Low-dose Combination Therapy Research Articles

Therapeutic Outcomes and Prognostic Factors in Childhood Absence Epilepsy.

Background and PurposeChildhood absence epilepsy (CAE) is one of the most common types of pediatric epilepsy. It is generally treated with ethosuximide (ESM), valproic acid (VPA), or lamotrigine (LTG), but the efficacy and adverse effects of these drugs remain controversial. This study compared initial therapy treatment outcomes, including VPA-LTG combination, and assessed clinical factors that may predict treatment response and prognosis.MethodsSixty-seven patients with typical CAE were retrospectively enrolled at the Korea University Medical Center. We reviewed patients' clinical characteristics, including age of seizure onset, seizure-free interval, duration of seizure-free period, freedom from treatment failure, breakthrough seizures frequency, and electroencephalogram (EEG) findings.ResultsThe age at seizure onset was 7.9±2.7 years (mean±SD), and follow-up duration was 4.4±3.7 years. Initially, 22 children were treated with ESM (32.8%), 23 with VPA (34.3%), 14 with LTG (20.9%), and 8 with VPA-LTG combination (11.9%). After 48 months of therapy, the rate of freedom from treatment failure was significantly higher for the VPA-LTG combination therapy than in the three monotherapy groups (p=0.012). The treatment dose administrated in the VPA-LTG combination group was less than that in the VPA and LTG monotherapy groups. The shorter interval to loss of 3-Hz spike-and-wave complexes and the presence of occipital intermittent rhythmic delta activity on EEG were significant factors predicting good treatment response.ConclusionsThis study showed that low-dose VPA-LTG combination therapy has a good efficacy and fewer side effects than other treatments, and it should thus be considered as a firstline therapy in absence epilepsy.

Worsening of proteinuria caused by combination therapy of hypertonic saline and low-dose furosemide for treatment of acute decompensated heart failure with overt diabetic nephropathy

A combination of hypertonic saline and furosemide has been proposed as a new therapeutic approach for treating acute decompensated heart failure (ADHF). The advantages of this combination have not only been demonstrated in ADHF but also in refractory ascites due to liver cirrhosis. However, the therapeutic effects of this regimen have never been evaluated in ADHF with overt diabetic nephropathy (ODN). Here, we present an interesting case of a 35-year-old patient admitted to our hospital for ADHF with shortness of breath and systemic edema, complicated with hypertension, type 2 diabetes, and ODN. Echocardiography showed left ventricular enlargement and diffuse hypokinesis, with ejection fraction of 33%. Urinary findings showed total proteinuria of 3597mg/day during the first day of hospitalization. We initiated decongestion therapy with continuous infusion of hypertonic saline and furosemide. In spite of increased diuresis, edema remained the same and serum albumin decreased from 2.7g/dl to 2.0g/dl, and proteinuria increased up to 7344mg/day. The amount of proteinuria and serum albumin level gradually recovered over time after cessation of the therapy. These data suggest that the combination therapy worsens glomerular hypertension and ODN. Therefore, hypertonic saline and furosemide combination therapy should not be recommended for patients with ODN.<Learning objective: Hypertonic saline and low-dose furosemide combination therapy has been proposed as a treatment option for ADHF, especially in refractory congestive heart failure cases. Nevertheless, the efficacy of this treatment in ADHF cases complicated with overt proteinuria is not fully elucidated. This therapy may induce increment of proteinuria in these patients due to aggravation of glomerular hypertension, and may be ineffective for decongestion or to treat edema.>

Study on the therapeutic effects of an extract of herb medicines, YiGanQingDuKeLi, in combination with adefovir dipivoxil on the rebound of duck hepatitis B virus multiplication

