Oral morphine dosing predictions based on single dose in healthy children undergoing surgery.

BACKGROUND: Oral morphine has been proposed as an effective and safe alternative to codeine for after-discharge pain in children following surgery but there are few data guiding an optimum safe oral dose. AIMS: The aim of this study was to characterize the absorption pharmacokinetics of enteral morphine in order to simulate time-concentration profiles in children given common oral morphine dose regimens. METHODS: Children (2-6 years, n = 34) undergoing elective surgery and requiring opioid analgesia were randomized to receive preoperative oral morphine (100 mcg·kg-1 , 200 mcg·kg-1 , 300 mcg·kg-1 ). Blood sampling for morphine assay was performed at 30, 60, 90, 120, 180, and 240 min. Morphine serum concentrations were determined by liquid chromatography-mass spectroscopy and pharmacokinetic parameters were calculated using nonlinear mixed effects models. Current data were pooled with published time-concentration profiles from children (n = 1059, age 23 weeks postmenstrual age - 3 years) administered intravenous morphine, to determine oral bioavailability (F), absorption lag time (TLAG ), and absorption half-time (TABS ). These parameter estimates were used to predict concentrations in children given oral morphine (100, 200, 300, 400, 500 mcg·kg-1 ) at different dosing intervals (3, 4, 5, 6, 8, 12 h). RESULTS: The oral morphine formulation had F 0.298 (CV 36.5%), TLAG 0.45 (CV 63.6%) h and TABS 0.71 (CV 55%) h. A single-dose morphine 100 mcg·kg-1 achieved a mean CMAX 10 mcg·l-1 . Repeat 4-hourly dosing achieved mean steady-state concentration 13-18 mcg·l-1 ; concentrations associated with good analgesia after intravenous administration. Serum concentration variability was large ranging from 5 to 55 mcg·l-1 at steady state. CONCLUSIONS: Oral morphine 200 mcg·kg-1 then 100 mcg·kg-1 4 h or 150 mcg·kg-1 6 h achieves mean concentrations associated with analgesia. There was high serum concentration variability suggesting that respiration may be compromised in some children given these doses.

Asthma in British Columbia: Are we finally breathing easier? A population-based study of the burden of disease over 14 years.

OBJECTIVE: Asthma presents a significant global burden, but whether the incidence and prevalence of asthma is rising is still debated. The objective of this study was to determine the prevalence and incidence of asthma in British Columbia (BC), Canada, and characterize associated health services utilization. METHODS: We extracted data from provincial administrative hospitalization, medical services, and prescription drug databases for patients aged 5 to 55 years, during 1996 to 2009 having ≥270 MSP registration days and meeting asthma definition of: ≥1 hospital admissions with asthma as the principal diagnosis, or ≥2 physician visits for asthma as the principal diagnosis, or ≥3 asthma drug dispensings. Regression models were used to test change in asthma incidence and prevalence, and use of various health care services, such as physician and emergency department (ED) visits, and hospitalizations. RESULTS: 379,950 patients met the study criteria. The prevalence (2.6%) and incidence (0.7%) of asthma was relatively stable over the study period. There was a decline in proportion of patients visiting family practitioners (FP) (OR 0.92; 95% CI 0.90-0.94), specialists (OR 0.60; 95% CI 0.58-0.62), using ED services (OR 0.31; 95% CI 0.30-0.32) and hospitalizations (OR 0.34; 95% CI 0.31-0.37). Regional differences were noted, with lower rates of FP and specialist visits and higher rates of ED visits for asthma in rural versus urban areas. CONCLUSIONS: In BC, the incidence and prevalence of asthma has remained stable over 14 years. Although health service utilization declined, there is variation between rural and urban regions.

Cisplatin Nephrotoxicity and Longitudinal Growth in Children With Solid Tumors: A Retrospective Cohort Study.

