A case study of foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson's disease: translational gaps or a failing industry innovation model?

INTRODUCTION: Approximately 40% of Parkinson's disease (PD) patients that take mostly dopamine receptor agonists for motor fluctuations, experience the return of symptoms between regular doses. This is a phenomenon known as 'OFF periods.' Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) are a promising non-dopaminergic mechanism with potential to address the unmet need of patients suffering from OFF periods. Foliglurax is the first mGluR4 PAM that has advanced into clinical testing in PD patients. AREAS COVERED: We summarize the chemistry, pharmacokinetics, and preclinical pharmacology of foliglurax. Translational PET imaging studies, clinical efficacy data, and a competitive landscape analysis of available therapies are presented to the readers. In this Perspective article, foliglurax is used as a case study to illustrate the inherent R&D challenges that companies face when developing drugs. These challenges include the delivery of drugs acting through novel mechanisms, long-term scientific investment, and commercial success and shorter-term positive financial returns. EXPERT OPINION: Failure to meet the primary and secondary endpoints in a Phase 2 study led Lundbeck to discontinue the development of foliglurax. Understanding the evidence supporting compound progression into Phase 2 will enable the proper assessment of the therapeutic potential of mGluR4 PAMs.

Limb Salvage Using Combined Linking Perforator Free Flaps.

Microsurgical free tissue transfer is the most effective method for extensive reconstruction of lower limb defects. The purpose of this report is to describe our experience of using microsurgically fabricated combined linking perforator flaps for one-stage reconstruction of extensive lower limb defects. Between April 2008 and November 2016, 16 cases of extensive lower defects were reconstructed using combined linking flaps. Of the patients, 10 were males, and the mean age was 45.3 years (range = 20-76 years). The flaps used were thoracodorsal artery perforator flaps together with deep inferior epigastric artery perforator flaps or anterolateral thigh flaps. There were no total flap failures; however, 3 anterolateral thigh flaps were partially lost and required skin grafts. One wound disruption healed conservatively. Donor site healing was achieved primarily without any dehiscence. The follow-up period was 15.4 months (range = 8-24 months). The use of combined linking perforator flaps for lower limb defects is uncommon; however, in cases of extensive limb defects these flaps can salvage limbs by means of one-stage operations.

Celebrating 45 years of postgraduate medical education.

We are delighted to be celebrating 45 years of publication of the British Journal of Hospital Medicine. The first issue was published in October 1966 (see right) and its introductory editorial is reproduced on p. 546-7. Here we have some brief thoughts from Professor John Blandy, one of the original members of the editorial board, from Mark Allen, the publisher who took the journal over from its previous publishers Thomson in 1985, and from Professor Rob Miller and Rebecca Linssen, the current Editor-in-Chief and Editor.

Mortality from HIV and TB coinfections is higher in Eastern Europe than in Western Europe and Argentina.

BACKGROUND AND OBJECTIVES: Tuberculosis (TB) is a leading cause of death in HIV-infected patients worldwide. We aimed to study clinical characteristics and outcome of 1075 consecutive patients diagnosed with HIV/TB from 2004 to 2006 in Europe and Argentina. METHODS: One-year mortality was assessed in patients stratified according to region of residence, and factors associated with death were evaluated in multivariable Cox models. RESULTS: At TB diagnosis, patients in Eastern Europe had less advanced immunodeficiency, whereas a greater proportion had a history of intravenous drug use, coinfection with hepatitis C, disseminated TB, and infection with drug-resistant TB (P < 0.0001). In Eastern Europe, fewer patients initiated TB treatment containing at least rifamycin, isoniazid, and pyrazinamide or combination antiretroviral therapy (P < 0.0001). Mortality at 1 year was 27% in Eastern Europe, compared with 7, 9 and 11% in Central/Northern Europe, Southern Europe, and Argentina, respectively (P < 0.0001). In a multivariable model, the adjusted relative hazard of death was significantly lower in each of the other regions compared with Eastern Europe: 0.34 (95% confidence interval 0.17-0.65), 0.28 (0.14-0.57), 0.34 (0.15-0.77) in Argentina, Southern Europe and Central/Northern Europe, respectively. Factors significantly associated with increased mortality were CD4 cell count less than 200 cells/microl [2.31 (1.56-3.45)], prior AIDS [1.74 (1.22-2.47)], disseminated TB [2.00 (1.38-2.85)], initiation of TB treatment not including rifamycin, isoniazid and pyrazinamide [1.68 (1.20-2.36)], and rifamycin resistance [2.10 (1.29-3.41)]. Adjusting for these known confounders did not explain the increased mortality seen in Eastern Europe. CONCLUSION: The poor outcome of patients with HIV/TB in Eastern Europe deserves further study and urgent public health attention.