Objective To investigate the in vivo therapeutic effects of an extract of herb medicines, YiGanQingDuKeLi, in combination with adefovir dipivoxil (ADV) on the rebound of duck hepatitis B virus (DHBV) multiplication after withdrawal of ADV treatment. Methods Peking ducks were infected with DHBV positive serum samples for 7 days and then screened by SYBR Green real-time PCR. The ducks positive for DHBV were randomly divided into five groups including the model control group, the ADV treatment group, the herb treatment group, the high-dose combination therapy group and the low-dose combination therapy group. The ducks in the ADV treatment and the herb treatment groups were respectively treated with distilled water and YiGanQingDuKeLi (1.2 g/ml) for 14 days after the treatment of ADV (0.25 mg/ml) for 21 days. The ducks in the high-dose group were treated with YiGanQingDuKeLi (1.2 g/ml) for 14 days after the combined treatment with high-dose YiGanQingDuKeLi (1.2 g/ml) and ADV (0.25 mg/ml) for 21 days. The ducks in the low-dose group were treated with YiGanQingDuKeLi (0.6 g/ml) for 14 days after the combined treatment with YiGanQingDuKeLi (0.6 g/ml) and ADV (0.125 mg/ml) for 21 days. Blood samples were collected from each duck via leg vein after 0, 7, 14 and 21 days of drug administration and after 7 and 14 days of drug withdrawal. The levels of DHBV-DNA, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in blood serum samples were detected. Results Compared with the model group, the levels of DHBV-DNA, ALT and AST in ducks from the herb treatment group and combined treatment groups were decreased before the discontinuation of ADV treatment (P<0.05 or P<0.01). Moreover, the titers of DHBV-DNA in ducks treated with high doses of drugs were much lower than those from ADV treatment group. The levels of DHBV-DNA, ALT and AST in ducks treated with herb medicine and high doses of drugs remained at relatively low levels after the cessation of ADV treatment, but rebounded significantly in ducks with ADV treatment. The levels of DHBV-DNA and ALT rebounded slightly in ducks treated with low doses of drugs as compared with those of ADV treatment group (P<0.01 or P<0.05). Conclusion The treatment of YiGanQingDuKeLi in combination with ADV could inhibit not only the in vivo replication of DHBV, but also the rebound of DHBV multiplication after ADV withdrawal. Key words: Adefovir dipivoxil; Duck hepatitis B virus; Rebound

Reduction in the level of antibodies against heat shock proteins 60 during different hormonal protocols in postmenopausal women.

IntroductionIn current literature, the immune-inflammatory theory of atherosclerosis is widely discussed. The role of how heat shock proteins 60 (HSP60) lead to the development of the atheromatous plaque is especially underlined. The aim of the study is to estimate the influence of three hormonal protocols on behavior of antibodies against HSP60. It determines the state of endothelium in postmenopausal women.Material and methodsThe study was carried out on 90 women between 2007 and 2012. All the women were in their menopausal age (51 ± 3 years), from the south region of Poland, with a follicle stimulating hormone (FSH) level above 25 mIU/ml, and with menopausal symptoms disturbing their normal daily activity. The study was done for a period of 6 months. Three groups of 30 randomized patients were formed. In the first group we used transdermal estrogen therapy in a 37.5 µg/24 h dose combined with a 10 mg dose of dydrogesterone. In the second group we applied transdermal estrogen therapy in a 50 µg/24 h dose with 2.5 mg of oral medroxyprogesterone. In both these groups, gestagens were administered continuously. In the third group, we prescribed continuous, oral, low-dose combined estrogen-gestagen therapy with 1 mg of ethinyl estradiol and 0.5 mg of norethisterone acetate. The control group consisted of 30 volunteers who were also from the south region of Poland, in good health, with menopausal symptoms, no menstrual period for the last 12 months, selected considering their age and weight, with an FSH level above 25 mIU/ml and with normal levels of thyroid stimulating hormone (TSH) and prolactin. All patients treated and in the control group were seronegative to Chlamydia pneumonia for the entire duration of the study. In the analysis conducted, nonparametric tests were used (Mann-Whitney U test, Wilcoxon test, Kruskal-Wallis test – ANOVA).ResultsAfter 6 months of hormonal therapy, we found that all schemes of treatment promote a significant reduction in antibodies against HSP60 in all treated groups vs. the control group.ConclusionsAll of the investigated estrogen protocols have a favorable impact on the blood level of HSP60 antibodies in early postmenopausal women who have no cardiovascular risk factors. It triggers a better condition of endothelium.

Successful Treatment of Livedoid Vasculitis with Primary Antiphospholipid Syndrome by Using Aspirin and Low Dose Warfarin Combination Therapy.

