BP Treatment Research Articles

Regulation of VEGF by mevalonate pathway inhibition in breast cancer

Aminobisphosphonates are used for the treatment of benign and malignant bone disorders. As inhibitors of the mevalonate pathway they exert direct anti-tumor effects in vitro and in preclinical models of bone metastases. Bisphosphonates are thought to have an anti-angiogenic activity as decreased levels of VEGF have been reported in some, although not all patients, following treatment with bisphosphonates. Direct effects of bisphosphonates on tumor derived VEGF have not been examined in detail. We therefore investigated VEGF expression in breast cancer cell lines following mevalonate pathway inhibition. Treatment of cell lines with increasing doses of zoledronic acid and atorvastatin resulted in increased levels of VEGF production. Similar results were seen with the geranylgeranyltransferase I inhibitor GGTI-298. The induction of VEGF was reversed by the supplementation of geranylgeranyl pyrophosphate but not by farnesyl pyrophosphate indicating that this effect is mediated by inhibited geranylgeranylation. Previous reports have reported decreased VEGF levels in patients following BP treatment in vivo. We assessed VEGF levels in patients with non-metastatic breast cancer following repeated treatment with zoledronic acid. In contrast to our in vitro findings, VEGF serum levels decreased in all patients after 6–9 months of treatment (by an average of 41%) as assessed in a small pilot trial. These results indicate that tissues other than breast tumors contribute to the serum pool of circulating VEGF and may be responsible for the observed VEGF decreases. The increases of VEGF in the cancer cells may provide a rationale for the combined treatment with VEGF inhibitors.

Severe Liver Cirrhosis Markedly Reduces AhR-Mediated Induction of Cytochrome P450 in Rats by Decreasing the Transcription of Target Genes

Although the induction of cytochrome P450 (CYP) has long been investigated in patients with cirrhosis, the question whether liver dysfunction impairs the response to CYP inducers still remains unresolved. Moreover, the mechanism underlying the possible effect of cirrhosis on induction has not been investigated. Since ethical constraints do not permit methodologically rigorous studies in humans, this question was addressed by investigating the effect of the prototypical inducer benzo[a]pyrene (BP) on CYP1A1 and CYP1A2 in cirrhotic rats stratified according to the severity of liver dysfunction. We simultaneously assessed mRNA level, protein expression and enzymatic activity of the CYP1A enzymes, as well as mRNA and protein expressions of the aryl hydrocarbon receptor (AhR), which mediates the BP effect. Basal mRNA and protein expressions of CYP1A1 were virtually absent in both healthy and cirrhotic rats. On the contrary, CYP1A2 mRNA, protein and enzyme activity were constitutively present in healthy rats and decreased significantly as liver function worsened. BP treatment markedly increased the concentrations of mRNA and immunodetectable protein, and the enzymatic activities of both CYP1A enzymes to similar levels in healthy and non-ascitic cirrhotic rats. Induced mRNA levels, protein expressions and enzymatic activities of both CYPs were much lower in ascitic rats and were proportionally reduced. Both constitutive and induced protein expressions of AhR were significantly lower in ascitic than in healthy rats. These results indicate that the inducibility of CYP1A enzymes is well preserved in compensated cirrhosis, whereas it is markedly reduced when liver dysfunction becomes severe. Induction appears to be impaired at the transcriptional level, due to the reduced expression of AhR, which controls the transcription of CYP1A genes.

Abstract TMP81: Cerebral Blood Flow and Blood Pressure Reduction Do Not Affect Perihematomal Edema Growth in Acute Intracerebral Hemorrhage

