2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

Reconciling the clinical practice guidelines on Bell's palsy from the AAO-HNSF and the AAN.

Bell palsy, named after the Scottish anatomist Sir Charles Bell, is the most common acute mononeuropathy, or disorder affecting a single nerve, and is the most common diagnosis associated with facial nerve weakness/paralysis. In the past 2 years, both the American Academy of Neurology and the Academy of Otolaryngology-Head and Neck Surgery Foundation have published clinical practice guidelines aimed at improving the quality of care and outcomes for patients diagnosed with Bell palsy. This commentary aims to address the similarities and differences in the scope and final recommendations made by each guideline development group.

Reconciling the clinical practice guidelines on Bell's palsy from the AAO-HNSF and the AAN.

Bell's palsy, named after the Scottish anatomist, Sir Charles Bell, is the most common acute mononeuropathy, or disorder affecting a single nerve, and is the most common diagnosis associated with facial nerve weakness/paralysis. In the past 2 years, both the American Academy of Neurology (AAN) and the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) have published clinical practice guidelines aimed to improve the quality of care and outcomes for patients diagnosed with Bell's palsy. This commentary aims to address the similarities and differences in the scope and final recommendations made by each guideline development group.

Implications of tissue magnetic susceptibility-related distortion on the rotating magnet in an MR-linac design.

PURPOSE: One of the recently published concepts that combine the soft-tissue imaging capabilities of MRI with external beam radiotherapy involves the rigid coupling of a linac with a rotating biplanar low-field MR imaging system. While such a system would prevent possible image distortion resulting from relative motion between the magnet and the linac, the rotation of the magnet around the patient can itself introduce possibilities for image distortion that need to be addressed. While there are straightforward techniques in the literature for correcting distortions from gradient nonlinearities and nonuniform magnetic fields during image reconstruction, the correction of distortions related to tissue magnetic susceptibility is more complex. This work investigates the extent of this latter distortion type under the regime of a rotating magnetic field. METHODS: CT images covering patient anatomy in the head, lung, and male pelvic regions were obtained and segmented into components of air, bone, and soft tissue. Each of these three components was assigned bulk magnetic susceptibility values in accordance with those found in the literature. A finite-difference algorithm was then implemented to solve for magnetic field distortion maps should the anatomies be placed in the uniform polarizing field of an MR system. The algorithm was repeated multiple times as the polarizing field was rotated axially about the virtual patient in 15 degrees increments. In this way, a map of maximum distortion, and the range of distortion as the magnetic field is rotated about each anatomical region could be determined. The consequence of these susceptibility distortions in terms of geometric signal shift was calculated for 0.2 T, as well as another low-field system (0.5 T), and a higher field 1.5 T system for comparison, using the assumption of a frequency encoding gradient strength of 5 mT/m. RESULTS: At 0.2 T, the susceptibility-related distortion was limited to less than 0.5 mm given an encoding gradient strength of 5 mT/m or higher. To maintain this same level of geometric accuracy, the 0.5 T system would require a moderately higher minimum gradient strength of 11 mT/m, and at a typical MR field strength of 1.5 T this minimum gradient strength would increase to 33 mT/m. The influence of magnetic susceptibility on mean frequency shift as the field orientation was rotated was also investigated and found to account for less than half a millimeter at 1.5 T, and negligible for low-field systems. CONCLUSIONS: A study of three sites (head, lung, and prostate) that are vulnerable to magnetic susceptibility-related distortions were studied, and showed that in the context of a rotating polarizing magnet, low-field systems can maintain geometric accuracy of 0.5 mm with at most moderate limitations on sequence parameters. This conclusion will likely apply only to endogenous tissues, as implanted materials such as titanium can create field distortions much in excess of what may normally be induced in the body. Items containing such materials (hip prostheses, for example) will require individual scrutiny.

MRI of prostate brachytherapy seeds at high field: a study in phantom.