Dear Editor: Livedoid vasculitis is a rare disorder clinically characterized by purpuric macules and papules on the lower legs and feet1. These lesions are caused by infarction of small vessels that affects young and middle-aged women. The bizarrely shaped ulcers may be painful, heal slowly, result in scarring, or cause atrophie blanche2. Livedoid vasculitis usually occurs in isolation; however, several reports have shown an association with systemic lupus erythematosus, other autoimmune diseases, and malignant disease3. However, an association with antiphospholipid antibodies has been rarely described. Antiphospholipid syndrome is an acquired hypercoagulable state, shows recurrent thrombosis, and can spontaneously resolve. It is correlated with systemic lupus erythematosus in about half of the patients. There are only a few reports about patients with livedoid vasculitis accompanying primary antiphospholipid syndrome without systemic lupus erythematosus. Primary antiphospholipid syndrome could be diagnosed by using the criteria of Miyakis et al.4 (small vessel thrombosis, spontaneous abortion/anticardiolipin antibody subclass immunoglobulin (Ig) G or IgM, anti-β2 glycoprotein IgG or IgM, and lupus anticoagulant). A 33-year-old female patient with painful tender erythematous ulcers on both lower legs visited our hospital in December 2012. The ulcers had been covered with exudate and crust for 4 months. She had been treated with a nonsteroidal anti-inflammatory drug for several months before visiting our institution. Irregular ulceration and purpura were observed on admission (Fig. 1A). Histological examination showed evidence of dilated capillaries in the upper dermis and thickened vessel walls containing fibrinoid materials (Fig. 2). She was initially treated with systemic methylprednisolone, but she failed to respond. Screening for vasculitis gave normal results, including lupus relevant antibodies (lupus anticoagulant, antinuclear antibody, and anti-dsDNA antibody), except for the increase in anti-cardiolipin antibody subclass IgG at 17.2 U/ml (reference, <9 U/ml) and a markedly increased anti-cardiolipin antibody subclass IgA at 20.8 U/ml (reference, <10 U/ml). Additionally, she had increased anti-phospholipid antibody subclass IgG at 18.4 U/ml. Therefore, the diagnosis was concluded to be livedoid vasculitis and primary antiphospholipid syndrome, and she was started on combination therapy with 100 mg aspirin and low-dose warfarin (2 mg) daily with a good clinical response (Fig. 1B). She remains in remission presently. Fig. 1 (A) Lesions showing purpura and irregular ulcerations at first visit. (B) Lesions showing almost complete clinical remission at 2 months after treatment. Fig. 2 (A) Dilated capillaries in the upper dermis (H&E, ×40). (B) Vessel walls are thickened and contain fibrinoid material (H&E, ×100). The treatment for livedoid vasculitis with antiphospholipid syndrome is not clearly defined. Corticosteroids have been used successfully5; however, they do not provide long-term benefits, and our patient showed no response. Antithrombotic agents, including tissue plasminogen activator, prostacyclin, antiplatelet therapy, and low-dose warfarin, can be used successfully1,2,3. The combination of low-dose warfarin and antiplatelet therapy was used in our patient to prevent further thrombosis. The patient demonstrated histologically thickened vessel walls containing fibrinoid material and clinically irregular ulcerations and purpura. Therefore, her condition was diagnosed as livedoid vasculitis with primary antiphospholipid syndrome and she was treated with low-dose warfarin, an antiplatelet agent. Livedoid vasculitis presents the clinical symptoms of other diseases that cause occlusive vasculopathy; thus, clinicians should find the underlying conditions and provide treatment if antiphospholipid antibodies are present. Aspirin and low-dose warfarin combination therapy is a valuable therapeutic option for livedoid vasculitis with primary antiphospholipid syndrome.

Optimizing clinical outcomes resulting from glucose‐lowering therapies in type 2 diabetes: increased confidence about the DPP‐4 inhibitors and continued concerns regarding sulphonylureas and exogenous insulin

Optimizing clinical outcomes resulting from glucose‐lowering therapies in type 2 diabetes: increased confidence about the <scp>DPP</scp>‐4 inhibitors and continued concerns regarding sulphonylureas and exogenous insulin

Nonresponse to PDE5 inhibitors in erectile dysfunction. Part 2

Human Andrology 2014, 4:45–53 Purpose Although oral phosphodiesterase 5 inhibitors (PDE5-Is) are efficacious for many men with erectile dysfunction, a relatively large subset of erectile dysfunction patients who do not respond to PDE5-Is has been identified. This review explored the possible alternative therapeutic strategies. Methods The review was based on a previously published literature, which involved a PubMed– MEDLINE search from January 1998 (year of sildenafil’s approval) through January 2014. To achieve the maximum sensitivity of the search strategy and identify all studies, we combined ‘oral phosphodiesterase 5 inhibitors’ or ‘sildenafil’ or ‘vardenafil’ or ‘tadalafil’ as Medical Subject Headings (MeSH) terms or keywords with ‘non-response’ or ‘response’ or ‘failure’ or ‘erectile dysfunction’ as MeSH terms or keywords. Results There are a number of options to manage these patients including re-education on sex with PDE5-Is and the pharmacokinetic/dynamics of PDE5-Is, psychosexual therapy, modification of lifestyle, optimal treatment of comorbidities, treatment of concomitant hypogonadism, the use of ‘high-dose’ PDE5-Is, switching patients to another PDE5-I, daily use of PDE5-Is, the use of combination therapies, endovascular treatment, and penile prosthesis implantation. Conclusion Many cases of pseudononresponders may be salvaged by diagnosing and addressing any related factors and this should be attempted before initiating more invasive therapy. For many true nonresponders, chronic low-dose PDE5-I therapy or combination therapies have all been proven to be effective in salvaging many patients. Penile prosthesis implantation is indicated after failure or rejection of other treatment options.

