Comprehensive evidence implies a higher social cost of CO2.

The social cost of carbon dioxide (SC-CO2) measures the monetized value of the damages to society caused by an incremental metric tonne of CO2 emissions and is a key metric informing climate policy. Used by governments and other decision-makers in benefit-cost analysis for over a decade, SC-CO2 estimates draw on climate science, economics, demography and other disciplines. However, a 2017 report by the US National Academies of Sciences, Engineering, and Medicine1 (NASEM) highlighted that current SC-CO2 estimates no longer reflect the latest research. The report provided a series of recommendations for improving the scientific basis, transparency and uncertainty characterization of SC-CO2 estimates. Here we show that improved probabilistic socioeconomic projections, climate models, damage functions, and discounting methods that collectively reflect theoretically consistent valuation of risk, substantially increase estimates of the SC-CO2. Our preferred mean SC-CO2 estimate is $185 per tonne of CO2 ($44-$413 per tCO2: 5%-95% range, 2020 US dollars) at a near-term risk-free discount rate of 2%, a value 3.6 times higher than the US government's current value of $51 per tCO2. Our estimates incorporate updated scientific understanding throughout all components of SC-CO2 estimation in the new open-source Greenhouse Gas Impact Value Estimator (GIVE) model, in a manner fully responsive to the near-term NASEM recommendations. Our higher SC-CO2 values, compared with estimates currently used in policy evaluation, substantially increase the estimated benefits of greenhouse gas mitigation and thereby increase the expected net benefits of more stringent climate policies.

Progression of Diabetic Complications in Subgroups of People with Long Term Diabetes Type 1 According to Clinical Course.

AIMS: Prevention and prediction of microvascular complications are important aims of medical care in people with type 1 diabetes. Since the course of the disease is heterogenous, we tried to identify subgroups with specific risk profiles for microvascular complications. METHODS: Retrospective analysis of a cohort of 285 people (22637 consultations) with >10 years of type 1 diabetes. Persons were grouped into slow (<15 years), fast (>15 years) and non progressors according to the average onset of microvascular complications. Generalized estimating equations for binary outcomes were applied and pseudo coefficients of determination were calculated. RESULTS: Progression to microvascular disease was associated with age (OR: 1.034 [1.001-1.068]; p=0.04), diabetes duration (OR: 1.057 [1.021-1.094]; p=0.002), HbA1c (OR: 1.035 [1.011-1.060]; p=0.005), BMI (OR: 0.928 [0.866-0.994]; p=0.034) and the social strata index (OR: 0.910 [0.830-0.998]; p=0.046). Generalized estimating equations predicted 31.02% and exclusion of HbA1c marginally reduced the value to 28.88%. The proportion of patients with LADA was higher in fast than slow progressors [13 (26.5%) vs. 14 (11.9%); p=0.019]. A generalized estimating equation comparing slow to fast progressors revealed no significant markers. CONCLUSION: In our analysis, we were able to confirm known risk factors for microvascular disease in people with type 1 diabetes. Overall, prediction of individual risk was difficult, the effect of individual markers minor and we could not find differences regarding slow or fast progression. We therefore emphasis the need for additional markers to predict individual risk for microvascular disease.

Antidiabetic Therapy and Rate of Severe Hypoglycaemia in Patients with Type 2 Diabetes and Chronic Kidney Disease of Different Stages - A Follow-up Analysis of Health Insurance Data from Germany.