Background: Both vasogenic and cytotoxic (ischemic) processes have been postulated to play a role in perihematoma edema formation. In the Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT), cerebral blood flow (CBF) was measured in ICH patients assigned to systolic blood pressure (SBP) targets of <150 or <180 mmHg. In this secondary analysis, we tested the hypotheses that edema growth is associated with reduced CBF and lower SBP. Methods: Non-contrast CT scans were obtained at baseline, 2h and 24h post-randomization. Mean relative CBF (rCBF) in the perihematoma region was calculated from raw CT Perfusion data obtained at 2h. Edema volume was measured using planimetric techniques and a Hounsfield unit threshold of ≤24 at baseline and 24h. Results: ICH patients were randomized (n=33 per group) at a median (IQR) of 7.6 (12.8) h after symptom onset. Mean SBP was significantly lower in the <150 mmHg (139±21 mmHg) than the <180 mmHg (163±11, p=<0.0001) at the time of CTP. Mean perihematoma rCBF in the <150 mmHg group (0.85±0.12) was similar to that in the <180 mmHg group (0.88±0.09, p=0.34). Treatment groups were balanced with respect to baseline SBP (180±18 vs. 185±25 mmHg, p=0.39) and acute ICH volume (20.7±22.0 vs. 28.0±25.8 ml, p=0.22). In all patients, median edema volume increased significantly between the baseline 1.8(2.5) ml and 24 h scans (3.1 (5.1) ml, p<0.0001). Linear regression indicated that ICH expansion predicted edema growth (β =0.3 [0.0, 0.2]). Lower perihematoma rCBF did not predict edema growth independently of ICH expansion (β =-0.2 [-229.5, 0.4]). Mean edema growth in the <150 group (2.4±6.9) was similar to that in the <180 group (2.9±6.4, p=0.737). Edema growth was not predicted by SBP change (β=0.12 [-0.45, 1.22]). Neither low SBP load (fraction of time SBP<150 mmHg over 24 h; β=0.07 [-0.13, 0.24]) nor high SBP load (time SBP >180 mmHg; β=0.07 [-0.13, 0.24]) predicted edema growth. Conclusion: Perihematoma edema growth is explained by ICH volume expansion. Lower perihematoma CBF and BP treatment do not exacerbate edema growth. These data are not consistent with a cytotoxic mechanism of edema formation and support the safety of early BP treatment.

Awareness, attitude, and distribution of high blood pressure among health professionals

BackgroundBP control is suboptimal Worldwide. Little is known about attitudes of health professionals toward their BP status. AimTo estimate awareness, attitudes, and distribution of blood pressure among health professionals. Study designProspective cross-sectional survey. MethodsStudy was conducted among health professionals in two tertiary hospitals in Riyadh, KSA during December 2010. Socio-demographics, risk factors for high BP, awareness, and adherence to treatment were recorded. ResultsSix hundred and seventy-two subjects, 66.6% females, mean age 36.2+13.9years. Prevalence of Hypertension (HTN) was 28%. 114 (60.6%) patients had self reported HTN in HTN group while 74 (11%) of total study population, were not aware that they have HTN which was detected on screening. Stress and lack of formal exercise were prevalent risk factors for HTN, present in 44.1% and 36.1%, of patients, respectively, while obesity was present in 19.4%. Many participants were not aware of recently recommended target value of blood pressure. 22.3% patients were irregular for their follow-up. 12.2% patients were not adherent to the treatment. Isolated systolic hypertension was more common in men. A point of serious concern was that relatively young health professionals, who were not known to be hypertensive did not monitor their BP, found to have HTN. ConclusionSuboptimal awareness and lack of adherence to the treatment for BP among health professionals is of serious concern, for increased chances of cardiovascular events. Physical exercise, correction of obesity and compliance with treatment may reduce the risk of HTN-related adverse outcome in this special subset of the population.

