Effects of flexible scheduling and virtual visits on burnout for clinicians.

OBJECTIVE: Burnout is a healthcare quality problem, linked to negative impacts in patient care and healthcare providers. The pandemic prompted clinicians to adapt virtual practices and adopt more flexible, autonomous schedules. However, the impact of flexible scheduling and autonomy on provider burnout is unknown. The study aim was to evaluate the effect of flexible schedules versus standard schedules, and the amount of digital care, on burnout. METHODS: This was a prospective survey study at two time points 6 months apart. Providers from Rheumatology, Neurology, and Pediatrics completed surveys at baseline, between 6/22/2020-9/8/2020, and six months later, between 12/20/20-3/12/21. The primary outcome was the Mini-Z work life survey which measured burnout in 2 different groups: flexible schedules (FS) and standard schedules (SS) during the height of the pandemic. RESULTS: The study included 149 providers, 47 with FS and 102 with SS, who completed the survey at baseline and 6 months later. At baseline providers reported high job satisfaction (85.9%) and low burnout (29.7%), which remained consistent at 6 months. Compared to those with SS, clinicians with FS participated in a greater number of telemedicine activities at baseline, but did not differ significantly in degree of burnout (25.5% FS, 31.7% SS, p=0.45). Participants in the FS group were significantly more likely to indicate improvement in control over workload and experience reduced work-related stress compared to those in the SS group. There was no association between amount of telemedicine visits and burnout. Predictors of burnout at 6 months included Rheumatology providers and those in the 20-39 year old age group. DISCUSSION: Schedule flexibility does not appear to influence overall burnout; however it does impact variables associated with burnout such as control over workload and perceived job stress. CONCLUSIONS: Participants reported overall job satisfaction, and FS did not impact overall burnout. FS was more likely to indicate improvement in control over workload and experienced reduced work-related stress compared to SS. In addition, burnout was more likely in the 20-39 year old age group, suggesting that special focus should be paid to this age group.

[Treatment of polyneuropathy: autonomic symptoms and pain]. / Therapie der Polyneuropathie ­ autonome Symptome und Schmerzen.

BACKGROUND: The treatment of polyneuropathy includes symptomatic therapy of sensory, motor and autonomic dysfunctions. AIM: This article provides an overview of the current treatment recommendations for polyneuropathy, focusing on pain. METHODS: Current treatment guidelines will be discussed based on a literature research. RESULTS: Calcium-channel anticonvulsants gabapentin/pregabalin as well as antidepressants duloxetine and amitriptyline are recommended as first line therapeutics. Alternatively, topical therapeutics can be used in the case of localized disorders. In individual cases, opioids or other antidepressants/anticonvulsants may be effective. Pharmacological treatment is often limited due to adverse events, which affect the central nervous system in particular. DISCUSSION: In general, treatment for polyneuropathy should follow a multimodal concept and include the treatment of other symptoms. When choosing pain medication, comorbidities, patient's age and adverse events need to be taken into consideration. Phenotype-based stratification may support specialized pain therapy and achieve the best medical treatment.

Propionibacterium acnes endocarditis: a case series.

OBJECTIVES: Propionibacterium acnes remains a rare cause of infective endocarditis (IE). It is challenging to diagnose due to the organism's fastidious nature and the indolent presentation of the disease. The purpose of this study was to describe the clinical presentation and management of P. acnes IE with an emphasis on the methods of diagnosis. METHODS: We identified patients from the Cleveland Clinic Infective Endocarditis Registry who were admitted from 2007 to 2015 with definite IE by Duke Criteria. Propionibacterium acnes was defined as the causative pathogen if it was identified in at least two culture specimens, or identified with at least two different modalities: blood culture, valve culture, valve sequencing or histopathological demonstration of microorganisms. RESULTS: We identified 24 cases of P. acnes IE, 23 (96%) of which were either prosthetic valve endocarditis or IE on an annuloplasty ring. Invasive disease (71%) and embolic complications (29%) were common. All but one patient underwent surgery. Propionibacterium acnes was identified in 12.5% of routine blood cultures, 75% of blood cultures with extended incubation, 55% of valve cultures, and 95% of valve sequencing specimens. In 11 of 24 patients (46%), no causative pathogen would have been identified without valve sequencing. CONCLUSIONS: Propionibacterium acnes almost exclusively causes prosthetic valve endocarditis and patients often present with advanced disease. The organism may not be readily cultured, and extended cultures appear to be necessary. In patients who have undergone surgery, valve sequencing is most reliable in establishing the diagnosis.