Postimplant evaluation of prostate brachytherapy using magnetic resonance imaging (MRI) at 1.5 T has met with some difficulties due to the uncertainty associated with seed localization despite the excellent anatomical delineation this imaging modality can achieve. Seeds in vascularized regions or outside the prostate, where signal heterogeneity or drop off can obscure their position, can be difficult to identify. The increase in SNR available at 3.0 T offers the potential to improve these issues with visualization. However, before moving directly to in vivo studies, it is important to investigate the effects of artifact size on the ability to localize multiple seeds in close proximity. These artifacts are of extra concern at higher field because of the increased induced field distortions surrounding the seeds. A single prostate brachytherapy seed (IMC6711, OncoSeed) and arrays of seed pairs were suspended in a porcine gel medium and imaged on 1.5 and 3 T MRI scanners for comparison. Two basic acquisition techniques utilized in a wide array of clinical sequences [spin-echo based and gradient-echo (GE) based] were investigated for the types of artifacts they produce, and their dependence on field. Analysis of the resulting voids was performed to determine the relative size of seeds as seen on the images, as well as the ability to distinguish seeds at close proximity. The seed voids at 3 T were only slightly larger than those obtained at 1.5 T (0.5 mm longer and wider) when using a spin-echo type sequence. For this work, the authors used a proton density fast spin-echo (FSE) sequence. These results are promising for the use of 3 T imaging for postimplant evaluation since the SNR will increase by roughly a factor of 2 with only a limited corresponding increase in artifact size. The minimum separation of the seeds to be completely distinguished using void analysis increased from between 1.5 and 3 mm to between 3 and 4.5 mm when going from 1.5 to 3 T FSE imaging. The minimum separation of the seeds for GE at the demonstration TE of 11 ms was found to be between 3 and 4.5 mm for 1.5 T and between 4.5 and 6 mm for 3 T. These GE artifact dimensions will scale down with TE and, as this happens, approach the dimensions of the FSE artifacts given above.

Characterization of the susceptibility artifact around a prostate brachytherapy seed in MRI.

Magnetic distortions surrounding a typical brachytherapy seed (IMC6711, OncoSeed) within a clinical magnetic resonance imager were modeled for a number of different seed orientations with respect to the main magnetic field. From these distortion maps, simulated images were produced. The simulated images were then compared to images experimentally acquired using a spin echo technique on a Philips 1.5 T magnetic resonance imaging scanner. The modeled images were found to conform very well to those acquired experimentally, thus allowing one to establish where the seed is positioned within the complex image distortion patterns. The artifact patterns were dependent on the orientation of the seed with the main magnetic field, as well as the direction of the read encode gradient. While all imaging schemes which employ a unidirectional linear read encode trajectory should produce the artifacts modeled in this article, sequences other than spin echo may produce additional artifacts. Gradient echo and steady-state free precession imaging techniques were also performed on the seed for comparison.

A Monte Carlo derived TG-51 equivalent calibration for helical tomotherapy.

Helical tomotherapy (HT) requires a method of accurately determining the absorbed dose under reference conditions. In the AAPM's TG-51 external beam dosimetry protocol, the quality conversion factor, kQ, is presented as a function of the photon component of the percentage depth-dose at 10 cm depth, %dd(10)x, measured under the reference conditions of a 10 x 10 cm2 field size and a source-to-surface distance (SSD) of 100 cm. The value of %dd(10)x from HT cannot be used for the determination of kQ because the design of the HT does not meet the following TG-51 reference conditions: (i) the field size and the practical SSD required by TG-51 are not obtainable and (ii) the absence of the flattening filter changes the beam quality thus affecting some components of kQ. The stopping power ratio is not affected because of its direct relationship to %dd(10)x. We derive a relationship for the Exradin A1SL ion chamber converting the %dd(10)x measured under HT "reference conditions" of SSD=85 cm and a 5 x 10 cm2 field-size [%dd(10)x[HT Ref]], to the dosimetric equivalent value under for TG-51 reference conditions [%dd(10)x[HT TG-51]] for HT. This allows the determination of kQ under the HT reference conditions. The conversion results in changes of 0.1% in the value of kQ for our particular unit. The conversion relationship should also apply to other ion chambers with possible errors on the order of 0.1%.