Abstract 18811: Plasma Renin Activity Test Versus US Joint National Committee Guidelines for Selecting Initial Antihypertensive Drug

Background: US National Guidelines promote initiating treatment for nearly all hypertensive patients with a natriuretic drug. We now report a double-blind, randomized controlled trial to compare that with a Plasma Renin Activity (PRA) test guided therapeutic approach. Methods: Hypertensive participants (n=164) consented to (i) replacement of antihypertensive drugs with placebo for at least 4 weeks and then (ii) a 5 month double blind study to compare BP control and BP change achieved by initial monotherapy: Experimental = guided by PRA (n=82) v. Control = hydrochlorothiazide (HCTZ) (n=82). Results: Eligible subjects were 45% males with a mean±SD age 60±9, entry BP 152±10/86±10mmHg,and median (IQR) PRA 0.7 (0.2, 1.4)ng/mL/hr. Experimental subjects were given a diuretic if PRA <0.65 (n=32?), or olmesartan if PRA ≥0.65 ng/mL/hr (n=50?). At 4 months, 72% of both Experimental and Control groups achieved BP <140/90mmHg, (132±15/76±11 v. 134±14/79±9mmHg,p=.39/.18 respectively). As expected, in subjects with PRA<0.65ng/mL/hr BP decline was similar in Experimental and Control groups. By contrast, in 91 patients with PRA ≥ .65ng/mL/hr, after adjusting for entry BP Experimental subjects (n=50) had a significantly greater mean±SE fall in systolic BP [_-4.9±2.4mmHg (p=.04)] and a borderline significantly greater fall when not adjusted (_-4.5±2.3mmHg, p=.06). Conclusions: Effectiveness of PRA guided therapy is identical to US National Guidelines for patients with PRA < 0.65 ng/mL/hr. However, it significantly improved BP treatment in patients with PRA ≥ 0.65ng/ml/hr. Moreover, in this clinical trial of moderately hypertensive patients, initial monotherapy lowered BP to <140/90 mmHg in nearly 3/4 of subjects. These results suggest that routine PRA determination can improve both the effectiveness and efficiency of hypertension treatment.

Performance Comparison among the Major Healthcare Financing Systems in Six Cities of the Pearl River Delta Region, Mainland China

BackgroundThe healthcare system of mainland China is undergoing drastic reform and the optimal models for healthcare financing for provision of primary care will need to be identified. This study compared the performance indicators of the community health centres (CHCs) under different healthcare financing systems in the six cities of the Pearl River Delta region.MethodsApproximately 300 hypertensive patients were randomly recruited from the computerized chronic disease management records provided by one CHC in each of the six cities in 2011 using a multi-stage cluster random sampling method. The major outcome measures included the treatment rate of hypertension, defined as prescription of ≥ one antihypertensive agent; and the control rate of hypertension, defined as systolic blood pressure levels <140 mmHg and diastolic blood pressure levels <90 mmHg in patients without diabetes mellitus, or <130/80 mmHg among patients with concomitant diabetes. Binary logistic regression analyses were conducted with these two measures as outcome variables, respectively, controlling for patients’ socio-demographic variables. The financing system (Hospital- vs. Government- vs. private-funded) was the independent variable tested for association with the outcomes.ResultsFrom 1,830 patients with an average age of 65.9 years (SD 12.8), the overall treatment and control rates were 75.4% and 20.2%, respectively. When compared with hospital-funded CHCs, patients seen in the Government-funded (adjusted odds ratio [AOR] 0.462, 95% C.I. 0.325–0.656) and private-funded CHCs (AOR 0.031, 95% C.I. 0.019–0.052) were significantly less likely to be prescribed antihypertensive medication. However, the Government-funded CHC was more likely to have optimal BP control (AOR 1.628, 95% C.I. 1.157–2.291) whilst the privately-funded CHC was less likely to achieve BP control (AOR 0.146, 95% C.I. 0.069–0.310), irrespective of whether antihypertensive drugs were prescribed.ConclusionsPrivately-funded CHCs had the lowest rates of BP treatment and control due to a variety of potential factors as discussed.