Comparative study of high dose mono-therapy of amlodipine or telmisartan, and their low dose combination in mild to moderate hypertension.

Hypertension is one of the major public health challenges worldwide. Angiotensin receptor blockers (ARBs) and Calcium channel blockers (CCBs) are among the first line antihypertensive drugs. However, optimal treatment strategies in mild to moderate hypertensives who failed to achieve blood pressure (BP) control with low-dose mono-therapy are not well established. This study was done to compare efficacy and safety of high dose mono-therapy of Amlodipine, Telmisartan and their low dose combination in mild to moderate hypertensives who failed to achieve BP control with low dose mono-therapy of either drug. A total of 96 patients, fulfilling inclusion and exclusion criteria were enrolled in the study after obtaining informed consent. Patients were randomized into three treatment groups i.e. Telmisartan 80 mg, Amlodipine 10 mg and low dose combination of Telmisartan 40 mg +Amlodipine 5 mg once daily for two months. The systolic BP, Diastolic BP, and ADRs were recorded at 0, 2, 4, 8 weeks. In the present study, significant reduction of mean systolic blood pressure (SBP) and mean diastolic blood pressure (DBP) was seen in all the three treatment groups. Low dose combination of Amlodipine 5 mg and Telmisartan 40 mg showed statistically significant reduction in SBP as compared to Telmisartan 80 mg mono-therapy and in DBP as compared to Amlodipine 10 mg mono-therapy. Maximum adverse drug reactions (ADRs) were reported in Amlodipine mono-therapy group, like ankle oedema, constipation, headache and fatigue. In term of BP control, low-dose combination therapy appears a better therapeutic approach than high-dose mono-therapy.

Efficacy and Tolerability of Telmisartan Plus Amlodipine in Asian Patients Not Adequately Controlled on Either Monotherapy or on Low-Dose Combination Therapy

Objective. To evaluate the efficacy and safety of the telmisartan plus amlodipine (T/A) single-pill combination (SPC) in Asian patients with hypertension whose blood pressure (BP) was not adequately controlled on either monotherapy or on low-dose combination therapy. Patients and Methods. Data are presented from five Boehringer Ingelheim-sponsored phase 3, double-blind, 8-week, studies: two studies in nonresponders to amlodipine (data pooled for amlodipine), two studies on nonresponders to telmisartan (pooled data), and one on nonresponders to low-dose T/A SPC. Results. After 8 weeks' treatment, mean reductions from the reference baseline in diastolic BP (DBP; primary endpoint), systolic BP (SBP), and SBP, DBP goal, and response rates were higher with the T/A SPC than respective monotherapies. The T80/A5 SPC resulted in greater reductions in DBP and SBP, and higher DBP goal and response rate than the low-dose T40/A5 SPC. Peripheral edema incidence was low (amlodipine 0.5%, telmisartan 0.0%, and T/A SPC 0.7%). Discussion and Conclusion. In Asian patients whose BP is not adequately controlled with telmisartan or amlodipine monotherapy, T/A SPC treatment results in greater BP reduction, and higher DBP and SBP goal and response rates. The safety and tolerability of the T/A SPC are comparable to those of the respective monotherapies and consistent with those reported in previous studies.

Meta-analysis of all-trans retinoic acid-linked arsenic trioxide treatment for acute promyelocytic leukemia

ObjectivesTo explore the combination therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO, As2O3) on acute promyelocytic leukemia (APL).MethodsA meta-analysis of six studies was performed. Among 415 included cases, 165 cases were in the ATRA + ATO group, 129 cases in the ATRA-alone group, and 121 cases in the ATO-alone group. The complete remission (CR) rate and incidences of three groups were compared, respectively, between the therapies of ATRA + ATO with ATRA-alone, ATRA + ATO with ATO-alone, and ATRA with ATO.ResultsThe assessment results showed that ATRA + ATO therapy significantly improved the CR rate and decreased the incidences of cutaneous reaction compared with ATRA-alone (P < 0.05). However, incidence of liver injury was higher in the ATRA + ATO and ATO-alone groups than that in ATRA-alone group (P < 0.05). Difference in the complications between ATRA + ATO therapy and ATO-alone was not significant (P > 0.05).ConclusionsIn conclusion, we suggest low-dose ATRA and ATO combination therapy may be more effective for the treatment of APL.

TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension (TRIUMPH): Study protocol

Hypertension management strategies have traditionally focused on "tailored therapy" and "stepped-care" approaches. These tend to be costly and time consuming and often fail to achieve adequate blood pressure (BP) control. The TRIUMPH study aims to investigate the effectiveness, cost-effectiveness, and acceptability of early use of a 3-in-1 BP-lowering pill ("Triple Pill") compared with usual care for the management of hypertension. The prospective, open, randomized controlled clinical trial (n = 700) will compare Triple Pill-based strategy to usual care among individuals with persistent mild-to-moderate hypertension (systolic BP >140 mm Hg and/or diastolic BP >90 mm Hg, or systolic BP >130 mm Hg and/or diastolic BP >80 mm Hg in patients with diabetes or chronic kidney disease) on no or minimal drug therapy. The study will be conducted within approximately 20 hospital-based clinics in India. Participants will be randomized to the Triple Pill (initially strength 1-telmisartan 20 mg, amlodipine 2.5 mg, hydrochlorothiazide 6.25 mg, with the option of subsequent titration to strength 2-telmisartan 40 mg, amlodipine 5 mg, hydrochlorothiazide 12.5 mg) or continued usual care. Participants will be followed up for 6 months. The primary outcome is the proportion of participants achieving target BP at the end follow-up. This study will determine whether early use of a low-dose triple combination therapy has the potential to address some of the challenges in hypertension control through earlier achievement of BP control, better adherence, and fewer adverse effects, in the context of less intensive clinical follow-up.

Is the BTS/SIGN guideline confusing? A retrospective database analysis of asthma therapy

Background:The British guideline on the management of asthma produced by the British Thoracic Society (BTS) and the Scottish Intercollegiate Guidelines Network (SIGN) describes five steps for the management of chronic asthma. Combination therapy of a long-acting β2-agonist (LABA) and an inhaled corticosteroid (ICS) is recommended as first-line therapy at step 3, although the dose of ICS at which to add a LABA is subject to debate.Aims:To classify the inhaled therapy prescribed to patients with asthma in NHS Forth Valley according to two interpretations of the BTS/SIGN guideline and to evaluate the use of combination therapy in this population.Methods:A retrospective analysis including patients from 46 general practitioner surgeries was conducted. Patients with physician-diagnosed asthma were classified according to the BTS/SIGN guideline based on treatment prescribed during 2008. Patient characteristics were evaluated for the overall step classification, and specifically for therapy in step 3.Results:12,319 patients were included. Guideline interpretation resulted in a shift of 9.2% of patients (receiving medium-dose ICS alone) between steps 2 and 3. The largest proportion of patients (32.3%) was classified at step 4. Age, sex, smoking status, chronic obstructive pulmonary disease co-morbidity, and utilisation of short-acting β2-agonists and oral corticosteroids all correlated with step; however, no differences in these characteristics were evident between low-dose combination therapy and medium-dose ICS alone at step 3.Conclusions:Further studies are needed to evaluate prescribing decisions in asthma. Guideline recommendations regarding the use of ICS dose escalation versus combination therapy need to be clarified relative to the published evidence.

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

IntroductionThiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes. MethodsA prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12weeks of combination therapy. ResultsOf fifteen IBD patients, XO activity decreased from 0.18 (IQR 0.08–0.3) during thiopurine monotherapy to 0.14 (IQR 0.06–0.2) and 0.11 (IQR 0.06–0.2; p=0.008) mU/hour/ml at 4 and 12weeks, respectively. HGPRT activity increased from 150 (IQR 114–176) to 180 (IQR 135–213) and 204nmol/(h×mg protein) (IQR 173–213; p=0.013). TPMT activity seemed not to be affected. 6-Thioguanine nucleotide concentrations increased from 138 (IQR 119–188) to 235 (223–304) and to 265pmol/8×10^8 (IQR 188–344), whereas 6-methyl mercaptopurine ribonucleotides concentrations decreased from 13230 (IQR 7130–17420) to 690 (IQR 378–1325) and 540 (IQR 240–790) pmol/8×10^8 at 4 and 12weeks of combination therapy (both p<0.001). ConclusionAllopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.