BACKGROUND: The presence of chronic kidney disease (CKD) influences the type of antiglycaemic therapy and the risk for hypoglycaemia. METHODS: In 2006, 2011 and 2016 health insurance data of people with diabetes type 2 were screened for CKD and the presence of severe hypoglycaemia (sHypo). The type of antihyperglycaemic therapy was recorded due to Anatomical Therapeutic Chemical (ATC) codes up to 3 months before suffering sHypo. RESULTS: The prevalence of CKD increased from 5.3% in 2006 to 7.3% in 2011 and 11.2% in 2016. Insulin-based therapies were used in 39.0, 39.1, and 37.9% of patients with, but only in 17.7, 17.4, and 18.8% of patients without CKD. Although the proportion of the CKD stages 1, 2 and 5 decreased, CKD stages 3 and 4 increased. The proportion of sHypo in CKD declined from 2006 (3.5%) to 2011 (3.0%) and 2016 (2.2%) but was still more than 10 times higher as compared to type 2 diabetic patients without CKD (0.3/0.2/0.2%) conferring a significantly higher probability of sHypo (OR 9.30, 95%CI 9.07-9.54) in CKD. The probability of sHypo was significantly lower in 2016 than in 2006 both in patients with (OR 0.58; CI 0.55-0.61) and without CKD (OR 0.70; CI 0.68-0.73). CONCLUSION: The prevalence of CKD increased from 2006 to 2016. Patients with CKD exhibited a 9-fold increased probability of sHypo, especially in patients treated with insulin plus oral anti-diabetic drugs. However, the rate and risk for sHypo decreased over time, probably as a consequence of new antidiabetic treatment options, better awareness of sHypo, and changed therapy goals.

Reduction of HbA1c and diabetes-related distress after intervention in a diabetes day care clinic in people with type 2 diabetes but not with type 1 diabetes.

OBJECTIVE: The aim of this prospective, longitudinal study was to assess diabetes-related distress in people with diabetes mellitus type 1 (DM1) and type 2 (DM2) treated for diabetes-related problems and to evaluate, whether distress by diabetes are reduced after intervention in a diabetes day care clinic (DDC). METHODS: Diabetes-related burden was assessed with the "Problem Area In Diabetes" (PAID) questionnaire before (T0), directly after (T1) and 6 months after intervention (T2) in the DDC in 72 people (18 DM1, 54 DM2) admitted with a diabetes-specific problem to a DDC in a University department for metabolic diseases. A PAID score of ≥40 was considered as high diabetes-related distress. RESULTS: The PAID score in people with DM1 was not significantly different between T0, T1 and T2. Furthermore, neither HbA1c nor insulin dose did change at T2. In participants with DM2, the PAID score decreased significantly from T0 to T1 (18.4±15.9 vs. 15.4+± 13.0, p=0.042) and preserved the benefit at T2 (15.0±13.3). In addition, there was a significant reduction in HbA1c (-1.2%, p<0.001) and body weight (-1.3 kg, p=0.038) between T0 and T2. Insulin dose per day was 15.0 IU/day lower at T1 (p=0.006) and 9.0 IU/day lower at T2 (p=0.212) in comparison to T0. CONCLUSIONS: Diabetes-related distress was reduced after a problem-oriented intervention in a DDC in people with DM2 but not with DM1. Although, all participants at tertiary care level had serious diabetes-specific problems before intervention, mean PAID score was far under the threshold of 40 points thus distress was low.

Derivation, Replication, and Validity Analyses of a Screener for the Behavioral Assessment of Executive Functions in Young Adults.

Ecologically valid indicators of executive functions are designed to capture dysfunction not easily measured in a lab setting. Here, we present two studies on the development and validity analyses of a behavioral screener for executive functions among young adults. In Study 1, we derived a four-factor (problem solving, attentional control, behavioral control, and emotional control) behavioral screener using a sample of 765 individuals. We used invariance analyses to evaluate the screener's measurement reliability across sex. In Study 2, we replicated the screener derivation analyses using an independent sample of 197 undergraduates. To further examine the screener's validity, we evaluated it against a well-known executive functions rating scale. The four-factor model was supported in both samples and analyses provided support for this screener as a valid and reliable measure for everyday executive functions among young adults.

Assessment of executive function in young children with and without ASD using parent ratings and computerized tasks of executive function.