N-Butylidenephthalide (BP) Maintains Stem Cell Pluripotency by Activating Jak2/Stat3 Pathway and Increases the Efficiency of iPS Cells Generation

In 2006, induced pluripotent stem (iPS) cells were generated from somatic cells by introducing Oct4, Sox2, c-Myc and Klf4. The original process was inefficient; maintaining the pluripotency of embryonic stem (ES) and iPS cell cultures required an expensive reagent–leukemia induced factor (LIF). Our goal is to find a pure compound that not only maintains ES and iPS cell pluripotency, but also increases iPS cell generation efficiency. From 15 candidate compounds we determined that 10 µg/ml n-Butylidenephthalide (BP), an Angelica sinensis extract, triggers the up-regulation of Oct4 and Sox2 gene expression levels in MEF cells. We used ES and iPS cells treated with different concentrations of BP to test its usefulness for maintaining stem cell pluripotency. Results indicate higher expression levels of several stem cell markers in BP-treated ES and iPS cells compared to controls that did not contain LIF, including alkaline phosphatase, SSEA1, and Nanog. Embryoid body formation and differentiation results confirm that BP containing medium culture was capable of maintaining ES cell pluripotency after six time passage. Microarray analysis data identified PPAR, ECM, and Jak-Stat signaling as the top three deregulated pathways. We subsequently determined that phosphorylated Jak2 and phosphorylated Stat3 protein levels increased following BP treatment and suppressed with the Jak2 inhibitor, AG490. The gene expression levels of cytokines associated with the Jak2-Stat3 pathway were also up-regulated. Last, we used pou5f1-GFP MEF cells to test iPS generation efficiency following BP treatment. Our data demonstrate the ability of BP to maintain stem cell pluripotency via the Jak2-Stat3 pathway by inducing cytokine expression levels, at the same time improving iPS generation efficiency.

Early BP treatment of intertrochanteric fracture does not delay healing

Early BP treatment of intertrochanteric fracture does not delay healing

Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: Results from the University of Washington Rapid Autopsy Series

Qualitative and quantitative bone features were determined in nondecalcified and decalcified bone from 20 predetermined bone sites in each of 44 patients who died with castration-resistant prostate cancer (CRPC), some of which received bisphosphonate treatment (BP) in addition to androgen-deprivation therapy (ADT). Thirty-nine of the 44 patients (89%) had evidence of bone metastases. By histomorphometric analysis, these bone metastases were associated with a range of bone responses from osteoblastic to osteolytic with a wide spectrum of bone responses often seen within an individual patient. Overall, the average bone volume/tissue volume (BV/TV) was 25.7%, confirming the characteristic association of an osteoblastic response to prostate cancer bone metastasis when compared with the normal age-matched weighted mean BV/TV of 14.7%. The observed new bone formation was essentially woven bone, and this was a localized event. In comparing BV/TV at metastatic sites between patients who had received BP treatment and those who had not, there was a significant difference (28.6% versus 19.3%, respectively). At bone sites that were not invaded by tumor, the average BV/TV was 10.1%, indicating significant bone loss owing to ADT that was not improved (11%) in those patients who had received BPs. Surprisingly, there was no significant difference in the number of osteoclasts present at the metastatic sites between patients treated or not treated with BPs, but in bone sites where the patient had been treated with BPs, giant osteoclasts were observed. Overall, 873 paraffin-embedded specimens and 661 methylmethacrylate-embedded specimens were analyzed. Our results indicate that in CRPC patients, ADT induces serious bone loss even in patients treated with BP. Furthermore, in this cohort of patients, BP treatment increased BV and did not decrease the number of osteoclasts in prostate cancer bone metastases compared with bone metastases from patients who did not receive BP.

Effects of starch content of calf starter on growth and rumen pH in Holstein calves during the weaning transition