Patient specific treatment verifications for helical tomotherapy treatment plans.

We performed two-dimensional treatment verifications for ten patients planned and treated with helical tomotherapy. The treatment verification consisted of a film measurement as well as point dose measurements made with an ion chamber. The agreement between the calculated and the measured film dose distributions was evaluated with the gamma index calculated for three sets of criteria (2 mm and 2%, 4 mm and 3%, and 3 mm and 5%) as recommended in the literature. Good agreement was found between measured and calculated distributions without any need of normalization of the dose data but with dose map registration using reference marks. In this case, 69.8 +/- 17.2%, 92.6 +/- 9.0%, and 93.4 +/- 8.5% passed the 2 mm and 2%, 4 mm and 3%, and 3 mm and 5% criteria, respectively. Agreement was excellent when both normalization and manual registration of the dose maps was employed. In this case 91.2 +/- 5.6%, 99.0 +/- 1.4%, and 99.5 +/- 0.8% passed the 2 mm and 2%, 4 mm and 3%, and 3 mm and 5% criteria, respectively. The mean percent discrepancy for the point dose measurements was -0.5 +/- 1.1%, -2.4 +/- 3.7%, -1.1 +/- 7.3% for the high dose, low dose, and critical structure point, respectively. Three criteria for a satisfactory treatment verification in the high dose regions of a plan were established. For the un-normalized reference mark registered data 80% of pixels must pass the 3 mm and 5% criteria. For the normalized and manually registered data, 80% must pass the 2 mm and 2% criteria, and the point dose measurement must be within 2% of the calculated dose. All low dose region/critical structure point dose measurements were evaluated on a patient by patient basis. The criteria we recommend can be useful for the routine evaluation of treatment plans for tomotherapy systems.

Psoralen-modified clamp-forming antisense oligonucleotides reduce cellular c-Myc protein expression and B16-F0 proliferation.

The c-myc protooncogene plays an important role in the abnormal growth pattern of melanoma cells. In an attempt to inhibit c-Myc expression and the growth of an established murine melanoma cell line, we targeted homopurine sequences within the mouse myc mRNA with modified antisense oligonucleotides (AS ODNs). Psoralen was conjugated to the 5'-end of these clamp-forming oligonucleotides (clamp ODNs). Gel mobility shift analysis demonstrated a sequence-specific interaction between the active clamp ODNs (Myc-E2C and Myc-E3C) and the 1.4 kb c-myc mRNA, but no interaction with the control clamp ODN (SCR**). This association was further confirmed by thermal denaturation studies. In vitro translation assays demonstrated that both Myc-E2C and Myc-E3C at 5 microM inhibited c-Myc expression >99% after UV activation at 366 nm. Immunostaining of B16-F0 cells with a c-Myc monoclonal antibody revealed a significant reduction in c-Myc after clamp ODN treatment compared with the untreated or SCR** control-treated cells. This result was corroborated by western blot analysis. Utilizing the MTT assay to determine the effects of ODN-mediated c-Myc reduction on B16-F0 growth, we observed 60 and 64% reductions in growth after treatment with 5 microM Myc-E3C and Myc-E2C, respectively. We attribute the enhanced effectiveness of the clamp ODNs to psoralen activation. Our preliminary data suggest that inhibiting c-Myc overexpression results in a significant reduction in abnormal proliferation of B16-F0 melanoma cells and that the increased efficiency of clamp ODNs may provide an important advantage for their use in antisense therapies.

Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides.

