The prevalence of cardiac complications and their impact on outcomes in patients with non-traumatic subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a serious condition, and a myocardial injury or dysfunction could contribute to the outcome. We assessed the prevalence and prognostic impact of cardiac involvement in a cohort with SAH. This is a prospective observational multicenter study. We included 192 patients treated for non-traumatic subarachnoid hemorrhage. We performed ECG recordings, echocardiographic examinations, and blood sampling within 24 h of admission and on days 3 and 7 and at 90 days. The primary endpoint was the evidence of cardiac involvement at 90 days, and the secondary endpoint was to examine the prevalence of a myocardial injury or dysfunction. The median age was 54.5 (interquartile range [IQR] 48.0-64.0) years, 44.3% were male and the median World Federation of Neurological Surgeons (WFNS) score was 2 (IQR 1-4). At day 90, 22/125 patients (17.6%) had left ventricular ejection fractions ≤ 50%, and 2/121 patients (1.7%) had evidence of a diastolic dysfunction as defined by mitral peak E-wave velocity by peak e' velocity (E/e') > 14. There was no prognostic impact from echocardiographic evidence of cardiac complications on neurological outcomes. The overall prevalence of cardiac dysfunction was modest. We found no demographic or SAH-related factors associated with 90 days cardiac dysfunction.

The potential impact of Covid-19 on the capacity of routine laboratory tests to detect heparin-induced thrombocytopenia.

In Covid-19, anticoagulation with heparin is often administered to prevent or treat thromboembolic events. Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin treatment, caused by heparin-dependent, platelet activating anti-platelet factor 4 (PF4)/heparin antibodies. Diagnosis of HIT is based on the combination of clinical parameters, allowing to determine the pretest probability, and laboratory testing for anti-PF4/heparin antibodies and confirmatory functional assays, such as the heparin-induced platelet activation (HIPA) test.We report the case of a patient with severe Covid-19 pneumonia requiring ECMO treatment, who developed recurrent clotting of the ECMO filter and a drop in platelet count under heparin treatment. He was therefore suspected to have HIT and the anticoagulation was switched to argatroban. Despite high clinical probability and high titres of anti-PF4/heparin antibodies, the functional HIPA test was negative. Nevertheless, argatroban was continued rather than to reinstate anticoagulation with heparin. Reevaluation 7 days later then demonstrated a strongly positive functional HIPA test and confirmed the diagnosis of HIT. Under anticoagulation with argatroban the patient gradually improved and was finally weaned off the ECMO.In conclusion, this case highlights the critical importance of clinical judgement, exploiting the 4 T score, given that Covid-19 patients may present a different pattern of routine laboratory test results in HIT diagnostics. The possibility of a false negative HIPA test has to be considered, particularly in early phases of presentation. In cases of a discrepancy with high clinical probability of HIT and/or high titre anti-PF4/heparin antibodies despite a negative HIPA test, a reevaluation within 3 to 5 days after the initial test should be considered in order to avoid precipitant reestablishment of unfractionated heparin, with potentially fatal consequences.

Implications of early respiratory support strategies on disease progression in critical COVID-19: a matched subanalysis of the prospective RISC-19-ICU cohort.

BACKGROUND: Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. METHODS: Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. RESULTS: Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). CONCLUSION: In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.

Indicators of external ventricular drainage-related infections--a retrospective observational study.

BACKGROUND: External ventricular drainage (EVD) is frequently used in different groups of patients in neurocritical care. Despite the frequent use of EVD, no consensus regarding the diagnosis of EVD-related infection currently exists, and diagnosis is commonly based on criteria for the diagnosis of non-EVD-related CNS infections. This study evaluates the diagnostic accuracy of clinical and laboratory parameters for the prediction of EVD-related infection in patients with proven EVD-related infection. METHODS: In two tertiary care centers, data on EVD insertions were matched with a microbiologic database of cultured microorganisms and positive Gram stains of cerebrospinal fluid (CSF) to identify patients with EVD-related infections. Available clinical data and results of blood tests and CSF analysis were retrospectively collected. Predefined potential clinical and laboratory predictors of EVD-related infection were compared between three time points: at the time EVD insertion and 48 h before and at the time of occurrence of EVD-related infection. RESULTS: Thirty-nine patients with EVD-associated infection defined by positive CSF culture or positive CSF Gram stains and concomitant clinical signs of infection were identified. At the time of infection, a significantly higher incidence of abnormal temperature, high respiratory rate, and a slightly but significantly higher incidence of decreased mental state were observed. The assessed blood and CSF parameters did not significantly differ between the different assessment time points. CONCLUSIONS: Our analysis of 39 patients with culture positive EVD-related infection showed that commonly used clinical and laboratory parameters are not reliable infection predictors.