OBJECTIVE: The current study investigated executive function (EF) in young children with and without autism spectrum disorder (ASD) using multiple methods of assessment. METHOD: Young children (M = 63.2 months) with and without ASD, matched on age, IQ, and maternal education, were assessed on computerized measures of working memory, inhibition, flexibility, and planning. Parents completed a behavior rating scale assessing children's EF within everyday contexts. RESULTS: There were no significant group differences on working memory, inhibition, flexibility, or planning. The mean difference on one aspect of the planning task (number of correct trials), however, approached significance and showed a medium to large effect size. There was also a significant difference between groups on the EF behavior rating scale, indicating that participants with ASD demonstrated greater executive dysfunction, as indexed by parent report. CONCLUSIONS: The results suggest that in young children with ASD, EF difficulties may only become apparent when situational demands require coordinating multiple abilities, as assessed with scales indexing children's abilities to manage their day-to-day EF-related behavior. We suggest that multiple methods are needed to achieve a comprehensive and valid EF assessment in young children with ASD.

Recommendations for the transition of patients with ADHD from child to adult healthcare services: a consensus statement from the UK adult ADHD network.

The aim of this consensus statement was to discuss transition of patients with ADHD from child to adult healthcare services, and formulate recommendations to facilitate successful transition. An expert workshop was convened in June 2012 by the UK Adult ADHD Network (UKAAN), attended by a multidisciplinary team of mental health professionals, allied professionals and patients. It was concluded that transitions must be planned through joint meetings involving referring/receiving services, patients and their families. Negotiation may be required to balance parental desire for continued involvement in their child's care, and the child's growing autonomy. Clear transition protocols can maintain standards of care, detailing relevant timeframes, responsibilities of agencies and preparing contingencies. Transition should be viewed as a process not an event, and should normally occur by the age of 18, however flexibility is required to accommodate individual needs. Transition is often poorly experienced, and adherence to clear recommendations is necessary to ensure effective transition and prevent drop-out from services.

History of mild hypoglycaemia does not affect the prevalence of diabetes-related distress in people with diabetes.

AIMS: The occurrence of hypoglycaemia is assumed to be associated with increased diabetes-related distress. We investigated the association of mild hypoglycaemia (MH) with diabetes-related distress in a large outpatient cohort with diabetes type 1 (DM1) and type 2 (DM2). METHODS: In a cross-sectional study, we recorded MH and simultaneously assessed diabetes-related distress with the PAID questionnaire in 783 people with diabetes [female 43.8 %, age 63.7 years, duration of diabetes 17.3 years, HbA1c 7.0 % (53 mmol/mol)] in an university outpatient department for metabolic diseases over a period of three months. Participants with and without MH were compared. RESULTS: People with DM1 (n = 191) had 1.09 MH per week. Diabetes-related distress was not different comparing people with DM1 with (n = 125) and without (n = 66) MH (PAID score 18.4 ± 16.2 vs. 16.6 ± 15.0, p = 0.449). The frequency of MH per week in people with DM2 on oral antidiabetic therapy (n = 182) and with insulin therapy (n = 410) is low (0.03 vs. 0.1 episodes). People with DM2 on insulin therapy with (n = 72) and without (n = 338) MH have a comparable PAID score (17.9 ± 13.3 vs. 16.8 ± 14.9, p = 0.552). 14.4 % of those with DM1 as well as 12.5 % of those with DM2 on insulin feel hypoglycaemic events to be a "somewhat serious problem" or "serious problem". CONCLUSIONS: In an outpatient setting, MH is not associated with increased diabetes-related distress or burden in people with DM1 or DM2.

Atom-economical synthesis of a high silica CHA zeolite using a solvent-free route.

A high silica CHA zeolite is successfully synthesized in the presence of a small amount of N,N,N-dimethylethylcyclohexylammonium bromide under solvent-free conditions. Catalytic tests for the selective catalytic reduction of NOx with NH3 (NH3-SCR) and methanol-to-olefins (MTO) show that the sample from the solvent-free route exhibits comparable catalytic properties to that from the conventional route.

A developmental systems approach to executive function.