The objective of this study was to evaluate the effects of substituting high fiber byproducts for dry ground corn in calf starter on growth and rumen pH during the weaning transition. Holstein bull calves were raised on an intensified nursing program using milk replacer containing 26% CP and 18% fat. Calves were fed a texturized calf starter containing either dry ground corn at 18.8% of dry matter (DM; CRN), beet pulp replacing dry ground corn at 10.2% dietary DM (BP), or triticale dried distillers grains with solubles replacing dry ground corn and high-protein feedstuffs at 18.6% of dietary DM (DDGS) in the pellet; treatment calf starters differed only in the pellet portion. Starch concentrations of CRN, BP, and DDGS were 35.3, 33.4, and 31.4%, respectively. After a calf consumed 2.50kg of starter for 3 consecutive days, a small ruminant rumen pH data logger was inserted orally and rumen pH was measured continuously for 4d. Calves were then killed and rumen fluid was sampled to determine volatile fatty acid profile. No difference was found in overall average daily gain or growth rates of hip height, withers height, and heart girth. During the weaning transition, rate of increase in calf starter intake was greater for calves fed DDGS compared with those fed CRN (87.7 vs. 77.5g/d), but lower for calves fed BP compared with CRN (68.1 vs. 77.5g/d). The area under pH 5.8 (470 vs. 295min × pH/d) or pH 5.2 (72.7 vs. 16.4min × pH/d) was greater for calves fed DDGS than those fed CRN. Rumen pH profile was not affected by BP treatment compared with CRN, but calves fed BP tended to have greater water intake than those fed CRN (6.6 vs. 5.8 L/d). Volatile fatty acid profile was not affected by treatment with the exception of molar proportion of butyrate, which tended to be lower for calves fed BP compared with those fed CRN (15.0 vs. 16.6%). Hay intake was positively correlated to mean rumen pH for calves used in this study (r=0.48). Decreasing dietary starch concentration did not mitigate rumen acidosis in calves during weaning transition, and low rumen pH did not adversely affect growth during the weaning transition.

COX-2 as a Potential Target in Chemoprevention of Benzo(a)pyrene Induced Lung Carcinogenesis in Mice-combined Role of Curcumin and Quercetin

The present study was undertaken to assess the cumulative effects of curcumin and quercetin in inhibiting the activity of COX-2 alongwith other biophysical parameters such as 3 H thymidine uptake as well as uptake and turnover of 14 C-glucose during BP induced lung carcinogenesis in mice. The mice were segregated into five groups viz., normal control, BP treated, BP + curcumin treated, BP + quercetin treated and BP + curcumin+ quercetin treated. Lung carcinogenesis was induced by a single intra-peritoneal (IP) injection of BP (100mg/Kg body weight). Curcumin and quercetin were supplemented to mice at dose levels of 60mg/Kg body weight and 40mg/Kg body wt in drinking water, respectively. All the treatments were continued for a period of 22 weeks. BP treatment brought about a significant increase in the activities of COX-2. Supplementation of phytochemicals individually as well in combination to BP treated mice brought about moderation in the enzymatic activity which was restored to within normal limits. Further, BP treatment recorded increased 3 H thymidine uptake as well as enhanced 14 C-glucose uptake and its turnover which were reduced significantly following simultaneous treatment with phytochemicals. Therefore, cumulative treatment with curcumin and quercetin has the potential of providing protection against lung cancer by inhibiting the COX-2 activity and moderating the 3 H thymidine uptake as well as 14 C-glucose uptake and its turnover.

Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry

The current statement is a systematic review of the available data concerning the efficacy of medication treatment of bipolar disorder (BP). A systematic MEDLINE search was made concerning the treatment of BP (RCTs) with the names of treatment options as keywords. The search was updated on 10 March 2012. The literature suggests that lithium, first and second generation antipsychotics and valproate and carbamazepine are efficacious in the treatment of acute mania. Quetiapine and the olanzapine-fluoxetine combination are also efficacious for treating bipolar depression. Antidepressants should only be used in combination with an antimanic agent, because they can induce switching to mania/hypomania/mixed states/rapid cycling when utilized as monotherapy. Lithium, olanzapine, quetiapine and aripiprazole are efficacious during the maintenance phase. Lamotrigine is efficacious in the prevention of depression, and it remains to be clarified whether it is also efficacious for mania. There is some evidence on the efficacy of psychosocial interventions as an adjunctive treatment to medication. Electroconvulsive therapy is an option for refractory patients. In acute manic patients who are partial responders to lithium/valproate/carbamazepine, adding an antipsychotic is a reasonable choice. The combination with best data in acute bipolar depression is lithium plus lamotrigine. Patients stabilized on combination treatment might do worse if shifted to monotherapy during maintenance, and patients could benefit with add-on treatment with olanzapine, valproate, an antidepressant, or lamotrigine, depending on the index acute phase. A variety of treatment options for BP are available today, but still unmet needs are huge. Combination therapy may improve the treatment outcome but it also carries more side-effect burden. Further research is necessary as well as the development of better guidelines and algorithms for the step-by-step rational treatment.

