Does Isolation of Enterococcus Affect Outcomes in Intra-Abdominal Infections?

BACKGROUND: Enterococci are isolated frequently as pathogens in patients with intra-abdominal infections (IAIs) and may predict poor clinical outcomes. It remains controversial whether enterococci warrant an altered treatment approach with regard to antimicrobial treatment. PATIENTS AND METHODS: The study population was derived from the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial database. Through post hoc analysis subjects were stratified into two groups based on isolation of Enterococcus. Fifty subjects of the cohort (n = 518) had Enterococcus isolated. Uni-variable and multi-variable analyses were conducted to determine whether isolation of Enterococcus constituted an independent predictor of the pre-defined STOP-IT composite outcome (surgical site infection, recurrent IAI, or death) and the individual components of the composite outcome. RESULTS: From the cohort of 50 subjects, we identified 52 isolates of Enterococcus spp. with a predominance of Enterococcus faecalis (40%) followed by other Enterococcus spp. (37%) and Enterococcus faecium (17%). Baseline demographic characteristics were statistically similar between the two groups. Antibiotic utilization distribution remained balanced between the Enterococcus and no Enterococcus groups with the majority receiving piperacillin-tazobactam (62% and 54%, respectively). The groups had comparable infection characteristics including setting of acquisition (>50% community acquired) and origin of infection (predominantly colon or rectum). Individual and composite clinical outcomes were not different statistically between the Enterococcus and no Enterococcus groups: surgical site infection (10% vs. 7.5%; p = 0.53), recurrent IAI (20% vs. 14.1%; p = 0.26), death (2% vs. 1%; p = 0.40), and composite of all three (30% vs. 20.9%; p = 0.14], respectively. Multi-variable analysis revealed that isolation of Enterococcus did not predict independently the incidence of the composite outcome (odds ratio [OR] 1.53 [95% confidence interval {CI} = 0.78-3.01]; p = 0.22; c-statistic = 0.65; goodness of fit, p = 0.71). CONCLUSIONS: Enterococcus was not a more common pathogen in health-care-associated IAIs and was not an independent risk factor for the composite outcome. The isolation of Enterococcus from IAIs may not warrant an alternative treatment approach but larger studies are needed to validate these findings.

The surgical Infection Society Revised Guidelines on the management of intra-abdominal infection

BACKGROUND: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations. METHODS: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council. RESULTS: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included. SUMMARY: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline.(AU)

Rash with DERMABOND PRINEO Skin Closure System Use in Bilateral Reduction Mammoplasty: A Case Series.

Background. Bilateral reduction mammoplasty is a common plastic surgery procedure that can be complicated by unfavorable scar formation along incision sites. Surgical adhesives can be utilized as an alternative or as an adjunct to conventional suture closures to help achieve good wound tension and provide an adequate barrier with excellent cosmesis. The recently introduced DERMABOND PRINEO Skin Closure System Skin Closure System combines the skin adhesive 2-octyl cyanoacrylate with a self-adhering polyester-based mesh. Proposed benefits of wound closure with DERMABOND PRINEO Skin Closure System, used with or without sutures, include its watertight seal, easy removal, microbial barrier, even distribution of tension, and reduction in wound closure time. Although allergic reactions to 2-octyl cyanoacrylate have been reported, few allergic reactions to DERMABOND PRINEO Skin Closure System have been noted in the literature. This case series describes three patients who experienced an allergic reaction to DERMABOND PRINEO Skin Closure System after undergoing elective bilateral reduction mammoplasties at our institution to further explore this topic. Methods. Retrospective chart review of bilateral reduction mammoplasty patients who received DERMABOND PRINEO Skin Closure System dressing at our institution was performed. Results. Three patients were identified as having a rash in reaction to DERMABOND PRINEO Skin Closure System after bilateral reduction mammoplasty. All three patients required systemic steroid treatment to resolve the rash. One patient was identified as having a prior adhesive reaction. Conclusions. DERMABOND PRINEO Skin Closure System has demonstrated its efficacy in optimizing scar healing and appearance. However, as we demonstrate these three allergic reactions to DERMABOND PRINEO Skin Closure System, caution must be utilized in its usage, namely, in patients with a prior adhesive allergy and in sites where moisture or friction may be apparent.

