Patient-specific genetic factors predict treatment failure in sofosbuvir-treated patients with chronic hepatitis C.

BACKGROUND & AIMS: According to pivotal clinical trials, cure rates for sofosbuvir-based antiviral therapy exceed 96%. Treatment failure is usually assumed to be because of virological resistance-associated substitutions or clinical risk factors, yet the role of patient-specific genetic factors has not been well explored. We determined if patient-specific genetic factors help predict patients likely to fail sofosbuvir treatment in real-world treatment situations. METHODS: We recruited sofosbuvir-treated patients with chronic hepatitis C from five Canadian treatment sites, and performed a case-control pharmacogenomics study assessing both previously published and novel genetic polymorphisms. Specifically studied were variants predicted to impair CES1-dependent production of sofosbuvir's active metabolite, interferon-λ signalling variants expected to impact a patient's immune response to the virus and an HLA variant associated with increased spontaneous and treatment-induced viral clearance. RESULTS: Three hundred and fifty-nine sofosbuvir-treated patients were available for analyses after exclusions, with 34 (9.5%) failing treatment. We identified CES1 variants as novel predictors for treatment failure in European patients (rs115629050 or rs4513095; odds ratio (OR): 5.43; 95% confidence interval (CI): 1.64-18.01; P = .0057), replicated associations with IFNL4 variants predicted to increase interferon-λ signalling (eg rs12979860; OR: 2.25; 95% CI: 1.25-4.06; P = .0071) and discovered a novel association with a coding variant predicted to enhance the activity of IFNL4's receptor (rs2834167 in IL10RB; OR: 1.81; 95% CI: 1.01-3.24; P = .047). CONCLUSIONS: Ultimately, this work demonstrates that patient-specific genetic factors could be used as a tool to identify patients at higher risk of treatment failure and allow for these patients to receive effective therapy sooner.

Novel variant in glycophorin c gene protects against ribavirin-induced anemia during chronic hepatitis C treatment.

BACKGROUND: The current use of ribavirin in difficult-to-cure chronic hepatitis C patients (HCV) and patients with severe respiratory infections is constrained by the issue of ribavirin-induced hemolytic anemia that affects 30% of treated patients, requiring dosage modification or discontinuation. Though some genetic variants have been identified predicting this adverse effect, known clinical and genetic factors do not entirely explain the risk of ribavirin-induced anemia. METHODS: We assessed the associations of previously identified variants in inosine triphosphatase (ITPA), solute carrier 28A2 (SLC28A2) and vitamin D receptor (VDR) genes with ribavirin-induced anemia defined as hemoglobin decline of ≥30 g/L on treatment, followed by a staged discovery (n = 114), replication (n = 74), and combined (n = 188) genome-wide association study to uncover potential new predictive variants. RESULTS: We identified a novel association in the gene coding glycophorin C (rs6741425; OR:0.12, 95%CI:0.04-0.34, P = 2.94 × 10-6) that predicts protection against ribavirin-induced anemia. We also replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04-0.41, P = 8.66 ×10-5; and rs1544410; OR:1.65, 95%CI:1.01-2.70, P = 0.0437). CONCLUSIONS: GYPC variation affecting erythrocyte membrane strength is important in predicting risk for developing ribavirin-induced anemia. ITPA and VDR genetic variants are also important predictors of this adverse reaction.

Patients' Perspectives on Early Liver Transplantation in Alcohol-Related Liver Disease.

Liver transplant programs in Canada require a period of 6 months of abstinence from alcohol before considering a patient with liver disease secondary to alcohol for transplantation. Although some studies have demonstrated good outcomes following a transplant in carefully selected patients before the 6-month abstinence period has been met, there have been arguments against this, including the claim that the public has a general negative perception of those with alcohol dependence. We performed a multicenter cross-sectional survey to determine the perception of people in British Columbia, Canada, toward liver transplantation in patients with liver disease due to alcohol who have not demonstrated the capacity to remain abstinent from alcohol for 6 months. A total of 304 patient questionnaires were completed, and 83.1% agreed with a period of abstinence of 6 months. In those patients who were unlikely to survive 6 months without a transplant, 34.1% of respondents agreed with, 44.1% did not agree with, and 21.4% were neutral about, early transplantation; 42.8% would have less trust in the process of transplantation if a period of abstinence was not maintained, but relaxing the requirement for an abstinence period would not have an impact on the majority's decision to donate organs. Only 30.5% would support abandoning the abstinence criteria. Conclusion: Among patients followed at general gastroenterology, medicine, or transplant clinics, there is a willingness to relax the criteria in selected patients unlikely to survive without a transplant, although a general consensus remains in support of the existing 6-month alcohol abstinence rule. A larger scale survey of all provinces in Canada would be required to assess support for such a change in policy.

