Triple-combination therapy in the treatment of hypertension: a review of the evidence.

Hypertension is a serious public health concern with inadequate control of blood pressure (BP) worldwide. Contributing factors include low efficacy of drugs, underuse of combination therapies, irrational combinations, physicians' therapeutic inertia and poor adherence to treatment. Current guidelines recommend the use of initial (dual) combination therapy in high-risk patients for immediate BP response, better short- and long-term BP control, and continued/improved patient adherence. This article aims to review the existing evidence of triple-combination therapies with respect to efficacy, safety and adherence to treatment. It is estimated that three drugs are required to achieve BP control in approximately one-fourth to one-third of patients. Randomised controlled trials (RCTs) have shown that triple combinations of amlodipine/valsartan/hydrochlorothiazide, amlodipine/olmesartan/hydrochlorothiazide and amlodipine/telmisartan/hydrochlorothiazide produce greater BP reductions, with greater proportions of patients achieving BP control compared with dual therapies. Further evidence also demonstrates that triple-combination therapy is efficacious for moderate to severe hypertension, with substantial additional BP reduction over dual regimens. Both RCTs and post-marketing observational studies have shown consistent and comparable efficacy in both the general population and high-risk hypertensive subgroups. Triple therapies are generally well tolerated with adverse event profiles similar to dual regimens. In addition, fixed-dose combinations used as single pill improve patient adherence leading to better long-term BP control. Depending on regional circumstances, they may also be cost effective. Thus, single-pill triple combinations of different classes of drugs with complementary mechanisms of action help to treat patients to goal with improved efficacy and better adherence to treatment.

Performance of Laser Megajoule's x-ray streak camera.

A prototype of a picosecond x-ray streak camera has been developed and tested by Commissariat à l'Énergie Atomique et aux Énergies Alternatives to provide plasma-diagnostic support for the Laser Megajoule. We report on the measured performance of this streak camera, which almost fulfills the requirements: 50-µm spatial resolution over a 15-mm field in the photocathode plane, 17-ps temporal resolution in a 2-ns timebase, a detection threshold lower than 625 nJ/cm2 in the 0.05-15 keV spectral range, and a dynamic range greater than 100.

Picosecond X-ray streak camera dynamic range measurement.

Streak cameras are widely used to record the spatio-temporal evolution of laser-induced plasma. A prototype of picosecond X-ray streak camera has been developed and tested by Commissariat à l'Énergie Atomique et aux Énergies Alternatives to answer the Laser MegaJoule specific needs. The dynamic range of this instrument is measured with picosecond X-ray pulses generated by the interaction of a laser beam and a copper target. The required value of 100 is reached only in the configurations combining the slowest sweeping speed and optimization of the streak tube electron throughput by an appropriate choice of high voltages applied to its electrodes.

First set of gated x-ray imaging diagnostics for the Laser Megajoule facility.

The Laser Megajoule (LMJ) facility located at CEA/CESTA started to operate in the early 2014 with two quadruplets (20 kJ at 351 nm) focused on target for the first experimental campaign. We present here the first set of gated x-ray imaging (GXI) diagnostics implemented on LMJ since mid-2014. This set consists of two imaging diagnostics with spatial, temporal, and broadband spectral resolution. These diagnostics will give basic measurements, during the entire life of the facility, such as position, structure, and balance of beams, but they will also be used to characterize gas filled target implosion symmetry and timing, to study x-ray radiography and hydrodynamic instabilities. The design requires a vulnerability approach, because components will operate in a harsh environment induced by neutron fluxes, gamma rays, debris, and shrapnel. Grazing incidence x-ray microscopes are fielded as far as possible away from the target to minimize potential damage and signal noise due to these sources. These imaging diagnostics incorporate microscopes with large source-to-optic distance and large size gated microchannel plate detectors. Microscopes include optics with grazing incidence mirrors, pinholes, and refractive lenses. Spatial, temporal, and spectral performances have been measured on x-ray tubes and UV lasers at CEA-DIF and at Physikalisch-Technische Bundesanstalt BESSY II synchrotron prior to be set on LMJ. GXI-1 and GXI-2 designs, metrology, and first experiments on LMJ are presented here.

Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial.

AIMS: To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit. METHODS: In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression. RESULTS: The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints). CONCLUSIONS: The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm.

Overview of the ARGOS X-ray framing camera for Laser MegaJoule.

Commissariat à l'Énergie Atomique et aux Énergies Alternatives has developed the ARGOS X-ray framing camera to perform two-dimensional, high-timing resolution imaging of an imploding target on the French high-power laser facility Laser MegaJoule. The main features of this camera are: a microchannel plate gated X-ray detector, a spring-loaded CCD camera that maintains proximity focus in any orientation, and electronics packages that provide remotely-selectable high-voltages to modify the exposure-time of the camera. These components are integrated into an "air-box" that protects them from the harsh environmental conditions. A miniaturized X-ray generator is also part of the device for in situ self-testing purposes.

Correlation between glove use practices and compliance with hand hygiene in a multicenter study with elderly patients.

In a study conducted in 11 health care settings for elderly patients, we demonstrated a significant negative correlation between the proportion of glove use outside any risk of exposure to body fluids and compliance with hand hygiene (P < .02). This result underscores a major limitation of strategies for controlling the spread of multidrug-resistant bacteria that recommend systematic glove use for each contact with carriers or their environment.

Aliskiren-based stepped-care treatment algorithm provides effective blood pressure control.

AIMS: Recent guidelines for the management of hypertension recommend an individualised stepped-care treatment approach in mild-to-moderate hypertensive patients, to achieve blood pressure (BP) goals. This study evaluated the probability of patients achieving BP targets with an aliskiren-based stepped-care treatment regimen. METHODS: This was a 24-week, open-label, non-comparator study design that included six sequential 4-week treatment periods in patients with mild-to-moderate hypertension. Over the potential 24 weeks of active treatment, incremental therapy included the following add-on therapies at 4-week intervals: aliskiren 150-300 mg once daily, hydrochlorothiazide (HCTZ) 12.5-25 mg once daily, and finally amlodipine 5-10 mg once daily, as needed to achieve target BP. Subjects achieving BP targets following any given 4 weeks of therapy were considered study completers, while subjects not achieving their clinical BP target entered into the next step of incremental therapy. The primary efficacy end-point was the estimated cumulative probability of patients achieving BP target. RESULTS: Of 256 patients treated, 232 (90.6%) completed the study. Baseline mean sitting BP was 155.7/91.7 mmHg. At study end-point, the estimated cumulative probability of reaching BP target was 86.12%. The stepped-care treatment regimen was well tolerated at the maximal recommended doses of all the individual complimentary therapies. CONCLUSION: An aliskiren-based stepped-care treatment regimen that subsequently included both HCTZ and amlodipine is effective in achieving BP goals in approximately 90% of patients with mild-to-moderate hypertension.

Spontaneous metritis related to the presence of vaginal septum in pregnant Sprague Dawley Crl:CD(SD) rats: impact on reproductive toxicity studies.

Recently, 6% of 1,176 Sprague Dawley rats examined in our reproductive toxicity studies presented with dark-red uterine contents with or without fetuses demonstrating delayed development. Sometimes, a high proportion of the litter was found dead, and dystocia with death or preterminal euthanasia of the dam occurred. Microscopic findings in the uterus consisted of necrohemorrhagic and suppurative periplacentitis associated with the presence of bacterial colonies identified as Escherichia coli. In the vagina, similar findings were observed that were associated with mucus accumulation and the presence of a transverse occlusive or partially occlusive thin membrane identified as a vaginal septum. Microscopically, this septum consisted of a thin band of connective tissue covered on both sides by a mucous epithelium that was continuous with vaginal epithelium. In some cases, there was only mucus accumulation retained by a septum in the vagina without evidence of bacterial infection. Serological and histological examinations did not reveal any specific pathogenic agent. The presence of these septa in the vagina most likely favored mucus accumulation, nonspecific ascending bacterial infection, and dystocia. This colony of rats presented with an unusually high incidence of vaginal septa as it was described in different strains of mice and rats in the past. We hypothesized that the use of an impedance meter by the breeder--to determine the phase of the estrous cycle by introducing a probe in the vagina--likely facilitated gestation by perforating the vaginal septum in some cases.

