Enhanced antithrombotic effect of warfarin associated with low-dose alcohol consumption

A 58-year-old Caucasian man was receiving long-term anticoagulation with warfarin for the prevention of ischemic stroke; his international normalized ratio (INR) had been stable. His INR increased when he began consistent, low-dose beer consumption for its perceived cardiovascular protection. After he stopped drinking the alcohol, his anticoagulation control improved and returned to previous levels. Information on the effects of alcohol, particularly beer, is limited in nonalcoholic patients who receive warfarin therapy. This case reveals a potential for low-dose beer consumption to elevate INR. We propose that the increased antithrombotic effect of warfarin involved protein-binding interactions and decreased warfarin metabolism through the cytochrome P450 (CYP) enzyme system. Concurrent administration of aspirin and other drugs that are metabolized through or are inhibitors of the CYP system may have enhanced the interaction that occurred in this patient. Caution should be used whenever warfarin and alcohol in any amount are taken together, especially in patients receiving many drugs, and close monitoring of the INR is warranted.     

Moxifloxacin and warfarin: additional evidence for a clinically relevant interaction

Several case reports have been published regarding an interaction between fluoroquinolones and warfarin; however, the exact mechanism of the interaction has yet to be established. We describe three patients who were receiving warfarin and experienced increases in international normalized ratio (INR) when moxifloxacin was added. Two of the patients had stable anticoagulation regimens and then experienced persistent elevations in their INRs shortly after therapy with moxifloxacin was started. The third patient experienced a dramatic rise in INR after the first dose of moxifloxacin was administered. These cases strengthen the evidence that an interaction does exist despite manufacturer-generated statements to the contrary. Increased awareness of this potential interaction is necessary to ensure appropriate monitoring and improve therapeutic decision making.     

The effect of parental history of myopia on eye size of pre-school children: a pilot study

PURPOSE: To evaluate parental history of myopia as a predictor of refractive error and eye size in Chinese pre-school children. METHODS: A total of 514 pre-school children (aged 2.3--6.4 years) were examined. Parental history of myopia, amount of near work performed, refractive status and ocular biometry were recorded. RESULTS: There was no significant difference in spherical equivalent refraction (SER) among children with no myopic parents (mean+0.94+/-0.05 D), one myopic parent (mean+0.77+- 0.07 D) and two myopic parents (mean+0.79+/- 0.12 D) (p=0.102) after controlling for age and amount of near work. Further, children with more myopic parents did not have longer eyeballs (p=0.335). Conclusions: In this study in Chinese pre-school children, parental history of myopia was not found to be associated with a myopic refractive error or increased eyeball length. Further studies with larger sample sizes would help to confirm these results.     

Intravenous IGF-I receptor antisense reduces IGF-IR expression and diminishes pressor responses to angiotensin II in conscious normotensive rats

Given the variety of cardiovascular effects of insulin-like growth factor-I (IGF-I), we investigated the effects of a functional deficit in IGF-I signalling in the conscious rat cardiovascular system using intravenous IGF-I receptor antisense (AS, 0.5 nmol) treatment.Insulin-like growth factor-I receptor (IGF-IR) immunoreactivity was reduced in IGF-IR AS-treated tail arteries. Western immunoblot analysis demonstrated a decrease in cardiac IGF-IR in IGF-IR AS-treated rats; treatment reduced the expression of IGF-IR to 83+/-6% of that in samples from vehicle-treated rats, compared to 99+/-3% for a control, full-mismatch oligonucleotide (MM-18) or 100% (vehicle).IGF-IR AS treatment had no effect on resting blood pressure during the 14-day treatment period.Pressor responses (as measured by increase in systolic arterial pressure) to angiotensin II (AngII) gradually decreased over 2 weeks treatment with IGF-IR AS (5 x 0.5 nmol per intravenous injection, 2 weeks), and were significantly reduced at treatment day 14 compared to day 7 (2.7-fold rightward shift). IGF-IR AS treatment caused a significant rightward shift in the angiotensin II (AngII) dose-response compared to both vehicle and full-mismatch treated rats (4.0-fold shift compared to vehicle, P<0.01, n=6-14).There was a significant decrease in cardiac angiotensin II type 1 receptor (AT(1)R) expression in AS-treated rats compared to vehicle-treated rats; cardiac AT(1)R was decreased to 80+/-6% in comparison to 100%. AT(1)R immunoreactivity was also reduced in IGF-IR AS-treated tail arteries.IGF-IR AS treatment resulted in structural changes in both the heart and aortae, with small but significant differences observed between left ventricle/bodyweight ratios of AS and both vehicle- and MM-18-treated rats (n=8, P<0.05). Aortic cross-sectional areas of AS-treated rats were significantly lower than MM-18- and vehicle-treated rats (27.4+/-5.7% reduction of vehicle-treated samples, n=8, P<0.01).The results of this study suggest that an induced loss of IGF-IR, while not affecting resting blood pressure, has a predominantly inhibitory effect on vascular response to vasoconstrictor agents including angiotensin II. This may occur through downstream effects on AT1R expression, via modulation of the expression of receptors for other vasoactive signalling molecules, or via changes in myocyte proliferation.     

