Biomedical subjects

Stephen Ward

Publications and source records attributed to Stephen Ward.

7 recordsLinked to original sources

PubMed2006

Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.

Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine-release syndrome, all six patients survived. Documentation of the clinical course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease.

APACHE↗

PubMed2006

Malaria chemotherapy.

Most malaria control strategies today depend on safe and effective drugs, as they have done for decades. But sensitivity to chloroquine, hitherto the workhorse of malaria chemotherapy, has rapidly declined throughout the tropics since the 1980s, and this drug is now useless in many high-transmission areas. New options for resource-constrained governments are few, and there is growing evidence that the burden from malaria has been increasing, as has malaria mortality in Africa. In this chapter, we have tried to outline the main pharmacological properties of current drugs, and their therapeutic uses and limitations. We have summarised the ways in which these drugs are employed, both in the formal health sector and in self-medication. We have briefly touched on the limitations of current drug development, but have tried to pick out a few promising drugs that are under development. Given that Plasmodium falciparum is the organism that kills, and that has developed multi-drug resistance, we have tended to focus upon it. Similarly, given that around 90% of global mortality from malaria occurs in Africa, there is the tendency to dwell on this continent. We give no apology for placing our emphasis upon the use of antimalarial drugs in endemic populations rather than their use for prophylaxis in travellers.

Africa↗

PubMed2005

Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing.

BACKGROUND & AIMS: Two G-protein-coupled cannabinoid receptors, termed CB1 and CB2, have been identified and several mammalian enteric nervous systems express CB1 receptors and produce endocannabinoids. An immunomodulatory role for the endocannabinoid system in gastrointestinal inflammatory disorders has been proposed and this study sought to determine the location of both cannabinoid receptors in human colon and to investigate epithelial receptor function. METHODS: The location of CB1 and CB2 receptors in human colonic tissue was determined by immunohistochemistry. Primary colonic epithelial cells were treated with both synthetic and endogenous cannabinoids in vitro, and biochemical coupling of the receptors to known signaling events was determined by immunoblotting. Human colonic epithelial cell lines were used in cannabinoid-binding studies and as a model for in vitro wound-healing experiments. RESULTS: CB1-receptor immunoreactivity was evident in normal colonic epithelium, smooth muscle, and the submucosal myenteric plexus. CB1- and CB2-receptor expression was present on plasma cells in the lamina propria, whereas only CB2 was present on macrophages. CB2 immunoreactivity was seen in the epithelium of colonic tissue characteristic of inflammatory bowel disease. Cannabinoids enhanced epithelial wound closure either alone or in combination with lysophosphatidic acid through a CB1-lysophosphatidic acid 1 heteromeric receptor complex. CONCLUSIONS: CB1 receptors are expressed in normal human colon and colonic epithelium is responsive biochemically and functionally to cannabinoids. Increased epithelial CB2-receptor expression in human inflammatory bowel disease tissue implies an immunomodulatory role that may impact on mucosal immunity.

Biomarkers↗

PubMed2004

Therapy of falciparum malaria in sub-saharan Africa: from molecule to policy.

The burden of falciparum malaria remains as great as ever, and, as has probably always been the case, it is carried mainly by tropical Africa. Of the various means available for the control of malaria, the use of effective drugs remains the most important and is likely to remain so for a considerable time to come. Unfortunately, the extensive development of resistance by the parasite threatens the utility of most of the affordable classes of drug: the development of novel antimalarials has never been more urgently needed. Any attempt to understand the vast complexities of falciparum malaria in Africa requires an ability to think "from molecule to policy." In consequence, the review ambitiously tries to examine the current pharmacopeia, the process by which new drugs are developed and the ways in which drugs are actually used, in both the formal and informal health sectors. The informal sector is particularly important in Africa, where around half of all antimalarial treatments are bought from informal outlets and taken at home without supervision by health care professionals: the potential impact of adherence on clinical outcome is discussed. Given that the full costs are carried by the patient in a large proportion of cases, the importance of drug affordability is explored. The review also discusses the splicing of new drugs into national policy. The various parameters that feed into deliberations on changes in drug policy are discussed.

Adolescent↗

PubMed2004

The contemporary use of removable orthodontic appliances.

Although apparently simple and efficient to use, removable appliances are no longer the appliance of choice for comprehensive orthodontic treatment in the permanent dentition. Their mechanical properties result in simple tipping of teeth, therefore multiple simultaneous tooth movements with apical control are not possible. It is for these and other reasons that removable appliances are usually only indicated for specific interventions in the mixed dentition, and as an adjunct to more complex fixed appliance treatment. Removable appliances, once popular because of their case of use, are no longer seen as the appliance of choice. This article discusses the rationale behind this statement and indicates cases suitable for removable appliance treatment.

Adult↗

PubMed2003

Therapeutic potential of phosphoinositide 3-kinase inhibitors.

At least one Holy Grail for many academic researchers and pharmaceutical research divisions alike has been to identify therapeutically useful selective PI3K inhibitors. There are several different but closely related PI3Ks which are thought to have distinct biological roles. Until now, however, researchers have been frustrated by poor selectivity of the available pharmacological inhibitors, which are unable to distinguish the different isoforms of PI3K adequately. Fortunately, recently published work gives cause for optimism; there are now several patent specifications published that describe new PI3K inhibitors, including some that are more selective for the delta isoform of PI3K. Given the involvement of PI3Ks in a plethora of biological settings, such isoform-selective inhibitors may have immense potential use for the treatment of patients with inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases.

Autoimmune Diseases↗

PubMed2002

Immunotherapeutic potential of whole tumour cells.

Despite the identification of tumour antigens and their subsequent generation in subunit form for use as cancer vaccines, whole tumour cells remain a potent vehicle for generating anti-tumour immunity. This is because tumour cells express an array of target antigens for the immune system to react against, avoiding problems associated with major histocompatibility complex (MHC)-restricted epitope identification for individual patients. Furthermore, whole cells are relatively simple to propagate and are potentially efficient at contributing to the process of T cell priming. However, whole cells can also possess properties that allow for immune evasion, and so the question remains of how to enhance the immune response against tumour cells so that they are rejected. Scenarios where whole tumour cells may be utilised in immunotherapy include autologous tumour cell vaccines generated from resected primary tumour, allogeneic (MHC-disparate) cross-reactive tumour cell line vaccines, and immunotherapy of tumours in situ. Since tumour cells are considered poorly immunogenic, mainly because they express self-antigens in a non-stimulatory context, the environment of the tumour cells may have to be modified to become stimulatory by using immunological adjuvants. Recent studies have re-evaluated the relative roles of direct and cross-priming in generating anti-tumour immunity and have highlighted the need to circumvent immune evasion.

Animals↗