Metabolically programmed iron chelators.

Extensive structure activity relationship (SAR) studies focused on the desferrithiocin [DFT, (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid] pharmacophore have led to three different DFT analogs being evaluated clinically for the treatment of iron overload diseases, for example, thalassemia. The SAR work revealed that the lipophilicity of a ligand, as determined by its partition between octanol and water, logP(app), could have a profound effect on the drug's iron clearing efficiency (ICE), organ distribution, and toxicity profile. While within a given structural family the more lipophilic a chelator the better the ICE, unfortunately, the more lipophilic ligands are often more toxic. Thus, a balance between lipophilicity, ICE, and toxicity must be achieved. In the current study, we introduce the concept of 'metabolically programmed' iron chelators, that is, highly lipophilic, orally absorbable, effective deferration agents which, once absorbed, are quickly converted to their nontoxic, hydrophilic counterparts.

Oxygen kinetics during 6-minute walk tests in patients with cardiovascular and pulmonary disease.

BACKGROUND: The 6-Minute Walk Test (6MWT) is representative of daily-life activities and reflects the functional capacity of patients. The change of oxygen uptake (VO2) in the initial phase of low-intensity exercise (VO2 kinetics) can be used to assess submaximal exercise performance of patients.The objective of the following study was to analyse VO2 kinetics in patients with different pulmonary and cardiovascular diseases. In addition, we investigated the extent to which VO2 kinetics at the onset of the 6MWT were associated with exercise capacity, morbidity and mortality. METHODS: VO2 kinetics of 204 patients and 16 healthy controls were obtained using mobile telemetric cardiopulmonary monitoring during a 6MWT. A new mean response time (MRT) index (wMRT) was developed to quantify VO2 kinetics by correcting MRT for work rate. The differences in wMRT between disease categories as well as the association between wMRT and patients' exercise capacity and outcome - time to hospitalization/death- were tested. RESULTS: The assessment of a robust wMRT was feasible in 86% (244/284) patients. wMRT was increased in patients compared to healthy controls (p <0.001). wMRT was largest in patients with pulmonary arterial hypertension (PAH). There were significant associations between wMRT and exercise capacity in all patients. High wMRT was found to be associated with a high rate of death and re-hospitalization in patients with CHF (p = 0.024). In patients with pulmonary diseases and pulmonary hypertension wMRT was not associated with outcome (p = 0.952). CONCLUSIONS: Submaximal exercise performance of patients is reduced. O2 kinetics at the onset of exercise are associated with exercise capacity in all patients. wMRT was found to be an important prognostic factor in patients with congestive heart failure (CHF), but not with pulmonary diseases.

Swiss Monitoring of Potential Organ Donors (SwissPOD): a prospective 12-month cohort study of all adult ICU deaths in Switzerland.

BACKGROUND: The Swiss Monitoring of Potential Organ Donors (SwissPOD) was initiated to investigate the causes of the overall low organ donation rate in Switzerland. The objective of our study was an assessment of the donation after brain death (DBD) process in Swiss adult intensive care units (ICUs), and to provide an overview of the donation efficiency as well as of the reasons for non-donation. METHODS: SwissPOD is a prospective cohort study of all deaths in Swiss ICUs and accident and emergency departments. This study is an analysis of SwissPOD data of all patients who deceased in an adult ICU between 1 September 2011 and 31 August 2012. RESULTS: Out of 3,667 patients who died in one of the 79 adult ICUs participating in SwissPOD, 1,204 were possible, 198 potential, 133 eligible, and 94 utilised DBD donors. The consent rate was 48.0% and the conversion rate 47.5%. In 80.0% of cases, the requests for donation took place before brain death was diagnosed, resulting in a similar proportion of consents and objections as when requests were made after brain death diagnosis. CONCLUSIONS: Despite the low donation rate, Swiss adult ICUs are performing well in terms of the conversion rate, similar to major European countries. The refusal rate is among the highest in Europe, which clearly has a negative impact on the donation rate. Optimising the request process seems to be the most effective means of increasing the donation rate.

Desferrithiocin: a search for clinically effective iron chelators.

