End Of Washout Period Research Articles

Comparative effect of Fenugreek and Cinnamon on management of newly diagnosed cases of Type-2 Diabetes Mellitus

Clinical evidence suggests that T2DM and its complications can be prevented through regular intake of functional foods. This cost-effective way of managing T2DM in developing world might prove very beneficial. A randomized controlled trial was done to compare effects of Fenugreek and Cinnamon on treatment of newly diagnosed cases of T2 DM. Subjects were selected from Pakistan Institute of Medical Sciences Hospital, Islamabad. Study was carried out in three phases: Phase I, baseline; Phase II, after 90 days and Pahse III at end of washout period. Subjects, from both genders, were within the age range of 40-65 years. There were 26 subjects in each group. Serum levels of FPG, HbA1c, fasting insulin levels, lipid profile were measured at baseline and at the end of 2nd and 3rd phases. BMI, WC and WHR were also studied in all phases of the study. SPSS (version 22) was used for analysis. Cinnamon seemed to have more effect on both anthropometric (BMI & WC) and biochemical (FPG, HbA1c, serum Insulin, serum cholesterol, HDL & LDL) parameters, as compared to Fenugreek, which had effect on WC, FPG, HbA1c, serum cholesterol and TG only. Although, the magnitude of these effects was similar in both groups.

Abstract 2123: A combinatorial approach using gemcitabine and bitter melon juice overcomes drug resistance impacting gemcitabine uptake and metabolism

Abstract Pancreatic cancer (PanC) has the lowest 5-year survival rate (<3%) of all cancer types and is projected to be the second leading cause of cancer-associated mortalities by the year 2030 in the United States. Surgery alone fails to suffice in a majority of cases; the disease relapses in 70-80% of patients and is fatal without additional therapy. Currently, of all the available treatment modalities for PanC, gemcitabine (GEM) is the standard of care frontline drug, with a moderate success rate in improving the median overall PanC patient survival by about 5.7-6.8 months. Although a modest improvement is achieved using a combination therapy approach, the patient survival still remains less than 12 months, and includes a poor quality of life due to the extensive side effects. Moreover, chemoresistance to GEM is a major contributing factor for PanC patient’ morbidity and mortality resulting from dysfunctional uptake and metabolism of GEM in cancer cells. Therefore, there is an urgent need for agents that could reverse GEM resistance and allow continued chemosensitivity in PanC. Here, we employed natural agent bitter melon juice (BMJ) and GEM to examine their anticancer potential alone and in combination in PanC patient derived xenograft (PDX) - pancreatic ductal adenocarcinomas explants in nude mice. Comparing single agents versus combination in three explants PDX272, PDX261, and PDX266, both at the end of the active dosing regimen as well as following a post treatment-washout period (no drug administration) revealed enhanced efficacy of the combination treatment over failed GEM-in the post treatment termination cohort. Extensive mechanistic assessments revealed that overcoming GEM resistance was possibly due to modulation of GEM metabolism pathway molecules by the BMJ administration. While all drug exposures led to a decreased RRM1 expression during treatments in PanC-explants, at the end of treatment washout period explants displayed increased RRM1 levels in GEM-only group but a sustained decrease in BMJ and Combo groups. Investigation into hENT1 (human equilibrative nucleoside transporter 1) expression, responsible for bidirectional GEM trafficking, revealed that at the end of washout period, combination therapy was the only group that continued to express high levels of hENT1 for all three explants, whereas GEM only group showed poor hENT1 expression. Furthermore, analysis for deoxycytidine kinase (dCK), the enzyme responsible for GEM metabolism, revealed that the combination group had the most augmented dCK expression levels by study end. Taken together, the study outcomes highlight the efficacy of BMJ in combination with GEM in modifying and regulating multiple key players in GEM uptake and metabolism. These conclusions make a compelling case for future clinical investigations in PanC patients wherein BMJ is combined with GEM to target and overcome GEM resistance. Citation Format: Deepanshi Dhar, Dileep Kumar, Komal Raina, David J. Orlicky, Chapla Agarwal, Rajesh Agarwal. A combinatorial approach using gemcitabine and bitter melon juice overcomes drug resistance impacting gemcitabine uptake and metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2123.

Green synthesized silver nanoparticles: Catalytic dye degradation, in vitro anticancer activity and in vivo toxicity in rats