Cisplatin, a major antineoplastic drug used in the treatment of solid tumors, is a known nephrotoxin. This retrospective cohort study evaluated the prevalence and severity of cisplatin nephrotoxicity in 54 children and its impact on height and weight.We recorded the weight, height, serum creatinine, and electrolytes in each cisplatin cycle and after 12 months of treatment. Nephrotoxicity was graded as follows: normal renal function (Grade 0); asymptomatic electrolyte disorders, including an increase in serum creatinine, up to 1.5 times baseline value (Grade 1); need for electrolyte supplementation <3 months and/or increase in serum creatinine 1.5 to 1.9 times from baseline (Grade 2); increase in serum creatinine 2 to 2.9 times from baseline or need for electrolyte supplementation for more than 3 months after treatment completion (Grade 3); and increase in serum creatinine ≥3 times from baseline or renal replacement therapy (Grade 4).Nephrotoxicity was observed in 41 subjects (75.9%). Grade 1 nephrotoxicity was observed in 18 patients (33.3%), Grade 2 in 5 patients (9.2%), and Grade 3 in 18 patients (33.3%). None had Grade 4 nephrotoxicity. Nephrotoxicity patients were younger and received higher cisplatin dose, they also had impairment in longitudinal growth manifested as statistically significant worsening on the height Z Score at 12 months after treatment. We used a multiple logistic regression model using the delta of height Z Score (baseline-12 months) as dependent variable in order to adjust for the main confounder variables such as: germ cell tumor, cisplatin total dose, serum magnesium levels at 12 months, gender, and nephrotoxicity grade. Patients with nephrotoxicity Grade 1 where at higher risk of not growing (OR 5.1, 95% CI 1.07-24.3, P=0.04). The cisplatin total dose had a significant negative relationship with magnesium levels at 12 months (Spearman r=-0.527, P=<0.001).

Liver-specific case fatality due to chronic hepatitis C virus infection: a systematic review.

Despite reports that mortality is increasing, overall case fatality due to hepatitis C virus (HCV) is thought to be low. Given the variability in published rates, we aimed to synthesize estimates of liver-specific case fatality and all-cause mortality in chronic HCV according to follow-up duration, sustained viral response (SVR) to treatment, and liver disease severity. A systematic review was conducted of studies published in English from 2003 to 2013, reporting liver-specific case fatality estimates from HCV-infected samples. Thirty-five eligible articles were identified; 26 also presented estimates of all-cause mortality. Among community-based samples, liver-specific case fatality ranged from 0.3% over 5.7 years to 9.2% over 8.2 years of follow-up; and of all-cause mortality, from 4.0% over 5.7 years, to 23.0% over 8.2 years of follow-up. Estimates were higher among clinic-based samples and those with more severe liver disease. Among treated patients achieving SVR, liver-specific case fatality was low: up to 1.4% over 11.5 years of follow-up among samples with any severity of liver disease. Estimates were higher among those without SVR: up to 14.0% over 10 years of followup among samples with any severity of liver disease, and higher still among samples with more severe liver disease. The proportion of deaths attributable to liver-specific causes ranged from 55 to 85% among those with severe liver disease. Published estimates of fatality are high among certain populations of chronic HCV patients, with liver-specific causes being an important contributor. Understanding current HCV mortality rates is important for quantifying the total burden of HCV disease.

A Compartmental Analysis for Morphine and Its Metabolites in Young Children After a Single Oral Dose.

BACKGROUND AND OBJECTIVES: Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children. METHODS: The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method. RESULTS: A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites. CONCLUSION: This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.

Hearing loss in Mexican children treated with cisplatin.

OBJECTIVE: Cisplatin is widely used to treat a variety of pediatric solid tumors. One of the most severe and debilitating adverse drug reactions experienced by patients who receive cisplatin therapy is permanent bilateral hearing loss. The aim of this study was to evaluate the incidence and risk factors for cisplatin-induced hearing loss in Mexican pediatric patients. METHODS: Detailed medical and drug histories, including use of cisplatin as well as other drugs known to cause hearing loss, were collected from patient medical records. Results of audiology tests on pediatric patients with solid tumors were collected at baseline, during treatment and at the end of cisplatin chemotherapy. Hearing loss was classified according to the Common Terminology Criteria for Adverse Events. Bivariate and multivariate analyses were performed using survival curves. RESULTS: Fifty-nine pediatric patients, median age 11 years (range, 3-17 years) were included in the study. The incidence of cisplatin-induced hearing loss was 56%. Individual risk factors including age (< 5 years), male sex, and concomitant medications were not associated with an increased risk of cisplatin-induced hearing loss. Patients with a diagnosis of osteosarcoma and a cumulative cisplatin dose greater than 400 mg/m(2) were at higher risk of hearing loss compared with all other tumor and cumulative dose combinations (HR = 2.47 [95% CI, 1.043-5.831]). CONCLUSIONS: Cumulative dose and tumor type are associated with an increased risk of cisplatin-induced hearing loss. Further research is required to characterize fully the interindividual variation in hearing loss in Mexican patients.

