumin. Albiglutide was designed to retain the therapeutic effects of native GLP-1 while extending its duration of action. This study was conducted to determine the pharmacokinetics and initial safety/tolerability profile of albiglutide in non-diabetic volunteers. METHODS: In this single-blind, randomized, placebo-controlled trial, 39 subjects (18-60 years, body mass index 19.9-35.0 kg/m(2)) received placebo (n = 10) or escalating doses of albiglutide (n = 29) on days 1 and 8 in the following sequential cohorts: cohort 1: 0.25 + 1 mg; cohort 2: 3 + 6 mg; cohort 3: 16 + 24 mg; cohort 4: 48 + 60 mg; and cohort 5: 80 + 104 mg. Dose proportionality was evaluated based on area under the plasma drug concentration versus time curve [area under the curve (AUC((0-7 days)))] and maximum plasma drug concentration (C(max)) for cohorts 2-5 during week 1. RESULTS: Albiglutide had a terminal elimination half-life (T(1/2)) of 6-8 days and time to maximum observed plasma drug concentration (T(max)) of 3-4 days. A greater-than-dose proportional increase in albiglutide exposure was observed. Albiglutide demonstrated a dose-dependent trend in reductions of glucose weighted mean AUC and fructosamine levels in healthy subjects. The incidence and severity of adverse events (AEs) was similar between placebo and albiglutide groups. Headache was the most frequent drug-related AE, followed by constipation, flatulence and nausea. CONCLUSIONS: Albiglutide has a half-life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non-diabetic subjects.

Meeting report: 30th International Conference on Antiviral Research, in Atlanta, GA, USA.

The 30th International Conference on Antiviral Research was held in Atlanta, GA, USA, from 21 to 25 May 2017. Each year, the International Society for Antiviral Research (ISAR) presents three major awards, this year to Mike Sofia (Elion award), David Chu (Holý award) and Maaike Everts (Prusoff award). Also this year, the inaugural ISAR Women in Science award lecture was presented by Priscilla Yang. For several years, International Conference on Antiviral Research (ICAR) has included at least one Keynote lecture, this year there were four. Although there are accounts of only these eight lectures, they reflect the diversity that is characteristic of ICAR - employment (academia, industry, public health), type of research (virus biology, potential antiviral targets, antiviral drugs, research organisation) and a range of viruses. For example, the viruses included were hepatitis C virus and hepatitis B virus (Mike Sofia), HIV and hepatitis B virus (David Chu), multiple antiviral projects (Maaike Everts), dengue (Priscilla Yang), rhinovirus C (Ann Palmenberg), polio (Mark Pallansch), HIV (Eric Hunter) and Zika virus (Pei-Yong Shi). This report ends with my personal comments giving examples in which this diversity can bring benefits. The 31st ICAR will be in Porto, Portugal, 11-15 June 2018.

Meeting report: 29th International Conference on Antiviral Research in La Jolla, CA, USA.

The 29th International Conference on Antiviral Research (ICAR) was held in La Jolla, CA, USA from April 17 to 21, 2016. This report opens with a tribute to the late Chris McGuigan, a Past-President of ISAR, then continues with summaries of the principal invited lectures. Doug Richman (Elion Award) investigated HIV resistance, Bob Vince (Holý Award) showed how carbocyclic nucleoside analogs led to abacavir and Jerome Deval (Prusoff Award) explained how his group chose to seek a nucleoside analog to treat RSV. ALS-8176 was active in a human RSV-challenge study and is being evaluated in children. The first keynote address, by Richard H. Scheuermann, reported on the remarkable progress made in viral genomics. The second keynote address, by Heinz Feldmann, gave an overview of Ebola virus disease. There were four mini-symposia, Structural Biology, Diagnostic Technologies, DNA viruses and Zika virus. Diagnostic assays are approaching an ideal aim, a compact instrument, simple to use with any type of sample, no sample preparation and a result within an hour. The diversity of HCMV is far greater than for other herpesviruses, typically, an individual having >20,000 single nucleotide polymorphisms (SNPs). During antiviral treatment, there is rapid CMV evolution which is presumed to be due to preferential selection of already present variants rather than by the creation of new variants. A selection of contributor presentations includes oral prodrugs for nucleoside triphosphate analogs, a new method for the synthesis of phosphoramidate prodrugs and the clinical evaluation of brincidofovir for treating transplant recipients with adenovirus infections.