The successful search for orally active iron chelators to treat transfusional iron-overload diseases, e.g., thalassemia, is overviewed. The critical role of iron in nature as a redox engine is first described, as well as how primitive life forms and humans manage the metal. The problems that derive when iron homeostasis in humans is disrupted and the mechanism of the ensuing damage, uncontrolled Fenton chemistry, are discussed. The solution to the problem, chelator-mediated iron removal, is clear. Design options for the assembly of ligands that sequester and decorporate iron are reviewed, along with the shortcomings of the currently available therapeutics. The rationale for choosing desferrithiocin, a natural product iron chelator (a siderophore), as a platform for structure-activity relationship studies in the search for an orally active iron chelator is thoroughly developed. The study provides an excellent example of how to systematically reengineer a pharmacophore in order to overcome toxicological problems while maintaining iron clearing efficacy and has led to three ligands being evaluated in human clinical trials.

Left ventricular torsion abnormalities in septic shock and corrective effect of volume loading: a pilot study.

BACKGROUND: Ventricular torsion is an important component of cardiac function. The effect of septic shock on left ventricular torsion is not known. Because torsion is influenced by changes in preload, we compared the effect of fluid loading on left ventricular torsion in septic shock with the response in matched healthy control subjects. METHODS: We assessed left ventricular torsion parameters using transthoracic echocardiography in 11 patients during early septic shock and in 11 age- and sex-matched healthy volunteers before and after rapid volume loading with 250 mL of a Ringer's lactate solution. RESULTS: Peak torsion and peak apical rotation were reduced in septic shock (10.2 ± 5.2° and 5.6 ± 5.4°) compared with healthy volunteers (16.3 ± 4.5° and 9.6 ± 1.5°; P = 0.009 and P = 0.006 respectively). Basal rotation was delayed and diastolic untwisting velocity reached its maximum later during diastole in septic shock patients than in healthy volunteers (104 ± 16% vs 111 ± 14% and 13 ± 5% vs 21 ± 10%; P = 0.03 and P = 0.034, respectively). Fluid challenge increased peak torsion in both groups (septic shock, 10.2 ± 5.3° vs 12.6 ± 3.9°; healthy volunteers, 16.3 ± 4.5° vs 18.1 ± 6°; P = 0.01). Fluid challenge increased left ventricular stroke volume in septic shock patients (P = 0.003). CONCLUSIONS: Compared with healthy volunteers, left ventricular torsion is impaired in septic shock patients. Fluid loading attenuates torsion abnormalities in parallel with increasing stroke volume. Reduced torsional motion might constitute a relevant component of septic cardiomyopathy, a notion that merits further testing in larger populations.

Hemodynamic assessment of critically ill patients using a miniaturized transesophageal echocardiography probe.

INTRODUCTION: Hemodynamic management in intensive care patients guided by blood pressure and flow measurements often do not sufficiently reveal common hemodynamic problems. Trans-esophageal echocardiography (TEE) allows for direct measurement of cardiac volumes and function. A new miniaturized probe for TEE (mTEE) potentially provides a rapid and simplified approach to monitor cardiac function. The aim of the study was to assess the feasibility of hemodynamic monitoring using mTEE in critically ill patients after a brief operator training period. METHODS: In the context of the introduction of mTEE in a large ICU, 14 ICU staff specialists with no previous TEE experience received six hours of training as mTEE operators. The feasibility of mTEE and the quality of the obtained hemodynamic information were assessed. Three standard views were acquired in hemodynamically unstable patients: 1) for assessment of left ventricular function (LV) fractional area change (FAC) was obtained from a trans-gastric mid-esophageal short axis view, 2) right ventricular (RV) size was obtained from mid-esophageal four chamber view, and 3) superior vena cava collapsibility for detection of hypovolemia was assessed from mid-esophageal ascending aortic short axis view. Off-line blinded assessment by an expert cardiologist was considered as a reference. Inter-rater agreement was assessed using Chi-square tests or correlation analysis as appropriate. RESULTS: In 55 patients, 148 mTEE examinations were performed. Acquisition of loops in sufficient quality was possible in 110 examinations for trans-gastric mid-esophageal short axis, 118 examinations for mid-esophageal four chamber and 125 examinations for mid-esophageal ascending aortic short axis view. Inter-rater agreement (Kappa) between ICU mTEE operators and the reference was 0.62 for estimates of LV function, 0.65 for RV dilatation, 0.76 for hypovolemia and 0.77 for occurrence of pericardial effusion (all P<0.0001). There was a significant correlation between the FAC measured by ICU operators and the reference (r=0.794, P (one-tailed)<0.0001). CONCLUSIONS: Echocardiographic examinations using mTEE after brief bed-side training were feasible and of sufficient quality in a majority of examined ICU patients with good inter-rater reliability between mTEE operators and an expert cardiologist. Further studies are required to assess the impact of hemodynamic monitoring by mTEE on relevant patient outcomes.

