Novel methods to deliver platinum(II) chemotherapeutics to the nose

Efforts to reduce side effects and improve efficacy of platinum-based drugs have seen the focus shift away from developing new drugs, towards improving the delivery of existing ones. This thesis presents an investigation into improving the delivery of platinum(II) drugs using lyophilised hydroxypropyl methylcellulose (HPMC) nasal insert formulations, designed to resist rapid mucociliary clearance in vivo and extend drug absorption. Cisplatin was conjugated to carbon nanotubes (CNTs), which was expected to improve tumour targeting through the enhanced permeability and retention effect; however this project was halted due to safety concerns. Cucurbiturils (CB[n]s) were investigated as an alternative drug delivery vehicle, as they have been shown to improve platinum(II) drug stability. The high cost of the most soluble homologue, CB[7] prompted an investigation into whether or not more readily available CB[6] could be used as reliable a model for CB[7] in nasal insert formulations. A series of investigations revealed that CB[6] had a similar effect on HPMC nasal inserts as CB[7]. A theory for the observed behaviour has been proposed, whereby the CB[n]s act as points of pseudo-cross-linking in the HPMC matrix by forming hydrogen bonds with adjacent polymer chains. CB[6] and CB[7] have been shown to increase the thermal stability of the di-nuclear platinum(II) drug di-Pt, and the fluorescent dye, K6. Additionally, the encapsulated forms have shown improved distribution throughout a lyophilised nasal insert. This work may represent the formulation of a pH-responsive supramolecular delivery system for di-Pt. Cucurbit[n]urils have, therefore, been shown to warrant further investigation as pharmaceutical excipients for controlled release. Finally, cisplatin protected in CB[7] was included in lyophilised nasal inserts. The encapsulation was shown to improve the thermal stability of cisplatin, but not significantly affect the hardness, spreadability or mucoadhesion of the nasal insert formulation. Additionally, the release of cisplatin@CB[7] was more repeatable than its cisplatin counterpart.Efforts to reduce side effects and improve efficacy of platinum-based drugs have seen the focus shift away from developing new drugs, towards improving the delivery of existing ones. This thesis presents an investigation into improving the delivery of platinum(II) drugs using lyophilised hydroxypropyl methylcellulose (HPMC) nasal insert formulations, designed to resist rapid mucociliary clearance in vivo and extend drug absorption. Cisplatin was conjugated to carbon nanotubes (CNTs), which was expected to improve tumour targeting through the enhanced permeability and retention effect; however this project was halted due to safety concerns. Cucurbiturils (CB[n]s) were investigated as an alternative drug delivery vehicle, as they have been shown to improve platinum(II) drug stability. The high cost of the most soluble homologue, CB[7] prompted an investigation into whether or not more readily available CB[6] could be used as reliable a model for CB[7] in nasal insert formulations. A series of investigations revealed that CB[6] had a similar effect on HPMC nasal inserts as CB[7]. A theory for the observed behaviour has been proposed, whereby the CB[n]s act as points of pseudo-cross-linking in the HPMC matrix by forming hydrogen bonds with adjacent polymer chains. CB[6] and CB[7] have been shown to increase the thermal stability of the di-nuclear platinum(II) drug di-Pt, and the fluorescent dye, K6. Additionally, the encapsulated forms have shown improved distribution throughout a lyophilised nasal insert. This work may represent the formulation of a pH-responsive supramolecular delivery system for di-Pt. Cucurbit[n]urils have, therefore, been shown to warrant further investigation as pharmaceutical excipients for controlled release. Finally, cisplatin protected in CB[7] was included in lyophilised nasal inserts. The encapsulation was shown to improve the thermal stability of cisplatin, but not significantly affect the hardness, spreadability or mucoadhesion of the nasal insert formulation. Additionally, the release of cisplatin@CB[7] was more repeatable than its cisplatin counterpart

64-slice computed tomography angiography in the diagnosis and assessment of coronary artery disease : systematic review and meta-analysis

