Background and objective
Cytochrome P450 (CYP) 1A2 activity is induced by cigarette smoking. Thus smoking cessation in patients while they are undergoing therapy with a CYP1A2 substrate such as ...theophylline or clozapine increases its concentrations and may cause adverse effects. Our objective was to determine the time course of CYP1A2 activity changes after smoking cessation in heavy smokers as the basis for dosing adaptation schemes.
Methods
The study was conducted in 8 men and 4 women (all white) who smoked 20 cigarettes or more per day. Sudden smoking cessation was carried out after a 14‐day run‐in period. Subjects were phenotyped for CYP1A2 activity at 6, 4, and 1 day before smoking cessation and at 0, 1, 2, 3, 6, 8, 10, and 13 days thereafter by use of the paraxanthine‐to‐caffeine ratio in plasma 6 hours after a 148‐mg caffeine test dose. A monoexponential decay of CYP1A2 activity to a residual value was fitted to the data by nonlinear regression analysis.
Results
On cessation of smoking, initial caffeine clearance (estimated geometric means and 95% confidence intervals) decreased significantly (P < .01), by 36.1% (30.9%‐42.2%), from 2.47 mL · min−1 · kg−1 body weight (2.03–3.00 mL · min−1 · kg−1 body weight) to a new steady state of 1.53 mL · min−1 · kg−1 body weight (1.24–1.89 mL · min−1 · kg−1 body weight). The apparent half‐life of CYP1A2 activity decrease was 38.6 hours (27.4–54.4 hours).
Conclusion
Doses of CYP1A2 substrates with a narrow therapeutic range should be decreased immediately on cessation of heavy smoking. As a rule of thumb, a stepwise daily dose reduction of approximately 10% until the fourth day after smoking cessation is proposed, which should be accompanied by therapeutic drug monitoring.
Clinical Pharmacology & Therapeutics (2004) 76, 178–184; doi: 10.1016/j.clpt.2004.04.003
: The cytochrome P450 enzyme CYP1A2 mediates the rate‐limiting step in the metabolism of many drugs including theophylline, clozapine, and tacrine as well as in the bioactivation of procarcinogens. ...CYP1A2 activity shows both pronounced intra‐ and interindividual variability, which is, among other factors, related to smoking causing enzyme induction, to drug intake and to dietary factors which may result in induction or inhibition. In contrast to these exogenous factors, genetic influences on enzyme activity seem to be less pronounced. Therefore, phenotyping of CYP1A2, i.e. the determination of the actual activity of the enzyme in vivo, represents a useful approach both for scientific and clinical applications. CYP1A2 is almost exclusively expressed in the liver. Since liver tissue cannot be obtained for direct phenotyping, a probe drug which is metabolized by CYP1A2 has to be given. Proposed probe drugs include caffeine, theophylline, and melatonin. Caffeine is most often used because of the predominating role of CYP1A2 in its overall metabolism and the excellent tolerability. Various urinary, plasma, saliva, and breath based CYP1A2 caffeine metrics have been applied. While caffeine clearance is considered as the gold standard, the salivary or plasma ratio of paraxanthine to caffeine in a sample taken approximately 6 hr after a defined dose of caffeine is a more convenient, less expensive but also fully validated CYP1A2 phenotyping metric. CYP1A2 phenotyping is applied frequently in epidemiologic and drug‐drug interaction studies, but its clinical use and usefulness remains to be established.
While experts have suspected a causal link between outbreaks of Zika virus and microcephaly, it was not demonstrated. The currently available data are here organized into the Austin Bradford Hill's ...aspects of evidence for the consideration of causality.
Giardia duodenalis is a leading cause of gastroenteritis worldwide. Humans are mainly infected by two different subtypes, i.e., assemblage A and B. Genotyping is hampered by allelic sequence ...heterozygosity (ASH) mainly in assemblage B, and by occurrence of mixed infections. Here we assessed the suitability of current genotyping protocols of G. duodenalis for epidemiological applications such as molecular tracing of transmission chains.