Substituent effects on desferrithiocin and desferrithiocin analogue iron-clearing and toxicity profiles.

Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure-activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto the aromatic ring resulted in orally active iron chelators that were much less toxic than 1. The purpose of the current study was to determine if a comparable reduction in renal toxicity could be achieved by performing the same structural manipulations on 1 itself. Accordingly, three DFT analogues were synthesized. The iron-clearing efficiency and ferrokinetics were evaluated in rats and primates; toxicity assessments were carried out in rodents. The resulting DFT ligands demonstrated a reduction in toxicity that was equivalent to that of the DADFT analogues and presented with excellent iron-clearing properties.

Diffuse descending necrotizing mediastinitis: surgical therapy and outcome in a single-centre series.

OBJECTIVES: Descending necrotizing mediastinitis (DNM) is a rare but rapidly progressing disease with a potentially fatal outcome, originating from odontogenical or cervical infections. The aim of this article was to give an up-to-date overview on this still underestimated disease, to draw the clinician's attention and particularly to highlight the need for rapid diagnosis and adequate surgical treatment. METHODS: We present a retrospective analysis of 17 patients diagnosed and treated for advanced DNM between 1999 and 2011 in a tertiary referral medical centre. Hence, this is one of the largest single-centre studies in recent years concerning the diffuse form (i.e. extending into the lower mediastinum) of DNM. Subsequently, we analysed and compared the international literature with our data, with the focus on surgical management and outcome. RESULTS: In our series of 17 adult patients, 16 were surgically treated by median sternotomy (n = 8) or the clamshell (n = 8) approach for diffuse DNM. One patient, referred with septic shock, died 2 days after surgery. The median interval from diagnosis of DNM by cervicothoracic computed tomography scan and thoracic surgery was 6 h (range 1-24 h) in all but the one patient with fatal outcome (48 h). Concomitant cervicotomy was performed in 11 patients (65%) and tracheotomy in 9 (53%). The median duration of hospitalization was 16 days (range 4-50 days), including an intensive care unit stay of 4 days (range 1-50 days). CONCLUSIONS: For DNM limited to the upper part of the mediastinum, which applies to the majority of cases, a transcervical approach and drainage may be sufficient. In advanced disease, extending below the tracheal carina, an immediate and more aggressive surgical approach is required to combat a much higher morbidity and mortality in this subset of patients. A timely situational approach via median sternotomy or a clamshell incision allowed us to maintain a very low morbidity, mortality and rate of reoperations, without major complications due to the surgical approach itself.

Influenza A(H1N1) infection and severe cardiac dysfunction in adults: A case series.

BACKGROUND: While viral myocarditis and heart failure are recognized and feared complications of seasonal influenza A infection, only limited information is available for 2009 influenza A(H1N1)-induced heart failure. METHODS AND MAIN FINDINGS: This case series summarizes the disease course of four patients with 2009 influenza A(H1N1) infection who were treated at our institution from November 2009 until September 2010. All patients presented with severe cardiac dysfunction (acute heart failure, cardiogenic shock or cardiac arrest due to ventricular fibrillation) as the leading symptom of influenza A(H1N1) infection. Two patients most likely had pre-existent cardiac pathologies, and three required catecholamine therapy to maintain hemodynamic function. Except for one patient who died before influenza A(H1N1) infection had been diagnosed, all patients received antiviral therapy with oseltamivir and supportive critical care. Acute respiratory distress syndrome due to influenza A(H1N1) infection developed in one patient. Heart function normalized in two of the three surviving patients but remained impaired in the other one at hospital discharge. CONCLUSIONS: Influenza A(H1N1) infection may be associated with severe cardiac dysfunction which can even be the leading clinical symptom at presentation. During an influenza pandemic, a thorough history may reveal flu-like symptoms and should indicate testing for H1N1 infection also in critically ill patients with acute heart failure.

Risk assessment in the first fifteen minutes: a prospective cohort study of a simple physiological scoring system in the emergency department.