Real-world health care utilization in treatment of HCV: Results from the Canadian SIMPLE observational trial.

Background: As hepatitis C virus (HCV) treatment continues to evolve, there is an ongoing need to understand and optimize real-world disease management. The primary objective of the SIMPLE study was to describe the real-life management of genotype 1 (G1) HCV in Canada treated with boceprevir + pegylated interferon and ribavirin therapy. Methods: This was an observational, prospective cohort, multicentre, non-interventional study of patients with G1 HCV. A single cohort of adult patients were to be managed as per standard of care (SoC) and treated with 4 weeks of PegRBV dual therapy, followed by boceprevir + PegRBV for 24-44 weeks, with 24-weeks follow-up. Treatment compliance, health care resource utilization (HCRU), HCV viral load, and hematological adverse event (AE) data were collected. Results: This study enrolled 159 patients. All investigators were well educated on the Canadian consensus guidelines for HCV management but only a minority of patients were treated according to treatment guidelines. Viral response was achieved by >50% of patients by week 8 of therapy and in 50%-60% of tested patients during follow-up. An average of 17.9 HCRU visits were reported during the study period. The most commonly used resources were nursing visits for routine follow-up. Conclusions: Results from this real-world study suggest that most patients were not treated according to the product monograph. Further studies are required to determine how oral treatments fit into this paradigm and how these findings extrapolate to the current treatment model. This study can serve as a benchmark for future real-world treatment including heath care utilization analyses.

Lamivudine, Entecavir, or Tenofovir Treatment of Hepatitis B Infection: Effects on Calcium, Phosphate, FGF23 and Indicators of Bone Metabolism

ABSTRACT Background. Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. Objective. To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. Material and methods. This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. Results. No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF treatment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (<-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. Conclusion. Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.

Lamivudine, Entecavir, or Tenofovir Treatment of Hepatitis B Infection: Effects on Calcium, Phosphate, FGF23 and Indicators of Bone Metabolism.

BACKGROUND: Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. OBJECTIVE: To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. MATERIAL AND METHODS: This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. RESULTS: No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF-treatment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (&lt;-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. CONCLUSION: Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.

Hepatitis B Awareness and Knowledge in Asian Communities in British Columbia.

Background. Our study examined hepatitis B virus (HBV) awareness and knowledge in Asian communities in British Columbia (BC). Methods. A statistical random sample representation of Chinese, Korean, Filipino, South Asian, and Southeast Asian populations in Greater Vancouver was surveyed by telephone. Multiple logistic regression analysis was performed to identify predictors of HBV knowledge. Results. General awareness of HBV was reported in 78.8% (798/1013). HBV awareness was the highest in Chinese (89%) and Filipino (88%) populations and the lowest in the South Asian (56%) population. "Reasonable" knowledge of HBV was elicited in 76.8% (778/1013). Higher HBV knowledge was associated with younger age (p = 0.014), higher education (p < 0.0001), Chinese ethnicity (p < 0.0001), and use of media (p = 0.01) and Internet (p = 0.024) for health information. Compared to the Chinese (OR = 1.0) population, "reasonable" knowledge of HBV was lower in Korean (OR = 0.3, 95% CI: 0.1-0.5), Filipino (OR = 0.3, 95% CI: 0.2-0.6), South Asian (OR = 0.3, 95% CI: 0.2-0.4), and Southeast Asian (OR = 0.3, 95% CI: 0.1-0.6) populations. 54.8% (555/1013) felt that HBV education was inadequate and 80.1% (811/1013) preferred HBV education in their native languages. Conclusion. Compared to the Chinese population, other Asian communities in BC have lower HBV awareness and knowledge. Public education should target older and less educated and Korean, Filipino, South Asian, and Southeast Asian populations in their native languages via media and Internet.

