Comparative total and unbound pharmacokinetics of cefazolin administered by bolus versus continuous infusion in patients undergoing major surgery: a randomized controlled trial.

BACKGROUND.: Perioperative administration of cefazolin reduces the incidence of perioperative infections. Intraoperative re-dosing of cefazolin is commonly given between 2 and 5 h after the initial dose. This study was undertaken to determine whether intraoperative continuous infusions of cefazolin achieve better probability of target attainment (PTA) and fractional target attainment (FTA) than intermittent dosing. METHODS.: Patients undergoing major surgery received cefazolin 2 g before surgical incision. They were subsequently randomized to receive either an intermittent bolus (2 g every 4 h) or continuous infusion (500 mg h -1 ) of cefazolin until skin closure. Blood samples were analysed for total and unbound cefazolin concentrations using a validated chromatographic method. Population pharmacokinetic modelling was performed using Pmetrics ® software. Calculations of PTA and FTA were performed for common pathogens. RESULTS.: Ten patients were enrolled in each arm. A two-compartment linear model best described the time course of the total plasma cefazolin concentrations. The covariates that improved the model were body weight and creatinine clearance. Protein binding varied with time [mean (range) 69 (44-80)%] with a fixed 21% unbound value of cefazolin used for the simulations (120 min post-initial dosing). Mean ( sd ) central volume of distribution was 5.73 (2.42) litres, and total cefazolin clearance was 4.72 (1.1) litres h -1 . Continuous infusions of cefazolin consistently achieved better drug exposures and FTA for different weight and creatinine clearances, particularly for less susceptible pathogens. CONCLUSIONS.: Our study demonstrates that intraoperative continuous infusions of cefazolin increase the achievement of target plasma concentrations, even with lower infusion doses. Renal function and body weight are important when considering the need for alternative dosing regimens. CLINICAL TRIAL REGISTRATION.: NCT02058979.

Cross-Sectional Survey on the Dengue Knowledge, Attitudes and Preventive Practices Among Students and Staff of a Public University in Malaysia.

Behavioural impact programmes are especially effective for dengue control and prevention. Universities are key settings for health promotion, so understanding factors that influence the practice of dengue prevention within a university community becomes important. This study aimed to examine the factors affecting dengue knowledge, attitude and preventive practices amongst students and staff of a public university. A cross-sectional survey study was conducted in Kuala Lumpur, Malaysia. A total of 372 students and staff of the NDUM were recruited by stratified sampling method. Data were collected via self-administered pre-tested structured questionnaires covering socio-demography and dengue KAP. Data were analysed descriptively. For bivariate analysis, Chi square test was applied. To explore the factors independently associated with the practice of dengue prevention, a logistic regression model was introduced. Overall, the participants had moderate dengue-related knowledge, good attitudes and good preventive practices. The majority had misconceptions about mosquito biting habits (83.8 %), seasonality of dengue epidemics (73.2 %), and mosquito breeding sites (70.3 %). Staff were more likely to have good dengue-related knowledge (p < 0.001) and attitudes (p = 0.008) than students. There was statistically significant positive association between the level of dengue knowledge and monthly average household income (p = 0.008), age (p < 0.001) and education (p < 0.001). Having good attitudes towards dengue was associated with being a non-Malay (p = 0.034), having higher monthly average household income (p = 0.047) and tertiary education (p < 0.001). In regression analysis, only dengue knowledge and dengue attitudes were significantly and positively associated with practice of dengue prevention. Dengue preventive strategies amongst university students and staff should focus on maintaining good dengue-related preventive practices. Educational campaigns should mainly target students, young staff members, and those with lower level of education and income.

Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy: comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration.

