| 1. |
- Ariano, R E, et al.
(författare)
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An evaluation of an optimal sampling strategy for meropenem in febrile neutropenics
- 2005
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Ingår i: Journal of Clinical Pharmacology. - : Wiley. - 0091-2700. ; 45:7, s. 832-835
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Tidskriftsartikel (refereegranskat)abstract
- Optimal sampling design with nonparametric population modeling offers the opportunity to determine pharma-cokinetic parameters for patients in whom blood sampling is restricted. This approach was compared to a standard individualized modeling method for meropenem pharmacokinetics in febrile neutropenic patients. The population modeling program, nonparametric approach of expectation maximization (NPEM), with a full data set was compared to a sparse data set selected by D-optimal sampling design. The authors demonstrated that the D-optimal sampling strategy, when applied to this clinical population, provided good pharmacokinetic parameter estimates along with their variability. Four individualized and optimally selected sampling time points provided the same parameter estimates as more intensive sampling regimens using traditional and population modeling techniques. The different modeling methods were considerably consistent, except for the estimation of CLd with sparse sampling. The findings suggest that D-optimal sparse sampling is a reasonable approach to population pharmacokinetic/pharmacodynamic studies during drug development when limited sampling is necessary.
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| 2. |
- Ariano, RE, et al.
(författare)
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Pharmacokinetics and pharmacodynamics of meropenern in febrile neutropenic patients with bacteremia
- 2005
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Ingår i: Annals of Pharmacotherapy. - 1060-0280. ; 39:1, s. 32-38
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pharmacodynamic investigations with antimicrobials define the relationship between the infecting organism and achievable drug concentrations with clinical outcome. Objective: To examine this relationship for meropenem in a population of patients who are at high risk of infection-related morbidity and mortality. Methods: The study was a retrospective analysis of a multicenter, randomized, blinded clinical trial. A population-based predictive model was created using data from adults with febrile neutropenia and the nonparametric modeling program, NPEM. Patient age, body weight, and serum creatinine level were covariates in the model used to predict unbound concentrations for each patient. Pathogen susceptibility was estimated using product literature minimum inhibitory concentrations for effectiveness against 50% of microorganisms (MIC50) for specific organisms. The pharmacodynamic index of percent time above MIC (% T>MIC) was analyzed for its association with clinical outcome. Results: A 2-compartment pharmacokinetic model using patient covariates of body weight and renal function best described the pharmacokinetics of meropenem in febrile neutropenic patients. Sixty patients with confirmed gram-positive or -negative bacteremia were studied. An average of 83% T>MIC was identified for the 42 clinical responders compared with 59% T>MIC for the 18 nonresponders (p=0.04). An 80% clinical response rate was evident when the % T>MIC for meropenem exceeded 75% of the dosing interval (p=0.01). Conclusions: To our knowledge, this is the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population. Based on this relationship, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections. Our model provides further justification for a prospective clinical trial to evaluate a pharmacodynamically targeted meropenem dosing schedule as to its ability to improve clinical outcome in these patients.
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| 3. |
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| 4. |
- Fridell, Mats, et al.
(författare)
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Prediction of psychiatric comorbidity on premature death in a cohort of patients with substance use disorders : A 42-year follow-up
- 2019
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Ingår i: BMC Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 19:1, s. 150-150
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Tidskriftsartikel (refereegranskat)abstract
- Background: We need to better understand how the use of different substances and psychiatric comorbidity influence premature death generally and cause-specific death by overdose, intoxication and somatic disorders in people with substance use disorders. Method: A cohort of 1405 patients consecutively admitted to a Swedish detoxification unit for substance use disorders in 1970-1995 was followed-up for 42 years. Substances were identified by toxicological analyses. Mortality figures were obtained from a national registry. Causes of death were diagnosed by forensic autopsy in 594 patients deceased by 2012. Predictions were calculated by competing risks analysis. Results: Forty-two per cent of the cohort died during follow-up; more men than women (46.3% vs 30.4%). The standardised mortality ratio (SMR) was calculated as the ratio of observed deaths in males and females in specific age groups in the cohort versus expected deaths in corresponding groups in the general population. SMR was 5.68 for men (CI 95%; 5.04-6.11) and 4.98 (CI 95%; 4.08-5.88) for women. The crude mortality rate (number of deaths divided by number of person observation years) was 2.28% for men and 1.87% for women. Opiates predicted increased risk of premature death while amphetamine and cannabis predicted lower risk. Comorbid psychiatric disorders were identified in 378 cases and personality disorders in 763 cases. Primary psychoses or mood/depression and anxiety disorders predicted a higher risk of premature mortality. Death by overdose was predicted by male gender, younger age at admission to substance treatment, opiate use, and comorbid depression and anxiety syndromes. Cannabis and amphetamine use predicted a lower risk of overdose. Death by intoxication was predicted by male gender, use of sedatives/hypnotics or alcohol/mixed substances, primary psychoses and depression/anxiety syndromes. Premature death by somatic disorder was predicted by male gender and alcohol/mixed abuse. Conclusion: Psychiatric comorbid disorders were important risk factors for premature drug-related death. Early identification of these factors may be life-saving in the treatment of patients with substance use disorders.