Subtherapeutic doses of angiotensin receptor blocker for attenuation of amlodipine-induced peripheral edema

Peripheral edema is one of the commonest troublesome adverse effects associated with the use of calcium channel blockers (CCBs). Here, we report a case of amlodipine-induced peripheral edema which could be adequately managed by subtherapeutic doses of angiotensin receptor blocker (ARBs); telmisartan. An elderly hypertensive patient prescribed amlodipine developed edema on both lower limbs to the extent of limiting her normal function and was thus changed to telmisartan monotherapy. Eventually, failure of antihypertensive response to maximal doses of telmisartan (80 mg) despite disappearance of edema made low-dose combination therapy inevitable for achievement of dual goals-Target blood pressure with limitation of adverse effect (edema). To conclude, we come up with two suggestions-First, ARBs can be added to CCBs even in patients who respond to monotherapy with CCBs in order to reduce the incidence of edema and thus improve compliance. Second, when used for attenuation of edema with amlodipine, we suggest use of titrated doses of ARBs.

A Phase II Study of Low-Dose Pomalidomide (0.5mg/day) and Prednisone Combination Therapy in Patients with Myelofibrosis and Significant Anemia

AbstractAbstract 1728 Introduction:Pomalidomide (POM) is an investigational immunomodulatory drug (IMID) that has shown efficacy in preliminary studies, with or without prednisone, as therapy for myelofibrosis (MF) with anemia, by eliminating the need for red blood cell (RBC) transfusions. In our experience, however, single agent low dose POM (0.5 mg/d) has very modest efficacy in achieving RBC transfusion independence in MF patients (Shastri A et al Blood 2011; 118). To further understand and define its activity, we have undertaken a single center phase II open label study to assess the efficacy of low dose POM in combination with prednisone therapy. In a prior study this combination resulted in a 36% response rate according to International Working Group for Myelofibrosis Research and Therapy (IWG-MRT) response criteria (Tefferi A, et al. JCO 2009; 27:4563). In the current study, benefit was assessed by the RAND-Delphi consensus criteria, which has been suggested as a better tool to evaluate RBC transfusion dependence/independence in clinical trials (Gale RP et al. Leuk Res 2011; 35:8) than IWG-MRT criteria. Patients were also evaluated for an increase in hemoglobin of at least 2g/dL for duration of 8 weeks, without transfusion support.Table 1RAND-Delphi criteria for RBC transfusion dependence/independenceRBC-transfusionsSurveillance intervalRBC-transfusion-dependence≥2 U/month3 monthsRBC-transfusion-independenceNone3 monthsReduced RBC-transfusion-dependence50% decrease3 months Patients & Results:21 patients, 14 male and 7 female, were enrolled in the study: 2 (10%) had post essential thrombocythemia MF, and 19 (90%) had primary MF. Median age was 69 years (range 48–85) and 15 (71%) were previously treated; 5 had been treated with other IMIDs previously. Four (19%) had splenomegaly; 1 had prior splenectomy. Seven (33%) had abnormal cytogenetics and 10 (48%) had JAK2V617F mutation. All patients had hemoglobin <10g/dL at study entry; patients with higher hemoglobin that were transfusion dependent were allowed to enroll if it was a result of a blood transfusion given just prior to enrollment. Median hemoglobin was 8.5 g/dL (range 7.3–11.1), WBC 4.7×109/L (1–20.7), and platelets 155×109/L (35–1191). The use of anagrelide during the study was allowed to control high platelets, if indicated; other concomitant therapies, including growth factors, were not allowed. Patients were administered POM 0.5mg continuously daily in 28-day cycles and prednisone was administered as 30mg daily for the first month, 15mg daily for second month, 15mg every other day for third month and then stopped. Thirteen (62%) patients were transfusion dependent by the RAND-Delphi consensus criteria.After a median follow up of 7.8 months (3.3–11.9), 6 (28%) patients were still on the therapy. The median number of cycles administered to patients was 6 (2–12). Fourteen patients were taken off the study for lack of response (N=12) or for loss of a response (N=2). One patient was taken off due to the development of grade 3 pneumonitis. Three died from unrelated causes. Three patients were noted to have RBC transfusion response per RAND-Delphi criteria. One of the responders had JAK2V617F mutation. Median time to response was 52.7 days (48 – 55 days). No patient had an increase in hemoglobin of at least 2g/dL for at least 8 weeks. This is an ongoing trial and updated results along with complete toxicity profile will be presented at the meeting. Conclusion:POM administered in combination with prednisone to patients with MF and significant anemia has modest efficacy, comparable to single agent POM. A Phase III blinded, placebo-controlled study is underway globally for MF patients with significant anemia and RBC transfusion dependency. Disclosures:Verstovsek:Celgene: Research Funding.