Two G. duodenalis isolate collections, from an outpatient tropical medicine clinic and from several primary care laboratories, were characterized by assemblage-specific qPCR (TIF, CATH gene loci) and a common multi locus sequence typing (MLST; TPI, BG, GDH gene loci). Assemblage A isolates were further typed at additional loci (HCMP22547, CID1, RHP26, HCMP6372, DIS3, NEK15411). Of 175/202 (86.6%) patients the G. duodenalis assemblage could be identified: Assemblages A 25/175 (14.3%), B 115/175 (65.7%) and A+B mixed 35/175 (20.0%). By incorporating allelic sequence heterozygosity in the analysis, the three marker MLST correctly identified 6/9 (66,7%) and 4/5 (80.0%) consecutive samples from chronic assemblage B infections in the two collections, respectively, and identified a cluster of five independent patients carrying assemblage B parasites of identical MLST type. Extended MLST for assemblage A altogether identified 5/6 (83,3%) consecutive samples from chronic assemblage A infections and 15 novel genotypes. Based on the observed A+B mixed infections it is estimated that only 75% and 50% of assemblage A or B only cases represent single strain infections, respectively. We demonstrate that typing results are consistent with this prediction.
Typing of assemblage A and B isolates with resolution for epidemiological applications is possible but requires separate genotyping protocols. The high frequency of multiple infections and their impact on typing results are findings with immediate consequences for result interpretation in this field.
Following outbreaks linked to frozen strawberries in Sweden and Austria in 2018, 65 cases linked to the same hepatitis A virus strain were detected in Germany between October 2018 and January 2020, ...presenting in two waves. Two case-control studies and a comparison of cases' consumption frequencies with purchase data from a large consumer panel provided strong evidence for frozen strawberry cake as the main vehicle of transmission. Of 46 cases interviewed, 27 reported consuming frozen strawberry cake and 25 of these identified cake(s) from brand A spontaneously or in product picture-assisted recall. Trace back investigations revealed that the Polish producer involved in the previous outbreaks in Sweden and Austria had received frozen strawberries from Egypt via a wholesaler that also delivered frozen strawberries to manufacturer of brand A. Phylogenetic analyses linked the outbreak strain to similar strains formerly isolated from sewage, stool and strawberries in Egypt. Complete trace back and timely recall of products with strong evidence of contamination is important to control an outbreak and prevent later resurgence, particularly for food items with a long shelf life. Continued molecular surveillance of hepatitis A is needed to identify outbreaks and monitor the success of food safety interventions.
Human norovirus accounts for the majority of viral gastroenteritis cases worldwide. It is a fast evolving virus generating diversity via mutation and recombination. Therefore, new variants and new ...recombinant strains emerge in the norovirus population. We characterized norovirus positive stool samples from one intensively studied district Märkisch-Oderland state Brandenburg with the samples from other states of Germany in order to understand the molecular epidemiological dynamics of norovirus outbreaks in Germany 2018. PCR systems, Sanger sequencing, and phylogenetic analyses were used for genotyping. Noroviruses of 250 outbreaks in Germany were genotyped, including 39 outbreaks for the district Märkisch-Oderland. Viral diversity in Märkisch-Oderland as compared to Germany was similar, but not identical. The predominant genogroup in Germany was GII with predominate genotype GII.P16-GII.4 Sydney, whereas GII.P31-GII.4 Sydney was the most frequent in Märkisch-Oderland. Genogroup I viruses were less frequently detected, regional and national. Within the sequences of GII.4 recombinants, two distinct clusters were identified with outbreaks from Märkisch-Oderland. Further analysis of sequence data and detailed epidemiological data are needed in order to understand the link between outbreaks in such clusters. Molecular surveillance should be based on samples collected nationally in order to trace comprehensive virus distribution and recombination events in virus population.
, also known as rat hepatitis E virus (HEV), has been shown to sporadically cause disease in immunocompromised and immunocompetent adults. While routine serological assays vary in reactivity, rat HEV ...is not detected in routine HEV RT-PCR. Thus, such infections could be either missed or misclassified as conventional HEV (
) infections. We conducted a retrospective screening study among serum and plasma samples from patients suspected of having HEV infection, which were archived at the national consultant laboratory for HAV and HEV between 2000 and 2020. We randomly selected
= 200 samples, which were initially tested reactive (positive or borderline) for HEV-IgM and negative for HEV RNA and re-examined them using a highly sensitive
genotype 1-specific in-house RT-qPCR (LoD 95: 6.73 copies per reaction) and a nested RT-PCR broadly reactive for
and
. Conventional sanger sequencing was conducted for resulting PCR products. No atypical HEV strains were detected (0 of 200 0.0%; 95% confidence interval: 0.0%-1.89%, indicating that
infections in the investigated population (persons with clinical suspicion of hepatitis E and positive HEV-IgM) are very rare.