According to recent claims from behavior genetics, executive function (EF) is almost entirely heritable. The implications of this claim are significant, given the importance of EF in academic, social, and psychological domains. This paper critically examines the behavior genetics approach to explaining individual differences in EF and proposes a relational developmental systems model that integrates both biological and social factors in the development of EF and the emergence of individual differences in EF. Problems inherent to behavioral genetics research are discussed, as is neuroscience research that emphasizes the plasticity of the prefrontal cortex. Empirical evidence from research on stress, social interaction, and intervention and training demonstrates that individual differences in EF are experience-dependent. Taken together, these findings challenge the claim that EF is almost entirely genetic but are consistent with an approach that considers biological differences in the context of social interaction.

Occupational issues of adults with ADHD.

BACKGROUND: ADHD is a common neurodevelopmental disorder that persists into adulthood. Its symptoms cause impairments in a number of social domains, one of which is employment. We wish to produce a consensus statement on how ADHD affects employment. METHODS: This consensus development conference statement was developed as a result of a joint international meeting held in July 2010. The consensus committee was international in scope (United Kingdom, mainland Europe, United Arab Emirates) and consisted of individuals from a broad range of backgrounds (Psychiatry, Occupational Medicine, Health Economists, Disability Advisors). The objectives of the conference were to discuss some of the occupational impairments adults with ADHD may face and how to address these problems from an inclusive perspective. Furthermore the conference looked at influencing policy and decision making at a political level to address impaired occupational functioning in adults with ADHD and fears around employing people with disabilities in general. RESULTS: The consensus was that there were clear weaknesses in the current arrangements in the UK and internationally to address occupational difficulties. More so, Occupational Health was not wholly integrated and used as a means of making positive changes to the workplace, but rather as a superfluous last resort that employers tried to avoid. Furthermore the lack of cross professional collaboration on occupational functioning in adults with ADHD was a significant problem. CONCLUSIONS: Future research needs to concentrate on further investigating occupational functioning in adults with ADHD and pilot exploratory initiatives and tools, leading to a better and more informed understanding of possible barriers to employment and potential schemes to put in place to address these problems.

A retrospective study on the incidence and risk factors of severe hypoglycemia in primary care.

AIMS: To investigate the incidence and risk factors of severe hypoglycemia (SH) in primary care. SH was defined as hypoglycemia with coma, or the need of glucose or glucagon injection. METHODS: We performed a cross-sectional retrospective study in patients with diabetes treated in primary care in Germany. We analyzed an unselected sample of participants with type 1 (n = 373) and type 2 diabetes (n = 4481) who participated in an insurance plan from the health care insurer Deutsche BKK. Data of participants with type 1 diabetes are as follows: women, n = 155 (42%); age, 49±16 years; diabetes duration, 20+13 years; BMI, 28±6 kg/m2; GHb, 7.1+1.5%; GHb≤7%, n = 263 (71%); GHb≥8.5%, n = 48 (13%). Data of participants with type 2 diabetes: women, n = 1979 (44%); age, 66±10 years; diabetes duration, 8±7 years; BMI, 30±5 kg/m2; GHb, 6.6±1.3%; GHb≤7%, n = 3747 (84%); GHb≥8.5%, n = 360 (8%); insulin therapy, n = 1175 (26%). RESULTS: The incidence of SH in type 1 diabetes: 1.3% (CI: 0.4%, 3.1%) per year; type 2 diabetes with insulin therapy: 0.9% (CI: 0.5%, 1.7%); without insulin therapy: 0.3% (CI: 0.1%, 0.6%). The event rate was 0.02 SH per patient/year in type 1 diabetes and 0.01 in type 2 diabetes, respectively. Low BMI, GHb, insulin therapy and female gender were associated with an increased risk of SH. CONCLUSIONS: In primary care, patients with diabetes can achieve good glycemic control with very rare events of SH. Due to low incidence, SH would have been an inappropriate parameter to evaluate the outcome quality of diabetes therapy in primary care.

The identification and management of ADHD offenders within the criminal justice system: a consensus statement from the UK Adult ADHD Network and criminal justice agencies.

