Structure-activity relationships of the antimalarial agent artemisinin. 6. The development of predictive in vitro potency models using CoMFA and HQSAR methodologies

Artemisinin (1) is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua L. Because of the effectiveness of Artemisinin in the treatment of drug-resistant Plasmodium falciparum and its rapid clearance of cerebral malaria, development of clinically useful semisynthetic drugs for severe and complicated malaria (artemether, artesunate) was prompt. However, recent reports of fatal neurotoxicity in animals with dihydroartemisinin derivatives such as artemether have spawned a renewed effort to develop nontoxic analogues of artemisinin. In our effort to develop more potent, less neurotoxic agents for the oral treatment of drug-resistant malaria, we utilized comparative molecular field analysis (CoMFA) and hologram QSAR (HQSAR), beginning with a series of 211 artemisinin analogues with known in vitro antimalarial activity. CoMFA models were based on two conformational hypotheses: (a) that the X-ray structure of artemisinin represents the bioactive shape of the molecule or (b) that the hemin-docked conformation is the bioactive form of the drug. In addition, we examined the effect of inclusion or exclusion of racemates in the partial least squares (pls) analysis. Databases derived from the original 211 were split into chiral (n = 157), achiral (n = 34), and mixed databases (n = 191) after leaving out a test set of 20 compounds. HQSAR and CoMFA models were compared in terms of their potential to generate robust QSAR models. The r(2) and q(2) (cross-validated r(2)) were used to assess the statistical quality of our models. Another statistical parameter, the ratio of the standard error to the activity range (s/AR), was also generated. CoMFA and HQSAR models were developed having statistically excellent properties, which also possessed good predictive ability for test set compounds. The best model was obtained when racemates were excluded from QSAR analysis. Thus, CoMFA of the n = 157 database gave excellent predictions with outstanding statistical properties. HQSAR did an outstanding job in statistical analysis and also handled predictions well.     

Arrested paradoxical emboli in transit diagnosed by intraoperative transesophageal echocardiography

IMPLICATIONS: We describe a patient who developed a deep venous thrombosis that subsequently embolized to both the pulmonary and systemic arterial circulations. The diagnosis of arrested paradoxical embolus in transit at two separate and unique anatomic locations was made with intraoperative transesophageal echocardiography, and the patient did not suffer organ damage as a result of the paradoxical emboli.     

Cardiac arrest after labetalol and metoclopramide administration in a patient with scleroderma

IMPLICATIONS: Although recent Food and Drug Administration warnings have noted proarrhythmic effects of droperidol, other antiemetic drugs may have similar effects. We report a case of cardiac arrest after uncomplicated regional anesthesia in a patient with scleroderma who received labetalol and metoclopramide after surgery. Metoclopramide should be used with caution when risk factors for dysrhythmia are present.     

Modeling the effect of progressive endotracheal tube occlusion on tidal volume in pressure-control mode

A recognized hazard of prolonged endotracheal intubation is progressive airway occlusion resulting from deposition of secretions on the inner surface of the endotracheal tube (ETT). When volume-controlled ventilation is used, progressive ETT occlusion may be detected by monitoring the difference between peak and plateau airway pressures. In pressure-controlled modes, however, inspiratory airway pressures are preset and thus cannot act as a warning indicator. Instead, changes in delivered tidal volumes may aid the diagnosis of ETT occlusion. To determine whether tidal volume monitoring effectively detects progressive ETT occlusion, we mathematically modeled the response of a ventilator operating in pressure-controlled mode to increasing airway resistance. To corroborate our model, we then bench-tested the Siemens 300 and Puritan-Bennett 7200 ventilators by using a test lung and a series of ETTs ranging in size from 9.0 to 3.5 mm inner diameter to simulate progressive occlusion. We found that when pressure-controlled mode was used, progressive ETT occlusion did not reduce delivered tidal volumes until occlusion was nearly complete. We conclude that prolonged use of pressure-controlled mode may allow significant ETT obstruction to build up undetected, risking complete ETT occlusion and complicating the perioperative care of patients ventilated with this mode. IMPLICATIONS: Although increasing airway pressures during volume-controlled ventilation allow early recognition of endotracheal tube (ETT) obstruction, airway pressures with pressure-controlled ventilation are fixed. We found during tests of two intensive care unit ventilators that although ETT obstruction reduces delivered tidal volumes during pressure-controlled ventilation, reductions do not occur until occlusion is advanced.     

Survival in a cohort of social services placements in nursing and residential homes: factors associated with life expectancy and mortality

The aim of this study was to examine the life expectancy of elderly people in nursing and residential care over a 20-month period and its relationship to specific risk factors. Using a retrospective cohort design, data obtained on 1888 residents placed between 1 July 1997 and 30 April 1999 in residential, nursing and dual registered homes within Nottingham Health Authority boundaries were examined. Additional data on physical and mental disability at placement were available for 514 residents. Main outcome measures comprised survival rate overall, and in relation to gender, age, home type (nursing, residential or dual), source of placement (hospital or community) and various disability factors.One-year survival rates were: overall, 66%; nursing homes, 59%; dual homes, 58%; and residential homes 76%. Median survival in nursing homes was 541 days, but was not reached in residential homes. Male gender, admission to nursing or dual registered homes, placement from hospital, decreased mobility and increased age were associated with decreased life expectancy. Although no association was found between length of survival and level of cognitive function, lack of cognitive impairment was associated with lower survival. In conclusion, mortality is high in nursing, dual and residential homes where life expectancy has been shown to be associated with gender, home type, origin of placement and mobility. Rates of survival are related to higher comorbidity and disability. Important data for planning and assessing care needs can be yielded through the analysis of mortality data.     

Assessing the quality of preschool child health surveillance in primary care: a pilot study in one health district

OBJECTIVE: To develop a framework for measuring the quality of preschool child health surveillance acceptable to primary health care teams and measurable at individual primary health care team level. DESIGN: Published research evidence was identified and criteria developed by a local multidisciplinary expert group. The criteria were discussed with primary health care teams. How well they were achieved was assessed. SETTING: Twenty-eight general practices in one health authority area. METHODS: Data collection included observation of baby clinics, interviews with health visitors and general practitioners (GPs), questionnaires to parents, collation of child health surveillance reviews recorded in personal child health records and immunization rates. RESULTS: The criteria for assessing preschool child health surveillance were thought to be acceptable and achievable by primary health care teams. Fifteen of the 22 criteria used to assess baby clinics were met by over 90 of practices. Almost all practices completed child health surveillance reviews within a standard time and achieved 90 coverage for primary immunizations. At many practices, less than 90 of parents felt welcome at the baby clinic, usually had enough time to talk to their health visitor or had the purpose or results of the 6 to 8 week child health surveillance review explained to them. GPs were less likely than health visitors to discuss health promotion at child health surveillance reviews (chi(2) 11.52, P = 0.0007). Few practices had a call-up and recall system for all reviews. CONCLUSION: The framework that we developed for assessing preschool child health surveillance was acceptable and achievable by primary health care teams.     

Description of a multifaceted strategy for recruiting general practitioners and community pharmacists to talk about medication errors

Objective To describe the use of a multifaceted strategy for recruiting general practitioners (GPs) and community pharmacists to talk about medication errors which have resulted in preventable drug‐related admissions to hospital. This is a potentially sensitive subject with medicolegal implications. Setting Four primary care trusts and one teaching hospital in the UK. Method Letters were mailed to community pharmacists and general practitioners asking for provisional consent to be interviewed and permission to contact them again should a patient be admitted to hospital as a result of a medication error. In addition, GPs were asked for permission to approach their patients should they be admitted to hospital. A multifaceted approach to recruitment was used including gaining support for the study from professional defence agencies and local champions. Key findings Eighty‐five percent (310/385) of GPs and 62% (93/149) of community pharmacists responded to the letters. Eighty‐five percent (266/310) of GPs who responded and 81% (75/93) of community pharmacists who responded gave provisional consent to participate in interviews. All GPs (14 out of 14) and community pharmacists (10 out of 10) who were subsequently asked to participate, when patients were admitted to hospital, agreed to be interviewed. Conclusion The multifaceted approach to recruitment was associated with an impressive response when asking healthcare professionals to be interviewed about medication errors which have resulted in preventable drug‐related morbidity.     

Characterization of a recombinant adenovirus vector encoding heat-inducible feline interleukin-12 for use in hyperthermia-induced gene-therapy.

Interleukin-12 (IL-12) is a pro-inflammatory cytokine that has shown great promise as a therapeutic agent in experimental models of infectious disease and cancer. However, it is also a highly toxic molecule and for that reason has not been accepted readily into the clinic. A replication-deficient adenoviral vector was designed to deliver the feline interleukin-12 gene into tumour cells. The interleukin-12 gene has been placed under control of a heat inducible promoter, human heat shock promoter 70b, with the intent of spatially and temporally controlling the expression of IL-12, thus limiting its toxicity. In vitro, the transfection efficiency of the adenoviral vector, the effect of multiplicity of infection and the production of biologically active feline IL-12 were studied in the infected cells in response to a range of temperatures. This adenoviral vector will be a useful tool to examine the effects of intra-tumoural IL-12 delivery in a spontaneously occurring feline soft tissue sarcoma model.