Intrathoracic fibrin sealant application using computed tomography fluoroscopy.

Persistent intrathoracic airspace and bronchopleural fistula remain a problem following lung resection or in patients with severe bullous disease experiencing a spontaneous pneumothorax. Although fibrin sealant has been used successfully to manage such air-leaks, precise nonoperative intrathoracic application is difficult. This report describes a novel technique using computed tomography fluoroscopy for catheter-directed FS application through a previously placed thoracostomy tube. Continuous computed tomography-fluoroscopy images allowed real-time catheter manipulation for precise placement of fibrin sealant.

Investigation of the positive response of ethyl acrylate in the mouse lymphoma genotoxicity assay.

To develop a better understanding of the relationship between ethyl acrylate (EA)-induced cytotoxicity and mutation frequency in the mouse lymphoma assay (MLA) we measured the effects of EA treatment to ML cells on: (1) nonprotein sulfhydryl (NPS) levels; (2) mitochondrial rhodamine 123 (Rh123) uptake; (3) the DNA elution slope (single-strand breakage) and Y intercept of fitted curves (cytotoxicity and double-strand breakage) in the alkaline elution assay; (4) the appearance of apoptosis; and (5) the pulsed-field gel electrophoretic resolution of high-molecular-weight DNA. EA reduced NPS in both a time- and concentration-dependent manner. By 30 min, > or = 20 micrograms/ml EA reduced NPS by 50% or greater. By 4 h, > or = 10 micrograms/ml markedly decreased both NPS cell content (> or = 71.5% reduction) and mitochondrial Rh123 uptake (10-50 micrograms/ml; 9-62%), the latter effect being further enhanced by washing and incubation for an additional 2 h (12-85%). EA did not induce single-strand breaks in the alkaline elution assay. Only highly cytotoxic EA concentrations (80-87% reduction in RCG at 40-50 micrograms/ml) caused both increases in the elution slope and parallel drops (Y intercept) in the elution curve in the alkaline elution assay. Conventional agarose gel electrophoretic analysis of the DNA neutral fraction of these high dose preparations showed evidence for both apoptosis (180-bp oligonucleosomal DNA laddering effect) and random smearing of DNA (necrosis). Pulsed-field gel electrophoresis of directly loaded high dose cell preparations revealed both high- and low-molecular-weight DNA double-strand breaks, but only at the highest concentrations. These observations indicated that the EA-induced mutagenic response correlated best with cellular cytotoxicity mediated by NPS depletion and mitochondrial membrane impairment.

Mechanism of splenic immunosuppression during sepsis: key role of Kupffer cell mediators.

Studies indicate that the liver, in particular the Kupffer cells, appear to be key contributors in the systemic inflammatory mediator response associated with shock and sepsis. Although several of these agents have been implicated as mediators of depressed immunoresponsiveness observed during sepsis, it remains unknown whether or not mediators released specifically by Kupffer cells play any significant role in producing the cellular dysfunction in distant organs. The aim of this study, therefore, was to determine whether or not acute Kupffer cell reduction before the onset of sepsis would protect splenic lymphocyte function. Kupffer cell number was reduced by prior (48 hours) treatment of mice with gadolinium chloride (GdCl2, 10 mg/kg of body weight, intravenously) or saline vehicle. Animals were then subjected to either sham-CLP (sham) or polymicrobial sepsis in the form of cecal ligation and puncture (CLP). Plasma and splenocytes were harvested at 2 or 24 hours after CLP. Splenocyte cultures were exposed to 2.5 micrograms concanavalin A/mL to assess their ability to release lymphokines. Cytokine (interleukin (IL)-2, IL-6, interferon-gamma, tumor necrosis factor-alpha) concentration in plasma or cell supernatants was assessed by bioassay. The results indicated that GdCl2 treated mice exhibited a marked reduction in circulating IL-6 levels at both 2 and 24 hours after CLP. Furthermore, the reduction of Kupffer cell number before the onset of sepsis completely prevented the depression of splenocyte IL-2 and interferon-gamma release, capacity. Thus mediators released by Kupffer cells during the systemic inflammatory response to polymicrobial sepsis play a significant role in producing immune dysfunction in resident splenic lymphocytes. In view of this, it appears that modulation of Kupffer cell hyperactivity during sepsis may be a novel approach for maintaining distant organ host defense mechanisms.