Highlights of the 30th International Conference on Antiviral Research.

The 30th International Conference on Antiviral Research (ICAR) was held in Atlanta, GA, USA from May 18 to 21, 2017. This report provides an account of award lectures, invited keynote addresses and oral presentations during the meeting. The 2017 Gertrude Elion Memorial Lecture Award by Michael Sofia highlighted one of the most important accomplishments in recent drug discovery in antiviral research, the identification of the hepatitis C virus direct-acting antiviral sofosbuvir and new alternatives to combat hepatitis B virus (HBV) infection. The Antonín Holý Lecture Award by David Chu on medicinal chemistry provided an overview of early developments of nucleoside analogs for the treatment of HIV and varicella zoster virus infection and how this knowledge serves to develop new drugs targeting HBV. Priscilla Yang gave the first ISAR Women in Science lecture. She reported on pharmacological validation of new antiviral targets for dengue, Zika and other flaviviruses. The William Prusoff Young Investigator Lecture Award by Maaike Everts described the Alabama Drug Discovery Alliance and the Antiviral Drug Discovery and Development Consortium, and how they are helping to accelerate the development of new antivirals. The 30th ICAR was a success in promoting new discoveries in antiviral drug development and research. The 31st ICAR will be held in Porto, Portugal, June 11-15, 2018.

Meeting report: 28th International Conference on Antiviral Research in Rome, Italy.

The 28th International Conference on Antiviral Research (ICAR) was held in Rome, Italy from May 11 to 15, 2015. This article summarizes the principal invited lectures. Phillip Furman, the Elion award recipient, described the research leading to sofosbuvir. Dennis Liotta, who received the Holý award, described how an investigation into HIV entry inhibitors led to a new therapy for cancer patients. Erica Ollmann Saphire, winner of the Prusoff Young Investigator award, explored the world of viral proteins and how they remodel to perform different essential roles in viral replication. The keynote addresses, by Raffaele De Francesco and Michael Manns, reported on the remarkable progress made in the therapy of chronic HCV infections. A third keynote address, by Armand Sprecher, related the difficulties and successes of Médicins Sans Frontières in West Africa ravaged by the Ebola outbreak. There were three mini-symposia on RNA Viruses, Antiviral Chemistry and Emerging Viruses. There was a good collection of talks on RNA viruses (norovirus, rabies, dengue, HEV, HCV, and RSV). A highlight of the chemistry was the preparation of prodrugs for nucleotide triphosphates as this opens a door to new options. The third mini-symposium emphasized how research work in the antiviral area is continuing to expand and needs to do so with a sense of urgency. Although this meeting report covers only a few of the presentations, it aims to illustrate the great diversity of topics discussed at ICAR, bringing together knowledge and expertise from the whole spectrum of antiviral research.

Costs and quality of life associated with acute upper gastrointestinal bleeding in the UK: cohort analysis of patients in a cluster randomised trial.

