Unimolecular Photodynamic O2-Economizer To Overcome Hypoxia Resistance in Phototherapeutics.

Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O2•-) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O2 consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O2•- through type-I photochemistry, and the generated O2•- can further trigger a biocascade to reduce the PDT's demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.

Comparing adherence to and persistence with antipsychotic therapy among patients with bipolar disorder.

BACKGROUND: Medication nonadherence is a significant problem among patients with bipolar disorder. OBJECTIVE: To compare adherence and persistence among patients with bipolar disorder initiated on antipsychotics in a state Medicaid system over a 12 month follow-up period. METHODS: Claims data for patients with bipolar disorder from a de-identified Medicaid database were examined. Patients were classified into 4 monotherapy treatment groups (risperidone, olanzapine, quetiapine, or typical antipsychotic) based on the first prescription filled between January 1, 1999, and December 31, 2001. Adherence and persistence were analyzed over a 12 month follow-up period. Adherence was measured using the Medication Possession Ratio (MPR). Persistence was defined as the total number of days from the initiation of treatment to therapy modification (ie, discontinuation, switching, or combination with another antipsychotic). Adjustment for confounding variables was undertaken using ordinary least-squares and Cox proportional hazard regression modeling. RESULTS: The mean MPRs were 0.68 for risperidone (n = 231), 0.68 for olanzapine (n = 283), 0.71 for quetiapine (n = 106), and 0.46 for typical antipsychotics (n = 205). Patients initiated on typical antipsychotics were 23.6% less adherent than patients initiated on risperidone (p < 0.001). Mean persistence (days) was 194.8 for risperidone, 200.9 for olanzapine, 219.8 for quetiapine, and 179.2 for typical antipsychotics. Extended Cox regression modeling indicated no significant differences between antipsychotics in hazards of therapy modification within 250 days of initiation. However, patients initiated on typical antipsychotics were 5.2 times more likely to modify therapy compared with those initiated on risperidone after 250 days of antipsychotic therapy (p < 0.001). CONCLUSIONS: Adherence and persistence were similar between atypical antipsychotic groups. The typical antipsychotic group, however, demonstrated lower adherence and a greater likelihood of patients modifying therapy compared with the risperidone cohort.

Disturbing post-operative symptoms are not reduced by prophylactic antiemetic treatment in patients at high risk of post-operative nausea and vomiting.

BACKGROUND: To give prophylactics or timely treatment for post-operative nausea and vomiting (PONV) is the question. We compared the intensity and number of disturbing post-operative symptoms (i.e. pain, PONV, headache, fatigue, etc.) after prophylactic antiemetic treatment in a group of patients with >30% risk for post-operative vomiting. METHODS: Four hundred and ninety-five patients, from three hospitals, planned for gynaecological surgery were randomized double blind. They were given granisetron 3 mg, droperidol 1.25 mg or no prophylactic antiemetic. Post-operative symptoms were followed for 24 h using a questionnaire. Symptoms were analyzed both according to their intensity and in a dichotomous fashion. RESULTS: The intensity of different symptoms differed depending on whether droperidol, granisetron or no antiemetic had been given (P = 0.005) but the overall incidence of moderate to very severe symptoms was similar in all groups. No group fared better in general. The total number of symptoms was higher in the groups given prophylactic treatment (P < 0.05). The relative risk reduction for PONV with granisetron or droperidol prophylaxis was 27%[95% confidence interval (CI) 8-43] and 22% (2-38), respectively. The NNT (number needed to treat) for granisetron (0-24 h) was 7 and for droperidol 8. The NNH (number needed to harm) (0-24 h) for headache and visual disturbances was 6 and 13 (NS) for granisteron and, 50 (NS) and 6 for droperidol. CONCLUSION: The intensity of symptoms or the total number of disturbing symptoms did not decrease after prophylactic antiemetic treatment in a group of patients, but the profile of disturbing symptoms changed. The relevance of post-operative symptoms in terms of patients' well-being needs to be addressed.

Pharmacoeconomics of the therapy of diarrhoeal disease.

We review the pathophysiology of intestinal water and electrolyte transport leading to diarrhoea, the currently available pharmacological strategies for its treatment, and the economic implications of such treatments. Diarrhoea occurs most frequently and is associated with highest mortality in children under 5. Oral rehydration therapy (ORT) is the cornerstone of its management. The safety and efficacy of ORT in the prevention of death from dehydration, both in field and also in hospital settings, are now well established. Because it is also inexpensive, ORT is widely applicable worldwide. More recently, rice-based ORT has emerged, based on well known traditional remedies for diarrhoea in southeast Asia and the Far East. Rice-based ORT has the advantage of being more culturally acceptable, readily available even in rural homes in developing countries, and is more effective in reducing stool output and the duration of diarrhoea, compared with conventional glucose-electrolyte solutions such as World Health Organization ORT. For infants, the well known antidiarrhoeal properties of human milk needs emphasis for a variety of reasons including economic ones. Data concerning the economic benefits to a nations' health budget as a result of nationwide implementation of oral rehydration solution (ORS) use are limited. Available data from individual centres in developing countries, if projected to national level, would incur considerable economic advantage. Except for a few notable infections such as shigellosis, cholera, amoebiasis and giardiasis, the widespread use of antibiotics in acute diarrhoea, still a common practice in many developing countries, has no proven value and may be detrimental. The economic implications of antibiotic abuse in the treatment of diarrhoea in developing countries is enormous. Despite the availability of a wide spectrum of pharmacological agents for diarrhoea reviewed in this article, only a few such agents are of proven clinical efficacy: corticosteroids, aminosalicylates and immunosuppressants in the treatment of inflammatory bowel disease and opioid derivatives such as loperamide which may be useful in protracted diarrhoea in children and in disorders where rapid gastrointestinal transit is the main cause of diarrhoea. Opioids are not recommended for acute infective diarrhoea in childhood. Octreotide, a somatostatin analogue, is reported to be useful in the treatment of secretory diarrhoea due to noninfective causes and in the treatment of intractable diarrhoea associated with AIDS. Its high cost and need for parenteral administration prevent its wider application.(ABSTRACT TRUNCATED AT 400 WORDS)

Assessment and management of chronic pain.

The approach to the management of patients with a variety of chronic pain problems who present to the multidisciplinary Grey's Hospital Pain Clinic is outlined.

Echocardiographic assessment of the haemodynamic effect of ethmozine and its diethylamine analogue etacizine in patients with heart failure.

The purpose of the study was to compare the haemodynamic effect of new antiarrhythmic preparations - ethmozine and its diethylamine analogue etacizine in 22 patients with heart failure (HF), stage IIa, of different etiology. The patients were given for one week ethmozine and then again for one week etacizine, during which periods they were followed echocardiographically, with pressure measurement in the pulmonary artery (PAP) and in the right atrium (RAP). Ethmozine in a daily dosis of 600-800 mg did not induce changes in left ventricular dimensions, percentual shortening of the anteroposterior left ventricular dimension (% delta S), in PAP, RAP, arterial pressure and heart rate. With application of etacizine in a dose of 150-200 mg/day, a clinically insignificant decrease was observed in % delta S (by 19.7%; p less than 0.05), which was not accompanied by a more marked augmentation of left ventricular dimensions, PAP, RAP or an intensification of clinical signs of heart failure. In spite of this, on administration of etacizine to patients with HF it is necessary to control haemodynamics, the most suitable method for this being echocardiography.