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| 5. |
- Nyhlén, Anna
(författare)
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Antibiotics in patients on chemotherapy; aspects on pharmacokinetic and pharmacodynamic interactions with antineoplastic drugs
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of these studies were to investigate the pharmacokinetics of two beta-lactam antibiotics in patients with fever and cytostatic-induced neutropenia and the influence of cytostatic-induced gastrointestinal damage on the absorption of co-trimoxazole. Furthermore to study the pharmacodynamic interactions between antibiotics and antineoplastic drugs and the impact of antineoplastic drugs on the intestinal microflora. Methods: Kinetic data were obtained by model-independent methods for the beta-lactam antibiotics and by population-based methods for co-trimoxazole. Bacterial killing curves and postantibiotic effects (PAE) of different antibiotics alone and in combination with antineoplastic drugs were studied in vitro. Faecal samples were obtained from patients with acute leukaemia on different cytostatic regimens before, during and after treatment and were cultured quantitatively and qualitatively. Results and Discussion: The faster elimination of meropenem and ceftazidime in our patients compared to historical controls results in shorter times above MIC for the most common pathogens. A dose interval of 6 h seems safer than the commonly used 8 h interval, since serum concentrations should stay above MIC for most of a dose interval in these immunocompromised patients. No correlation was found between the degree of cytostatic-induced gastrointestinal damage and the bioavailability of co-trimoxazole, indicating that the dose of co-trimoxazole needs not be adjusted in these patients.Antibacterial effect and PAEs of the combinations of antibiotics and antineoplastic drugs did not differ markedly from the effects of the antibiotics alone. In the presence of 5-FU and doxorubicin, the antibacterial effect of tobramycin was increased against S. aureus. The PAEs of meropenem and ciprofloxacin against S. epidermidis were synergistically prolonged by 5-FU. This might be due to inhibition of slime production in these strains by 5-FU. The antineoplastic regimens caused only minor changes of the intestinal microflora.
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| 6. |
- Nyhlén, Anna, et al.
(författare)
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Bactericidal Effect of Combinations of Antibiotic and Antineoplastic Agents against Staphylococcus aureus and Escherichia coli.
- 2002
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Ingår i: Chemotherapy. - : S. Karger AG. - 0009-3157 .- 1421-9794. ; 48:2, s. 71-77
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Tidskriftsartikel (refereegranskat)abstract
- Background: The bactericidal effect of some antibiotic and antineoplastic agents commonly used in clinical practice was investigated to analyse whether the combinations act synergistically, have indifferent or antagonistic antibacterial effects compared to the effect of the antibiotics alone. Methods: The rate of killing of meropenem, ceftazidime and tobramycin was studied against six different strains of Staphylococcus aureus and Escherichia coli, and the results were compared to the rate of killing of the antibiotics in combination with the cytostatic drugs doxorubicin, etoposide and 5-fluorouracil (5-FU). Results: Tobramycin showed synergy against two strains of S. aureus after 3 h in the presence of 5-FU and against one strain of S. aureus in the presence of doxorubicin. Meropenem induced an antagonistic bactericidal effect against one isolate of S. aureus after 24 h. Ceftazidime expressed an indifferent bactericidal effect together with the cytostatic agents. The antineoplastic agents had no impact on the bacterial killing of any of the antibiotics against E. coli. Conclusions: Tobramycin expressed a significantly better bactericidal effect against S. aureus after 3 h in the presence of doxorubicin and 5-FU than tobramycin alone. Meropenem expressed antagonism against one clinical strain of S. aureus, but the cytostatic drugs did not affect the killing of other strains tested. Ceftazidime expressed indifferent bactericidal activity together with the antineoplastic agents.
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| 7. |
- Nyhlén, Anna, et al.
(författare)
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Causes of premature mortality in Swedish drug abusers : a prospective longitudinal study 1970-2006
- 2011
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Ingår i: Journal of Forensic and Legal Medicine. - : Elsevier BV. - 1752-928X .- 1878-7487. ; 18:2, s. 66-72
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Forskningsöversikt (refereegranskat)abstract
- AimsTo evaluate premature mortality and causes of death from young adulthood to middle age in a cohort of drug users followed during almost four decadesDesignFollow-up study of a consecutive cohort of patients with drug abuse/dependence.MethodsA cohort of 561 drug abusers, admitted to a detoxification and short-term rehabilitation unit 1970–1978 was followed to December 31st, 2006. Standardized interviews and hospital records with toxicological analyses were used for demographic data, substance use and psychiatric diagnoses at admission. For Follow-up analyses, autopsy protocols including toxicology tests and death certificates were obtained for assessment of causes of death which were coded according to ICD-10. Age-group standardized mortality ratios were calculated independently for both sexes.Results204 persons (36.4%) were deceased by 2006. SMR was 5.94 for the cohort. Compared to an age- and gender-matched population, the risk of premature death was about eighteen times higher between the ages of 20–44 and about five times higher from 45 up to the age of 69. Of 120 (59%) drug-related deaths, 43 were opiate overdoses, and 3 were overdose from amphetamine. A total of 53 (26%) persons died violent deaths: 39 suicides, of which 25 were drug-related, 3 homicides and 12 accidents. The Swedish national causes of death register underestimated drug-related death by 37% and suicide by 85% compared to the results from this study.ConclusionsThe cohort of drug abusers had an increased risk of premature often drug-related and violent death well into middle age, and to a great extent the drug addicts died from the same drug they had abused when they were first admitted for treatment. The underestimation of drug-related death and suicide in some national death cause registers could be reduced if the doctor routinely records ICD codes when issuing death certificates and autopsy protocols.