The non-specific lipid transfer protein, Ara h 9, is an important allergen in peanut.

BACKGROUND: Plant food allergy in the Mediterranean area is mainly caused by non-specific lipid transfer proteins (nsLTP). The aim of this study was to characterize peanut nsLTP in comparison with peach nsLTP, Pru p 3, and assess its importance in peanut allergy. METHODS: Peanut-allergic patients from Spain (n=32) were included on the basis of a positive case history and either a positive skin prick test or specific IgE to peanut. For comparison, sera of 41 peanut-allergic subjects from outside the Mediterranean area were used. Natural Ara h 9 and two isoforms of recombinant Ara h 9, expressed in Pichia pastoris, were purified using a two-step chromatographic procedure. Allergen characterization was carried out by N-terminal sequencing, circular dichroism (CD) spectroscopy, immunoblotting, IgE inhibition tests and basophil histamine release assays. RESULTS: Compared with natural peanut nsLTP, the recombinant proteins could be purified in high amounts from yeast supernatant (> or =45 mg/L). The identity of the proteins was verified by N-terminal amino acid sequencing and with rabbit nsLTP-specific antibodies. CD spectroscopy revealed similar secondary structures for all preparations and Pru p 3. The Ara h 9 isoforms showed 62-68% amino acid sequence identity with Pru p 3. IgE antibody reactivity to rAra h 9 was present in 29/32 Spanish and 6/41 non-Mediterranean subjects. Recombinant Ara h 9 showed strong cross-reactivity to nPru p 3 and similar IgE-binding capacity as nAra h 9. The two Ara h 9 isoforms displayed similar IgE reactivity. In peanut-allergic patients with concomitant peach allergy, Ara h 9 showed a weaker allergenic potency than Pru p 3 in histamine release assays. CONCLUSIONS: Ara h 9 is a major allergen in peanut-allergic patients from the Mediterranean area. Ara h 9 is capable of inducing histamine release from basophils, but to a lesser extent than Pru p 3.

Outcomes with daptomycin versus standard therapy for osteoarticular infections associated with Staphylococcus aureus bacteraemia.

OBJECTIVES: To evaluate the clinical characteristics, treatment and outcomes of patients with osteoarticular infections (OAIs) associated with Staphylococcus aureus bacteraemia (SAB). METHODS: The clinical characteristics and outcomes for patients with OAI were described using a post hoc analysis of an open label, randomized trial comparing daptomycin with standard therapy (vancomycin or anti-staphylococcal penicillin with initial gentamicin) for the treatment of SAB. RESULTS: OAI occurred in 32 of 121 patients (21 daptomycin and 11 standard therapy) with complicated SAB (18 septic arthritis, 9 vertebral osteomyelitis and 7 others). Two patients had osteomyelitis in more than one site. Success rates seen in two groups were as follows: vertebral osteomyelitis [3/5 (60%) daptomycin versus 0/2 (0%) comparator], septic arthritis [7/11 (64%) versus 3/5 (60%)], sternal osteomyelitis [3/3 (100%) versus 1/2 (50%)] and long bone osteomyelitis [0/1 (0%) versus 1/1 (100%)]. Success rates in both treatment groups improved with surgical therapy. Creatine phosphokinase elevations to >500 IU/L occurred in one patient on daptomycin who discontinued therapy, whereas renal impairment developed in three patients on standard therapy, two of whom discontinued therapy. Two patients treated with daptomycin and one patient on vancomycin had increases in S. aureus MICs to daptomycin and vancomycin, respectively. Three patients treated with daptomycin died following completion of therapy, with mortality attributed to multiple co-morbid conditions and inadequate debridement of OAIs in these patients. No deaths were reported in the standard therapy group. CONCLUSIONS: Daptomycin may be considered an alternative to standard therapy in the treatment of patients with complicated SAB and OAI.

[Intermediate-term results after arthroscopic subacromial decompression with special reference to ongoing disability claims]. / Mittelfristige Ergebnisse nach arthroskopischer subakromialer Dekompression (ASD) unter besonderer Berücksichtigung laufender Rentenantragsverfahren.