Seroprevalences of hepatitis B virus and hepatitis C virus among participants of an Asian health fair in the Lower Mainland, British Columbia.

BACKGROUND: The seroprevalences of hepatitis B virus (HBV) and hepatitis C virus (HCV) are 0.4% and 0.8%, respectively, in Canada, but varying rates have been reported in different populations. OBJECTIVES: To determine the seroprevalences of HBV and HCV among attendees of an Asian health fair in the Lower Mainland, British Columbia, as well as to correlate questionnaire answers regarding vaccination status to serological profiles. METHODS: Attendees at an Asian health fair were invited to participate in the present study on a voluntary basis. They provided answers to a questionnaire including ethnicity and vaccination status. Blood was then drawn for HBV and HCV serology. Active HBV was defined as HBV surface antigen (HBsAg) positive while HCV seroprevalence was defined as HCV antibody reactive. Previous exposure to HBV was defined as HBV core antibody (anti-HBc) positive and HBsAg negative. Nonimmunity was defined as anti-HBc negative and HBV surface antibody negative. Only those with correct demographic information matched to serological results were included in the study. RESULTS: There were 192 consenting attendees of the fair, of whom 112 were included in the study. Of the participants, 91% were Chinese. Active HBV infection was found in three participants (2.7% [95% CI 0.6% to 7.6%]) and HCV infection was found in two participants (1.8% [95% CI 0.2% to 6.3%]). More than 40% of participants had been previously exposed to HBV (42% [95% CI 33% to 51%]). Almost 20% demonstrated nonimmunity to HBV (19% [95% CI 12% to 27%]). There was significant discordance when questionnaire answers regarding vaccination status were compared with serological profiles. CONCLUSION: The seroprevalences of HBV and HCV in this cohort were 2.7% and 1.8%, respectively - higher than nationally reported rates. Our results highlight that the lack of knowledge of HBV infection and vaccination status remains a significant clinical issue in the Asian community of British Columbia.

HISTORIQUE: La séroprévalence des virus de l'hépatite B (VHB) et de l'hépatite C (VHC) s'élève à 0,4 % et à 0,8 %, respectivement, au Canada, mais les taux sont variables dans diverses populations. OBJECTIFS: Déterminer la séroprévalence du VHB et du VHC chez les participants à une foire asiatique sur la santé du Lower Mainland, en Colombie-Britannique, et lier les réponses au questionnaire sur le statut vaccinal avec les profils sérologiques. MÉTHODOLOGIE: Les participants à une foire asiatique sur la santé ont été invités à participer volontairement à l'étude. Ils ont répondu à un questionnaire contenant des questions sur l'ethnie et le statut vaccinal. Du sang a ensuite été prélevé en vue d'une sérologie du VHB et du VHC. Le VHB actif était défini comme un résultat positif à l'antigène de surface du VHB (AgHBs), tandis que la séroprévalence du VHC était définie comme une réaction aux anticorps anti-VHC. Une exposition passée au VHB était définie comme un résultat positif à l'antigène capsidique du VHB (anti-HBc) et négatif à l'AgHBs. La non-immunité était définie comme des résultats négatifs à l'anti-HBc et à l'anticorps de surface du VHB. Seulement ceux dont l'information démographique exacte correspondait aux résultats sérologiques ont participé à l'étude. RÉSULTATS: Au total, 192 participants consentants ont participé à la foire, dont 112 à l'étude. Des participants, 91 % étaient Chinois. Trois étaient atteints d'une infection active par le VHB (2,7 % [95 % IC 0,6 % à 7,6 %]) et deux, d'une infection par le VHC (1,8 % [95 % IC 0,2 % à 6,3 %]). Plus de 40 % des participants avaient déjà été exposés au VHB (42 % [95 % IC 33 % à 51 %]). Près de 20 % ont démontré une non-immunité au VHB (19 % [95 % IC 12 % à 27 %]). On constatait une importante discordance entre les réponses au questionnaire sur le statut vaccinal et les profils sérologiques. CONCLUSION: La séroprévalence du VHB et le VHC de cette cohorte s'élevait à 2,7 % et à 1,8 %, respectivement, soit des résultats plus élevés que les taux nationaux. Ces résultats font ressortir que l'absence de connaissances sur l'infection par le VHB et le statut vaccinal demeure un problème clinique significatif dans la communauté asiatique de la Colombie-Britannique.

