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.

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.

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.

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.

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.

Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy.

OBJECTIVE: To assess the risks and benefits of administering highly active antiretroviral therapy (HAART) during the treatment of tuberculosis (TB) in HIV-infected patients. DESIGN AND METHODS: HIV-1 patients presenting to 12 HIV centres in Greater London and south-east England with culture-proven TB were identified from January 1996 to June 1999. Case-notes were reviewed retrospectively. RESULTS: Patients (n = 188) were severely immunocompromised with a median CD4 cell count at TB diagnosis of 90 x 106 cells/l (IQR: 30-180). At presentation, 85% (n = 159) were not taking antiretrovirals. A total of 45% commenced HAART during TB treatment, which was associated with significant reductions in viral load, AIDS-defining illness (ADI) [3.5 versus 24.5%; relative risk (RR) = 0.14] and mortality. Only nine of 91 (10%) patients with a CD4 count > 100 x 106 cells/l at TB diagnosis experienced a further ADI, whereas 18 of 92 (20%) patients with a CD4 count < 100 x 106 cells/l developed this complication. Adverse events (AE) occurred in 99 (54%) of 183 patients, one-third of whom changed or interrupted HIV and/or TB medication. The majority of AE occurred within the first 2 months, with peripheral neuropathy (21%), rash (17%) and gastrointestinal upset (10%) occurring most commonly. CONCLUSIONS: Many physicians delay HAART in patients presenting with TB because of pill burden, drug/drug interactions and toxicity. Although the use of HAART led to significant reductions in viral load, ADI and mortality, co-infected patients commonly experienced AE leading to interruptions in TB/HIV therapy. We therefore recommend starting HAART early for patients with advanced HIV disease (CD4 < 100 x 106 cells/l) and deferring HAART until the continuation phase of TB therapy (i.e. after 2 months) for patients who are clinically stable (CD4 > 100 x 106 cells/l).

Frequency responses to hypoxia and hypercapnia in carotid body-denervated conscious rats.

The ventilatory response to brief, severe hypoxia is biphasic consisting of an initial facilitation followed by a slowing of breathing frequency (fR). After the hypoxic stimulus is removed, fR drops below baseline levels. This phenomenon is called the post-hypoxic frequency decline (phfd). These fR changes are due to reciprocal changes in expiratory time (TE), mediated by the ventrolateral pontine A5 region (J. Physiol. (London) 497 (1996) 79; Am. J. Physiol. 274 (1998) R1546). The purpose of this study was to determine if carotid body input is required for full manifestation of phfd by quantifying ventilation in intact and carotid sinus denervated rats in response to hypoxic, and contrasted with hypercapnic stimuli. Following carotid denervation the initial facilitation of fR was eliminated in response to hypoxia, but the phfd remained. In contrast the pattern in response to increased CO2 remained constant before and after carotid denervation. These results suggest that phfd is not dependent upon carotid body stimulation, but is mediated centrally.

Co-infection with gonorrhoea and chlamydia: how much is there and what does it mean?

A cross-sectional study of new clients with either gonorrhoea or chlamydia attending King's College Hospital in 1998. One thousand two hundred and thirty-nine women and 1141 men had gonorrhoea, chlamydia or both. Overall, 24.2% (124/512) of heterosexual men and 38.5% (136/353) of women with gonorrhoea also had chlamydia (P<0.001). Of heterosexual males 18.8% (124/660) and 13% (136/1022) of females with chlamydia also had gonorrhoea (P=0.002). Ethnicity had no effect on the proportion of co-infection after controlling for age and gender. Clients with dual infection were younger than those with either infection alone (P=0.0001). Over half of women and a quarter of men aged 15 to 19 years were dually infected so testing for both gonorrhoea and chlamydia may be appropriate in this age group in settings outside genitourinary clinics. The high proportion of cases of gonorrhoea that also have chlamydia justifies the policy of epidemiological treatment for chlamydia.

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.