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| 8. |
- Nyhlén, Anna, et al.
(författare)
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Impact of combinations of antineoplastic drugs on intestinal microflora in 9 patients with leukaemia.
- 2002
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Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 34:1, s. 17-21
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Tidskriftsartikel (refereegranskat)abstract
- The impact of antineoplastic drugs on the intestinal microflora was studied in 9 patients with acute leukaemia during chemotherapy and in 5 patients also during chemotherapy-induced neutropenia. Quantitative and qualitative microbiological analyses of faecal samples obtained before and during chemotherapy showed significantly increased counts of Bacteroides spp. in 3/9 patients and, during neutropenia, significantly increased counts of yeasts in 2/5 patients; however, the intestinal microflora was stable in most patients.
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| 9. |
- Nyhlén, Anna, et al.
(författare)
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Postantibiotic effect of meropenem and ciprofloxacin in the presence of 5-fluorouracil
- 2002
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Ingår i: Chemotherapy. - 0009-3157. ; 48:4, s. 182-188
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Tidskriftsartikel (refereegranskat)abstract
- Background: The postantibiotic effect (PAE) of meropenem and ciprofloxacin was studied in the presence of the antineoplastic agent 5-fluorouracil (5-FU). The purpose of the study was to investigate whether the PAEs of the combinations differed from the PAEs of the antibiotics alone. Methods: The PAEs of the combinations of 5-FU plus meropenem or ciprofloxacin were determined with viable counts against four reference strains of Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli and two clinical isolates of S. epidermidis. The results were compared with the PAEs of the antibiotics drugs and 5-FU alone. The gram-positive strains were tested for slime production, both alone and in the presence of 5-FU. Results: Against two of the three tested strains of S. epidermidis, the combination of ciprofloxacin and 5-FU gave a synergistic prolongation of the PAE in comparison with the PAEs induced by the drugs alone. The combinations showed indifference against the other bacteria. The combination of meropenem and 5-FU had a synergistic PAE against one of the three tested strains of S. epidermidis and an additive effect against E coli but showed indifference against the rest of the strains. Conclusions:The presence of 5-FU did not influence the PAEs of the antibiotics against most of the tested strains, but caused a synergistic prolongation of the PAEs induced by ciprofloxacin and meropenem against some of the tested strains of S. epidermidis. 5-FU inhibited slime production in the same S. epidermidis strains, which might have contributed to the longer PAE.
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| 10. |
- Nyhlén, Anna, et al.
(författare)
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Substance abuse and psychiatric co-morbidity as predictors of premature mortality in Swedish drug abusers a prospective longitudinal study 1970 - 2006
- 2011
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Ingår i: BMC Psychiatry. - : BioMed Central (BMC). - 1471-244X. ; 11
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Forskningsöversikt (refereegranskat)abstract
- BackgroundFew longitudinal cohort studies have focused on the impact of substances abused and psychiatric disorders on premature mortality. The aim of the present study was to identify predictors of increased risk of drug related death and non drug related death in substance abusers of opiates, stimulants, cannabis, sedatives/hypnotics, hallucinogens and alcohol over several decades.MethodsFollow-up study of a consecutive cohort of 561 substance abusers, admitted to a detoxification unit January 1970 to February 1978 in southern Sweden, and followed up in 2006. Demographic and clinical data, substance diagnoses and three groups of psychiatric diagnoses were identified at first admission. Causes of death were coded according to ICD-10 and classified as drug related deaths or non drug related deaths. To identify the incidence of some probable risk factors of drug related premature death, the data were subjected to a competing risks Cox regression analysis.ResultsOf 561 patients in the cohort, 11 individuals had either emigrated or could not be located, and 204/561 patients (36.4%) were deceased by 2006. The cumulative risk of drug related death increased more in the first 15 years and leveled out later on when non drug related causes of death had a similar incidence. In the final model, male gender, regular use of opiates or barbiturates at first admission, and neurosis were associated with an increased risk of drug related premature death, while cannabis use and psychosis were associated with a decreased risk. Neurosis, mainly depression and/or anxiety disorders, predicted drug related premature death while chronic psychosis and personality disorders did not. Chronic alcohol addiction was associated with increased risk of non drug related death.ConclusionsThe cohort of drug abusers had an increased risk of premature death to the age of 69. Drug related premature death was predicted by male gender, the use of opiates or barbiturates and depression and anxiety disorders at first admission. The predicted cumulative incidence of drug related death was significantly higher in opiate and barbiturate abusers over the observed period of 37 years, while stimulant abuse did not have any impact. Alcohol contributed to non drug related death.
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