Patient preference and willingness to pay for transient elastography versus liver biopsy: A perspective from British Columbia.

BACKGROUND: The cost of liver biopsy (LB) is publicly funded in British Columbia, while the cost of transient elastography (FibroScan [FS], Echosens, France) is not. Consequently, there is regional variation regarding FS access and monitoring of liver disease progression. OBJECTIVE: To evaluate patient preference for FS versus LB and to assess the willingness to self-pay for FS. METHODS: Questionnaires were distributed in clinic and via mail to LB-experienced and LB-naive patients who underwent FS at Vancouver General Hospital, Vancouver, British Columbia. RESULTS: The overall response rate was 76%. Of the 422 respondents, 205 were LB-experienced. The mean age was 53.5 years, 50.2% were male, 54.7% were Caucasian, 38.2% had hepatitis C and 26.3% had an annual household income >$75,000. Overall, 95.4% of patients preferred FS to LB. FS was associated with greater comfort than LB, with the majority reporting no discomfort during FS (84.1% versus 7.8% for LB), no discomfort after (96.2% versus 14.6% LB) and no feelings of anxiety after FS explanation (78.2% versus 12.7% LB). FS was also associated with greater speed, with the majority reporting short test duration (97.2% versus 48.3% LB) and short wait for the test result (95.5% versus 30.2% LB). Most (75.3%) respondents were willing to self-pay for FS, with 26.3% willing to pay $25 to $49. Patients with unknown liver disease preferred LB (OR [FS preference] 0.20 [95% CI 0.07 to 0.53]). CONCLUSIONS: FS was the preferred method of assessing liver fibrosis among patients, with the majority willing to self-pay. To ensure consistency in access, provincial funding for FS is needed. However, LB remains the procedure of choice for individuals with an unknown diagnosis.

The effect of doxorubicin loading on response and toxicity with drug-eluting embolization in resectable hepatoma: a dose escalation study.

AIM: The dose-response relationship between doxorubicin and superabsorbent drug-eluting microspheres has not been established. In this study, we investigated the relationships between dose and delivery parameters as they pertain to toxicity and response in surgically resectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Twenty-five patients with resectable HCC were randomly assigned and divided into four groups, each receiving either bland, 25 mg, 50 mg or 75 mg of doxorubicin loaded Super Absorbent Polymer microspheres, with 24 patients undergoing surgical resection. Response Evaluation and Criteria in Solid Tumors (RECIST) 1.0 and European Association for the Study of the Liver (EASL)-based volumetric response was performed at one month and surgical resection of the reference tumor was performed at two months. Adverse events were collected at regular intervals. RESULTS: Fifty-six percent of patients demonstrated complete response according to EASL criteria as opposed to 0% according to RECIST (v1.0) criteria. Residual tumor was identified in all groups (0 mg: 35%±28.5%; 25 mg: 42%±30.4%; 50 mg: 3.6%±3.3%; and 75 mg: 49.29%±32.6%. A total of 112 adverse events of grades 1-3 occurred (average 5.1 per patient), with no grade 4 or 5. No difference was noted between bland embolic and drug-loaded groups. Subset analysis did demonstrate a significantly increased degree of necrosis in the 50 mg-loaded group (p=0.018). Strong correlation existed between arterial phase Computer Tomography EASL-based response and histopathology (r=0.81; p<0.0001). All groups had residual tumor. CONCLUSION: Histology correlates strongly with one-month post-procedural imaging and response optimized at 50 mg of loading per vial. Adverse events were a reflection of embolization, with no relationship between loading dose or administered dose of doxorubicin.

First successful treatment of post-liver transplant hepatitis C fibrosing cholestatic hepatitis with boceprevir, peginterferon and ribavirin in a pre-transplant null responder.