The discovery of G-rich oligonucleotides (GROs) that have non-antisense antiproliferative activity against a number of cancer cell lines has been recently described. This biological activity of GROs was found to be associated with their ability to form stable G-quartet-containing structures and their binding to a specific cellular protein, most likely nucleolin (Bates, P. J., Kahlon, J. B., Thomas, S. D., Trent, J. O., and Miller, D. M. (1999) J. Biol. Chem. 274, 26369-26377). In this report, we further investigate the novel mechanism of GRO activity by examining their effects on cell cycle progression and on nucleic acid and protein biosynthesis. Cell cycle analysis of several tumor cell lines showed that cells accumulate in S phase in response to treatment with an active GRO. Analysis of 5-bromodeoxyuridine incorporation by these cells indicated the absence of de novo DNA synthesis, suggesting an arrest of the cell cycle predominantly in S phase. At the same time point, RNA and protein synthesis were found to be ongoing, indicating that arrest of DNA replication is a primary event in GRO-mediated inhibition of proliferation. This specific blockade of DNA replication eventually resulted in altered cell morphology and induction of apoptosis. To characterize further GRO-mediated inhibition of DNA replication, we used an in vitro assay based on replication of SV40 DNA. GROs were found to be capable of inhibiting DNA replication in the in vitro assay, and this activity was correlated to their antiproliferative effects. Furthermore, the effect of GROs on DNA replication in this assay was related to their inhibition of SV40 large T antigen helicase activity. The data presented suggest that the antiproliferative activity of GROs is a direct result of their inhibition of DNA replication, which may result from modulation of a replicative helicase activity.

Thalidomide is distributed into human semen after oral dosing.

As part of a double-blind placebo-controlled study of the effect of thalidomide on body weight and the viral load of human immunodeficiency virus-seropositive patients, plasma and semen samples were analyzed for the presence of thalidomide. Patients were orally dosed with 100 mg of thalidomide/day for 8 weeks. Blood samples were obtained at baseline and weeks 4, 8, and 12, and semen was obtained at baseline and weeks 4 and 8. Samples were extracted with solid-phase cartridges and analyzed by liquid chromatography/tandem mass spectrometry using atmospheric pressure chemical ionization in the negative ion mode. Two of four patients taking thalidomide were able to provide semen samples. Both had detectable levels of thalidomide in their plasma (10-350 ng/ml) and semen (10-250 ng/g) at weeks 4 and 8. There was an apparent correlation between plasma and semen levels. Semen levels could be significantly greater for therapeutic doses of more than 100 mg/day. Since the threshold dose for birth defects and thalidomide exposure is not known, male patients are advised to use barrier contraception.

Safety profile of thalidomide after 53 weeks of oral administration in beagle dogs.

Fifty-six adult beagle dogs (28 male, 28 female) were orally administered thalidomide at 43, 200, or 1000 mg/kg/day for 53 weeks. Sixteen (2/sex/dose group) and 32 (4/sex/dose group) dogs were euthanized and necropsied after 26 and 53 weeks of dosing, respectively. The remaining 8 animals (2/sex/group; high-dose and control groups) were dosed for 53 weeks, euthanized, and necropsied at 58 weeks after a 5-week recovery period. There were no deaths during the study. The only observed clinical signs attributable to thalidomide administration were green-colored urine, white-colored fecal residue presumed to be unchanged thalidomide, enlarged and/or blue coloration of female mammary tissue, and prolonged estrus. There were no thalidomide-related changes in body weights, food consumption, electrocardiography, ophthalmoscopy, neurological function, and endocrine function. The mostly slight and/or transient variations observed in some hematology and blood chemistry values of dosed dogs were considered to be toxicologically insignificant and were supported by the lack of histopathologic correlates. The only gross finding attributable to thalidomide was a yellow-green discoloration of the femur, rib, and/or calvarium that was observed at each euthanization interval including recovery. There was no microscopic correlate for this finding. No thalidomide-related microscopic changes were seen in any of the organs and tissues at 26 weeks. Mammary duct dilatation and/or glandular hyperplasia observed in females at 53 and 58 weeks and hepatic bile pigment exhibited by high-dose males at 53 weeks were microscopic changes considered to be thalidomide-related. There was no gross and histopathologic evidence of any tumors. In summary, thalidomide at up to 1000 mg/kg/day for 53 weeks did not induce any major systemic toxicity or tumors in dogs. The NOAEL was 200 mg/kg/day.

Effects of temperature strategy during cardiopulmonary bypass on cerebral oxygen balance.