In this study, silver nanoparticles were synthesized (AgNPs) using aqueous rhizome extract of Acorus calamus (ACRE) and evaluated their in vitro anticancer activity and in vivo toxicity in a Wistar rat model. The synthesized AgNPs showed good catalytic activity against different organic pollutant dyes. In vitro cytotoxic effects of AgNPs were assessed in Hep2, COLO 205 and SH-SY5Y cells using MTT assay. Further, the apoptotic changes induced by AgNPs in more susceptible Hep2 cells were observed through AO/EB, DCFH-DA, Rhodamine 123, PI/DAPI staining, oxidative stress markers and Western blotting. In vivo toxicity study revealed substantial alterations in the levels of serum biochemical markers including AST, ALT, LDH and inflammatory markers such as TNF-α and IL-6 on day 29 when rats treated with AgNPs as compared to control, however, these levels were restored to normal at the end of washout period on day 89. No remarkable changes were observed in liver oxidative stress enzymes. ICP-OES analysis indicated bio-distribution of silver in spleen (5.67 μg/g) and liver (4.98 μg/g) in rats treated with 10 mg/kg b.w of AgNPs on day 29 and elimination of silver from all organs was observed at the end of washout period on day 89. Histopathological analysis revealed no significant changes in kidney, spleen, lungs, heart, testis and brain with 5 and 10 mg/kg b.w of AgNP. However, 10 mg/kg b.w of AgNPs showed moderate degree of cell swelling and vacuolar degeneration in liver and these alterations were reverted back to normal at the end of washout period. Findings from this study signify green synthesized AgNPs at low concentrations might be useful in many ways with ecofriendly nature.

Effectiveness of hydrochlorothiazide in combination with telmisartan and olmesartan in adults with moderate hypertension not controlled with monotherapy: a prospective, randomized, open-label, blinded end point (PROBE), parallel-arm study

Background: The potential combinations of antihypertensive agents are many, and making rational choices depends on the characteristics of each drug and on their complementary mechanisms of action. Objective: The aim of this study was to evaluate the effectiveness of adding hydrochlorothiazide (HCTZ) 12.5 mg to olmesartan 20 mg or telmisartan 80 mg on blood pressure (BP) in patients with moderate hypertension. Methods: Consecutive outpatients at the Centro per l'Ipertensione e la Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy, of both sexes aged 39 to 75 years were considered eligible for enrollment if they had a sitting diastolic BP (DBP) ->99 mm Hg and <110 mm Hg at the end of an initial 2-week washout period. Patients were random- ized to olmesartan 20 mg QD or telmisartan 80 mg QD according to a prospective, open-label, blinded end point, parallel-arm design. After 8 weeks of monotherapy, patients whose BP was not controlled (DBP ->90 mm Hg) received HCTZ 12.5 mg QD for 8 additional weeks. Clinical and ambulatory BPs were measured at the end of the washout period and at the end of both treatment periods. Adverse events (AEs) were recorded from spontaneous reports and direct inquiry from investigators. Results: One hundred forty-five patients, all of whom were white, were recruited for the study. After the initial washout period, 13 patients did not meet the inclusion criteria and 6 refused to continue. A total of 126 white patients (69 men, 57 women; mean [SD] age, 60.2 [11.6] years) were randomized to receive monotherapy. Of these, 35 patients (56%) in the olmesartan group and 33 (52%) in the telmisartan group had previously received antihypertensive therapy. At the end of monotherapy, the 52 patients in the olmesartan group and the 49 patients in the telmisartan treatment group who were still in the study and had their BP inadequately controlled by treatment had HCTZ 12.5 mg QD added to their treatment regimen. Both combinations induced a greater ambulatory mean (SD) systolic BP (SBP) and DBP reduction than monothera- py (SBP: 145.3 [6.1] in the olmesartan group and 140.1 [6.4] in the telmisartan group, P < 0.05; DBP: 88.1 [5.1] in the olmesartan group and 84.9 [4.9] in the telmisartan group, P < 0.05). The mean (SD) reduction from baseline in the telmisartan/HCTZ-treated patients (21.5 [10.1]/14.6 [5.2] mm Hg for 24 hours, 21.8 [10.2]/14.9 [5.2] mm Hg for daytime, and 20.4 [10.3]/13.7 [5.9] mm Hg for nighttime; all, P < 0.001 vs baseline) was significantly greater than that observed in the olmesartan/HCTZ-treated patients (18.8 [9.8]/12.3 [4.9] mm Hg for 24 hours, 19.3 [9.8]/12.8 [4.9] mm Hg for daytime, and 17.4 [10.2]/10.6 [5.5] mm Hg for nighttime; all, P < 0.001 vs baseline), with a significant difference between the 2 treatment groups (P < 0.01). Compared with mono- therapy, the add-on effect of HCTZ 12.5 mg QD administration was significantly greater in the telmisartan group than in the olmesartan group (P < 0.05); the differ- ence being more evident for nighttime BP values (SBP, P 0.031; DBP, P 0.025). Reported AEs were similar in the olmesartan/HCTZ and the telmisartan/HCTZ groups (4 patients [7%] vs 3 patients [6%]). Conclusion: The addition of HCTZ 12.5 mg to telmisartan 80 mg monothera- py was associated with greater BP reduction than the addition of the same dose of HCTZ to olmesartan 20 nag monotherapy in these patients previously uncontrolled on monotherapy.