The objective was to evaluate mid-term results after arthroscopic subacromial decompression (ASD) with special focus on the bias due to an application to social insurance for pension based on sickness disability. The study group consisted of 42 patients (28 male, 14 female). ASD was performed in 1993 or 1994 for impingement stage II. The mean age was 49.5 years. Thirty-nine patients (93%) were evaluated by an independent observer for an average follow-up of 3.5 years (range 1.5-5). Patients satisfaction with the outcome was assessed by a visual analog scale graded from 0 (extremely dissatisfied) to 10 (extremely satisfied). The functional result was assessed using the Constant score. At follow-up the mean VAS value was 6.4 +/- 3.4. The Constant score improved from 49.6 +/- 18.5 to 84.8 +/- 14.3. The subgroup of patients having applied to social insurance for pension had significantly worse results compared with the remaining patients: VAS: 4.9 +/- 3.1 vs. 7.5 +/- 3.1; Constant-Score: 76.1 +/- 12.7 vs. 88.3 +/- 13.5. The fact that patients try to get benefit from social insurance based on sickness disability significantly biased the outcome after ASD.

Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin.

Clinicians caring for patients with vancomycin-resistant Enterococcus faecium (VREF) infections face severe constraints in the selection of treatment. Quinupristin/dalfopristin (Synercid) is active in vitro against VREF, with a MIC(90) of 1.0 microg/mL. We investigated the clinical efficacy and safety of this agent in a multicenter, prospective, noncomparative, emergency-use study of 396 patients. Patients were included if they had signs and symptoms of active infection, including bacteremia of unknown origin, intra-abdominal infection, and skin and skin-structure infection, with no alternative antibiotic therapy available. The mean duration of treatment was 20 days (range, 4-40 days). The clinical response rate was 68.8% in the evaluable subset, and the overall response rate was 65.6%. The most common adverse events related to quinupristin/dalfopristin were arthralgias and myalgias. Related laboratory abnormalities were rare. In this severely ill patient population, quinupristin/dalfopristin was efficacious and demonstrated an acceptable safety profile in the treatment of VREF infection.

Protease-sparing regimen in a real-life practice with naïve patients: an equal opportunity approach?

PURPOSE: Proven clinical efficacy of protease-sparing regimens (PSR) has been shown. Concerns exist about broad applicability of these regimens in advanced naïve patients. Recent reports have associated a rise in liver enzymes with nevi rapine; however, no data exist with efavirenz. METHOD: 17 consecutive antiretroviral-naïve HIV patients were started on a PSR with efavirenz plus two nucleoside reverse transcriptase inhibitors. Baseline liver enzymes, serum CD38, CD4, and HIV viral load data were collected. Correlation between change in viral load and immune reconstitution on therapy were compared to baseline laboratory values. RESULTS: All patients had a mean viral load decrease of >2 logs, including patients with low initial CD4% or high viral load, and there was no increase of liver enzymes observed at a median follow-up of 42 weeks (range 17-78). There was a perfect correlation between the change in viral load and the initial viral load (p <.0001, r = 1.00) including patients with viral load > or =100,000 copies/mL and CD4 count< or =50 (n = 5). Even patients with low initial CD4 had a significant percentage increase in CD4 count (p <.0002, r = 0.7880). CD38% showed a positive correlation with change in viral load (p =.046, r = 0.522). CONCLUSION: All patients experienced a mean viral load decrease of >2 logs (88% less than 400 copies/mL and 35% less than 20 copies/mL). There were no observed increases in liver enzymes. Patients with low CD4 counts, high initial viral load, or high CD38 expression still experienced a significant change in viral load.

Successful administration of quinupristin/dalfopristin in the outpatient setting.

Intravenous administration of quinupristin/dalfopristin outside the hospital setting has not been reported previously. We describe 37 outpatients receiving quinupristin/dalfopristin iv for infections including osteomyelitis, bacteraemia, abscesses and cellulitis. The most frequent aetiological pathogens found were Enterococcus faecium, Staphylococcus aureus and coagulase-negative staphylococci. Patients received an average of 9 days therapy as inpatients and 22 days as outpatients. Quinupristin/dalfopristin was administered using various access devices, most commonly peripherally inserted central catheters and tunnelled central catheters. The bacteriological and clinical success rates were both 89.2%. Five patients were readmitted to hospital; one patient developed catheter-related bacteraemia. The most frequently reported non-venous adverse events were nausea (18.9% of patients), myalgia (18.9%) and arthralgia (13.5%). Sixteen patients experienced venous access-related events, most commonly infusion pain, oedema and phlebitis. In this group of patients, for those who had difficult-to-treat infections, intravenous quinupristin/dalfopristin therapy was generally effective and safe outside the hospital setting.