Fibrosing cholestatic hepatitis (FCH) is a less common but well-recognized severe complication of recurrent hepatitis C virus (HCV) infection post-liver transplant. This condition is fatal without successful treatment and to date; post-transplant antiviral interferon-based antiviral therapy has been associated with guarded success. The new era of protease inhibitors in the treatment of chronic HCV infection may alter the dismal outcome of this condition. To date, however, the experience with protease inhibitors in this condition is unreported. We report a post-liver transplant recipient with HCV associated FCH treated successfully with boceprevir, peginteferon and ribavirin for severe FCH. The patient was young woman who was a null responder pre-transplant to peginterferon and ribavirin. The peak serum bilirubin 391 µmol/L normalized to 15 µmol/L by week 8 of therapy. The pre-treatment HCV viral load of > 78 million IU/mL, decreased to 78 IU/mL at week 8 of therapy and was undetectable by week 12 and at the end of 48 week of treatment. 12 weeks post treatment, the HCV viral load remains undetectable. Significant anemia and neutropenia were encountered. Tacrolimus dosage titrated to trough levels, required marked reduction to 0.5 mg three times weekly. Despite the suboptimal peginterferon and ribavirin dosing, limited by adverse effects, full boceprevir dosing was maintained, with resolution of liver dysfunction. Boceprevir was obtained on compassionate grounds from the manufacturer before its licensure in Canada and this was the first use of boceprevir in the world for post-transplant FCH.

Review of boceprevir and telaprevir for the treatment of chronic hepatitis C.

OBJECTIVE: To summarize and evaluate the published literature pertaining to boceprevir and telaprevir, and to provide clinicians with suggestions for use in patients with chronic hepatitis C infection. METHODS: A standardized search strategy was performed using the MEDLINE, EMBASE, Google Scholar and International Pharmaceuticals Abstracts databases using the search terms "boceprevir", "telaprevir", "boceprevir and hepatitis C", and "telaprevir and hepatitis C". A manual search of references was performed to identify articles missed by the electronic search. Studies were included in the review if they assessed either boceprevir or telaprevir in comparison with standard of care in chronic hepatitis C patients. RESULTS: The studies identified assessed boceprevir and telaprevir in genotype-1 hepatitis C patients. In both treatment-naive and treatment-experienced patients, sustained virological response rates were achieved more often with boceprevir or telaprevir in combination with pegylated interferon and ribavirin compared with pegylated interferon and ribavirin alone. Both medications were well tolerated, with anemia presenting as the most treatment-limiting adverse effect. CONCLUSIONS: Boceprevir and telaprevir will revolutionize the management of hepatitis C genotype 1 patients and will most likely decrease the burden of end-stage disease worldwide. However, current clinical limitations include establishing appropriate and cost-effective treatment durations, and use in special populations such as transplant patients and patients coinfected with HIV. Future research will need to clarify these clinical obstacles to clearly define the role of these agents in hepatitis C management.

A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients.

PURPOSE: Chronic hepatitis C virus (HCV) is a major problem affecting up to 170 million people worldwide. Two protease inhibitors have recently been approved that will revolutionize treatment. Our objective was to summarize and evaluate the literature pertaining to the pharmacokinetics of boceprevir and telaprevir, in order to provide clinicians with insight into the management of actual and potential drug interactions. SUMMARY: A standardized search using MEDLINE (1948-November 2011), EMBASE (1980-November 2011), IPA (1970-November 2011), Google, and Google Scholar that combined the search terms boceprevir, telaprevir, pharmacokinetics, drug interaction, and drug metabolism was performed. Manual reference searches of chosen articles were completed. Monographs and articles, conference proceedings, and abstracts were evaluated. Boceprevir and telaprevir are both substrates and inhibitors of cytochrome P450 3A4 and telaprevir is a substrate of p-glycoprotein. Levels of boceprevir are decreased in patients taking efavirenz but effects with other antiretrovirals are minimal or unknown. Coadministration with efavirenz may compromise telaprevir levels and should be avoided. Telaprevir may increase levels of cyclosporine, tacrolimus, atorvastatin, and amlodipine, which may expose patients to increased adverse effects. Conclusions. Significant drug-drug interactions occur with both boceprevir and telaprevir. Until studies are reported and experience is gained with these agents, clinicians will need to be careful when administering in high-risk populations and those receiving chronic therapy with interacting agents. Studies are urgently needed in HIV patients taking antiretrovirals and patients taking chronic immunosuppression as these populations are at increased risk of experiencing clinically significant interactions.