Influence of investigator experience and microscopic field size on microvessel density in node-negative breast carcinoma.

In this study on the determination of intratumoral microvessel density (MVD) in breast cancer, we have investigated the influence of the observer experience and the microscopic field size. We have used the sample set reported on earlier in the J Natl Cancer Inst 87: 1797-1798, 1995. This case-control study has shown a positive association of high MVD and unfavorable outcome when comparing node-negative pT1-2 breast carcinoma (NNBC) patients with a disease-free period of over ten years with those with an early distant relapse. Tumor sections of both outcome groups (favorable: n = 19; unfavorable: n = 19) were immunostained for factor VIII related-antigen (FVIII r-Ag). Microvessels were counted in the areas of most intense vascularization ('hot spots'), both at magnification x 200 (field size of 0.61 square mm) and x 400 (field size of 0.15 square mm), by one inexperienced and three experienced observers. Microphotographs of individual vascular hot spots were analyzed using overlays resembling the two field sizes. The main results obtained are: i) a confirmation of the prognostic value of microvessel density in the case-control sample set (n = 38) was established by all experienced but not by the unexperienced investigator; ii) both at x 200 and x 400 magnification, angiogenesis quantification in vascular hot spots contained prognostic information. The results of this study indicate that the selection of vascular hot spots in tumor sections immunostained for an antigen expressed on endothelial cells is more prone to inter-observer variability and more dependent on training than the counting of the microvessels within predefined hot spots itself. The microscopic magnification and resulting field size do not influence the prognostic significance of MVD in NNBC. This information validates the development of more objective methods of measuring the amount of angiogenesis within malignant tissue. This will allow more accurate implementation of the angiogenesis parameter in multiparametric and prospective prognostic factor studies in NNBC.

Trans-jugular extraction of bullet embolus to the heart.

Bullet emboli to the heart are rare and are typically treated by operative extraction through a median sternotomy and cardiotomy. This report details the case of an 18-year-old male who sustained two gunshot wounds, one of which lodged in his left renal vein. At laparotomy, the bullet embolized to the right atrium via the inferior vena cava. Under fluoroscopic guidance the bullet was retrieved with a snare introduced percutaneously through the right internal jugular vein. Sternotomy and possible cardiopulmonary bypass were avoided.

Care-giver evaluation of anti-gastroesophageal reflux procedures in neurologically impaired children: what is the real-life outcome?

Although the pediatric surgical literature is replete with reports of the success of operations for gastroesophageal reflux, postoperative complications are being reported with increasing frequency for the neurologically impaired subpopulation. Because a large portion of a care-giver's life is involved in attending to a neurologically impaired child, parental satisfaction with the outcome of these operations should be an important consideration when the use of such procedures is contemplated. The purpose of the present study was to assess the impact of antireflux operations with respect to care-giver opinions regarding the procedure. The authors retrospectively reviewed 25 charts (of 13 girls and 12 boys; age range, 3 months to 18 years) and documented (through survey results) perceived child well-being, objective care requirements, and overall care-giver satisfaction with the procedure. Results indicate there was significant improvement in feeding indexes, care-giver perception of the child's comfort, and quality of life postoperatively. Moreover, there was significant improvement in the care-givers' attitudes regarding their child, including the level of frustration in caring for the child, and the parents' overall quality of life. Care-givers also believed that the operation's result was about or better than what they had expected. In conclusion, the study documents care-giver satisfaction with antireflux procedures. Postoperatively, child care is easier and the quality of time spent with the child is better. The impression of better quality of life postoperatively for a neurologically impaired child may be the greatest success in this sometimes frustrating endeavor.

The morphology of the dorsal eye of the hydrothermal vent shrimp, Rimicaris exoculata.