BACKGROUND: Cerebral injury is the most serious complication of cardiopulmonary perfusion (CPB). With the advent of warm heart surgery, the effect of temperature strategy during perfusion and its effect on cerebral oxygen balance needs further study. METHODS: Three groups of patients (n=8, each) undergoing coronary artery bypass graft (CABG) surgery were studied. Group H, M and N underwent CPB at 28 degrees C, 32 degrees C and normothermia (>36 degrees C), respectively. The extracorporeal circuit was primed with Hartmann's solution 2.5 l and flow of 1.8 l min(-1) m(-2) at 28 degrees C, and 2.4 1 min-1 m(-2) at 32 degrees C and normothermia. All patients had a 4F oximetry catheter (Opticath, Oximetrix, Abbott Laboratories) inserted in the right jugular bulb for continuous measurement of jugular venous oxygen saturation (sjvO2). Data was collected at six specific times: T1- within 5 min before initiation of CPB, T2 - within the first minute after CPB, T3 - during stable temperature on CPB (28 degrees C, 32 degrees C, >36 degrees C), T4 - during rewarming at 34 degrees C in groups H and M, 15 min before coming off CPB in group N, T5 - 15 min after CPB, T6 - skin closure. At each time mean arterial pressure (MAP) and sjvO2 were recorded. Arterial blood and jugular venous blood were sampled for measurement of arterial oxygen saturation (saO2) and jugular venous lactate (sjv(lactate)), respectively. RESULTS: SjvO2 values decreased at times T2, T3 and T4 when compared to baseline (p<0.05) but there were no significant group differences at any time. Cerebral arteriovenous oxygen saturation (a-jvO2) differences mirrored sjvO2 changes. Sjv(lactate) values increased from baseline following CPB but fell consistently with time - there were no significant group differences at each time point. SjvO2 and a-jvO2 values were not significantly correlated with sjv(lactate). CONCLUSION: During pump flows employed in this study, cerebral oxygen balance and perfusion appear unaffected by temperature.

Induction of anaesthesia in patients with coronary artery disease: a comparison between sevoflurane-remifentanil and fentanyl-etomidate.

In a prospective, randomized study, sevoflurane-remifentanil (Group SR) was compared with fentanyl-etomidate (Group FE) for induction of anaesthesia in patients with ischaemic heart disease. Cardiovascular stability, heart rate, mean arterial pressure, rate pressure product, rescue medications and associated myocardial ischaemia were measured. For Group SR (n = 20), anaesthesia was induced with vital capacity breaths of sevoflurane 5% in oxygen. After loss of consciousness, the inspired sevoflurane was reduced to 3% and remifentanil was administered as a 0.5 microgram.kg-1 bolus over 90 seconds (0.33 microgram.kg-1.min-1) followed by a 0.025 microgram.kg-1.min-1 infusion. After intubation, the inspired sevoflurane was reduced to 2%. For Group FE (n = 20), anaesthesia was induced with fentanyl 10.5 micrograms.kg-1 and etomidate 0.2 mg.kg-1 given 60 seconds later. Isoflurane 1% in oxygen was administered after loss of consciousness. Both groups received rocuronium and the trachea was intubated two minutes later. Sevoflurane gaseous induction was smooth, with cardiovascular stability comparable to fentanyl-etomidate. Significantly more patients in Group SR (P < 0.05) were on beta-blocking medication, and, overall, the HR and RPP was lower pre-intubation in Group SR. Remifentanil administration was associated with severe bradycardia in three patients and asystole in a fourth. All four patients were on beta-blocking medication and three of the four were on diltiazem. The study was terminated due to the high incidence of bradycardic/asystolic complications in Group SR.

Antiproliferative activity of G-rich oligonucleotides correlates with protein binding.