Suspected opioid overdose case resolved by CYP2D6 genotyping.

A 14-year-old female with suspected narcotic overdose had CYP2D6 genotyping performed to verify opiate intoxication. The role of pharmacogenetics in pain management and individualization of opiate pharmacotherapy is discussed.

Hepatitis C seroprevalence and correlation between viral load and viral genotype among primary care clients in Mexico.

OBJECTIVE: To measure hepatitis C virus (HCV) sero-prevalence, prevalence, hepatitis risk characteristics frequency, and genotype correlation with viral load among clients attending health care clinics. MATERIAL AND METHODS: Venous blood samples from l12 226 consecutive consenting adults were collected from January 2006 through December 2009. HCV antibodies were detected by immunoassay. HCV RNA was detected by qRT-PCR and viral genotype was performed by PCR and LIPA test. RESULTS: The HCV seroprevalence observed was l.5 % (C.I. 95% l.3-l.7), from seropositive individuals 60.9 % reported previous blood transfusion, 28.3% declared to have relatives with cirrhosis, 25.2% had tattoos or piercings, and 6.9% referred to have used drugs. Male gender and transfusion (p<0.001) were the most frequent hepatitis risk characteristics in the HCV seropositive group. Among seropositive subjects 48.3% presented HCV RNA.The most frequent genotype detected in all geographic areas of Mexico was l (subtype lA, 33%; subtype lB, 21.4%) followed by genotype 2 (subtype 2A, 8.50%). Subjects with genotype 1 had a significant correlation with the highest viral load. CONCLUSIONS: Our results show that nearly half of seropositive individuals are chronically infected. HCV infection has been shown in this study to be an emerging health problem in Mexico.

Hepatitis C seroprevalence and correlation between viral load and viral genotype among primary care clients in Mexico

OBJECTIVE: To measure hepatitis C virus (HCV) sero-prevalence, prevalence, hepatitis risk characteristics frequency, and genotype correlation with viral load among clients attending health care clinics. MATERIAL AND METHODS: Venous blood samples from l12 226 consecutive consenting adults were collected from January 2006 through December 2009. HCV antibodies were detected by immunoassay. HCV RNA was detected by qRT-PCR and viral genotype was performed by PCR and LIPA test. RESULTS: The HCV seroprevalence observed was l.5 percent (C.I. 95 percent l.3-l.7), from seropositive individuals 60.9 percent reported previous blood transfusion, 28.3 percent declared to have relatives with cirrhosis, 25.2 percent had tattoos or piercings, and 6.9 percent referred to have used drugs. Male gender and transfusion (p<0.00l) were the most frequent hepatitis risk characteristics in the HCV seropositive group. Among seropositive subjects 48.3 percent presented HCV RNA.The most frequent genotype detected in all geographic areas of Mexico was l (subtype lA, 33 percent; subtype lB, 21.4 percent) followed by genotype 2 (subtype 2A, 8.50 percent). Subjects with genotype 1 had a significant correlation with the highest viral load. CONCLUSIONS: Our results show that nearly half of seropositive individuals are chronically infected. HCV infection has been shown in this study to be an emerging health problem in Mexico.

OBJETIVO: Medir la seroprevalencia y prevalencia del virus de hepatitis C (VHC), la frecuencia de caracteristicas de riesgo y la correlacion genotipica con la carga viral en sujetos asistentes a clinicas de medicina familiar. MATERIAL Y METODOS: muestras de sangre venosa se colectaron de l12 226 adultos, previo consentimiento informado, de enero 2006 hasta diciembre 2009, para la deteccion de anticuerpos contra VHC por ELISA. La deteccion de RNA-VHC y el genotipo viral se realizo mediante qRT-PCR. RESULTADOS: La seroprevalencia de VHC fue l.5 por ciento (C.I. 95 por ciento l.3-l.7), 60.9 por ciento reportaron transfusion sanguinea previa, 28.3 por ciento dijo tener familiares cercanos con cirrosis, 25.2 por ciento tenian tatuajes o piercing y 6.9 por ciento refirio ser usuario de drogas intravenosas. El ser hombre, el antecedente de transfusiones y el uso de drogas (p<0.00l), fueron los factores con mayor frecuencia en el grupo VHC seropositivo. La prevalencia del RNA-VHC en seropositivos fue de 48.3 por ciento. El genotipo mas frecuente en todas las areas geograficas de Mexico fue el l (subtipo lA, 33 por ciento; subtipo lB, 21.4 por ciento) seguido por el genotipo 2 (subtipo 2A, 8.50 por ciento). Se observó una correlación positiva de 51 por ciento con la carga viral más alta y el genotipo viral 1A. CONCLUSIONES: Nuestros resultados muestran que cerca de la mitad de individuos seropositivos están infectados crónicamente. Esta infección debe considerarse como un problema emergente de salud pública en México.