Spontaneous testicular lesions in purpose-bred beagle dogs.

Spontaneous testicular lesions were assessed in 50 control purpose-bred male beagle dogs. They were selected from 13 toxicology studies conducted over the period 1988-1999. Age of the dogs at study termination varied from 8-20 months with an average age of 13 months. Regardless of age, the most significant finding was bilateral segmental hypospermatogenesis in 15/50 (30%) of the dogs. Cross sections of tubules with hypospermatogenesis were distributed randomly throughout the testes and were characterized by reduced proportions of germ cells, tubular shrinkage, and Sertoli cell prominence. These changes were occasionally associated with giant cells, with cellular debris, and in 6/15 (40%) with atrophic tubules devoid of germ cells, indicating a degenerative process. Focal subcapsular tubular atrophy or hypoplasia (tubules lined by Sertoli cells only) was also found in 9/35 (26%) of dogs without hypospermatogenesis. Inhibited spermiation with retention of mature sperm in tubules was seen in 6/50 dogs, 3 of which also showed hypospermatogenesis. Other findings of high incidence but low prevalence included tubules with multinucleated giant cells, swollen spermatocytes, or apoptotic germ cells. These latter changes are probably a constituent of normal spermatogenesis. In conclusion, about 30% of control beagle dogs show segmental hypospermatogenesis, which may be associated with degenerative changes, and an additional 18% of the dogs exhibit focal tubular atrophy/hypoplasia in otherwise normal testes. These changes have to be distinguished from compound-related toxic effects.

Preclinical development of keliximab, a Primatized anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies.

The preclinical safety assessment of biopharmaceuticals necessitates that studies be conducted in species in which the products are pharmacologically active. Monoclonal antibodies are a promising class of biopharmaceuticals for many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. In order to conduct a comprehensive preclinical safety assessment of this antibody to support chronic treatment of rheumatoid arthritis in patients, a human CD4 transgenic mouse was used for chronic and reproductive toxicity studies and for genotoxic studies. In addition, immunotoxicity studies were conducted in these mice with Candida albicans, Pneumocystis carinii and B16 melanoma cells to assess the effects of keliximab on host resistance to infection and immunosurveillance to neoplasia. The results of these studies found keliximab to be well tolerated with the only effects observed being related to its pharmacologic activity on CD4+ T lymphocytes. The use of transgenic mice expressing human proteins provides a useful alternative to studies in chimpanzees with biopharmaceutical agents having limited species cross-reactivity.

Repeated cadmium exposures enhance the malignant progression of ensuing tumors in rats.

Prior studies show that a single subcutaneous (sc) exposure to cadmium (Cd) will induce injection site sarcomas (ISS) in rats. These tumors, thought clearly malignant, do not often metastasize or invade subdermal muscle layers because of their location. Recent evidence indicates that when tumorigenic cells chronically exposed to Cd in vitro are inoculated into mice, tumor progression and invasiveness in the mice are enhanced. Thus, we studied the effects of repeated Cd exposures on tumor incidence, progression, and metastatic potential in rats. Wistar (WF) and Fischer (F344) rats (30 per group) were injected sc in the dorsal thoracic midline with CdCl2 once weekly for 18 weeks with doses of 0, 10, 20, or 30 micromol Cd/kg. This resulted in total doses of 0, 180, 360, or 540 micromol/kg. One other group of each strain received a low, loading dose of Cd (3 micromol/kg) prior to 17 weekly injections of 30 micromol/kg (total dose 513 micromol/kg). Rats were observed for 2 years. Many F344 rats (57%) died within one week after the first injection of the highest dose, but WF rats were not affected. The low loading dose prevented acute lethality of the high dose in F344 rats. Surprisingly, latency (time to death by tumor) of ISS was the shortest in the groups given the low loading dose in both strains. ISS in these groups also showed the highest rate of metastasis and subdermal muscle layer invasion. Based on ISS incidence in the groups given the lowest total dose of Cd (180 micromoles/kg), F344 rats were more sensitive to tumor induction, showing an incidence of 37% compared to 3% in WF rats. On the other hand, Cd-induced ISS showed a higher overall metastatic rate in WF rats (18 metastatic ISS/68 total tumors in all treated groups; 27%) compared to F344 rats (6%). Immunohistochemically, the primary ISS showed high levels of metallothionein (MT), a cadmium-binding protein, while metastases were essentially devoid of MT. These results indicate that repeated Cd exposures more rapidly induce ISS. An initial low exposure to Cd further accelerates the appearance and enhances the metastatic potential and invasiveness of these tumors. The primary and metastatic ISS appear to have a differing phenotype, at least with regard to MT production. The association between multiple Cd exposures and enhanced metastatic potential of the ensuing tumors may have important implications in chronic exposures to Cd, or in cases of co-exposure of Cd with organic carcinogens, as in tobacco smoking.