OBJECTIVES: Data on costs associated with acute upper gastrointestinal bleeding (AUGIB) are scarce. We provide estimates of UK healthcare costs, indirect costs and health-related quality of life (HRQoL) for patients presenting to hospital with AUGIB. SETTING: Six UK university hospitals with >20 AUGIB admissions per month, >400 adult beds, 24 h endoscopy, and on-site access to intensive care and surgery. PARTICIPANTS: 936 patients aged ≥18 years, admitted with AUGIB, and enrolled between August 2012 and March 2013 in the TRIGGER trial of AUGIB comparing restrictive versus liberal red blood cell (RBC) transfusion thresholds. PRIMARY AND SECONDARY OUTCOME MEASURES: Healthcare resource use during hospitalisation and postdischarge up to 28  days, unpaid informal care, time away from paid employment and HRQoL using the EuroQol EQ-5D at 28  days were measured prospectively. National unit costs were used to value resource use. Initial in-hospital treatment costs were upscaled to a UK level. RESULTS: Mean initial in-hospital costs were £2458 (SE=£216) per patient. Inpatient bed days, endoscopy and RBC transfusions were key cost drivers. Postdischarge healthcare costs were £391 (£44) per patient. One-third of patients received unpaid informal care and the quarter in paid employment required time away from work. Mean HRQoL for survivors was 0.74. Annual initial inhospital treatment cost for all AUGIB cases in the UK was estimated to be £155.5 million, with exploratory analyses of the incremental costs of treating hospitalised patients developing AUGIB generating figures of between £143 million and £168 million. CONCLUSIONS: AUGIB is a large burden for UK hospitals with inpatient stay, endoscopy and RBC transfusions as the main cost drivers. It is anticipated that this work will enable quantification of the impact of cost reduction strategies in AUGIB and will inform economic analyses of novel or existing interventions for AUGIB. TRIAL REGISTRATION NUMBER: ISRCTN85757829 and NCT02105532.

Estimating compliance with diuretic therapy: urinary hydrochlorothiazide-creatinine ratios in normal subjects.

We gave 21 healthy young men 100 mg of hydrochlorothiazide daily to determine whether or not urinary detection of the drug was feasible as a measure of compliance on a standard antihypertensive regimen. All subjects took the drug daily for 6 days, after which they were divided into four groups with differing patterns of medication administration. Urine hydrochlorothiazide and creatinine measurements were obtained to validate the urinary hydrochlorothiazide-creatinine ratio (UHCR) as an accurate quantitative index of compliance. The subjects achieved a constant level of UHCR of 13 +/- 3.0 within 48 hours of hydrochlorothiazide administration. The UHCR levels decreased to 5.0 +/- 0.8 48 hours after discontinuation of the drug (p less than 0.001). UHCR values in the range of 13 +/- 6 indicate that the subject has ingested hydrochlorothiazide 24 hours previously. The UHCR is a potentially useful means of assessing compliance in hypertensive patients taking hydrochlorothiazide.

Labile exocyclic amine protection of nucleosides in DNA, RNA and oligonucleotide analog synthesis facilitating N-deacylation, minimizing depurination and chain degradation.

The use of tert-butylphenoxyacetyl for N-protection of nucleoside bases during oligonucleotide synthesis facilitates its removal under mild conditions. This protecting group reduces depurination of deoxyadenosine residues, and minimizes premature desilylation resulting in chain degradation during post-synthesis workup of synthetic RNA.

Biologically oriented organic sulfur chemistry. 14. Antiinflammatory properties of some aryl sulfides, sulfoxides, and sulfones.

To extend earlier work, to examine the possibility that certain sulfoxides might serve as counterparts of amines in receptor-site interactions, and to add to the little information available about sulfoxides in medicinal chemistry, sulfoxides were prepared of the general structure XArS(O)C6H4(CHR)nCO2H, together with the sulfides and some of the sulfones. The products were evaluated as antiinflammatory agents by carrageenan-edema inhibition and uv-erythema inhibition. Four of the compounds had activity roughly comparable to aspirin or phenylbutazone in one or the other of these assays (2a-c, 3b). Sulfoxides did not seem especially promising as a class and usually were less active than the corresponding sulfides. The two most interesting compounds in these assays, o-(phenylthio)phenylacetic acid (2b) and its sulfoxide 3b, had no significant activity in adjuvant arthritis. Hydrogen-bonding effects are indicated in certain of the acids by their absence in the corresponding esters.

Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (BRL 39123) with improved gastrointestinal absorption properties.

Potential oral prodrugs of the antiherpesvirus acyclonucleoside 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (1, BRL 39123) have been synthesized and evaluated for bioavailability of 1 in the blood of mice. Reduction of 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-amino-6-chloropurine (13) using ammonium formate and 10% palladium on carbon afforded the 2-aminopurine 14, which was hydrolyzed to the monoacetate 15 and to 2-amino-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purine (5). The 2-aminopurine 5 was subsequently converted to additional monoester (17, 21-23) and diester (16, 24) derivatives and to its di-O-isopropylidene derivative 18. Both 5 and its esters (14-17, 21, 22) and also 18 were well absorbed after oral administration and converted efficiently to 1, the diacetyl (14) and dipropionyl (16) esters providing concentrations of 1 in the blood that were more than 15-fold higher than those observed after dosing either 1 or its esters (25-27). Some 6-alkoxy-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines (8-10), the preparation of which has been reported previously, also showed improved absorption properties, but their conversion to 1 was less efficient than for the 2-aminopurine derivatives. On the basis of these results and subsequent experiments involving determinations of rates of conversion to 1 in the presence of rat and human tissue preparations, 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine (14, BRL 42810) was identified as the preferred prodrug of 1. Oral bioavailability studies in healthy human subjects confirmed 14 as an effective prodrug, and this compound is now being evaluated in clinical trials.

Double-blind crossover comparison of piroxicam and naproxen in the treatment of active osteoarthritis.

Since the initial marketing in the early 1970s of the nonsteroidal anti-inflammatory agents of the propionic acid type, there has been a gradual escalation of the dosage recommendation for each of these drugs. In contrast, the dosage recommendation for piroxicam has remained constant. In this 12-week, double-blind crossover study, the standard dose of piroxicam 20 mg/d has been compared with the newly recommended dosage of naproxen 500 mg twice a day in 19 patients with active osteoarthritis. In the piroxicam treatment interval, there was statistically significant improvement in six of nine clinical parameters as compared with five of nine clinical parameters for the naproxen treatment interval. Adverse experiences with both drugs were mild to moderate. Both piroxicam and naproxen resulted in statistically significant improvement in right grip strength, the time to walk 50 feet, daily activity assessment, and in the total joint pain. In addition, piroxicam resulted in statistically significant improvement in both the physician and patient assessment of disease activity. Naproxen treatment was associated with a statistically significant decrease in total joint swelling.

Telbivudine/Torcitabine Idenix/Novartis.

Idenix (formerly Novirio) and Novartis are developing two beta-L-deoxynucleosides, telbivudine and torcitabine, for the potential treatment of hepatitis B virus infection. Phase III trials of telbivudine were underway by August 2002 and phase I/II trials of the torcitabine prodrug, valtorcitabine, were ongoing in November 2003.

Identification of male epithelial cells in routine postcoital cervicovaginal smears using fluorescence in situ hybridization. Application in sexual assault and molestation.

In a prospective blinded controlled study, the efficacy of fluorescence in situ hybridization (FISH) to detect non-sperm male cells verifying sexual contact was examined. Cervicovaginal smears (CVS) from 40 women with reported post-coital intervals were examined for sperm by cytology and for sperm and non-sperm male cells by FISH using X and Y chromosome specific DNA probes. Fluorescence in situ hybridization identified sperm and/or non-sperm male cells in all specimens from women with positive coital histories, including when the partner had a vasectomy. Male cells were also detectable by FISH in CVS up to 3 weeks after coitus. In comparison, cytology identified sperm in 41% of the positive coital history cases, and none beyond 2 weeks. Fluorescence in situ hybridization is highly sensitive and specific in detecting male cells, and can be performed rapidly on routine CVS. Application of this technique can provide new and additional evidence of sexual contact when current tests are inconclusive.