INTRODUCTION: The survival of patients admitted to an emergency department is determined by the severity of acute illness and the quality of care provided. The high number and the wide spectrum of severity of illness of admitted patients make an immediate assessment of all patients unrealistic. The aim of this study is to evaluate a scoring system based on readily available physiological parameters immediately after admission to an emergency department (ED) for the purpose of identification of at-risk patients. METHODS: This prospective observational cohort study includes 4,388 consecutive adult patients admitted via the ED of a 960-bed tertiary referral hospital over a period of six months. Occurrence of each of seven potential vital sign abnormalities (threat to airway, abnormal respiratory rate, oxygen saturation, systolic blood pressure, heart rate, low Glasgow Coma Scale and seizures) was collected and added up to generate the vital sign score (VSS). VSSinitial was defined as the VSS in the first 15 minutes after admission, VSSmax as the maximum VSS throughout the stay in ED. Occurrence of single vital sign abnormalities in the first 15 minutes and VSSinitial and VSSmax were evaluated as potential predictors of hospital mortality. RESULTS: Logistic regression analysis identified all evaluated single vital sign abnormalities except seizures and abnormal respiratory rate to be independent predictors of hospital mortality. Increasing VSSinitial and VSSmax were significantly correlated to hospital mortality (odds ratio (OR) 2.80, 95% confidence interval (CI) 2.50 to 3.14, P < 0.0001 for VSSinitial; OR 2.36, 95% CI 2.15 to 2.60, P < 0.0001 for VSSmax). The predictive power of VSS was highest if collected in the first 15 minutes after ED admission (log rank Chi-square 468.1, P < 0.0001 for VSSinitial;,log rank Chi square 361.5, P < 0.0001 for VSSmax). CONCLUSIONS: Vital sign abnormalities and VSS collected in the first minutes after ED admission can identify patients at risk of an unfavourable outcome.

Desferrithiocin analogue iron chelators: iron clearing efficiency, tissue distribution, and renal toxicity.

The current solution to iron-mediated damage in transfusional iron overload disorders is decorporation of excess unmanaged metal, chelation therapy. The clinical development of the tridentate chelator deferitrin (1, Table 1) was halted due to nephrotoxicity. It was then shown by replacing the 4'-(HO) of 1 with a 3,6,9-trioxadecyloxy group, the nephrotoxicity could be ameliorated. Further structure-activity relationship studies have established that the length and the position of the polyether backbone controlled: (1) the ligand's iron clearing efficiency (ICE), (2) chelator tissue distribution, (3) biliary ferrokinetics, and (4) tissue iron reduction. The current investigation compares the ICE and tissue distribution of a series of (S)-4,5-dihydro-2-[2-hydroxy-4-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 3-5) and the (S)-4,5-dihydro-2-[2-hydroxy-3-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 8-10). The three most effective polyether analogues, in terms of performance ratio (PR), defined as mean ICE(primate)/ICE(rodent), are 3 (PR 1.1), 8, (PR 1.5), and 9, now in human trials, (PR 2.2). At the onset of the clinical trial on 9, no data were available for ligand 3 or 8. This is unfortunate, as 3 has many advantages over 9, e.g., the ICE of 3 in rats is 2.5-fold greater than that of 9 and analogue 3 achieves very high levels in the liver, pancreas, and heart, the organs most affected by iron overload. Finally, the impact of 3 on the urinary excretion of kidney injury molecule-1 (Kim-1), an early diagnostic biomarker for monitoring acute kidney toxicity, has been carried out in rats; no evidence of nephrotoxicity was found. Overall, the results suggest that 3 would be a far superior clinical candidate to 9.

Six-minute walk test enhanced by mobile telemetric cardiopulmonary monitoring.

BACKGROUND: The 6-min walk test (6MWT) is frequently used to assess overall cardiopulmonary fitness and to predict outcome, but it yields little diagnostic information. Portable telemetric devices allow performing the 6MWT with real-time cardiopulmonary monitoring. OBJECTIVES: The study was designed to analyze feasibility, safety and clinical usefulness of a mobile cardiopulmonary monitoring (MOB)-enhanced 6MWT. METHODS: From August 2003 to June 2007, 261 consecutive patients with chronic lung and/or heart disease as well as healthy controls underwent MOB-enhanced 6MWTs. A subgroup of 33 individuals had the test done with and without cardiopulmonary monitoring on independent days. RESULTS: No test-related adverse events occurred throughout the study. Whether the 6MWT was done without or with cardiopulmonary monitoring (n = 33) did not significantly influence the walking distance (WD: 528 ± 183 vs. 525 ± 192 m; nonsignificant). Fifty-nine percent (155/261) of the patients fulfilled the maximal test criteria. Distinct disease-specific exercise response patterns as well as treatable co-pathologies were observed. The validity of response patterns was better in case of a maximal test. CONCLUSION: An MOB-enhanced 6MWT is feasible within daily routine and safe in patients with various diseases. It does not negatively affect WD. MOB is a valuable tool to identify factors limiting exercise in patients irrespective of their underlying disease.