Best practice recommendations for the prevention and treatment of venous leg ulcers: update 2006.

PURPOSE: To provide the specialist in skin and wound care with an update in recommended management of venous leg ulcers. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in wound care and related disorders. OBJECTIVES: After reading this article and taking this test, the reader should be able to:Editor's note: This "Best Practice Recommendations" article is reprinted with permission from Wound Care Canada, The Official Publication of the Canadian Association of Wound Care (2006;4[1]:45-55). It is the third installment of 4 articles originally published in 2006, following the latest Nursing Best Practice Guidelines from the Registered Nurses Association of Ontario (RNAO), which are updated approximately every 3 years. In 2000, the Canadian Association of Wound Care produced and had published its first best practice recommendations for the prevention and treatment of pressure ulcers. In this article, best practice recommendations are discussed for the prevention and treatment of pressure ulcers. The evidence presented is connected to the RNAO's recommendations from its review of the literature up to the writing of its 2006 guidelines. Clinical decision-making in the treatment of pressure ulcers can be guided by the algorithm that directs the clinician to identify and treat the underlying causes, to identify and manage patient-centered concerns, and to provide for good local wound care, considering adjunctive therapies or biologically active dressings when the edge of the wound is not advancing. Finally, the recommendations advise putting into place those organizational and educational activities that support the translations of the guidelines into practice.

Spontaneous retropharyngeal hemorrhage causing airway obstruction: a case report with a review of the literature.

Spontaneous retropharyngeal hemorrhage, although uncommon, can be rapidly progressive and potentially life-threatening. Timely recognition and appropriate treatment are essential for a successful outcome. We report a case of retropharyngeal hemorrhage in an 81-year-old male with a history of arteriosclerotic disease who presented with cough, dysphagia, dyspnea, and cervical ecchymosis. Lateral plain films and computerized tomography (CT) revealed a diffuse soft tissue density distending the retropharyngeal space and adjacent fascial compartments but sparing the glottic and subglottic airway. Emergency tracheostomy was required to relieve progressive upper airway obstruction. The literature on spontaneous retropharyngeal hematoma is reviewed including clinical presentation, causative factors, and recommended treatment.

UK National Audit of Early Syphilis Management. Case notes audit: diagnosis and treatment.

A national audit of 781 early syphilis cases presenting during 2002-03 in UK genitourinary medicine clinics was conducted in late 2004, organized through the Regional Audit Groups. Data were aggregated by region and National Health Service trust, allowing practice to be compared between regions, between trusts within regions, as well as to national averages and the UK National Guidelines. An enzyme immunoassay was used to diagnose 695 (89%) cases (regional range 18-100%). Use of a non-treponemal test was not recorded for 44 (6%) cases. Dark ground microscopy was used in the diagnosis of only 80 (29%) primary cases. Uptake of HIV testing was 77% (range 69-94%). Nationally, 527 (67%) treatments were parenteral, with almost equal use of benzathine penicillin G for 262 (50%, range 0-97%) cases and procaine penicillin G (PPG) for 260 cases (49%, range 3-100%). There were 14 (5%) treatments with less than the recommended 750 mg dose of PPG. One hundred and five (40%) PPG treatments were with greater than 750 mg and/or for longer than 10 days of which 76 (72%) were for early latent syphilis and/or cases with HIV infection. One hundred and ninety two (86%, range 0-100%) of all oral treatments were with doxycycline. The recommended regimen of 100 mg doxycycline twice daily for 14 days was used for 104 (53%) cases; the other 91 (47%) treatments were with a variety of regimens, mainly treatments with larger doses and/or longer treatment intervals and some combination treatments. Fourteen (2%) cases were not treated; treatment was not reported for seven (0.9%) and not known for 10 (1.3%) cases, who were treated at other centres.