Effects of Low-Dose Fluticasone Propionate/Salmeterol Combination Therapy on Exhaled Nitric Oxide and Nitrite/Nitrate in Breath Condensates from Patients with Mild Persistent Asthma

Objective. The long-acting β2-agonist salmeterol in combination with the corticosteroid fluticasone propionate is used in clinical practice for the treatment of mild persistent asthma. Although the effect of fluticasone propionate alone in asthmatic patients is well documented, the effect of fluticasone propionate/salmeterol (FSC) combination therapy on airway inflammation and airway hyperresponsiveness (AHR) is not well characterized. Thus, we evaluated AHR, exhaled nitric oxide (FENO), and nitrite and nitrate in exhaled breath condensates (EBCs) from mild persistent asthmatic patients treated with a low-dose FSC (100/50). Methods. In this open label study, 18 mild persistent, steroid-naïve asthmatics (age, 22–62 years, forced expiratory volume in 1 s (FEV1) > 70% predicted, provocative dose resulting in 20% reduction (PD20) < 10 mg/mL) were treated with FSC 100/50 for 4 weeks. PD20 to methacholine, FEV1, FENO, and EBC nitrite and nitrate was measured before and after treatment. Results. After 4 weeks of therapy with FSC 100/50, FENO decreased from 74 ppb (SD = 37) to 34 ppb (SD = 15) (p < .001). FEV1 (% predicted) increased from 89.4 (SD = 10.7) to 93.3 (SD = 9.5) (p < .01). The PD20 for methacholine increased from 3.0 (±3.2) to 10.3 (±8.4) mg/mL (p < .01) in 3 of 18 patients reaching the maximum allowable dose (25 mg/mL). FENO correlated with the log of the methacholine dose. There was no statistically significant change in EBC nitrite and nitrate before and after treatment. Conclusions. Treatment of mild persistent, steroid-naïve asthmatics with low-dose combination therapy is effective in rapidly reducing airway inflammation and AHR. Our results suggest different metabolic origins for nitrite, nitrate, and FENO in this group of patients.

Use of low-dose combined therapy with gemcitabine and paclitaxel for advanced urothelial cancer patients with resistance to cisplatin-containing therapy: a retrospective analysis

PurposeThe prognosis of patients with advanced and recurrent urothelial cancer (UC) is poor. Although cisplatin (CDDP)-containing chemotherapy is the most effective regimen in these patients, there is no other established chemotherapeutic regimen. We administered combination therapy with low-dose gemcitabine (GEM) and paclitaxel (PTX), named low-dose gemcitabine–paclitaxel (LD-GP) therapy, as salvage therapy for these patients. The aim was to evaluate the anti-tumoral effects, relief of pain, and toxicity of LD-GP therapy in patients with resistance to CDDP-containing therapy.Patients and methodsThirty-five patients with advanced UC, previously treated with CDDP-containing regimens, were treated with LD-GP therapy (GEM, 700 mg/m2 + PTX, 70 mg/m2 on day 1 and 8, repeated every 28 days). Pain was measured on a visual analog scale before and after treatment. Pain relief and survival were compared between this and other treatment regimens.ResultsNone of the patients had complete response to LD-GP therapy. Partial response and stable disease were seen in 25.7 and 62.9 % of patients, respectively. Kaplan–Meier curves showed better survival in patients with LD-GP therapy than with others (p = 0.034). Twenty-eight patients (80.0 %) had adequate pain relief, and only two patients needed to increase their analgesics. Other regimens demonstrated pain relief in 30.4 % of patients. Common toxicities included leukopenia, with five patients requiring granular colony-stimulating factor therapy (14.3 %). The most common non-hematologic toxicity was fatigue (n = 7, 17.1 %).ConclusionsLD-GP therapy is feasible and well tolerated as salvage therapy in patients with advanced UC with resistance to CDDP-containing therapy.