Curcumin and resveratrol in combination modulates benzo(a)pyrene-induced genotoxicity during lung carcinogenesis

The present study attempted to explore the efficacy of curcumin and resveratrol in modulating mitotic catastrophe and apoptosis during lung carcinogenesis. The mice were segregated into five groups, which included normal control, benzo(a)pyrene (BP)-treated, BP + curcumin (C)-treated, BP + resveratrol (R)-treated and BP + C + R-treated groups. The BP treatment resulted in a significant increase in the formation of micronuclei as well as in the protein expression of bcl-2 in the lungs of mice. On the other hand, a significant decrease was observed in the number of apoptotic cells and protein expression of bax in the lungs of BP-treated mice. Supplementation of curcumin and resveratrol individually to BP-treated animals resulted in a decrease in the micronuclei formation; however, it was not statistically significant. Interestingly, combination of curcumin and resveratrol resulted in a statistically significant decrease in micronuclei formation. Moreover, phytochemicals in combination significantly reduced the protein expression of bcl-2 in BP-treated mice. Furthermore, supplementation of phytochemicals in combination brought a noticeable improvement in the number of apoptotic cells as well as in the protein expression of bax. The present study, therefore, concludes that the combined treatment with curcumin and resveratrol modulates mitotic catastrophe by stimulating apoptosis in BP-treated mice.

Osteopathology induced by bisphosphonates and dental implants: clinical observations

Although there are many reports about risk factors for the development of BP-associated osteonecrosis of the jaws, the role of dental implants as a local risk factor is still discussed, especially in patients with oral BP treatment. Until now, a few case reports and surveys display a possible minor risk in patients with oral BP therapy, whereas the avoidance of implant placement is generally accepted in patients with intravenous BP therapy. In this study, the cases of 14 patients with osteonecrosis of the jaws in association with BP therapy and dental implant placement were analyzed carefully with a detailed literature review. Of 14 patients, nine had underlying malignant disease and five patients had osteoporosis. In ten patients, implants were placed either in the posterior mandible or maxilla; the mean interval between implant insertion and disease onset was 20.9 months. Pain (n12) and signs of infection (n10) were the most common symptoms. Histologically, signs of infection were found in nine of 11 analyzed patients with presence of Actinomyces in six patients. Two patients turned out to have infiltration of underlying malignant disease. Posteriorly placed implants seem to be of higher risk of development of osteonecrosis of the jaws. Not only the implant placement but also the inserted implant itself seems to be a continuous risk factor. The herein elaborated risk factors help dentists plan dental rehabilitation with implants in this high-risk group of patients and indicate careful and regular dental recall.

Tissue-specific expression of hormonal carcinogenesis target genes in rats treated with polycyclic aromatic hydrocarbons

We have investigated the effect of polycyclic aromatic hydrocarbons (PAHs) on estrogen- metabolizing genes CYP1A1, CYP1B1, CYP19 and ERα and cyclin D1 genes, which control of cell division in estrogen-depended tissues. Treatment of rats with benzo(a)pyren (BP) or 3-methylcholantrene (MC) significantly up-regulated CYP1A1, CYP1B1 gene expression in liver, uterus and ovary, whereas alfa-naphthoflavone (α-NF) did not have any effect. The high level of aromatase gene (CYP19) expression was detected in ovary only. Treatment of rats with BP or MC significantly down-regulated expression of this gene (15- and 5,5-fold, respectively), whereas α-NF did not have any effect. BP produced an increase in ERα and cyclin D1 gene expression in rat liver. This effect was not seen with MC and α-NF. ERα and cyclin D1 mRNA levels were unchanged in uterus of rats after PAHs treatment. On the other hand, BP treatment caused an increase of the ERα and cyclin D1 mRNA levels (3,5- and 2,5-fold, respectively) in ovary, whereas MC and α-NF did not have any effects. Thus, our results give evidence for tissue-specific effects of PAHs on expression of genes, which participate in hormonal carcinogenesis. Moreover, the fact that BP and MC treatment affects the expression of estrogen-metabolizing genes and genes, which control of cell division, supports the view that PAHs may be one of the causes of endocrine disorder and consequent hormonal carcinogenesis.