The bresiliid shrimp, Rimicaris exoculata, lives in large masses on the sides of hydrothermal vent chimneys at two sites on the Mid-Atlantic Ridge. Although essentially no daylight penetrates to depths of 3500 m, very dim light is emitted from the hydrothermal vents themselves. To exploit this light, R. exoculata has evolved a modified compound eye on its dorsal surface that occupies about 0.5% of the animal's body volume. The eye's morphology suggests that it is extremely sensitive to light. The cornea of the dorsal eye is smooth with no dioptric apparatus. The retina consists of two wing-shaped lobes that are fused across the midline anteriorly. The rhabdomeral segments of the 7000 ommatidia form a compact layer of photosensitive membrane with an entrance aperture of more than 26 mm2. Within this layer, the volume density of rhabdom is more than 70%. Below the rhabdomeral segments, a thick layer of white diffusing cells scatters light upward into the photoreceptors. The arhabdomeral segments of the five to seven photoreceptors of each ommatidium are mere strands of cytoplasm that expand to accommodate the photoreceptor nuclei. The rhabdom is comprised of well-organized arrays of microvilli, each with a cytoskeletal core. The rhabdomeral segment cytoplasm contains mitochondria, but little else. The perikaryon contains a band of mitochondria, but has only small amounts of endoplasmic reticulum. There is no ultrastructural indication of photosensitive membrane cycling in these photoreceptors. Vestigial screening pigment cells and screening pigment granules within the photoreceptors are both restricted to the inner surface of the layer of the white diffusing cells. Below the retina, photoreceptor axons converge in a fanshaped array to enter the dorsal surface of the brain. The eye's size and structure are consistent with a role for vision in shrimp living at abyssal hydrothermal vents.

In vitro and in vivo metabolism of the antianxiolytic agent fenobam in the rat.

Fenobam [(Fn); N-(3-chlorophenyl)-N-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] sulfate is a novel agent with potent anxiolytic activity in rats. [14C]Fn sulfate was administered as an oral solution (250 mg/kg) to male Wistar rats, and 52% of the administered dose was excreted in urine (0-5 days). In vitro metabolism of Fn was studied by incubating [14C]Fn with rat hepatic 9000 x g supernatant preparations. Unchanged Fn and a total of six metabolites were isolated, quantified, and identified from the urine and liver 9000 x g supernatant samples by column chromatography; TLC; UV, IR, and NMR spectroscopy; MS; and comparison with synthetic samples. Four metabolic pathways for Fn are proposed: (1) hydroxylation at the phenyl ring to form 4-hydroxyphenyl-Fn, a major pathway in vivo (12% of the sample radioactivity) but a minor pathway in vitro (4% of the sample radioactivity); (2) hydroxylation at the creatinine ring to form 5-hydroxy-Fn (19%) of the sample radioactivity), a dominant pathway in vitro but not in vivo; (3) oxidative cleavage at the creatinine ring (loss of a ketene unit), a minor pathway for Fn but an important pathway for 4-hydroxyphenyl-Fn in vivo; and (4) N-demethylation, a minor pathway for Fn in vivo.

The genetic toxicology of ethylenethiourea: a case study concerning the evaluation of a chemical's genotoxic potential.

Ethylenethiourea (ETU) is a metabolite, environmental degradation product and minor technical impurity of the ethylenebisdithiocarbamate (EBDC) class of fungicides. The genetic toxicology of ETU is important given that ETU causes thyroid tumors in rodents and liver tumors in mice. Although it is clear that ETU induces thyroid tumors via a non-genotoxic, threshold mechanism, the role ETU plays in inducing mouse liver tumors remains to be fully elucidated. Recently, Dearfield (Mutation Res., 317, 111-132, 1994) reviewed the genetic toxicology of ETU, and concluded that, although ETU is not a potent genotoxic agent, it is weakly genotoxic. This view stands in contrast to reports from several independent authorities that have generally concurred that ETU is not a mammalian genotoxin (IARC, 1987; MAFF, 1990; NTP, 1992; FAO/WHO, 1994). These conflicting reports highlight a generic problem in genotoxicity safety assessment: although individual test results typically yield either a positive or negative response, the overall evaluation of an extensive battery of tests for a particular chemical rarely yields an unambiguous conclusion. Recently, Mendelsohn et al. (Mutation Res., 266, 43-60, 1992) showed that the response of a chemical to a battery of genotoxicity tests is not a dichotomous (i.e., either positive or negative) property, but rather, appears to be a continuous property that ranges from strongly negative to strongly positive. We have used these data, together with a four-step weight of the evidence procedure, to evaluate ETU. Our analysis indicates that ETU is not genotoxic in mammalian systems and suggests that ETU likely induces mouse liver tumors by a non-genotoxic mechanism.