The impact of polyether chain length on the iron clearing efficiency and physiochemical properties of desferrithiocin analogues.

(S)-2-(2,4-Dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (2) was abandoned in clinical trials as an iron chelator for the treatment of iron overload disease because of its nephrotoxicity. However, subsequent investigations revealed that replacing the 4'-(HO) of 2 with a 3,6,9-trioxadecyloxy group, ligand 4, increased iron clearing efficiency (ICE) and ameliorated the renal toxicity of 2. This compelled a closer look at additional polyether analogues, the subject of this work. The 3,6,9,12-tetraoxatridecyloxy analogue of 4, chelator 5, an oil, had twice the ICE in rodents of 4, although its ICE in primates was reduced relative to 4. The corresponding 3,6-dioxaheptyloxy analogue of 2, 6 (a crystalline solid), had high ICEs in both the rodent and primate models. It significantly decorporated hepatic, renal, and cardiac iron, with no obvious histopathologies. These findings suggest that polyether chain length has a profound effect on ICE, tissue iron decorporation, and ligand physiochemical properties.

Vibriobactin antibodies: a vaccine strategy.

A new target strategy in the development of bacterial vaccines, the induction of antibodies to microbial outer membrane ferrisiderophore complexes, is explored. A vibriobactin (VIB) analogue, with a thiol tether, 1-(2,3-dihydroxybenzoyl)-5,9-bis[[(4S,5R)-2-(2,3-dihydroxyphenyl)-4,5-dihydro-5-methyl-4-oxazolyl]carbonyl]-14-(3-mercaptopropanoyl)-1,5,9,14-tetraazatetradecane, was synthesized and linked to ovalbumin (OVA) and bovine serum albumin (BSA). The antigenicity of the VIB microbial iron chelator conjugates and their iron complexes was evaluated. When mice were immunized with the resulting OVA-VIB conjugate, a selective and unequivocal antigenic response to the VIB hapten was observed; IgG monoclonal antibodies specific to the vibriobactin fragment of the BSA and OVA conjugates were isolated. The results are consistent with the idea that the isolated adducts of siderophores covalently linked to their bacterial outer membrane receptors represent a credible target for vaccine development.

Desferrithiocin analogue uranium decorporation agents.

PURPOSE: Previous systematic structure-activity studies of the desferrithiocin (DFT) platform have allowed the design and synthesis of analogues and derivatives of DFT that retain the exceptional iron-clearing activity of the parent, while eliminating its adverse effects. We hypothesized that a similar approach could be adopted to identify DFT-related analogues that could effectively decorporate uranium. MATERIALS AND METHODS: The decorporation properties of nine DFT-related analogues were determined in a bile duct-cannulated rat model. Diethylenetriaminepentaacetic acid (DTPA) served as a positive control. Selected ligands also underwent multiple and delayed dosing regimens. Uranium excretion in urine and bile or stool was determined by inductively coupled plasma mass spectroscopy (ICP-MS); tissue levels of uranium were also assessed. RESULTS: The two best clinical candidates are (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE (9)], with a 57% reduction in kidney uranium levels on oral (p.o.) administration and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE (10)], with a 62% renal reduction on p.o. administration. The majority of the metal excretion promoted by these analogues is in the bile, thus further reducing kidney actinide exposure. CONCLUSIONS: While 9 administered p.o. or subcutaneously (s.c.) immediately post-metal is an effective decorporation agent, withholding the dose (s.c.) until 4 h reduced the activity of the compound. Conversion of 9 to its isopropyl ester may circumvent this issue.

Desferrithiocin analogues and nephrotoxicity.

The syntheses of a series of 4'-O-alkylated ( S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazole-carboxylic acid and 5'-O-alkylated ( S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, log P(app), is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of log P(app) versus ICE in a rodent model for both the 4'-O-alkylated 2,4-dihydroxy and 5'-O-alkylated 2,5-dihydroxy series produced an inverse parabola plot with r(2) values of 0.97 and 0.81, respectively. The plots indicate an optimum log P(app)/ICE relationship. Because of the nature of the data spread in the 4'-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties?