Interaction between udenafil and tamsulosin in rats: non-competitive inhibition of tamsulosin metabolism by udenafil via hepatic CYP3A1/2

Background and purpose:

Orthostatic hypotension has been observed when PDE 5 (cGMP-specific phosphodiesterase type 5) inhibitors are co-administered with α-adrenoceptor antagonists. Here we assessed the pharmacokinetic and haemodynamic interactions between udenafil and tamsulosin in rats, as both drugs are metabolized via rat hepatic cytochrome P450 3A1/2.

Experimental approach:

Interactions between the two drugs were evaluated in rats after simultaneous 1 or 15 min i.v. infusion or after p.o. administration of udenafil (30 mg·kg⁻¹) and/or tamsulosin (1 mg·kg⁻¹). In vitro metabolism of tamsulosin with udenafil was measured to obtain the inhibition constant (K_i) and [I]/K_i ratio of udenafil.

Key results:

The total area under the plasma concentration–time curve from time zero to time infinity (AUC)s (or AUC_0–4h) of tamsulosin were significantly greater after 15 min of i.v. infusion or after oral administration with udenafil, compared with tamsulosin alone. The hepatic first-pass metabolism of tamsulosin was inhibited by udenafil, and the inhibition in vitro was in a non-competitive mode. The arterial systolic blood pressure was significantly lower at 5, 10 and 60 min after oral co-administration of the drugs.

Conclusions and implications:

The significantly greater AUC of tamsulosin after i.v. and p.o. administration of both drugs may be attributable to non-competitive inhibition of cytochrome P450 3A1/2-mediated hepatic tamsulosin metabolism by udenafil. The inhibition was also observed in human liver S9 fractions, suggesting that a reassessment of the oral dosage of tamsulosin is necessary when udenafil and tamsulosin are co-administered to patients with benign prostatic hyperplasia.     

Triazole cross-resistance among Candida spp.: case report, occurrence among bloodstream isolates, and implications for antifungal therapy

Candida spp. are common causes of bloodstream infections among hospitalized patients. Fluconazole (FLC) remains a first-line therapy for candidemia; and voriconazole (VRC), an expanded-spectrum triazole, was recently approved for the treatment of candidemia in nonneutropenic patients. In vitro studies have suggested that VRC has potent activity against Candida spp. with reduced susceptibilities to FLC. We present a case report of invasive candidiasis and candidemia due to a Candida glabrata isolate that developed resistance to all currently available triazole antifungals after a course of FLC treatment. This case prompted us to determine the frequency of cross-resistance among bloodstream Candida isolates collected during a recent 12-month period at a large, academic medical center. FLC MICs were determined for 125 of 153 isolates (81.7%). Thirty of 125 isolates (24%) were resistant or showed reduced susceptibilites to FLC (MICs >/= 16 microg/ml). When 28 of these 30 isolates were tested for their VRC susceptibilities, 9 (32%) had MICs that were >/=2 microg/ml. Five of these nine isolates were C. glabrata, two isolates were Candida tropicalis, one isolate was Candida albicans, and one isolate was Candida parapsilosis. All five Candida krusei isolates tested had VRC MICs 相似文献   

Development of injury prevention materials for people with low literacy skills

OBJECTIVE: Children living in low income urban environments are at high risk for preventable injuries, which result in thousands of Pediatric Emergency Department (PED) visits every year. The development and evaluation of written injury prevention materials used in a PED-based intervention trial are presented. The purpose is to describe the development of injury prevention materials for people with low literacy skills, and explain literacy and comprehension abilities among a sample of parents from the PED. METHODS: Materials were developed using rules of plain language and with consideration of the needs of a low literacy population. Materials were assessed using the Flesch-Kincaid and Suitability Assessment of Materials. Literacy and comprehension abilities in a PED sample were tested using the Rapid Estimate of Adult Literacy in Medicine (REALM) and the Cloze. RESULTS: REALM results for n=59 parents sampled from the PED indicated that 27% (n=16) read below 9th grade reading level. Cloze results demonstrate that materials were appropriate for 71% (n=21) when written for 8th grade reading level and 80% (n=23) when rewritten for 6th grade reading level. CONCLUSION: Others designing similar interventions can use these methods to develop interventions for low literacy populations. PRACTICE IMPLICATIONS: When developing injury prevention materials for use with PED populations, health professionals should consider reading ability, reading level, content, and design of materials.     

Estimation of the age at onset in spinocerebellar ataxia type 2 Cuban patients by survival analysis

Almaguer‐Mederosa LE, Falcón NS, Almira YR, Zaldivar YG, Almarales DC, Góngora EM, Herrera MP, Batallán KE, Armiñán RR, Manresa MV, Cruz GS, Laffita‐Mesa J, Cyuz TM, Chang V, Auburger G, Gispert S, Pérez LV. Estimation of the age at onset in spinocerebellar ataxia type 2 Cuban patients by survival analysis. Previous studies have investigated the close association that exists between CAG repeat number and the age at onset in SCA2 = spinocerebellar ataxia type 2. These studies have focused on affected individuals. To further characterize this association and estimate the risk of a carrier developing SCA2 at a particular age as a function of a specific CAG repeat size, we have analyzed a large group of 924 individuals, including 394 presymptomatic and 530 affected individuals with a CAG repeat length of 32–79 units. Using a Kaplan–Meier survival analysis, we obtained cumulative probability curves for disease manifestation at a particular age for each CAG repeat length in the 34–45 range. These curves were significantly different (p < 0.001) and showed small overlap. All these information may be very valuable in predictive‐testing programs, in the planning of studies for the identification of other genetic and environmental factors as modifiers of age at onset, and in the design of clinical trials for people at enlarged risk for SCA2.     

Clinically significant human papilloma virus in squamous cell carcinoma of the head and neck in UK practice

Aims

The association between squamous cell carcinoma of the head and neck (HNSCC) and infection with human papilloma viruses (HPV) has created considerable interest. Rates of primary oropharyngeal cancers have shown increasing incidence and declining age at presentation over the last decade, believed to relate to infection with oncogenic or high-risk subtypes of HPV (HR-HPV). HR-HPV-associated tumours have reportedly improved outcomes when compared with HPV-negative cancers. Within the UK, rates of HR-HPV in HNSCC have not yet been reported.

Materials and methods

We analysed consecutive retrospective cases of oropharyngeal cancer presenting between 2004 and 2007.

Results

Thirty-seven per cent of 83 oropharyngeal tumours stained positively for p16^INK4A, a marker of HPV infection (73% tonsillar cancers being p16 ^INK4A positive, 30% tongue and 43% floor of mouth tumours). HPV16 DNA was demonstrated in 75% p16 ^INK4A cases. Despite being more advanced with higher T-stage and nodal burden at presentation, HR-HPV-associated HNSCC showed significantly improved rates of disease-free and overall survival, in particular with improved rates of response to radical radiotherapy.

Conclusion

HPV16 infection seems to be a clinically significant cause of oropharyngeal HNSCC in the UK and the collection of national data should be supported.     

Phrenic neuropathy due to neuralgic amyotrophy

The authors reviewed the medical records of 33 patients diagnosed with idiopathic phrenic neuropathy and found that 17 patients had clinical features of neuralgic amyotrophy. They concluded that a careful clinical and electrodiagnostic evaluation may implicate neuralgic amyotrophy as a causative disease in patients with apparently isolated phrenic neuropathy.     