Measurement and interpretation of hand hygiene compliance rates: importance of monitoring entire care episodes.

Our objective was to assess the importance of monitoring hand hygiene compliance (HHC) during series of successive contacts with patients or surroundings for measurement and interpretation of the compliance rates. A direct observational study of HHC was performed in four intensive care units (ICUs) and four healthcare settings with non-intensive care wards (NICWs). Hand hygiene (HH) opportunities were differentiated into two categories: extra-series opportunities (ESOs) (before or after a single contact, and before the first contact or after the last contact of a series of successive contacts) or as intra-series opportunities (ISOs) (from the opportunity following the first contact to the opportunity preceding the last in the same series). In all, 903 opportunities of HH were performed in ICUs and 760 in NICWs. The proportion of ISOs was 46.0% in ICUs and 22.9% in NICWs. The overall HHC was significantly higher in NICWs than in ICUs (61.2% vs 47.5%, P<0.00001). The HHC was significantly higher for ESOs than for ISOs (67.7% vs 28.5%, P<0.00001). The HHC for ISOs was significantly higher in ICUs (32.2% vs 19.0%, P<0.005). If the distribution of categories of HH opportunities observed in NICWs had been the same as in ICUs, the overall HHC would have been similar in NICWs (46.4%) and in ICUs (47.5%). Monitoring HHC during entire care episodes in series of successive contacts is necessary to avoid a strong overestimation of the overall compliance rates. Concurrently, comparison of compliance data should take into account the proportion of ISOs included in the evaluation study.

Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study.

The strategy of initiating hypertension treatment with combination versus single-drug therapy was formally tested in a prospective, double-blind, parallel-group trial in blacks with stage 2 hypertension (mean sitting systolic BP (MSSBP) >or=160 and <200 mm Hg). Participants were randomized equally to amlodipine/valsartan (A/V) (n=286) or amlodipine (A) monotherapy (n=286). After 2 weeks, there was forced titration of A/V 5/160 mg to A/V 10/160 mg and of A 5 to A 10 mg followed by 10 additional weeks of treatment. If SBP was >or=130 mm Hg at week 4, the protocol allowed optional titration of A/V to the 10/320 mg dose and, at week 8, hydrochlorothiazide 12.5 mg was optionally added to both A/V and A if SBP >or=130 mm Hg. Amlodipine/valsartan at week 8 lowered MSSBP last observation carried forward significantly>A (33.3 vs 26.6 mm Hg, P<0.0001). Lowering of MSSBP with A/V significantly exceeded that of A in several specified subgroups-the elderly (>or=65 years), isolated systolic hypertension, and those with body mass index (BMI) >or=30 kg/m(2). More patients treated with A/V than A achieved BP control (<140/90 mm Hg) both at weeks 8 (49.8 vs 30.2%; P<0.0001) and 12 (57.2 vs 35.9%; P<0.0001). Both treatment regimens were well tolerated. In conclusion, the strategy of initiating combination antihypertensive drug therapy in blacks with stage 2 hypertension with amlodipine /valsartan achieves greater and quicker reductions in BP as well as significantly higher BP control rates than starting treatment with amlodipine monotherapy.

The combination of amlodipine/valsartan 5/160 mg produces less peripheral oedema than amlodipine 10 mg in hypertensive patients not adequately controlled with amlodipine 5 mg.