In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials

The development of vaginal microbicides for the prevention of sexual transmission of HIV is becoming an increasingly important strategy in the battle against the AIDS epidemic. Several first generation microbicide candidates are entering Phase III efficacy trials, and several other candidates are in earlier stages of clinical development. The capacity to make accurate clinical assessments of the safety and efficacy of microbicide formulations is critical. Since microbicide trials will rely on a blinded, randomized, placebo-controlled design, it is important to employ a placebo formulation that does not distort either safety or efficacy assessments. Efficacy of the microbicide would be underestimated if the placebo itself provided a degree of protection. Conversely, a placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. To address these issues, a hydroxyethylcellulose (HEC) placebo formulation has been developed and has been adopted for use in clinical evaluations of investigational microbicides as a "universal" placebo. In this report, the chemical and physical properties of this formulation are described, as well as its in vitro and in vivo effects on safety and efficacy. The results show that this "universal" placebo has adequate physical properties, is sufficiently stable as a vaginal gel formulation, and is safe and sufficiently inactive for use in the clinical study of investigational microbicides.     

Effect of release from prison and re-incarceration on the viral loads of HIV-infected individuals

OBJECTIVES: The purpose of this study was to determine the effect of release from prison and subsequent re-incarceration on the viral loads of HIV-infected individuals receiving highly active antiretroviral therapy (HAART). METHODS: Fifteen re-incarcerated HIV-infected prisoners on HAART were identified from a retrospective cohort of HIV-infected prison inmates released from January 1, 1997, to August 31, 1999. The re-incarcerated prisoners were matched (1:2) to 30 HIV-infected incarcerated prisoners on HAART who remained incarcerated during the re-incarcerated participants' release time period. The outcomes measured were plasma HIV RNA levels, CD4+ lymphocyte counts, percentage of re-incarcerated and incarcerated participants with plasma HIV RNA levels <400 copies/mL, and the median change in plasma HIV RNA levels of the re-incarcerated and incarcerated participants at the end of the study. RESULTS: At the beginning of the study, 8/15 re-incarcerated participants had plasma HIV RNA levels <400 copies/mL, compared with 15/30 incarcerated participants. At the end of the study, only three of those eight re-incarcerated participants had plasma HIV RNA levels <400 copies/mL, compared with 14/15 incarcerated participants (p=0.0086). The median change in plasma HIV RNA levels of the re-incarcerated participants was 1.29 log10 copies/mL (interquartile range 0.04 to 1.70), compared with -0.03 log10 copies/mL (interquartile range -0.65 to 0.09) in the incarcerated participants (p=0.0183). CONCLUSIONS: Release from prison was associated with a deleterious effect on virological and immunological outcomes. These data suggest that comprehensive discharge planning efforts are required to make certain that HIV-infected inmates receive access to quality care following incarceration.     