Vigabatrin: 2008 Update

Vigabatrin (VGB) is a structural analogue of γ‐aminobutyric acid (GABA) that irreversibly inhibits GABA‐transaminase (GABA‐T), increasing brain levels of GABA. VGB is under assessment for treatment of infantile spasms (IS) and refractory complex partial seizures (CPS). Response can be rapid with spasm cessation following approximately 2 weeks of therapy. Patients with symptomatic tuberous sclerosis (TS) and other patients have achieved spasm cessation. Comparison with ACTH has been performed. Patients with refractory CPS have responded as well. Adverse effects and structural findings on imaging occur with VGB treatment. T2 hyperintensities within brain have been observed. Psychotic disorders or hallucinations have occurred rarely. A specific adverse effects is associated VGB, with a peripheral visual field defect (VFD) detected in some patients. Prevalence and incidence of the VGB‐induced peripheral VFD varied depending on the age of the patient and the extent of exposure to VGB, with 25% to 50% prevalence in adults; the prevalence in children was 15% and retinal defect in infants ranged from 15% to 31%. A bilateral nasal defect may be the first clinical indication and may progress to a concentric, bilateral field defect observed in many affected patients; central visual acuity is almost always preserved. The earliest finding of the first abnormal field examination in adults was after 9 months of treatment; with a mean duration of VGB exposure of 4.8 years. In children, the earliest onset of a first abnormal field examination was after 11 months, with a mean time to onset of 5.5 years. The earliest sustained onset of the VGB‐induced retinal defect in infants was 3.1 months. Recommendation: Cognitive, age‐appropriate visual field testing is required at baseline and then repeated at intervals in patients who continue therapy. Infants are tested at baseline and at 3‐month intervals for the first 18 months of treatment, and then every 6 months thereafter. Adults with CPS are tested at baseline and at 6‐month intervals. To select patients who are appropriate for VGB therapy, physicians must consider the benefits of fewer seizures and improved quality of life versus the potential risk of developing a VGB‐induced peripheral VFD. Effectiveness of VGB can be detected within 12 weeks of initiating therapy. There appears to be minimal risk associated with a 2‐ to 3‐month trial of VGB to evaluate effectiveness before there is a demonstrable risk of developing the VGB‐induced peripheral VFD. If patients do not have a clinical benefit from VGB within 12 weeks of treatment initiation, VGB should be discontinued. If patients have a meaningful reduction in seizures or achieve seizure freedom, then the physician and patient or caregiver must determine if the benefits outweigh the potential risk of developing a peripheral VFD. When VGB is prescribed, the patient must be closely monitored for visual field changes. In cases where spasm or seizure improvement is not achieved within 12 weeks of initiation, VGB should be discontinued. In cases where complete spasm cessation, seizure control, or meaningful improvement is achieved within 12 weeks, continued treatment with VGB is warranted; subsequent periodic monitoring for the peripheral VFD is necessary and should be used to mitigate the risk of the defect. The risk of developing the peripheral VFD with short‐term exposure seems to be low, therefore, VGB is an appropriate option for patients with IS or refractory CPS who receive a clinical benefit from its effectiveness, given the clinical consequences of uncontrolled seizures and spasms.     

Stressful life events and posttraumatic stress symptoms in children with cancer

This study examined the contribution of stressful life events in posttraumatic stress symptoms (PTSS) stemming from childhood cancer among 121 patients. When controlling for demographic characteristics (age, gender, ethnicity, and socioeconomic status), cancer factors (treatment status, time since diagnosis, and cancer type), and intensity of parental PTSS, history of stressful life events in the child's life emerged as a salient correlate of PTSS across the different measures and reporting methods used in the study. Overall, children who had experienced more frequent and severe life stressors endorsed greater PTSS in relation to the cancer experience. Clinical work and future research on children with cancer should focus accordingly on the potential cumulative impact of stressful life events on PTSS.     

Early massive transfusion in trauma patients: Canadian single-centre retrospective cohort study

Purpose

To determine associations between red blood cell (RBC) transfusion and early and late clinical outcomes in massively transfused adult trauma patients.

Methods

A retrospective cohort study (1992–2001) including 260 patients receiving ≥10 RBC units ≤24 hr after admission to a university-affiliated trauma centre. We extracted demographic and clinical data and used multivariable regression to determine independent effects of RBC transfusion on clinical outcomes.

Results

Patients had a high (mean [standard deviation]) injury severity score (ISS) (42.5 [15.1]), a high admission sequential organ failure assessment (SOFA) score (8.4 [3.8]), and a high hospital mortality (58.5%). They received 38 (25–64) (median [interquartile range]) blood components within 48 hr, including 19 (14–28) RBC units. For 143 patients surviving ≥48 hr, the maximum SOFA score was associated with RBC units transfused before 48 hr (linear regression beta coefficient 0.075, P < 0.0001), lower nadir hemoglobin before 48 hr (0.034, P = 0.03), age (0.032, P = 0.015), and admission SOFA (0.59, P < 0.0001). The RBC units transfused by 48 hr were not associated with either hospital mortality (n = 35) among patients surviving ≥48 hr (independent predictors, age [logistic regression odds ratio (OR) 1.06, 95% confidence interval 1.03–1.10], ISS [OR 1.07, 1.02–1.13], and maximum SOFA score [OR 1.56, 1.27–1.93]) or 48-hr mortality (n = 117) (independent predictors, admission SOFA [1.65, 1.45–1.88] and later year of hospital admission [OR 1.15, 1.02–1.29]).

Conclusions

Hospital mortality is high among massively transfused trauma patients. Among early survivors, 48-hr RBC transfusion volume is associated with increased organ dysfunction, but not hospital mortality. Also, it is not associated with 48-hr mortality. Future research should continue to explore methods to improve hemostasis and minimize the need for RBC transfusion.