AIMS: To demonstrate the benefit of the combination amlodipine/valsartan 5/160 mg over amlodipine 10 mg, in producing a lower incidence of peripheral oedema for a comparable mean sitting systolic blood pressure (MSSBP) reduction. METHODS: After a 4-week amlodipine 5 mg run-in phase, inadequately controlled hypertension patients (aged > or = 55 years, MSSBP > or = 130 and < or = 160 mmHg) were randomised to receive amlodipine/valsartan 5/160 mg or amlodipine 10 mg for 8 weeks, followed by amlodipine/valsartan 5/160 mg for 4 weeks for all patients. Primary variables were MSSBP change from baseline to week 8 and incidence of peripheral oedema reported as an AE. Resolution of peripheral oedema was assessed 4 weeks after switching patients from amlodipine 10 mg to amlodipine/ valsartan 5/160 mg. RESULTS: At week 8, MSSBP showed greater reduction with amlodipine/valsartan 5/160 mg than amlodipine 10 mg (least square mean: -8.01 vs.-5.95 mmHg, p < 0.001 for non-inferiority and p = 0.002 for superiority). Systolic control, overall BP control and systolic response rate at week 8 were significantly higher with combination than amlodipine 10 mg (34 vs. 26%; 57 vs. 50%; 36.57 vs. 27.77%, respectively). Incidence of peripheral oedema was significantly lower with the combination than amlodipine 10 mg (6.6 vs. 31.1%, p < 0.001). Peripheral oedema resolved in 56% patients who switched from amlodipine 10 mg to the combination, without the loss of effect on BP reduction. CONCLUSION: In non-responders to amlodipine 5 mg, treatment with amlodipine/valsartan 5/160 mg induced significantly less peripheral oedema than amlodipine 10 mg for similar BP reduction. Peripheral oedema resolved in > 50% patients switching from amlodipine 10 mg to the combination.

Exploring the social image of anabolic steroids users through motivation, sportspersonship orientations and aggression.

The authors explored social perceptions related to the use of anabolic steroids (AS) in sports. More specifically, 78 women and 102 men read one of two scenarios depicting a male athlete facing either a drug use or non-drug use situation. Then, participants reported their perceptions of the scenario protagonist in terms of self-determined sport motivation, sportspersonship orientations, and athletic aggression. Results of a multivariate analysis of covariance indicated that, in comparison with a non-using protagonist, the AS-using athlete was regarded as less self-determined in one's motivation (i.e., sport participation based on predominant feelings of pressure to obtain external rewards or avoid punishment) and as displaying weaker sportspersonship orientations (i.e., lesser concerns for opponents, the social conventions of sport, and for one's own athletic commitment). In addition, the AS-using athlete was perceived as resorting more readily to reactive aggression than to instrumental aggression (i.e., intent to injure one's opponent vs merely hinder his performance). Finally, the analyses did not disclose significant gender or interaction effects. The findings are discussed in view of theoretical and practical implications.

[Efficacy of repeat injections of botulinum A toxin to the detrusor in neurogenic bladder overactivity]. / Efficacité des injections intradétrusoriennes répétées de toxine A dans l'hyperactivité vésicale d'origine neurologique.

PURPOSE: Toxin injections are an effective treatment for neurogenic detrusor overactivity. The efficacy of repeat injections is not well documented. The objective of this study was to evaluate the efficacy of repeat injections of toxin A to the detrusor in patients with neurogenic overactive bladders. MATERIALS AND METHODS: Patients who had received 300-UI injections of Botox(R) were retrospectively studied. The clinical data included continence, duration of the absence of incontinence, changes in anticholinergic dosage or pad use and patient satisfaction. Urodynamic data analyzed were maximal cystometric capacity, bladder contraction and detrusor pressure during contraction. Data were analyzed by Wilcoxon and Kruskal-Wallis tests. RESULTS-DISCUSSION: Data for 42 patients (30 men, 12 women) were analysed. Pathologic features were trauma to the spinal cord, multiple sclerosis or varied causes of myelopathy. Patients received 1 to 6 injections of Botox(R). The mean duration of efficacy was 6 months. Efficacy did not differ among successive injections. Anticholinergic drugs were discontinued in 43% of patients and pad use in 48%. A total of 80% of the patients were satisfied with the treatment. Bladder contraction disappeared in 70% of patients. The mean maximal cystometric capacity increase was 144 ml. CONCLUSION: Clinical and urodynamic data show that repeat injection of toxins to the detrusor remains an effective therapy for neurogenic bladder overactivity. Efficacy for continence is maintained during successive injections.

Management in general practice of hypertensive patients poorly controlled with a fixed-dose renin-angiotensin system inhibitor and diuretic combination: results from a French national survey.