The UK Adult ADHD Network (UKAAN) was founded by a group of mental health specialists who have experience delivering clinical services for adults with Attention Deficit Hyperactivity Disorder (ADHD) within the National Health Service (NHS). UKAAN aims to support mental health professionals in the development of services for adults with ADHD by the promotion of assessment and treatment protocols. One method of achieving these aims has been to sponsor conferences and workshops on adult ADHD.This consensus statement is the result of a Forensic Meeting held in November 2009, attended by senior representatives of the Department of Health (DoH), Forensic Mental Health, Prison, Probation, Courts and Metropolitan Police services. The objectives of the meeting were to discuss ways of raising awareness about adult ADHD, and its recognition, assessment, treatment and management within these respective services. Whilst the document draws on the UK experience, with some adaptations it can be used as a template for similar local actions in other countries. It was concluded that bringing together experts in adult ADHD and the Criminal Justice System (CJS) will be vital to raising awareness of the needs of ADHD offenders at every stage of the offender pathway. Joint working and commissioning within the CJS is needed to improve awareness and understanding of ADHD offenders to ensure that individuals are directed to appropriate care and rehabilitation. General Practitioners (GPs), whilst ideally placed for early intervention, should not be relied upon to provide this service as vulnerable offenders often have difficulty accessing primary care services. Moreover once this hurdle has been overcome and ADHD in offenders has been identified, a second challenge will be to provide treatment and ensure continuity of care. Future research must focus on proof of principle studies to demonstrate that identification and treatment confers health gain, safeguards individual's rights, improves engagement in offender rehabilitation programmes, reduces institutional behavioural disturbance and, ultimately, leads to crime reduction. In time this will provide better justice for both offenders and society.

Risk assessment in anaphylaxis: current and future approaches.

Risk assessment of individuals with anaphylaxis is currently hampered by lack of (1) an optimal and readily available laboratory test to confirm the clinical diagnosis of an anaphylaxis episode and (2) an optimal method of distinguishing allergen-sensitized individuals who are clinically tolerant from those at risk for anaphylaxis episodes after exposure to the relevant allergen. Our objectives were to review the effector mechanisms involved in the pathophysiology of anaphylaxis; to explore the possibility of developing an optimal laboratory test to confirm the diagnosis of an anaphylaxis episode, and the possibility of improving methods to distinguish allergen sensitization from clinical reactivity; and to develop a research agenda for risk assessment in anaphylaxis. Researchers from the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergology and Clinical Immunology held a PRACTALL (Practical Allergy) meeting to discuss these objectives. New approaches being investigated to support the clinical diagnosis of anaphylaxis include serial measurements of total tryptase in serum during an anaphylaxis episode, and measurement of baseline total tryptase levels after the episode. Greater availability of the test for mature beta-tryptase, a more specific mast cell activation marker for anaphylaxis than total tryptase, is needed. Measurement of chymase, mast cell carboxypeptidase A3, platelet-activating factor, and other mast cell products may prove to be useful. Consideration should be given to measuring a panel of mediators from mast cells and basophils. New approaches being investigated to help distinguish sensitized individuals at minimum or no risk from those at increased risk of developing anaphylaxis include measurement of the ratio of allergen-specific IgE to total IgE, determination of IgE directed at specific allergenic epitopes, measurement of basophil activation markers by using flow cytometry, and assessment of allergen-specific cytokine responses. Algorithms have been developed for risk assessment of individuals with anaphylaxis, along with a research agenda for studies that could lead to an improved ability to confirm the clinical diagnosis of anaphylaxis and to identify allergen-sensitized individuals who are at increased risk of anaphylaxis.

Combined PET and microdialysis for in vivo assessment of intracellular drug pharmacokinetics in humans.