Tramadol/paracetamol fixed-dose combination in the treatment of moderate to severe pain

Pain is the most common reason patients seek medical attention and pain relief has been put forward as an ethical obligation of clinicians and a fundamental human right. However, pain management is challenging because the pathophysiology of pain is complex and not completely understood. Widely used analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) have been associated with adverse events. Adverse event rates are of concern, especially in long-term treatment or at high doses. Paracetamol and NSAIDs are available by prescription, over the counter, and in combination preparations. Patients may be unaware of the risk associated with high dosages or long-term use of paracetamol and NSAIDs. Clinicians should encourage patients to disclose all medications they take in a “do ask, do tell” approach that includes patient education about the risks and benefits of common pain relievers. The ideal pain reliever would have few risks and enhanced analgesic efficacy. Fixed-dose combination analgesics with two or more agents may offer additive or synergistic benefits to treat the multiple mechanisms of pain. Therefore, pain may be effectively treated while toxicity is reduced due to lower doses. One recent fixed-dose combination analgesic product combines tramadol, a centrally acting weak opioid analgesic, with low-dose paracetamol. Evidence-based guidelines recognize the potential value of combination analgesics in specific situations. The current guideline-based paradigm for pain treatment recommends NSAIDs for ongoing use with analgesics such as opioids to manage flares. However, the treatment model should evolve how to use low-dose combination products to manage pain with occasional use of NSAIDs for flares to avoid long-term and high-dose treatment with these analgesics. A next step in pain management guidelines should be targeted therapy when possible, or low-dose combination therapy or both, to achieve maximal efficacy with minimal toxicity.

Biweekly combination therapy with gemcitabine and carboplatin compared with gemcitabine monotherapy in elderly patients with advanced non-small-cell lung cancer: A randomized, phase-II study

IntroductionThe strategy of chemotherapy in the elderly is controversial. We wanted to evaluate the efficacy and safety of biweekly gemcitabine and low-dose carboplatin combination therapy in elderly patients with advanced non-small-cell lung cancer (NSCLC). MethodsIn this phase-II trial, chemotherapy-naive elderly patients (aged ≥76 years) with NSCLC were randomly treated with biweekly combination therapy with gemcitabine and carboplatin (1000mg/m2 gemcitabine and carboplatin at an area under the curve (AUC) of 3 on days 1 and 15, every 4 weeks) or gemcitabine monotherapy (1000mg/m2 on days 1, 8 and 15, every 4 weeks). The primary endpoint was overall response rate and analysis was based on intention-to-treat. ResultsThirty-one patients were randomly assigned combination therapy and 30 were assigned monotherapy. The median age was 79.0 years. Response rate was 22.6% (95% confidence interval (CI): 11.4–39.8%) for biweekly combination therapy and 10.0% (95% CI: 3.5–25.6%) for monotherapy. Median progression-free survival in combination chemotherapy was 3.9 months (95% CI: 0.5–8.5 months), which was significantly longer that that in monotherapy (2.4 months, 95% CI: 0.5–6.7 months). The prevalence of hematological and non-hematological adverse events reaching grade 3/4 was not significantly different between combination therapy and monotherapy. ConclusionsBiweekly gemcitabine and low-dose carboplatin combination chemotherapy showed acceptable efficacy, toxicity, and tolerability in those aged ≥76 years with NSCLC. Further investigations with a large population are required to confirm our results.

Low-Dose Anticholinergic Combination Therapy in Male Benign Prostatic Hyperplasia Patients with Overactive Bladder Symptoms.

Most men with lower urinary tract symptoms have both storage and voiding symptoms. Overactive bladder symptoms occur in 50-75% of men with benign prostatic obstruction. Alpha-blockers are usually the first option in medical therapy. Even though voiding symptoms are alleviated by the use of medicines or transurethral resection of the prostate, storage symptoms continue in 30-65% of patients. Combination therapy with an alpha1-receptor antagonist and an anticholinergic agent in benign prostatic hyperplasia patients with overactive bladder symptoms significantly alleviates symptoms and improves quality of life. In clinical practice, the efficacy and safety of anticholinergic combination therapy may not be comparable with well-controlled studies. Overactive bladder symptoms usually require long-term treatment, and benign prostatic hyperplasia tends to progress with time. When male LUTS patients are treated with anticholinergic combination therapy, there are still some concerns about the development of acute urinary retention, voiding difficulty, and other anticholinergic side-effects. If the drug is prescribed in a relatively low dosage, however, this approach could be appealing regarding adverse effects. There is a relatively small number of clinical reports about low-dose combination therapy, which is in its early stages. Promising results are being reported, though the level of evidence is low. We await the final results.