High rates of uncontrolled hypertensives have been reported in France as well as in other countries, partly owing to an inadequate management of hypertension by clinicians. The objectives of the study were (1) to describe the therapeutic decisions faced by general practitioners (GP) in hypertensives not controlled by fixed-dose combination antihypertensive therapy with a renin-angiotensin system (RAS) inhibitor and a diuretic (D) and (2) to evaluate the frequency with which ambulatory blood pressure monitoring (ABPM) is used in these patients. Each GP had to include five uncontrolled hypertensives on fixed-dose RAS inhibitor and D combination. A total of 2118 GPs included 9551 patients; 8643 patients were receiving at least one of the two drugs at a low dose (group 1) and the remaining 908 patients were receiving high doses of both drugs (group 2). The most common therapeutic choice was that of a new combination, either a fixed-dose in one pill or with separate preparations: 65% (n=5621) in group 1 and 56% (n=505) in group 2. An increase in dose was chosen in 28% of patients in group 1 (n=2467) and continuation of treatment without modification in 27% of patients in group 2 (n=242). A third active principle was only added in 2.5% of patients in group 1 (n=219) and 11% in group 2 (n=103). Ambulatory blood pressure monitoring was employed in 25% of patients (n=2413). An improvement in hypertension management should be expected from the implementation of the 2005 French guidelines. Journal of Human Hypertension (2006) 20, 407-418. doi:10.1038/sj.jhh.1002000; published online 30 March 2006.

[Tracheotomy in brain injured patients: which patients? Why? When? How?]. / Trachéotomie et traumatisme crânien grave: pour qui? Pourquoi? Quand? Comment?

The aim of this study is to determine, from the data available in the literature, the indications of tracheostomy in brain injured patients, the incidence and risk factors for complications and the follow-up required until decannulation. The incidence of tracheostomy is 10% in TBI and 50 to 70% in subpopulations with a Glasgow Coma Scale (GCS) below 9. Early complications are not specific. The most frequent late complication is laryngotracheal stenosis, which occurs in 15% and is more frequently observed in the most severe patients with major hypertonia. It is likely that tracheostomy, if needed, should be performed early and the prognosis as to whether it will be required, can be made at the end of the first week. The follow-up of these patients includes surveillance of multiresistant colonisations and systematic performance of fibroscopy before decannulation. Cuffless, small diameters, soft tracheostomy tubes, are preferred on the long-term unless the risk of aspiration remains high.

[Gait orthosis in patients with complete thoracic paraplegia. Review of 43 patients]. / Place actuelle de la marche appareillée chez les patients paraplégiques complets de niveau thoracique. A propos d'une cohorte de 43 patients.

OBJECTIVE: To evaluate of the effective use of gait orthosis in patients with spinal cord injuries. PATIENTS AND METHODS: A total of 43 patients with complete paraplegia, level T3 to L1, who had a gait orthosis (hip-knee-ankle-foot orthosis, reciprocating gait orthosis, hybrid orthosis and functional electrical stimulation) answered a telephone questionnaire. RESULTS: Orthotic gait use was discontinued in 65% of patients who used the orthosis twice a week for 15 to 60 minutes. Two-thirds of the patients were able to fit the orthosis independently, 60% for standing and 25% for walking. The main reasons for discontinuing use were psychological reasons in 30% of patients, the lack of functional use and the necessity for human help or supervision. CONCLUSION: Presently available devices do not allow functional and independent use of gait orthoses. Their use is limited to physical training, and the only demonstrated physiological benefits are the effects of functional electrical stimulation on cardiovascular status. Prescription for gait orthosis appears justified only if requested by a motivated and well-informed patient or if it appears a useful step in the acceptation of the loss of the gait.

Impact of restricting fluoroquinolone prescription on bacterial resistance in an intensive care unit.

The purpose of this study was to assess the effect of reducing prescription of fluoroquinolones in an intensive care unit (ICU) upon bacterial resistance, particularly as regards Pseudomonas aeruginosa. For six months between January 2001 and June 2001, administration of fluoroquinolones was kept to a minimum. A bacteriological screening of patients was performed to assess the incidence of fluoroquinolone-resistant bacteria. There was a 75.8% restriction in prescriptions of fluoroquinolones. There was no significant change in bacterial ecology between the periods preceding (12 months) and following (12 months) restriction. There was a significant recovery of sensitivity of P. aeruginosa to ciprofloxacin (P

Restoration of early insulin secretion after a meal in type 2 diabetes: effects on lipid and glucose metabolism.