Characterization and identification of the metabolites of fenoctimine using in vitro drug metabolizing systems.

Fenoctimine sulphate (4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine sulphate) and one of its metabolites, 1-formyl-4-(diphenylmethyl) piperidine (RWJ-34321), were incubated with a rat liver post-mitochondrial supernatant preparation and an NADPH generating system. The metabolites, 7-hydroxyoctyl fenoctimine and 7-oxoocytl fenoctimine were identified as in vitro oxidative metabolites of fenoctimine on the basis of mass spectrometry and thin layer chromatography in comparison to authentic samples. RWJ-34321, a third metabolite, was confirmed as a hydrolyzed product of fenoctimine on the same basis. In separate incubations with RWJ-34321, one metabolite (4-(diphenylmethyl)piperidine), was identified as an in vitro metabolite of RWJ-34321 by mass spectrometry and thin layer chromatography. Thus, the in vitro metabolism of fenoctimine by rat liver homogenates resulted in the oxidation of the aliphatic chain at the seven carbon, initially to an alcohol and then to a ketone. The metabolism of RWJ-34321 resulted in decarbonylation of the formyl carbon.

Aggressive fluid resuscitation following intestinal ischemia-reperfusion in immature rats prevents metabolic derangements and down regulates interleukin-6 release.

We have recently shown improved survival following intestinal ischemia-reperfusion in a model that utilized aggressive crystalloid resuscitation sufficient to eliminate reperfusion-induced cardiovascular instability. The aims of this study were to determine whether the salutary effects associated with this regimen were due to: 1) prevention of systemic metabolic derangements; 2) attenuation of secondary organ injury; or 3) modulation of the systemic immune response. Under anesthesia, 4-week-old (65-85 g) male Sprague-Dawley rats (N = 63) received crystalloids at either 15 or 65 ml.kg-1.h-1 intravenously and were subjected to 90 min of superior mesenteric artery occlusion followed by 90 min of reperfusion (IR15, IR65) or time-matched sham (SH) operation (SH15, SH65). Results indicate that inadequate fluid resuscitation following intestinal IR was associated with significant serum hyperkalemia and hyperphosphatemia, acute renal insufficiency, and enhanced serum interleukin-6 levels. Maintenance of cardiovascular stability with aggressive fluid resuscitation was associated with an attenuation of these alterations. Therefore, the prevention of circulatory shock and the attenuation of distant organ injury and inflammatory response are associated with improved survival when an aggressive crystalloid resuscitation regimen is applied after intestinal ischemiareperfusion in immature rats.

Role of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation.

Although interleukin-6 (IL-6) plays an important role in the pathophysiology of trauma-hemorrhage and resuscitation, the cellular origin of this inflammatory cytokine remains unknown. This study was undertaken to determine whether Kupffer cells (KC) are a major source of IL-6 release following trauma-hemorrhage and resuscitation. KC numbers were significantly (p < .05) reduced in vivo with gadolinium chloride (GdCl3; 10 mg/kg IV). KC-reduced (KC(-)) and KC-normal (saline-treated; KC(+)) rats underwent laparotomy (i.e., trauma-induced), followed by either sham operation or hemorrhage. Hemorrhaged rats were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the shed blood volume was returned as Ringer's lactate, and then resuscitated with Ringer's lactate (four times shed blood volume over 1 h). Results indicate that KC reduction per se had no effect on any measured parameter at any time. At 0.5 and 2.0 h postresuscitation, mean arterial pressure, heart rate, cardiac output, stroke volume, and hematocrit were reduced to a similar extent in both the KC(+) and KC(-) hemorrhage groups. KC reduction did, however, significantly reduce plasma IL-6 concentration (means +/- S.E.; U/ml) at both 0.5 h (KC(+) = 709 +/- 391 vs. KC(-) = 159 +/- 5) and at 2.0 h (KC(+) = 527 +/- 394 vs. KC(-) = 83 +/- 20) postresuscitation. In conclusion, this study demonstrates that KC are a major source of in vivo IL-6 release following trauma-hemorrhage and resuscitation.

Prevention of secondary cardiovascular instability after intestinal ischemia and reperfusion improves survival.