UNLABELLED: Because many drugs possess an intracellular site of action, the knowledge of intracellular concentration-time profiles is desirable. In the present study, PET, which measures total (i.e., intracellular, extracellular, and intravascular) concentrations of radiolabeled drugs in tissue, and microdialysis, which determines unbound drug concentrations in the extracellular space fluid of tissue, were combined to describe the intracellular pharmacokinetics of a model compound--that is, the (18)F-labeled antibiotic (18)F-ciprofloxacin--in vivo in humans. METHODS: Ten healthy male volunteers received a mixture of 687 +/- 50 MBq of (18)F-ciprofloxacin and 200 mg of unlabeled ciprofloxacin as an intravenous bolus infusion over 10 min. The pharmacokinetics of ciprofloxacin in skeletal muscle tissue were assessed by means of combined PET and in vivo microdialysis for 5 h after drug administration. A 3-compartment pharmacokinetic model was fitted to the tissue concentration-time profiles of ciprofloxacin measured by PET to estimate the rate constants of ciprofloxacin uptake and transport. RESULTS: In muscle tissue, mean total and extracellular peak concentration (C(max)) values of ciprofloxacin of 1.8 +/- 0.4 microg/mL and 0.7 +/- 0.2 microg/mL were attained at 95 +/- 34 min and 48 +/- 20 min after drug administration, respectively. The extracellular-to-intracellular exchange appeared to be very fast, with an estimated rate constant k(3) of 1.69 +/- 0.25 min(-1). An intracellular-to-extracellular concentration ratio (C(intra)/C(extra)) of 3.2 +/- 0.8 was reached at 110 min after injection and followed by sustained intracellular retention of the antibiotic for the remainder of the experiment. The predicted extracellular concentration-time profiles from the compartmental modeling were in good agreement with the measured microdialysis data. CONCLUSION: The results obtained in the present study were in accordance with previous in vitro data describing cellular ciprofloxacin uptake and retention. The presently used PET/microdialysis combination might be useful during research and development of new drugs, for which knowledge of intracellular concentrations is of interest.

[Costs of therapy of insulin-treated patients with Diabetes mellitus in Germany. Results of the JEVIN trial]. / Therapiekosten bei insulinbehandelten Patienten mit Diabetes mellitus in Deutschland am Beispiel der JEVIN-Studie.

BACKGROUND AND PURPOSE: Diabetes mellitus, its treatment with oral antidiabetic drugs and insulin, self-monitoring and the development of diabetesrelated long-term complications raise multiple socioeconomic problems. Hence, diabetes is one of the major challenges to modern health care systems. To date, there are only few data analyzing diabetes-related costs. Therefore, it was the aim of this trial to assess the costs of therapy of insulin-treated patients with diabetes mellitus out of a selection-free population over a period of 5 years. PATIENTS AND METHODS: JEVIN (Jena's St. Vincent trial) is a prospective population-based trial of all patients with type 1 and insulin-treated type 2 diabetes mellitus aged 16-60 years and living in the city of Jena, Thuringia, Germany. In addition to parameters of diabetes control (relative hemoglobin A(1c) [= HbA(1c)/mean normal], long-term complications, blood pressure), the costs of therapy in respect of insulin and oral antidiabetic drugs and materials to perform self-monitoring were analyzed in 1999/2000 compared to 1994/95. In 1994/95, 244 patients, in 1999/2000, 291 patients were examined. RESULTS: During the period from 1994/95 to 1999/2000, relative HbA(1c) improved in both patients with type 1 (1.65 +/- 0.35 [n = 127] vs 1.48 +/- 0.30 [n = 114]; p < 0.0001) and insulin-treated type 2 diabetes (1.75 +/- 0.40 [n = 117] vs. 1.47 +/- 0.25 [n = 147]; p < 0.0001). The quality of blood pressure control remained constant. In 1999/2000 the costs per unit insulin for patients with type 1 diabetes were calculated at about 0.078 +/- 0.035 DM, in 1994/95 at 0.075 +/- 0.032 DM (p = 0.873). For patients with type 2 diabetes the costs were calculated at 0.070 +/- 0.032 DM in 1999/2000 and at 0.070 +/- 0.028 DM (p = 0.954) in 1994/95. In 1999/2000, to perform blood glucose self-monitoring the costs were 4.08 +/- 1.39 DM/d for patients with type 1 diabetes and 3.07 +/- 1.36 DM/d for patients with type 2 diabetes. In 1994/95 the costs for patients with type 1 diabetes amounted to 3.56 +/- 1.69 DM/d (p = 0.012), and for patients with insulin-treated type 2 diabetes mellitus to 2.77 +/- 1.66 DM/d (p = 0.138). In 1999/2000 the costs for antihypertensive drugs in 46/114 patients with type 1 diabetes were calculated at about 1.43 +/- 1.10 DM/d. In 1994/95 the costs for 32/127 patients amounted to 1.76 +/- 1.00 DM/d (p = 0.501). For 104/147 patients with insulin-treated type 2 diabetes, the costs of antihypertensive drugs were 2.02 +/- 1.48 DM/d in 1999/2000. In 1994/95 the costs amounted to 1.77 +/- 1.11 DM/d (p = 0.141) for 54/117 patients. In 1994/95 the total costs for patients with type 1 diabetes mellitus were calculated at about 7.10 +/- 2.69 DM/d. In 1999/2000 the costs amounted to 7.70 +/- 2.75 DM/d (p = 0.085). In patients with insulin-treated type 2 diabetes mellitus there was a significant increase in 1999/2000 versus 1994/95 (1994/95: 6.43 +/- 3.16, 1999/2000: 7.57 +/- 3.56 DM/d; p = 0.007). CONCLUSION: Despite a tendency toward an increase in the costs for daily life, the therapy-related costs for patients with type 1 diabetes mellitus were constant in 1999/2000 versus 1994/95. In patients with type 2 diabetes, there was an increase of about 18%. For both patients with type 1 and type 2 diabetes, the costs were substantially higher than calculated in theoretical models.