Oligonucleotides have been extensively studied as antisense or antigene agents that can potentially modulate the expression of specific genes. These strategies rely on sequence-specific hybridization of the oligonucleotide to mRNA or genomic DNA. Recently, it has become clear that oligonucleotides often have biological activities that cannot be attributed to their sequence-specific interactions with nucleic acids. Here we describe a series of guanosine-rich phosphodiester oligodeoxynucleotides that strongly inhibit proliferation in a number of human tumor cell lines. The presence of G-quartets in the active oligonucleotides is demonstrated using an UV melting technique. We show that G-rich oligonucleotides bind to a specific cellular protein and that the biological activity of the oligonucleotides correlates with binding to this protein. The G-rich oligonucleotide-binding protein was detected in both nuclear and cytoplasmic extracts and in proteins derived from the plasma membrane of cells. We present strong evidence that this protein is nucleolin, a multifunctional phosphoprotein whose levels are related to the rate of cell proliferation. Our results indicate that binding of G-rich oligonucleotides to nucleolin may be responsible for their non-sequence-specific effects. Furthermore, these oligonucleotides represent a new class of potentially therapeutic agents with a novel mechanism of action.

Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects.

Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15+/-0.24 microg/ml (100 mg) and 1.92+/-0.47 microg/ml (200 mg; p<0.001), which were achieved (Tmax) at 2.5+/-1.5 h and 3.3+/-1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-15.6 liters (100 mg) and 82.7+/-34.9 liters (200 mg) while total body clearances (Cl/F) were 10.4+/-2.1 and 10.8+/-1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.

Thalidomide does not alter estrogen-progesterone hormone single dose pharmacokinetics.

OBJECTIVES: To determine the single- and multiple-dose pharmacokinetics of oral thalidomide (200 mg/day, administered for 21 days) and to assess the effects of steady-state plasma concentrations of thalidomide on the single-dose pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: A randomized, 2-period crossover study was performed in 10 healthy premenopausal female volunteers. The pharmacokinetic profiles of plasma concentrations of thalidomide were evaluated with both noncompartmental and compartmental methods, whereas those of ethinyl estradiol and norethindrone were calculated with noncompartmental methods. The effects of steady-state plasma thalidomide concentrations on the pharmacokinetics of ethinyl estradiol and norethindrone were determined with use of an ANOVA model that included treatment sequence, subject within sequence, period, and treatment as factors. RESULTS: Thalidomide plasma concentrations were best predicted by a 1-compartment model with first-order absorption and elimination and an absorption time-lag. There were no significant differences between pharmacokinetic parameters for thalidomide after 1 dose and those after 18 consecutive doses. Except for a minor decrease of the elimination rate constant (k(e)) for ethinyl estradiol, coadministration of thalidomide had no significant effects on the pharmacokinetic profiles for either ethinyl estradiol or norethindrone. The change in k(e) for ethinyl estradiol during thalidomide administration was not associated with any alteration in the clearance or elimination half-life for this hormone. CONCLUSIONS: Multiple-dose pharmacokinetics of thalidomide is similar to the single-dose profile. This study did not investigate the efficacy of the 21-day fixed ethinyl estradiol-norethindrone regimen, but the results suggest that thalidomide is unlikely to affect the pharmacokinetics of orally administered hormonal contraceptives.

Myocardial ischaemia after coronary artery bypass grafting: early vs late extubation.

The technique of early extubation after coronary artery bypass grafting is increasing in popularity, but its safety and effect on myocardial ischaemia remain to be established. In a randomized, prospective study, patients undergoing routine elective coronary artery bypass grafting were managed with either early or late tracheal extubation. The incidence and severity of electrocardiographic myocardial ischaemia were compared. Data were analysed from 85 patients (43 early extubation; 42 late extubation). Median time to extubation was 110 min in the early extubation patients and 757 min in the late extubation patients. After correction for randomization bias, there were no significant differences between groups in ischaemic burden, maximal ST-segment deviation, incidence of ischaemia and area under the ST deviation-time curve (integral of ST deviation and time). Similarly, there were no differences between groups in postoperative creatine kinase MB-isoenzyme concentrations and duration of stay in the ICU or hospital. Therefore, this study provides evidence for the safety of early extubation after routine coronary artery bypass grafting.