Characteristics of hepatitis C treatment with pegylated interferons and ribavirin.

The effect of interferon alfa against hepatitis C virus has been well documented. However, clinical efficacy is low due to the short interferon residence in the body. To prolong half-life, interferon molecules have been bound to the biologically inert polymer, polyethyleneglycol. Pegylated interferons exhibit a longer residence time with an improved clinical efficacy, although the rate of therapeutic failure is still important. Addition of ribavirin to interferon, either pegylated or not, significantly increases efficacy. Therefore, the combination of a pegylated interferon with ribavirin has become the standard treatment of chronic hepatitis C. As the efficacy and safety of such combinations are not yet optimal, different drugs, including other types of long-acting interferons and ribavirin analogs, are presently been investigated.

Distribution of HCV genotypes and HCV RNA viral load in different regions of Mexico.

BACKGROUND AND AIM: To identify the geographic distribution of hepatitis C virus (HCV) genotypes and HCV RNA viral load in a large number of HCV-infected carriers in Mexico. METHODS: Patients with chronic hepatitis C (n = 8,802) were studied to identify HCV genotype using an immune line probe assay in samples shown previously to be positive for viral RNA by an RT-PCR test. Baseline HCV RNA was also evaluated. RESULTS: Genotype 1 accounted for 70.3%, genotype 2 for 21.8%, genotype 3 for 7.2%, genotype 4 for 0.3%, and genotype 5 for 0.1% of all cases; coinfection was present in 0.3%. Overall, Genotype 1 was the most prevalent Genotype. Regionally, genotype 1 occurred more frequently in the North-East, North, and Center- East regions of Mexico; genotype 2 was more prevalent in the South, East, and Peninsula regions; and genotype 3 was more prevalent in the North and North-West regions. Only 22.4% of patients with genotype 1 were classified in the low HCV RNA viral load category, and the distribution of this genotype did not differ significantly between regions. CONCLUSION: The prevalence of HCV genotypes and viral load in Mexico was 70.3% for genotype 1, but only 22.4% of these patients had a low HCV viral load. Distribution was not uniform in Mexico, with greater frequency of genotype 2 in South, East and Peninsula Regions and Genotype 3 in North and North-West Regions.

High antibody level: an accurate serologic marker of viremia in asymptomatic people with hepatitis C infection.

BACKGROUND: The screening and diagnosis of hepatitis C virus (HCV) infection is initiated by testing for antibody to HCV (anti-HCV). A positive anti-HCV test in blood donors represents ongoing infection in only a variable proportion of individuals. Because a high anti-HCV level has been associated with viremia, a study was conducted to determine whether a high antibody level is an accurate serologic marker for viremia in asymptomatic anti-HCV-positive persons. STUDY DESIGN AND METHODS: In a diagnostic test study, we included 856 anti-HCV-positive blood donors in a blood bank at Guadalajara, Jalisco, Mexico, between 2002 and 2007. A third-generation amplified chemiluminescence assay (ChLIA HCV) was used to detect anti-HCV. A positive result of the qualitative nucleic acid test (HCV RNA) was considered the gold standard for viremia. RESULTS: By receiver operating characteristic analysis, the signal-to-cutoff (S/CO) ratio of 20 or more was chosen as optimal to identify viremia and so was defined as high anti-HCV level. There was a significant difference in the proportion of viremia between subjects with high antibody level and those with lower levels (93.7% vs. 1.8%, respectively; p < 0.001). A high antibody level showed a sensitivity for viremia of 96.6% (95% confidence interval [CI], 93.8%-98.1%), a specificity of 96.6% (95% CI, 94.8%-97.8%), and a likelihood ratio of 28.6 (95% CI, 18.4%-44.6%). CONCLUSION: A high antibody level (S/CO ratio >/=20 by ChLIA HCV) clearly divides the viremic from the nonviremic blood donors and functions as an accurate serologic marker to guide the use of routine HCV RNA testing to confirm hepatitis C infection.