OBJECTIVES: Few data are available to guide linezolid dosing during renal replacement therapy. The objective of this study was to compare the population pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVHF, 30 mL/kg/h) and continuous venovenous haemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h). METHODS: Patients requiring linezolid 600 mg iv every 12 h and CVVHF or CVVHDF were eligible for this prospective study. Seven blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis was undertaken using Pmetrics. Monte Carlo simulations evaluated achievement of a pharmacodynamics target of an AUC from 0-24 h to MIC (AUC0-24/MIC) of 80. RESULTS: Nine CVVHDF and eight CVVHF treatments were performed in 13 patients. Regimens of CVVHDF and CVVHF were similar. A two-compartment linear model best described the data. CVVHDF was associated with a 20.5% higher mean linezolid clearance than CVVHF, without statistical significance (P = 0.39). Increasing patient weight and decreasing SOFA score were associated with increasing linezolid clearance. The mean (SD) parameter estimates were: clearance (CL), 3.8 (2.2) L/h; volume of the central compartment, 26.5 (10.3) L; intercompartmental clearance constants from central to peripheral, 8.1 (12.1) L/h; and peripheral to central compartments, 3.6 (4.0) L/h. Achievement of pharmacodynamic targets was poor for an MIC of 2 mg/L with the studied dose. CONCLUSIONS: During CVVHF and CVVHDF, there is profound pharmacokinetic variability of linezolid. Suboptimal achievement of therapeutic targets occurs at the EUCAST breakpoint MIC of 2 mg/L using 600 mg iv every 12 h.

Household survey on Human Papilloma Virus vaccine awareness among women of reproductive age in Ibadan, Nigeria.

BACKGROUND: Cervical cancer is the commonest female genital tract malignancy associated with high mortality in sub-Saharan Africa due to poor prevention plan. Human Papilloma Virus (HPV) is a necessary cause of cervical cancer, and the infection is vaccine preventable. Since the introduction of HPV vaccine, robust community surveys on awareness of the vaccine that capture end-users perspective is scarce. The aim of this study is to determine HPV vaccine awareness among women of reproductive age group. METHODS: This was a household survey that used multi-stage random sampling conducted amongst 1002 women aged 18-49 years from August to September 2012 in Mokola area, Ibadan, south western Nigeria. A self-administered pre-tested questionnaire was used for data collection. Descriptive, bivariate and multivariable analyses were performed, and statistical significance was set at 95% confidence level. RESULTS: The mean age was 29.8 +/- 8.2 years and 49.9% had female children. Only 4.6% had heard of HPV vaccine. A significantly higher odds of HPV vaccine awareness was found among highly skilled women, those initiating sexual intercourse at older ages; women with multiple sexual partners and those aware that cervical cancer is preventable. CONCLUSION: The awareness of HPV vaccine is low. Policies and programs that will improve awareness utilising culturally sensitive messages are imperative.

Pharmacodynamics of ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus: is it a viable treatment option?

Ceftriaxone is a broad-spectrum cephalosporin that may be one option to treat methicillin-susceptible Staphylococcus aureus (MSSA). Although MSSA may be susceptible to ceftriaxone, the minimum inhibitory concentration (MIC) is generally two- to four-fold higher than other susceptible bacterial pathogens. This study aimed to explore the pharmacodynamics of ceftriaxone against MSSA and to determine the likely optimal dose. A hollow-fibre infection model was used with one clinical MSSA isolate (MIC = 4 mg/L) at an initial inoculum of 1 × 106 CFU/mL. Ceftriaxone dosing regimens of 1 g once and twice daily and 2 g once and twice daily were simulated. Ceftriaxone 1 g dosing regimens did not substantially impact bacterial killing within the first 12 h. Conversely, when administered as a 2 g dose either once or twice daily, an approximate 1-log10 bacterial reduction was observed where it plateaued for up to 96 h. No resistance was identified. Only a high ceftriaxone dose of 2 g twice daily achieves bacterial killing and sustained inhibition of bacterial growth. Ceftriaxone at routinely used doses is unsuitable for the treatment of MSSA infections and alternative agents should be preferentially used.

The phenomenology of auditory verbal hallucinations in emotionally unstable personality disorder and post-traumatic stress disorder.