Comparison of Angiogenic Factor Levels in Tumor Drainage and Peripheral Venous Blood From Colorectal Cancer Patients

Background The main objective of this study was to determine whether there was a correlation in the levels of various angiogenesis-related factors between the tumor drainage and peripheral venous blood and whether appraisal of angiogenic factor levels in the tumor drainage venous blood could provide better prognostic information for patients with colorectal cancer than assessment of the peripheral venous blood.Methods Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and endostatin were measured and compared in both tumor drainage and peripheral venous blood from 52 patients with colorectal cancer. Plasma levels of angiogenesis-related factors were also correlated with tumor stage and clinical outcomes.Results The plasma endostatin level was significantly higher in peripheral blood than in tumor drainage venous blood (P < .001). The plasma VEGF level was significantly correlated with plasma endostatin levels (P = .028 in tumor drainage venous blood and P = .002 in peripheral venous blood). In both tumor drainage and peripheral venous blood, the VEGF level (but not the basic fibroblast growth factor or endostatin level) was significantly correlated with tumor stage and disease recurrence. However, in multivariate analysis, only plasma VEGF level in tumor drainage venous blood remained an independent predictor of disease recurrence.Conclusions The plasma VEGF level in tumor drainage venous blood provided better prognostic information than that in peripheral venous blood. The plasma endostatin level was paradoxically significantly higher in peripheral than in tumor drainage blood, and this strongly suggests additional sources of endostatin in peripheral blood.     

Transmetatarsal amputation: predictors of healing

The objective of this study is to determine the predictors of healing after transmetatarsal amputations (TMA) and factors leading to a higher level of amputation. A total of 33 TMA was performed in 31 patients during the 5 years between January 2000 and Jul 2005. All patients were men between the ages of 44 and 82 years (mean, 68 years). The mean follow-up period was 36 months (range, 1-65 months). Twelve (40%) TMA required a subsequent higher level of amputation. Seventeen (57%) TMA were successful. The average time until further proximal amputation after TMA was 3.5 months. Risk factors for subsequent higher amputation by univariate analysis included infrapopliteal arterial occlusion (P < 0.05), tobacco smoking greater than 20 years (P < 0.05), and further TMA debridement (P < 0.05). Upon multivariate analysis, only patients undergoing further TMA debridement were at risk for TMA failure (P = 0.01). The difference in ankle-to-brachial pressure ratio (ABI) between the higher amputation group (ABI = 0.51) and the successful TMA group (ABI = 0.54) was not significant. There were no perioperative deaths after TMA. Five (18%) deaths occurred at a mean of 8.2 months after the TMA. In patients who are walking preoperatively, aggressive TMA is warranted in an attempt to maintain ambulation, recognizing that requirement for further debridement, smoking history, and infrapopliteal occlusion may be predictors of nonhealing and subsequent higher amputation.     

The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock: a randomized, controlled, double-blinded trial

OBJECTIVE: To investigate the potential immunologic and anti-inflammatory effects of hypertonic saline plus dextran (HSD) in hemorrhagic trauma patients. BACKGROUND: Unbalanced inflammation triggered by shock has been linked to multiorgan dysfunction (MOD) and death. In animal and cellular models, HSD alters the inflammatory response to shock, attenuating MOD and improving outcome. It remains untested whether HSD has similar effects in humans. METHODS: A single 250-mL dose of either HSD (7.5% NaCl, 6% dextran-70) or placebo (0.9% NaCl) was administered to adult blunt trauma patients in hemorrhagic shock. The primary outcome was to measure changes in immune/inflammatory markers, including neutrophil activation, monocyte subset redistribution, cytokine production, and neuroendocrine changes. Patient demographics, fluid requirements, organ dysfunction, infection, and death were recorded. RESULTS: A total of 27 patients were enrolled (13 HSD) with no significant differences in clinical measurements. Hyperosmolarity was modest and transient, whereas the immunologic/anti-inflammatory effects persisted for 24 hours. HSD blunted neutrophil activation by abolishing shock-induced CD11b up-regulation and causing CD62L shedding. HSD altered the shock-induced monocyte redistribution pattern by reducing the drop in "classic" CD14 and the expansion of the "pro-inflammatory" CD14CD16 subsets. In parallel, HSD significantly reduced pro-inflammatory tumor necrosis factor (TNF)-alpha production while increasing anti-inflammatory IL-1ra and IL-10. HSD prevented shock-induced norepinephrine surge with no effect on adrenal steroids. CONCLUSIONS: This first human trial evaluating the immunologic/anti-inflammatory effects of hypertonic resuscitation in trauma patients demonstrates that HSD promotes a more balanced inflammatory response to hemorrhagic shock, raising the possibility that similar to experimental models, HSD might also attenuate post-trauma MOD.