BACKGROUND: In type 2 diabetes (T2D) insulin secretion after a meal is delayed; this may have an impact on the development of hyperglycaemia and hyperlipidaemia. DESIGN: To investigate this, a meal was given to 15 T2D (age 52 +/- 2 years, BMI 25 +/- 0.8 kg m(-2)) on three different occasions: (1) without treatment, (2) after 120 mg of nateglinide before the meal (acute treatment), and (3) after 3 months of nateglinide (120 mg t.i.d., chronic treatment). Fifteen healthy subjects (CON, age 48 +/- 2 years, BMI 24 +/- 0.5 kg m(-2)) were also studied. Blood was withdrawn for 360 min from veins draining the anterior abdominal subcutaneous adipose tissue (AD) and from an arterialized hand vein. Blood flow (BF) in AD was measured with (133)Xe. Lipoprotein lipase activity (LPL) was calculated as the triacylglycerol (TAG) flux across AD, and hormone-sensitive lipase (HSL) as the glycerol flux minus LPL. RESULTS: (1) In T2D the increase in prandial insulin secretion was delayed; postprandial nonesterified fatty acid (NEFA) and TAG levels in blood were increased, while BF, LPL and TAG clearance were blunted vs. CON. (2) Acute or chronic nateglinide treatment induced a prompt increase in prandial insulin secretion, resulting in a decrease in blood glucose and NEFA levels owing to suppression of HSL, while BF, LPL and TAG clearance remained suppressed. CONCLUSIONS: In T2D, restoration of early phase insulin secretion improved postprandial hyperglycaemia and suppressed endogenous lipolysis, resulting in suppression of NEFA levels. These results suggest that in nonobese T2D, metabolic defects may result, to a large extent, from the delay in prandial insulin secretion.

Different embryo-fetal toxicity effects for three VLA-4 antagonists.

BACKGROUND: VLA-4 (Very late antigen 4, integrin alpha4beta1) plays an important role in cell-cell interactions that are critical for development. Homozygous null knockouts of the alpha4 subunit of VLA-4 or VCAM-1 (cell surface ligand to VLA-4) in mice result in abnormal placental and cardiac development and embryo lethality. Objectives of the current study were to assess and compare the teratogenic potential of three VLA-4 antagonists. METHODS: IVL745, HMR1031, and IVL984 were each evaluated by the subcutaneous route in standard embryo-fetal developmental toxicity studies in rats and rabbits. IVL984 was also evaluated in mice. Fetuses were examined externally, viscerally, and skeletally. RESULTS: IVL745 did not cause significant maternal or fetal effects at doses up to 100 or 250 mg/kg/day in rats or rabbits, respectively. HMR1031 treatment resulted in marked maternal toxicity and slight fetal toxicity at the highest tested doses of 200 and 75 mg/kg/day in rats and rabbits, respectively. HMR1031 embryo-fetal effects consisted of slightly lower body weight and crown-rump length in rats and minor sternebral defects in rabbits. IVL984 treatment resulted in minimal maternal effects at doses up to 40, 15, and 100 mg/kg/day in rats, rabbits, and mice, respectively (excluding abortions in rabbits). However, marked developmental effects were observed at the lowest tested IVL984 doses, 1, 0.2, and 3 mg/kg/day in rats, rabbits, and mice, respectively. IVL984 embryo-fetal effects consisted of increased total post-implantation loss due to early resorptions and high incidences of cardiac malformations and skeletal malformations and/or variations. Notably, spiral septal defects were observed in up to 76% of rat fetuses and up to 58% of rabbit fetuses. CONCLUSIONS: Dramatic differences in teratogenic potential were observed: IVL745 was not teratogenic, HMR1031 caused slight embryo-fetal effects at maternally-toxic doses, and IVL984 was a potent teratogen at doses where direct maternal toxicity was limited to abortions in rabbits. Prominent effects of IVL984 included embryo lethality and cardiac malformations including spiral septal defects in three species.