Zusammenfassung
Mit Virushepatitis A bis E werden verschiedene infektiöse Entzündungen des Leberparenchyms bezeichnet, die durch die Hepatitisviren A bis E (HAV, HBV, HCV, HDV und HEV) ausgelöst ...werden. Zwar ähneln sich die Krankheitsbilder, die Erreger gehören jedoch zu verschiedenen Virusfamilien und unterscheiden sich bezüglich der Pathogenese, der Übertragungswege, des klinischen Verlaufs und der Präventions- und Therapiemöglichkeiten. In Deutschland besteht eine namentliche Meldepflicht nach Infektionsschutzgesetz (IfSG) für den direkten oder indirekten Nachweis und für Verdacht, Erkrankung und Tod. Die Daten werden an das Robert Koch-Institut übermittelt.
In diesem Beitrag wird die Epidemiologie der Hepatitiden A bis E anhand publizierter Studien und Meldedaten beschrieben und es werden aktuelle Herausforderungen und Präventionsansätze aufgezeigt. Letztere bestehen insbesondere in der verbesserten Umsetzung bereits bestehender Impfempfehlungen (Hepatitis A und B), dem verbesserten Zugang zu Prävention, Testung und Versorgung, einschließlich Therapie mit antiviralen Medikamenten (Hepatitis B, C und D), und der Erkennung und Verhinderung lebensmittelbedingter Infektionen und Ausbrüche und Verbesserungen auf dem Gebiet der Lebensmittelsicherheit (Hepatitis A und E).
The largest known outbreak caused by a rare hybrid strain of Shiga toxin-producing E.coli (STEC) and enteroaggregative E. coli (EAEC) (E.coli O104:H4) of serotype O104:H4 occurred in Germany in 2011. ...Fenugreek sprouts acted as a transmission vehicle and were widely consumed in the outbreak area at the time of the epidemic. In total 3,842 people developed a clinical illness caused by this strain; however the rates of asymptomatic infections remain unclear. We aimed to develop a serological assay for detection of E.coli O104 LPS specific antibodies and to establish the post-outbreak levels of seropositivity among people with documented exposure to contaminated sprouts.
Developed serological assays (ELISA with 84% sensitivity, 63% specificity and Western Blot with 100% sensitivity, 82.5% specificity) identified 33% (16/49) level of asymptomatic infection. Relatively small sample size and a significant time- lapse between the onset of symptoms and serum samples collection (appr. 8 weeks) might explain the assay variability. No association was found between clinical or demographic characteristics and assay positivity. Larger studies are needed to understand the complexity of human immune response and factors influencing development of clinical symptoms. Development of intra-outbreak research plans will substantially aid the conduct of more thorough scientific investigation during an outbreak period.
•The outbreak in Germany’s gay hotspot Berlin included 222 cases, most self-identifying as MSM.•Hepatitis A vaccination is recommended and free of charge for MSM in Germany.•The vaccination coverage ...was low among MSM, in particular among young and foreign-born.•Various measures were implemented targeting the MSM community, physicians, and the public.•Increased vaccination uptake shows the success of the interventions.
To describe the characteristics of a large hepatitis A virus (HAV) outbreak among men who have sex with men (MSM) in Berlin and to assess the impact of measures implemented.
Cases of laboratory-confirmed, symptomatic HAV infection notified in Berlin, Germany between August 2016 and February 2018 were analysed using routine and enhanced surveillance data including genotyping results. Several studies involving different groups of participants were conducted to further investigate the outbreak, including surveys on knowledge and practices of HAV vaccination among physicians and vaccination coverage and determinants of vaccination status among MSM. The measures implemented were categorized by target group in a Gantt chart. To assess their impact, health insurance data on HAV vaccination uptake were analysed, comparing Berlin and other federal states.
During the outbreak period, a total of 222 cases were reported (of which 91 were sequence-confirmed), with a peak in case numbers in January 2017. Physicians were aware of the existing vaccination recommendations, but vaccination coverage among 756 MSM was low, with 32.7% being completely vaccinated and 17.3% being incompletely vaccinated before 2017. HAV vaccination before 2017 was associated with being born in Germany (odds ratio 2.36) and HIV-positive (odds ratio 1.80). HAV monovalent vaccination uptake increased by 164% from 2016 to 2017 among males in Berlin, compared to 7% in other federal states.
Multiple measures targeting the MSM community, physicians, and public health to increase HAV vaccination uptake were successfully implemented. To prevent future HAV outbreaks, we recommend monitoring vaccination coverage among MSM, promoting awareness of existing recommendations among physicians, and ensuring access for foreign-born and young MSM.
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