P-194 - Response to mood stabilizer monotherapies in maintenance treatment of bipolar disorder

Introduction The main aims of long-term management for bipolar disorder (BD) are the prevention of new mood episodes and maintaining symptomatic and functional remission. Although several pharmacological and psychosocial interventions have shown effectiveness in maintenance treatment of BP, long-term recovery is achieved only in some patients. Little is known how these treatments are effective in routine clinical practice. Methods 121 patients (76 women) with BD confirmed by the Schedule for Affective Disorders and Schizophrenia (SADS) interview, with mean age of 44.6 and mean duration of illness of 13.1 years who were at least one year on maintenance monotherapy with the mood stabilizers (lithium, carabamazepine, valproate, lamotrigine and olanzapine) were assessed using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder (TRS). Results Total score ≥ 7 in TRS (“full responders”) reached 22 (18%) patients. For particular mood stabilizers, we found response rate from 5% (valproate) to 28% (lithium). Responders did not differ from non-responders in the length of illness, age of onset, the polarity of first episode, number of episodes, the occurrence of psychotic symptoms and suicide attempts, rapid cycling, positive family history, and the presence of comorbid disorders. Conclusions Although mood stabilizer monotherapies remain recommended and desirable strategies for maintenance treatment of BD, our results show that a satisfactory response is achieved only in a minority of patients. This research was supported by the project 1M0517 MSMT CR.

Comparison of Analgesic Effects of Caudal Epidural 0.25% Bupivacaine with Bupivacaine Plus Morphine or Bupivacaine Plus Ketamine for Analgesia in Conscious Horses

The aim of this study was to compare the effects of caudal epidural bupivacaine alone (BP), bupivacaine plus morphine (BPMP), and bupivacaine plus ketamine (BPKE) for perineal analgesia in horses. Each of the six saddle horses received a caudal epidural catheter and underwent 3 treatments: BP, 0.25% (0.04 mg/kg) bupivacaine hydrochloride without epinephrine; BPMP, 0.02 mg/kg of bupivacaine combined with 0.1 mg/kg of morphine-preservative free; and BPKE, 0.02 mg/kg of bupivacaine combined with 0.5 mg/kg of ketamine. The order of treatments was randomized. The cardiovascular system, respiratory rate, quality of analgesia, sedation, and motor blockade were assessed before drug administration (baseline), at 5, 10, 15, and 30 minutes, and every 30 minutes thereafter until loss of analgesia. The median time to onset of analgesia was 5 minutes after BP treatment, faster than after BPKE or BPMP treatments, which were 10 minutes and 15 minutes, respectively (P < .05). The BPMP treatment produced analgesia (315 minutes) for a longer duration than BP treatment (210 minutes) or BPKE treatment (240 minutes), in the regions of the tail, perineum, and upper hind limb in horses. All treatments presented mild sedation or motor blockade. There were minimal effects on the cardiovascular system and respiratory rate. BPMP may be preferable to a high dose of BP or BPKE. Caudal epidural BPMP can be an appropriate choice for regional perineal analgesia in horses.