The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting.

NIH sponsored a meeting of medical and veterinary pathologists with mammary gland expertise in Annapolis in March 1999. Rapid development of mouse mammary models has accentuated the need for definitions of the mammary lesions in genetically engineered mice (GEM) and to assess their usefulness as models of human breast disease. The panel of nine pathologists independently reviewed material representing over 90% of the published systems. The GEM tumors were found to have: (1) phenotypes similar to those of non-GEM; (2) signature phenotypes specific to the transgene; and (3) some morphological similarities to the human disease. The current mouse mammary and human breast tumor classifications describe the majority of GEM lesions but unique morphologic lesions are found in many GEM. Since little information is available on the natural history of GEM lesions, a simple morphologic nomenclature is proposed that allows direct comparisons between models. Future progress requires rigorous application of guidelines covering pathologic examination of the mammary gland and the whole animal. Since the phenotype of the lesions is an essential component of their molecular pathology, funding agencies should adopt policies ensuring careful morphological evaluation of any funded research involving animal models. A pathologist should be part of each research team.

Idoxifene: a novel selective estrogen receptor modulator prevents bone loss and lowers cholesterol levels in ovariectomized rats and decreases uterine weight in intact rats.

Idoxifene, a novel selective estrogen receptor modulator, was tested for its effects on bone loss, serum cholesterol, and uterine wet weight and histology in the ovariectomized (Ovx) rat. Idoxifene (0.5 mg/kg x day) completely prevented loss of both lumbar and proximal tibial bone mineral density (BMD). In an intervention study, idoxifene (0.5 and 2.5 mg/kg x day) completely prevented further loss of both lumbar and proximal tibial BMD during a 2-month treatment period commencing 1 month after surgery, when significant loss of BMD had occurred in the Ovx control group. Idoxifene reduced total serum cholesterol, which was maximal at 0.5 mg/kg x day. Idoxifene alone displayed minimal uterotrophic activity in Ovx rats and inhibited the agonist activity of estrogen in intact rats. Histologically, myometrial and endometrial atrophy were observed in both idoxifene and vehicle-treated Ovx rats. In this report, we also provide molecular-based evidence to support the observations in vivo of a novel selective estrogen receptor modulator (SERM) mechanism of action in bone and endometrial cells. Idoxifene is an agonist through the estrogen response element (ERE) and exhibits similar postreceptor effects to estrogen in bone-forming osteoblasts. Idoxifene also stimulates osteoclast apoptosis, and these pleiotropic effects ultimately could contribute to the maintenance of bone homeostasis. However, idoxifene differs from estrogen in a tissue-specific manner. In human endometrial cells, where estrogen is a potent agonist through the ERE, idoxifene has negligible agonist activity. Moreover, idoxifene was able to block estrogen induced gene expression in endometrial cells, which is in agreement with the observation in the intact rat study. In the uterus, idoxifene has a pharmacologically favorable profile, lacking agonist and therefore growth-promoting activity. Together with its cholesterol lowering effect and lack of uterotrophic activity, these data suggest that idoxifene may be effective in the prevention of osteoporosis and other postmenopausal diseases without producing unwanted estrogenic effects on the endometrium.

Lack of carcinogenicity of cadmium chloride in female Syrian hamsters.

Cadmium is very effective at inducing necrosis within the ovaries of rodents, and the Syrian hamster appears particularly sensitive. The extent of cadmium-induced necrosis depends on the stage of the estrous cycle and is most pronounced when injected on the day prior to ovulation (proestrous). In male rodents cadmium induces a similar necrosis within the testes, which given sufficient time can lead to the development of testicular tumors. In this study we tested the hypothesis that cadmium-induced ovarian necrosis could eventually lead to tumor formation. In sexually mature groups of female Syrian hamsters (> 8 weeks old; n = 50-59), the estrous cycle was determined by visual inspection of vaginal discharge for four consecutive cycles. The animals were then given cadmium (0, 30, 40 and 50 micromol/kg) subcutaneously as a single injection in the dorsal thoracic midline on cycle day 4 (proestrous). Based on prior work, these doses are sufficient to induce extensive acute ovarian damage. Animals were then observed over the next 78 weeks. Although survival and body weight were reduced by cadmium, treatment with the metal did not result in an enhanced incidence of tumors at any site including the ovaries. Non-neoplastic lesions such as amyloidosis and pancreatic hepatocytes were linked to cadmium exposure. These results indicate that the association of cadmium-induced testicular necrosis with tumor development seen in males does not occur in the Syrian hamster ovaries.