Previous studies of small intestinal ischemia and reperfusion (I/R) in immature rats report secondary systemic organ injury and low survival rates; however, in these studies the cardiovascular stability of the rat was not established. To prevent the secondary hemodynamic deterioration accompanying intestinal I/R, we have developed a model that utilizes aggressive fluid resuscitation. Under anesthesia, 4-wk-old male Sprague-Dawley rats (n = 189) underwent 90 min of I/R (superior mesenteric artery occlusion) or sham (SH) operation while receiving lactated Ringer with 5% dextrose at 15 (IR15, SH15) or 65 (IR65, SH65) ml.kg-1 x h-1 i.v. The results indicate that aggressive fluid resuscitation in the IR65 group significantly attenuated the hypotension, hemoconcentration, metabolic acidosis, and amount of gross bowel injury observed in the IR15 group, while increasing postreperfusion renal and intestinal blood flow, prolonging survival time of nonsurvivors, and improving overall group survival. These findings suggest that maintenance of hemodynamic stability is necessary in models of bowel I/R. Furthermore, this model allows for selective study of the isolated effects of intestinal I/R without the additional complications resulting from secondary cardiovascular instability.

Moyamoya-like disease with inflammation.

A 29-year-old Caucasian male died from massive cerebral infarction due to unilateral occlusion of the terminal internal carotid artery. The carotid occlusion was secondary to subendothelial fibrous tissue proliferation which was associated with a considerable mononuclear cell infiltration of the carotid wall, characterised as T cells by immunoperoxidase methods. Angiography showed vascular network at the base of the brain compatible with Moyamoya disease. We suggest that the pathogenesis of Moyamoya-like disease in our patient involved a T-cell-mediated attack to a vascular antigen.

Reperfusion injury following testicular torsion and detorsion in prepubertal rats.

Acute testicular torsion is a surgical emergency which requires immediate intervention. Although damage to the gonad has been well documented, it remains unknown whether the majority of injury occurs during the period of torsion (ischemia) or following detorsion (reperfusion). The aims of this study were to determine: (1) whether damage following testicular torsion-detorsion has a reperfusion component similar to that described in other tissues, and (2) whether iron-catalyzed oxygen radical formation or altered calcium homeostasis plays a role in this injury. To study this, anesthetized prepubertal rats underwent 720 degrees intravaginal testicular torsion and were divided into groups of torsion only (ischemia) and torsion with reperfusion (ischemia/reperfusion). Reperfusion groups were treated prior to detorsion with either deferoxamine (iron chelator), diltiazem (calcium channel blocker), or saline vehicle. The results indicated that detorsion produces a qualitatively distinct reperfusion injury from that of non-reperfused testicles; however, such damage was not ameliorated by deferoxamine or diltiazem. Thus, testicular torsion-detorsion appears to have a significant reperfusion component that appears to not be mediated by iron-catalyzed oxygen radical formation or calcium injury.

Disposition of bepridil in laboratory animals and man.

1. The disposition and pharmacokinetics of bepridil (Bp) were studied in mouse, rat, rabbit, rhesus monkey, and man. Bp was essentially completely absorbed by all species. 2. Maximum plasma Bp concentrations were achieved within 2 h of drug administration. Linear but non-proportional, dose-related increases in the area under the curve (AUC) for plasma Bp vs. time were noted after increasing oral doses of Bp.HCl to rats (30-300 mg/kg) and monkeys (25-200 mg/kg). 3. Daily administration of Bp.HCl to rats (100 mg/kg per day for 15 days) and monkeys (200 mg/kg per day for 13 days) produced no statistically significant changes in Bp pharmacokinetic parameters. 4. Oral plasma clearance (CLp) of Bp was very low in man (ca. 0.93 l/h per kg) compared to experimental animals (14.8-63.8 l/h per kg). Terminal elimination half-lives were 1.5-2.0 h for mouse and rat, ca. 4.4 h for monkey and ca. 48 h for man. 5. Bp and a total of 12 metabolites were identified and quantified. Metabolite formation in the five species was adequately described by four interrelated pathways, namely, aromatic hydroxylation, followed by N-dealkylation, N-debenzylation, and N-acetylation. Metabolites produced by this pathway included 4-hydroxy-Bp, N-benzyl-4-aminophenol, 4-aminophenol, and N-acetyl-4-aminophenol. Comparison of the proposed pathways revealed qualitative similarity among species.