OBJECTIVE: To explore the phenomenology of auditory verbal hallucinations (AVHs) in a clinical sample of young people who have a 'non-psychotic' diagnosis. METHODS: Ten participants aged 17-31 years with presentation of emotionally unstable personality disorder or post-traumatic stress disorder and frequent AVHs were recruited and participated in a qualitative study exploring their subjective experience of hearing voices. Photo-elicitation and ethnographic diaries were used to stimulate discussion in an otherwise unstructured walking interview. RESULTS: 'Non-psychotic' voices comprised auditory qualities such as volume and clarity. Participants commonly personified their voices, viewing them as distinct characters with which they could interact and form relationships. There appeared to be an intimate and unstable relationship between participant and voice, whereby voices changed according to the participants' mood, insecurities, distress and circumstance. Equally, participants reacted to provocation by the voice, leading to changes in mood and circumstance through emotional and physical disturbances. In contrast to our previous qualitative work in psychosis, voice hearing was not experienced with a sense of imposition or control. CONCLUSIONS: This phenomenological research yielded in-depth and novel accounts of 'non-psychotic' voices which were intimately linked to emotional experience. In contrast to standard reports of voices in disorders such as schizophrenia, participants described a complex and bi-directional relationship with their voices. Many other features were in common with voice hearing in psychosis. Knowledge of the phenomenology of hallucinations in non-psychotic disorders has the potential to inform future more successful management strategies. This report gives preliminary evidence for future research.

Runoff infiltration, a desktop case study.

The use of sustainable drainage systems (SuDS) or best management practice is becoming increasingly common. However, rather than adopting the preferred 'treatment train' implementation, many developments opt for end-of-pipe control ponds. This paper discusses the use of SUDS in series to form treatment trains and compares their potential performance and effectiveness with end-of-pipe solutions. Land-use, site and catchment characteristics have been used alongside up-to-date guidance, Infoworks CS and MUSIC to determine whole-life-costs, land-take, water quality and quantity for different SuDS combinations. The results presented show that the use of a treatment train allows approaches differing from the traditional use of single SuDS, either source or 'end-of-pipe', to be proposed to treat and attenuate runoff. The outcome is a more flexible solution where the footprint allocated to SUDS, costs and water quality can be managed differently to fully meet stakeholder objectives.

Meropenem dosing in critically ill patients with sepsis receiving high-volume continuous venovenous hemofiltration.

Use of high ultrafiltrate flow rates with continuous venovenous hemofiltration (CVVHF) in critically ill patients is an emerging setting, for which there are few data to guide drug dosing. The objectives of this study were, firstly, to investigate the pharmacokinetics of meropenem in critically ill patients with severe sepsis who are receiving high-volume CVVHF with high-volume exchanges (> or = 4 liters/h); secondly, to determine whether standard dosing regimens (1,000 mg intravenously [i.v.] every 8 h) are sufficient for treatment of less susceptible organisms such as Burkholderia pseudomallei (MIC, 4 mg/liter); and, finally, to compare the clearances observed in this study with data from previous studies using lower-volume exchanges (1 to 2 liters/h). We recruited 10 eligible patients and collected serial pre- and postfilter blood samples and ultrafiltrate and urine samples. A noncompartmental method was used to determine meropenem pharmacokinetics. The cohort had a median age of 56.6 years, a median weight of 70 kg, and a median APACHE II (acute physiology and chronic health evaluation) score of 25. The median (interquartile range) values for meropenem were as follows: terminal elimination half-life, 4.3 h (2.9 to 6.0); terminal volume of distribution, 0.2 liters/kg (0.2 to 0.3); trough concentration, 7.7 mg/liter (6.2 to 12.9); total clearance, 6.0 liters/h (5.2 to 6.2); hemofiltration clearance, 3.5 liters/h (3.4 to 3.9). In comparing the meropenem clearance here with those in previous studies, ultrafiltration flow rate was found to be the parameter that accounted for the differences in clearance of meropenem (R(2) = 0.89). In conclusion, high-volume CVVHF causes significant clearance of meropenem, necessitating steady-state doses of 1,000 mg every 8 h to maintain sufficient concentrations to treat less susceptible organisms such as B. pseudomallei.

Care home residents admitted to hospital through the emergency pathway: characteristics and associations with inpatient mortality.

BACKGROUND: Routinely collected hospital information could help to understand the characteristics and outcomes of care home residents admitted to hospital as an emergency. METHODS: This retrospective 2-year service evaluation included first emergency admissions of any older adult (≥75 years) presenting to Cambridge University Hospital. Routinely collected patient variables were captured by an electronic patient record system. Care home status was established using an official register of care homes. RESULTS: 7.7% of 14,777 admissions were care home residents. They were older, frailer, more likely to be women and have cognitive impairment than those admitted from their own homes. Additionally, 42% presented with an Emergency Department Modified Early Warning Score above the threshold triggering urgent review, compared to 26% of older adults from their own homes. Admission from a care home was associated with higher 30-day inpatient mortality (11.1 vs 5.7%), which persisted after multivariable adjustment (hazard ratio: 1.42; 95% confidence interval: 1.09-1.83; p = 0.008). CONCLUSION: Care home residents admitted to hospital as an emergency have high illness acuity and inpatient mortality.

Optimised dosing of vancomycin in critically ill Indigenous Australian patients with severe sepsis.

Vancomycin is a commonly used antibiotic due to the high burden of methicillin-resistant Staphylococcus aureus infections. This study aimed to describe the pharmacokinetics (PK) of vancomycin in Australian Indigenous patients with severe sepsis, and advise an optimal dosing strategy. A population PK study was conducted in a remote Australian intensive care unit (ICU). Serial plasma samples were collected over one to two dosing intervals and assayed by validated chromatography. Concentration-time data collected were analysed using Pmetrics® software. The final population PK model was then used for Monte Carlo dosing simulations to determine optimal loading and intermittent maintenance doses. Fifteen Indigenous subjects were included for analysis with a median (interquartile range, IQR) age, weight and creatinine clearance (CrCL) of 43 (34-46) years, 73 (66-104) kg and 99 (56-139) ml/minute respectively. A two-compartment model described the data adequately. Vancomycin clearance (CL) and volume of distribution of the central compartment (Vc) were described by CrCL and patient weight respectively. Median (IQR) CL, Vc, distribution rate constants from central to peripheral, and from peripheral to central compartments were 4.6 (3.8-5.6) litres per hour, 25.4 (16.1-31.3) litres, 0.46 (0.28-0.52)/hour and 0.25 (0.12-0.37)/hour respectively. No significant interethnic PK differences were observed in comparison to published data. Therapeutic loading doses were significantly dependent on both weight and CrCL, whereas maintenance doses were dependent on CrCL. In the absence of severe renal impairment, initiation of maintenance dose eight hours post-loading dose achieved higher probability of target attainment at 24 hours. This is the first report of vancomycin PK in this patient group.

The alpha isoform of protein kinase C is involved in signaling the response of desmosomes to wounding in cultured epithelial cells.

Initiation of reepithelialization upon wounding is still poorly understood. To enhance this understanding, we focus here on changes in the adhesive state of desmosomes of cultured Madin-Darby canine kidney cells in response to wounding of confluent cell sheets. Previous results show that desmosomal adhesion in Madin-Darby canine kidney cells changes from a calcium-dependent state to calcium independence in confluent cell sheets. We show that this change, which requires culture confluence to develop, is rapidly reversed upon wounding of confluent cell sheets. Moreover, the change to calcium dependence in wound edge cells is propagated to cells hundreds of micrometers away from the wound edge. Rapid transition from calcium independence to calcium dependence also occurs when cells are treated with phorbol esters that activate PKC. PKC inhibitors, including the conventional isoform inhibitor Gö6976, cause rapid transition from calcium dependence to calcium independence, even in subconfluent cells. The cellular location of the alpha isoform of PKC correlates with the calcium dependence of desmosomes. Upon monolayer wounding, PKCalpha translocates rapidly to the cell periphery, becomes Triton X-100 insoluble, and also becomes concentrated in lamellipodia. The PKCalpha translocation upon wounding precedes both the increase in PKC activity in the membrane fraction and the reversion of desmosomes to calcium dependence. Specific depletion of PKCalpha with an antisense oligonucleotide increases the number of cells with calcium-independent desmosomes. These results show that PKCalpha participates in a novel signaling pathway that modulates desmosomal adhesion in response to wounding.

Burnout and the learning environment of anaesthetic trainees.

Burnout has a high prevalence among healthcare workers and is increasingly recognised as an environmental problem rather than reflecting a personal inability to cope with work stress. We distributed an electronic survey, which included the Maslach Burnout Inventory Health Services Survey and a previously validated learning environment instrument, to 281 Victorian anaesthetic trainees. The response rate was 50%. We found significantly raised rates of burnout in two of three subscales. Ninety-one respondents (67%) displayed evidence of burnout in at least one domain, with 67 (49%) reporting high emotional exhaustion and 57 (42%) reporting high depersonalisation. The clinical learning environment tool demonstrated a significant negative correlation with burnout (r=-0.56, P <0.001). Burnout was significantly more common than when previously measured in Victoria in 2008 (62% versus 38%). Trainees rated examination preparation the most stressful aspect of the training program. There is a high prevalence of burnout among Victorian anaesthetic trainees. We have shown a significant correlation exists between the clinical learning environment measure and the presence of burnout. This correlation supports the development of interventions to improve the clinical learning environment, as a means to improve trainee wellbeing and address the high prevalence of burnout.

Using mathematical modelling to inform on the ability of stormwater ponds to improve the water quality of urban runoff.

This paper concerns the mathematical modelling of flow and solute transport through stormwater ponds. The model is based on appropriate lumped system conservation equations that are solved using standard numerical techniques. The model was used to route a first flush pollution scenario through a cylindrical pond for 16 combinations of elevation and diameter of a submerged pipe outlet, in conjunction with a high level weir. Higher pipe elevations and smaller pipe diameters created larger pond volumes and hence led to greater dilution of the pollutant. In contrast, lower pipe elevations created larger storage volumes, leading to better flow attenuation. Interestingly, larger pipe diameters improved peak flow attenuation, even though the storage used decreased.

Characterization of complementary DNA encoding the rat neuromedin U precursor.

Neuromedin U (NmU), a peptide originally isolated from porcine spinal cord, is known for its ability to stimulate uterine smooth muscle contraction and to cause selective vasoconstriction. It was subsequently isolated from a number of species. Among the species studied, the five amino acids at the C-terminus of the peptide are totally conserved, suggesting that this region is of major importance. We have cloned and sequenced the cDNA encoding the rat NmU precursor protein using the anchor polymerase chain reaction technique. Sequence analysis revealed that NmU is synthesized as a 174-amino acid precursor. Like the precursors of most other small regulatory peptides, it has a hydrophobic signal peptide and a number of paired dibasic amino acids, which may serve as signals for enzymatic cleavage, to release NmU and a series of other peptides. These predicted flanking peptides of NmU show no significant homology with entries in the protein databases searched, and the cDNA likewise shows no homology with entries in the GenBank database. Northern blot analysis using total RNA extracted from different rat tissues shows high levels of NmU mRNA in the ileum, thyroid, and anterior pituitary. Southern blot analysis of rat genomic DNA demonstrates that NmU is a single copy gene.

Association of the clinical frailty scale with hospital outcomes.

BACKGROUND: The clinical frailty scale (CFS) was validated as a predictor of adverse outcomes in community-dwelling older people. In our hospital, the use of the CFS in emergency admissions of people aged ≥ 75 years was introduced under the Commissioning for Quality and Innovation payment framework. AIM: We retrospectively studied the association of the CFS with patient characteristics and outcomes. DESIGN: Retrospective observational study in a large tertiary university National Health Service hospital in UK. METHODS: The CFS was correlated with transfer to specialist Geriatric ward, length of stay (LOS), in-patient mortality and 30-day readmission rate. RESULTS: Between 1st August 2013 and 31st July 2014, there were 11 271 emergency admission episodes of people aged ≥ 75 years (all specialties), corresponding to 7532 unique patients (first admissions); of those, 5764 had the CFS measured by the admitting team (81% of them within 72 hr of admission). After adjustment for age, gender, Charlson comorbidity index and history of dementia and/or current cognitive concern, the CFS was an independent predictor of in-patient mortality [odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.48 to 1.74, P < 0.001], transfer to Geriatric ward (OR = 1.33, 95% CI: 1.24 to 1.42, P < 0.001) and LOS ≥ 10 days (OR = 1.19, 95% CI: 1.14 to 1.23, P < 0.001). The CFS was not a multivariate predictor of 30-day readmission. CONCLUSIONS: The CFS may help predict in-patient mortality and target specialist geriatric resources within the hospital. Usual hospital metrics such as mortality and LOS should take into account measurable patient complexity.

A Paleoarchean coastal hydrothermal field inhabited by diverse microbial communities: the Strelley Pool Formation, Pilbara Craton, Western Australia.

The 3.4-Ga Strelley Pool Formation (SPF) at the informally named 'Waterfall Locality' in the Goldsworthy greenstone belt of the Pilbara Craton, Western Australia, provides deeper insights into ancient, shallow subaqueous to possibly subaerial ecosystems. Outcrops at this locality contain a thin (<3 m) unit of carbonaceous and non-carbonaceous cherts and silicified sandstones that were deposited in a shallow-water coastal environment, with hydrothermal activities, consistent with the previous studies. Carbonaceous, sulfide-rich massive black cherts with coniform structures up to 3 cm high are characterized by diverse rare earth elements (REE) signatures including enrichment of light [light rare earth elements (LREE)] or middle rare earth elements and by enrichment of heavy metals represented by Zn. The massive black cherts were likely deposited by mixing of hydrothermal and non-hydrothermal fluids. Coniform structures in the cherts are characterized by diffuse laminae composed of sulfide particles, suggesting that unlike stromatolites, they were formed dominantly through physico-chemical processes related to hydrothermal activity. The cherts yield microfossils identical to previously described carbonaceous films, small and large spheres, and lenticular microfossils. In addition, new morphological types such as clusters composed of large carbonaceous spheroids (20-40 µm across each) with fluffy or foam-like envelope are identified. Finely laminated carbonaceous cherts are devoid of heavy metals and characterized by the enrichment of LREE. This chert locally contains conical to domal structures characterized by truncation of laminae and trapping of detrital grains and is interpreted as siliceous stromatolite formed by very early or contemporaneous silicification of biomats with the contribution of silica-rich hydrothermal fluids. Biological affinities of described microfossils and microbes constructing siliceous stromatolites are under investigation. However, this study emphasizes how diverse the microbial community in Paleoarchean coastal hydrothermal environment was. We propose the diversity is at least partially due to the availability of various energy sources in this depositional environment including reducing chemicals and sunlight.

Expanding the Clinical Spectrum Associated With GLIS3 Mutations.

CONTEXT: GLIS3 (GLI-similar 3) is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with 5 C2H2-type zinc finger domains. The protein is expressed early in embryogenesis and plays a critical role as both a repressor and activator of transcription. Human GLIS3 mutations are extremely rare. OBJECTIVE: The purpose of this article was determine the phenotypic presentation of 12 patients with a variety of GLIS3 mutations. METHODS: GLIS3 gene mutations were sought by PCR amplification and sequence analysis of exons 1 to 11. Clinical information was provided by the referring clinicians and subsequently using a questionnaire circulated to gain further information. RESULTS: We report the first case of a patient with a compound heterozygous mutation in GLIS3 who did not present with congenital hypothyroidism. All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation. We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency. CONCLUSION: We report new findings within the GLIS3 phenotype, further extending the spectrum of abnormalities associated with GLIS3 mutations and providing novel insights into the role of GLIS3 in human physiological development. All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.

The implications of genetic variation in human pathology.

Each human cell contains enough DNA to code for several million proteins. As a result of the technical advances which are broadly described as 'genetic engineering', each of these sequences can be isolated and purified in large amounts, free from those surrounding it in the genome. The sequences are not identical from person to person, nor even for each of a pair of chromosomes for a single person, but contain many variations. These include single base changes in both coding and non-coding regions, deletions, insertions and rearrangements. Using these changes as markers, the molecular geneticist can compare the structure and expression of normal and mutated human gene sequences and follow their inheritance in families.

Co-administration of sub-antinociceptive doses of oxycodone and morphine produces marked antinociceptive synergy with reduced CNS side-effects in rats.

Oxycodone and morphine are structurally related, strong opioid analgesics, commonly used to treat moderate to severe pain in humans. Although it is well-established that morphine is a mu-opioid agonist, this is not the case for oxycodone. Instead, our recent studies have shown that oxycodone appears to be a kappa-opioid agonist (Ross and Smith, 1997). In the current study, we now show that co-administration of sub-antinociceptive doses of oxycodone (putative kappa-opioid agonist) with morphine (mu-opioid agonist) to rats by both the intracerebroventricular and by systemic routes (intraperitoneal and subcutaneous), results in markedly increased (synergistic) levels of antinociception. Behaviourally, rats co-administered sub-antinociceptive doses of oxycodone and morphine were similar to control rats dosed with saline, whereas rats that received equi-potent doses of either opioid alone, were markedly sedated. These results suggest that co-administration of sub-analgesic doses of oxycodone and morphine to patients may provide excellent pain relief with a reduction in opioid-related CNS side-effects. Controlled clinical trials in appropriate patient populations are required to evaluate this possibility.(1)