Combined therapy with danazol, pegilated interferon, and ribavirin improves thrombocytopenia and liver injury in rats with fibrosis.

The aim of this study was to investigate the effects of combinations of pegilated-interferon (PEG-IFN), ribavirin, and danazol on thrombocytopenia and liver injury in rats with fibrosis. Male adult Wistar rats were treated with either mineral oil, danazol (0.83 mg/kg per day), PEG-interferon alpha-2a (PEG-IFN, 0.3 microg/ week) + ribavirin (12 mg/kg per day), PEG-IFN + ribavirin + danazol, CCl(4) (4 g/kg for eight weeks), CCl(4) + PEG-IFN + ribavirin, or CCl(4) + PEG-IFN + ribavirin+ danazol. The following assays were conducted: hematology, clinical chemistry, liver function, liver fibrosis, lymphocyte cytokine mRNA expression, and bone-marrow DNA content. Platelet counts were low in sham-treated animals and animals treated with PEG- IFN + ribavirin (30% and 25% respectively; P < 0.05). PEG-IFN + ribavirin + danazol reduced platelet counts of fibrotic animals by only 9% (P < 0.05). PEG- IFN + ribavirin reduced hepatic collagen content by 50%, whereas danazol + PEG-IFN + ribavirin reduced hepatic collagen content by 60% (P < 0.05). PEG-IFN + ribavirin reduced the total bilirubin concentration by 27%, alanine amino transferase (ALT) activity by 75% and gamma-glutamyl transpeptidase (gamma-GTP) activity by 74% (P < 0.05). In contrast, danazol + PEG-IFN + ribavirin reduced total bilirubin levels by 61%, alkaline phosphatase activity by 45%, ALT activity by 76%, and gamma-GTP activity by 74% (P < 0.05). The only treatment that increased interleukin 10 (IL-10) mRNA in fibrotic rats was PEG-IFN + ribavirin. However, danazol + PEG-IFN + ribavirin reduced the expression of IL-6, IL-10, tumor necrosis factor alpha and transforming growth factor ss. Bone-marrow DNA content was not altered by any treatment. In conclusion, PEG-IFN + ribavirin + danazol could be a new therapeutic option for patients with liver injury, fibrosis, and thrombocytopenia.

Hepatitis C antibody intraassay correlation: is retest in duplicate necessary?

BACKGROUND: The hepatitis C virus antibody (anti-HCV) can be identified with third-generation immunoassays. The purpose of this study was to define the correlation or agreement between first and second reactive results of anti-HCV microparticle-based enzyme immunoassay (MEIA) and of chemiluminescence assays (ChLIAs) in blood donors, to determine whether repeat testing is necessary. STUDY DESIGN AND METHODS: Commercially available assays, third-generation HCV MEIA (Abbott), third-generation HCV ChLIA (Ortho), and third-generation HCV ChLIA (Abbott), were used to evaluate anti-HCV repeatedly reactive blood obtained from donations made at 23 Mexican blood centers over a period of 1 year. The intraassay correlation between first and second reactive anti-HCV tests with the Pearson r test and the coefficient of variation (CV) were determined. RESULTS: The intraassay correlation of 565 anti-HCV repeatedly reactive samples was 0.996 for the Abbott third-generation HCV MEIA, 0.995 for the Ortho third-generation HCV ChLIA, and 0.993 for the Abbott third-generation HCV ChLIA. The CVs of these assay systems were 2.82, 5.33, and 5.69 percent, respectively. CONCLUSION: A highly significant intraassay correlation between anti-HCV duplicates was found. Specimens with a single reactive anti-HCV result with the Abbott third-generation HCV MEIA, Ortho third-generation HCV ChLIA, and Abbott third-generation HCV ChLIA assays should be considered as positive and need not be retested. Such a change in the algorithm for blood donor screening is feasible because of the availability of highly automated platforms.