Regional bone metabolism at the lumbar spine and hip following discontinuation of alendronate and risedronate treatment in postmenopausal women

The aim of this study was to examine the effects of bisphosphonate discontinuation on bone metabolism at the spine and hip measured using (18) F-fluoride PET. Bone metabolism at the spine remained stable following discontinuation of alendronate and risedronate at 1year but increased in the hip in the alendronate group only. Bisphosphonates such as alendronate (ALN) or risedronate (RIS) have persistent effects on spine BMD following discontinuation. Positron emission tomography (PET) was used to examine regional bone metabolism in 20 postmenopausal women treated with ALN (n = 11) or RIS (n = 9) for a minimum of 3years at screening (range 3-9years, mean 5years for both groups). Subjects underwent a dynamic scan of the lumbar spine and a static scan of both hips at baseline and 6 and 12months following treatment discontinuation. (18) F-fluoride plasma clearance (K(i)) at the spine was calculated using a three-compartment model. Standardised uptake values (SUV) were calculated for the spine, total hip, femoral neck and femoral shaft. Measurements of BMD and biochemical markers of bone turnover were also performed. With the exception of a significant decrease in spine BMD in the ALN group, BMD remained stable. Bone turnover markers increased significantly from baseline by 12months for both study groups. Measurements of K(i) and SUV at the spine and femoral neck did not change significantly in either group. SUV at the femoral shaft and total hip increased significantly but in the ALN group only, increasing by 33.8% (p = 0.028) and 24.0% (p = 0.013), respectively. Bone metabolism at the spine remained suppressed following treatment discontinuation. A significant increase in SUV at the femoral shaft and total hip after 12months was observed but for the ALN group only. This study was small, and further clinical studies are required to fully evaluate the persistence of BP treatment.

Blood pressure modulation following activation of mast cells by cationic cell penetrating peptides

Short cell penetrating peptides (CPP) are widely used in vitro to transduce agents into cells. But their systemic effect has not been yet studied in detail. We studied the systemic effect of the cell penetrating peptides, penetratin, transportan and pro-rich, on rat hemodynamic functions. Intra-arterial monitoring of blood pressure showed that injection of the positively charged penetratin and transportan in a wide range of concentrations (2.5–320 μg/kg) caused highly significant transient decrease in the systolic and diastolic blood pressure in a dose dependent manner ( p < 0.01). Pretreatment with histamine receptors blockers or with cromolyn, a mast cell stabilizing agent, significantly attenuated this effect. Furthermore, in vitro incubation of these both peptides with mast cells line, LAD2, caused a massive mast cell degranulation. In vitro studies showed that these CPP in a wide range of concentrations were not cytotoxic without any effect on the survival of LAD2 mast cell line. In contrast, the less positively charged and proline-rich CPP, pro-rich, had no systemic effects with no effect on mast cell degranulation. Our results indicate that intravenously administrated positively charged CPP may have deleterious consequences due to their induced BP drop, mediated by mast cell activation. Therefore, the major effect of mast cell activation on BP should be considered in developing possible future drug therapies based on the injection of membrane-permeable and positively charged CPP. Nevertheless, lower levels of such CPP may be considered as a treatment of systemic high BP through moderate systemic mast cell activation.

Curcumin and resveratrol synergistically stimulate p21 and regulate cox-2 by maintaining adequate zinc levels during lung carcinogenesis

This study explored the efficacy of curcumin and resveratrol in maintaining adequate zinc levels to regulate p21 and cyclooxygenase-2 (cox-2) during benzo[a]pyrene (BP)-induced lung carcinogenesis. The mice were segregated into five groups, which included normal control, BP treated, BP plus curcumin treated, BP plus resveratrol treated, and BP plus curcumin plus resveratrol-treated groups. BP treatment resulted in a significant decrease in the zinc levels and protein expression of p21. On the contrary, the enzyme activity of cox-2 showed a significant increase in the BP-treated mice. Interestingly, combined supplementation of curcumin and resveratrol to BP-treated mice resulted in an appreciable improvement in the zinc levels and protein expression of p21. In contrast, synergistic supplementation with phytochemicals resulted in a significant decrease in the enzyme activities of cox-2 in BP-treated mice. This study, therefore, concludes that combined treatment with curcumin and resveratrol maintains adequate zinc levels and regulates inflammation by cox-2 and cell cycle arrest by p21 during lung carcinogenesis in mice.