The PALS prevention program and its long-term impact on student intentions to use alcohol, tobacco, and marijuana.

A unique Alcohol, Tobacco, and Other Drug (ATOD) prevention program called PALS (Prevention through Alternative Learning Styles) was implemented with middle school students with the goal of enhancing student knowledge of the harmful effects of ATOD, promoting the use of refusal skills and reducing intentions to use ATOD in the future. Intentions to use were measured at four points: pre-PALS, post-PALS, and at 1-year and 2-year follow-ups. Student survey responses were then matched and compared across the four time periods. This article reports on the long-term effectiveness of PALS on student intentions to use ATOD in high school. When follow-up surveys of PALS students were compared to students not exposed to PALS (comparison group), the PALS students had significantly lower intentions to use alcohol and tobacco, providing evidence that the PALS intervention did have a long-term impact on intentions to use these substances.

Elution characteristics of doxorubicin-loaded microspheres differ by drug-loading method and microsphere size.

PURPOSE: To examine the loading and elution behavior of doxorubicin and superabsorbent polymer microspheres (SAP-MS) as they relate to particle size and loading techniques. MATERIALS AND METHODS: SAP-MS, 30-60 µm and 50-100 µm, were subject to loading 50 mg of doxorubicin from a dry lyophilized state. Doxorubicin loading was performed after prehydration of SAP-MS (one-step method) or serially in two divided administrations (two-step method). Loading rate and elution characteristics were determined after doxorubicin analysis using a high-pressure liquid chromatography (HPLC) assay. All experiments were performed in triplicate. RESULTS: All systems showed the ability to load and elute doxorubicin effectively in the specified time frame (loading 15 minutes to 2 hours and elution 1 hour to 14 days). For the two loading methods, 30-60 µm SAP-MS showed no statistically significant difference in loading rate but a statistically significant difference in cumulative elution at 14 days (19.13 mg vs 17.83 mg, one-step vs two-step; P = .02). For the two loading methods, 50-100 µm SAP-MS showed no statistically significant difference in loading rate and no statistically significant difference in cumulative elution at 14 days (14.87 mg vs 12.77 mg, one-step vs two-step; P = .20). CONCLUSIONS: SAP-MS exhibit the ability to load and release doxorubicin. In comparing particle size and loading methods, higher cumulative elution rates were associated with smaller (30-60 µm) particle size and one-step loading. Higher elution from the one-step loading method may be due to release of unbound doxorubicin. Differences in the loading and elution of doxorubicin may depend on the increased surface area of smaller SAP-MS resulting in alterations of behavior of doxorubicin and its interactions with the polymer microspheres.

Evaluating the prevention through alternative learning styles program.

This article reports on the evaluation of a two-year alcohol, tobacco and other drug (ATOD) intervention, the Prevention through Alternative Learning Styles (PALS) program, targeting both teachers and middle-school students. Teachers are taught to recognize students' unique learning styles in the context of the ATOD curriculum and adapt the ATOD messages to these learning styles. The student curriculum consists of 5 topic areas with two lessons per topic area. Student goals include enhancing students' knowledge of the effects of ATOD, promoting students' use of refusal skills and decreasing students' intentions to use ATOD. The program was implemented in school dis-tricts in the greater Dayton Ohio area. Support was found for the intervention's overall effectiveness in both years, with statistically significant improvements demonstrated by the students who participated in the PALS program. Students had an increase in their knowledge of ATOD topic areas and a decrease in their intentions to use ATOD.

Iron overload disorders: treatment options for patients refractory to or intolerant of phlebotomy.

Iron overload disorders involve excess accumulation of iron in body tissues as a result of hereditary and nonhereditary diseases. If left untreated, tissue iron deposition can result in organ damage. Treatment options such as phlebotomy, chelating agents, and erythrocytapheresis can prevent complications and target organ damage. Although phlebotomy is the gold standard for iron overload treatment in the setting of hereditary hemochromatosis, this procedure is usually not feasible for other iron overload conditions, especially those associated with anemia. With the introduction of newer, oral chelating agents, more options are available for patients refractory to or intolerant of parenteral chelating agents.