UK National Audit of Early Syphilis Management. Case-notes audit: contact tracing, information giving, follow-up and outcomes.

Contact tracing was provided for 683/781 (87%, regional range 57-97%) cases, and identified 997 traceable contacts of whom 511 (51%) were seen, short of the recommended standard of 60%. However, the performance range for this standard was 26-70%, with seven regions achieving 60% or more. Of 511, 215 (42%, range 3-73%) contacts had syphilis. Treatment completion was recorded for 691 (88%, range 71-100%) cases, and resolution of lesions for 348/469 (74%, range 40-96%) cases. Nationally, 419/764 (55%, range 37-70%) cases were recorded as having a two dilution (four-fold) or greater decrease in non-treponemal test titre within 3-6 months after treatment; not achieving this titre decrease was mainly attributable to non-attendance for follow-up and failure of titre levels to fall. Follow-up of infectious syphilis in UK genitourinary medicine clinics is poor and falls far short of that recommended by National Guidelines. Only 16 (2%) cases had follow-up at intervals approximating to 1, 2, 3, 6 and 12 months, and only 312 (40%, range 5-61%) cases attended at least two follow-up visits. Only 17 (7%) of all 236 oral treatments (including switches to oral treatment), and 33 (27%) of 123 cases with HIV infection were recorded as designated annual follow-up. Further work is needed to determine factors that account for the wide variation between regions in contact tracing and follow-up performance.

UK National Audit of Early Syphilis Management. Clinics audit: screening for and management of early syphilis.

Data were provided by 131 clinics, and 56% of cases were managed in clinics in the London regions in 2003. Three clinics (2%) do not routinely screen new patients for syphilis, and 28 clinics (21%) do not routinely screen 'rebook' patients who have had a new partner. More than 80% of clinics routinely conduct cardiovascular and neurological examinations, although chest radiography is only performed by 50% of clinics and lumbar puncture by 13%. Only 19 (14%) clinics indicated not routinely using the recommended procaine penicillin G (PPG) regimen or one- or two-dose benzathine penicillin G (BPG) regimens for early syphilis, with 57% providing two doses of BPG 2.4 g, 40% providing PPG 750 mg for 10 days, and 15% providing one dose of BPG 2.4 g. Only seven clinics (5%) indicated that they provided treatment for early syphilis with PPG that is inferior to that recommended in the national guidelines. Only 18 clinics specified using the recommended dose and duration (or in excess of this) of PPG for neurosyphilis for cases with HIV infection. Provision for management of severe penicillin reaction is good, although few patients are desensitized. All clinics report that contact tracing for early syphilis is provided, and is mainly the responsibility of health advisers. Compared with auditing outcomes, audit of management policies overestimated performance in contact tracing and provision of dark ground microscopy.

Determinants of HIV drug resistance mutations in plasma virus after treatment interruption.

This study examines the utility of resistance testing during treatment interruption, making comparisons with the current IAS guidelines. A total of 188/1279 tests (14%) were performed during treatment interruption; 69/188 tests (36.7%) demonstrated key mutations. Time off therapy and the total number of previous drugs were both significantly associated with the presence of mutations. We conclude that resistance testing is of value up to 3 months after treatment interruption, and may convey some benefit up to 12 months.