[18F]Ciprofloxacin, a new positron emission tomography tracer for noninvasive assessment of the tissue distribution and pharmacokinetics of ciprofloxacin in humans.

The biodistribution and pharmacokinetics of the fluorine-18-labeled fluoroquinolone antibiotic [(18)F]ciprofloxacin in tissue were studied noninvasively in humans by means of positron emission tomography (PET). Special attention was paid to characterizing the distribution of [(18)F]ciprofloxacin to select target tissues. Healthy volunteers (n = 12) were orally pretreated for 5 days with therapeutic doses of unlabeled ciprofloxacin. On day 6, subjects received a tracer dose (mean injected amount, 700 +/- 55 MBq, which contained about 0.6 mg of unlabeled ciprofloxacin) of [(18)F]ciprofloxacin as an intravenous bolus. Thereafter, PET imaging and venous blood sampling were initiated. Time-radioactivity curves were measured for liver, kidney, lung, heart, spleen, skeletal muscle, and brain tissues for up to 6 h after radiotracer administration. The first application of [(18)F]ciprofloxacin in humans has demonstrated the safety and utility of the newly developed radiotracer for pharmacokinetic PET imaging of the tissue ciprofloxacin distribution. Two different tissue compartments of radiotracer distribution could be identified. The first compartment including the kidney, heart, and spleen, from which the radiotracer was washed out relatively quickly (half-lives [t(1/2)s], 68, 57, and 106 min, respectively). The second compartment comprised liver, muscle, and lung tissue, which displayed prolonged radiotracer retention (t(1/2), >130 min). The highest concentrations of radioactivity were measured in the liver and kidney, the main organs of excretion (standardized uptake values [SUVs], 4.9 +/- 1.0 and 9.9 +/- 4.4, respectively). The brain radioactivity concentrations were very low (<1 kBq. g(-1)) and could therefore not be quantified. Transformation of SUVs into absolute concentrations (in micrograms per milliliter) allowed us to relate the concentrations at the target site to the susceptibilities of bacterial pathogens. In this way, the frequent use of ciprofloxacin for the treatment of a variety of infections could be corroborated.