An evaluation of the novel selective estrogen receptor modulator, idoxifene, for effects on reproduction in rats and rabbits.

Idoxifene, a tissue-specific selective estrogen receptor modulator, was evaluated in male and female rats and female rabbits after oral administration for effects on fertility and/or embryo-fetal development. In all studies, adult toxicity was evident at doses >/=0.03 mg/kg/day in rats and >/=0.1 mg/kg/day in rabbits as evidenced by decreased body weight and/or food consumption. In the male fertility study, rats were treated with 0.003, 0.3, or 3.0 mg/kg/day for 64 to 68 days. Doses >/=0.3 mg/kg/day decreased seminal vesicle and prostate weights and impaired posttesticular sperm development, resulting in decreased epididymal sperm count and weight, but did not affect male fertility. In the female fertility study, rats were treated for 2 weeks prior to mating until insemination with 0.003, 0.03, or 3.0 mg/kg/day. Disrupted estrous cycles, impaired fertility, increased preimplantation loss, and increased vaginal fluid at necropsy were evident at >/=0.03 mg/kg/day. In the early embryonic development study, pregnant female rats were treated from days 0 to 6 postcoitus (pc) with 0.003, 0.03, or 3.0 mg/kg/day idoxifene. Partial or complete preimplantation loss was seen at 0.03 and 3.0 mg/kg/day, respectively. In the embryo-fetal development study, pregnant rats were treated from days 6 to 17 pc with 0.003, 0.03, or 3.0 mg/kg/day. At 3.0 mg/kg/day there was maternal lethality, excess vaginal fluid, embryo-fetal death, generalized fetal edema, and developmental delays. Excess vaginal fluid but no fetal effects were seen at 0.03 mg/kg/day. There were no treatment-related effects at 0.003 mg/kg/day in any rat reproduction study performed. In the rabbit embryo-fetal development study, pregnant New Zealand White rabbits were treated from days 6 to 20 pc with 0.01, 0.1, or 1.0 mg/kg/day idoxifene. At 1.0 mg/kg/day there was maternal lethality, vaginal or uterine bleeding, abortion/premature deliveries, and embryolethality. Vaginal or uterine bleeding was seen at 0.1 mg/kg/day. No treatment-related effects were observed at 0.01 mg/kg/day. Although systemic toxicity was evident in all the studies, the effects of idoxifene on rat and rabbit reproduction were considered to be due to the pharmacological activity of the compound.

Altered hemostasis in male rats following administration of the ACAT inhibitor SKF-99085.

SKF-99085, an acyl-CoA:cholesterol acyltransferase (ACAT) was evaluated in male and female Sprague-Dawley rats at oral doses of 0, 10, 100, or 400 mg/kg/day for 6 months as part of the preclinical safety assessment of this drug candidate. In male rats given 400 mg/kg/day SKF-99085, hemorrhage and death were observed in males during the first month of the study, prompting collection of blood samples at weeks 6, 17, and 24 to monitor coagulation parameters. A dose-related increase in activated partial thromboplastin time (APTT) and Thrombotest clotting time (TCT) was observed in all male drug-treated groups. Mean APTT values for male rats given 10, 100, or 400 mg/kg/day were increased maximally to 17.5, 20.8, and 34.7 s (control, 15.4-16.0 s), and mean TCT values were increased to 86, 100, and >300 s (control, 71-74 s), respectively. Mean prothrombin times (PT) for male rats given 400 mg/kg/day were increased to 16.5 s (control, 12.9-13.1 s). Activities of factors II, VII, IX, and X were decreased in males at dosages of 10, 100, or 400 mg/kg/day. Factor V and VIII activities were unaffected. In summary, the drug-related hemorrhagic disorder observed in male rats given high doses of the ACAT inhibitor SKF 99085 was attributed to a reduction in the activity of vitamin-K-dependent coagulation factors. In contrast to humans and some other species, the APTT and TCT were more sensitive than the PT in detecting this effect.