Objective To assess whether 64-slice computed tomography (CT) angiography might replace some coronary angiography (CA) for diagnosis and assessment of coronary artery disease (CAD). Methods We searched electronic databases, conference proceedings and scanned reference lists of included studies. Eligible studies compared 64-slice CT with a reference standard of CA in adults with suspected/known CAD, reporting sensitivity and specificity or true and false positives and negatives. Data were pooled using the hierarchical summary receiver operating characteristic model. Results Forty studies were included; 28 provided sufficient data for inclusion in the meta-analyses, all using a cutoff of ≥ 50% stenosis to define significant CAD. In patient-based detection (n=1286) 64-slice CT pooled sensitivity was 99% (95% credible interval (CrI) 97 to 99%), specificity 89% (95% CrI 83 to 94%), median positive predictive value (PPV) across studies 93% (range 64 to 100%) and negative predictive value (NPV) 100% (range 86 to 100%). In segment-based detection (n=14,199) 64-slice CT pooled sensitivity was 90% (95% CrI 85 to 94%), specificity 97% (95% CrI 95 to 98%), median positive predictive value (PPV) across studies 76% (range 44 to 93%) and negative predictive value (NPV) 99% (range 95 to 100%). Conclusions 64-slice CT is highly sensitive for patient-based detection of CAD and has high NPV. An ability to rule out significant CAD means that it may have a role in the assessment of chest pain, particularly when the diagnosis remains uncertain despite clinical evaluation and simple non-invasive testing.UK National Institute for Health Research Health Technology Assessment programme (project number 06/15/01). The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health Directorates.Peer reviewedAuthor versio

The status of platinum anticancer drugs in the clinic and in clinical trials

Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, LipoplatinTM and ProLindacTM). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade

Neutropenic acute acalculous cholecystitis (AAC) in a 12-year-old boy with T-acute lymphoblastic leukemia successfully managed with conservative treatment

Peer reviewedPostprin

Population screening for lung cancer using computed tomography, is there evidence of clinical effectiveness? A systematic review of the literature

Lung cancer is the leading cause of death among all cancer types in the UK, killing approximately 34 000 people per year. By the time symptoms develop, the tumour is often at an advanced stage and the prognosis is bleak. Treatment at a less advanced stage of disease by surgical resection has been shown to substantially reduce mortality. Screening would be attractive if it could detect presymptomatic lung cancer at a stage when surgical intervention is feasible but has been the subject of scientific debate for the past three decades. The aim of this review was to examine the current evidence on the clinical effectiveness of screening for lung cancer using computed tomography. A systematic literature review searching 15 electronic databases and Internet resources from 1994 until December 2004/January 2005 was carried out. Information was summarised narratively. A total of 12 studies of computed tomography screening for lung cancer were identified including two RCTs and 10 studies of screening without comparator groups. The two RCTs were of short duration (1 year). None examined the effect of screening on mortality compared with no screening. The proportion of people with abnormal computed tomography findings varied widely between studies (5–51%). The prevalence of lung cancer detected was between 0.4% and 3.2% (number needed to screen to detect one lung cancer  = 31 to 249). Incidence rates of lung cancer were lower (0.1–1%). Among the detected tumours, a high proportion were stage I or resectable tumours, 100% in some studies. Currently, there is insufficient evidence that computed tomography screening is clinically effective in reducing mortality from lung cancer

Synthesis, processing and solid state excipient interactions of cucurbit[6]uril and its formulation into tablets for oral drug delivery

The synthesis, processing, and solid state excipient interactions of cucurbit[6]uril (CB[6]) and its formulation into oral tablets has been examined using a range of physical chemistry techniques. Rapid precipitation from HCl by the addition of water yields microcrystalline CB[6] with smaller and more consistent particle size (30-165 μm) compared with the sieved CB[6] (50-540 μm) produced from large crystals grown by slow evaporation from HCl. The microcrystalline particles also contain fewer water molecules in the crystal compared with the sieved particles: 10 and 16% respectively. Microcrystalline CB[6] can be formulated into tablets suitable for oral delivery with a CB[6] content of 1-50% w/w, with the other excipients including lactose, talc, Avicel, magnesium stearate and Ac-Di-Sol. In the solid state microcrystalline CB[6] does not interact significantly with the talc, Ac-Di-Sol or Avicel, but significant interactions are observed when mixed or ground with either magnesium stearate or lactose, resulting in the lowering of the melting points of both excipients. This work represents the first study of the physical processing and solid state chemistry of CB[n]s for pharmaceutical formulation and represents an important development step in the use of CB[n]s as drug delivery vehicles