Effects of valsartan/ hydrochlorothiazide and amlodipine on ambulatory blood pressure and plasma norepinephrine levels in high-risk hypertensive patients

The efficacy and tolerability of the combination of valsartan and hydrochlorothiazide (HCTZ) were compared with that of amlodipine in reducing ambulatory blood pressure and plasma norepinephrine levels in patients with mild to moderate hypertension and at least 1 cardiovascular risk factor. At the end of a 2-week washout period, 92 outpatients with a sitting diastolic blood pressure > or =95 and <110 mm Hg, associated with at least 1 additional risk factor, were randomly assigned to receive either valsartan 160 mg and HCTZ 12.5 mg once daily (n=46) or amlodipine 10 mg alone once daily (n=46) for 12 weeks, according to a prospective, randomized, open-label, blinded end point, parallel-group design. At the end of the washout period and after 6 and 12 weeks of active treatment, 24-hour ambulatory blood pressure monitoring was performed, and clinical blood pressure and heart rate and plasma norepinephrine levels were assessed (by high-performance liquid chromatography). Both the valsartan/HCTZ combination and amlodipine had a demonstrable antihypertensive effect, but the combination showed an antihypertensive effect significantly greater than that of amlodipine, as demonstrated by the 24-hour (P<.001), daytime (P<.001), and nighttime ambulatory blood pressure values (P<.01) and by the clinical blood pressure values at trough, which were all significantly lower. Although the trough-to-peak ratios were similar in both groups, the smoothness indexes pertaining to both systolic and diastolic pressures were significantly higher (P<.05 and P<.001, respectively) in patients receiving valsartan/HCTZ, suggesting the combination produces a more homogeneous anti-hypertensive effect. A significant increase in plasma norepinephrine levels was associated with amlodipine (+9% at 6 weeks, +15% at 12 weeks) but not with the valsartan/HCTZ combination. The valsartan/HCTZ combination was better tolerated than amlodipine, which was associated with a higher frequency of ankle edema. These results indicate that the combination of valsartan 160 mg and HCTZ 12.5 mg provides more sustained and homogeneous control of blood pressure than does amlodipine 10 mg in high-risk hypertensive patients, without producing reflex sympathetic activation.

RenaGel®, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone

This multicenter, open-label, dose-titration study assessed the safety and efficacy of RenaGel(R), a nonabsorbed calcium- and aluminum-free phosphate binder, in lowering serum phosphorus. Secondary outcomes were its effects on serum intact parathyroid hormone (iPTH) and serum lipids. Phosphate binders were discontinued during a two-week washout period. Patients whose serum phosphorus was more than 6.0 mg/dl during washout were eligible for treatment. RenaGel(R), at starting doses of two, three, or four 440 mg capsules three times per day with meals, was administered to 172 hemodialysis patients for eight weeks. RenaGel(R) could be increased by one capsule per meal every two weeks as necessary to achieve serum phosphorus control. A second two-week washout period followed. Mean serum phosphorus rose from 6.8 +/- 2.0 mg/dl at prewashout to 9.1 +/- 2.4 mg/dl at the end of the washout period. It then declined to 6.6 +/- 1.9 mg/dl by the end of the eight-week RenaGel(R) treatment period (P < 0. 0001). Serum phosphorus increased to 8.0 +/- 2.2 mg/dl at the end of the second washout period. The mean dose at the end of RenaGel(R) treatment was 5.4 g per day. Eighty-four percent of the patients previously used calcium-based phosphate binders. As expected, calcium declined during the initial washout period when calcium-based phosphate binders were discontinued. Mean serum calcium declined from 9.6 +/- 1.0 mg/dl at prewashout to 9.1 +/- 0.8 mg/dl after washout. It then increased to 9.4 +/- 0.9 mg/dl by the end of RenaGel(R) treatment. Median serum iPTH increased during the two-week washout from 208 pg/ml to 316 pg/ml and then declined to 224 pg/ml at the end of the eight-week treatment period (P < 0.0001 vs. end of initial washout). After eight weeks of treatment, RenaGel(R) reduced mean serum total cholesterol from 171.0 +/- 43.1 mg/dl to 145.0 +/- 38.7 mg/dl (P < 0.0001) and mean serum low-density lipoprotein cholesterol from 102.0 +/- 34.9 mg/dl to 75. 6 +/- 29.4 mg/dl (P < 0.0001). High-density lipoprotein cholesterol, triglycerides, and serum albumin did not change. RenaGel(R), a novel and calcium- plus aluminum-free effective phosphate binder, can control serum phosphorus and reduce the levels of PTH and cholesterol without inducing hypercalcemia or other side effects. Thus, this new phosphate binder may be effective in the treatment of renal osteodystrophy in uremic patients.

Task‐Dependent Development of Cross‐Tolerance to Psychomotor Effects of Lorazepam in Man

Development of cross-tolerance between lorazepam and four other benzodiazepines (BZ) was studied in two trials by measuring objective psychomotor performance and by subjective assessments. In trial I, nitrazepam 10 mg (NZ), temazepam 20 mg (TZ) or placebo were administered to 14 healthy students for 10 consecutive nights. After each pretreatment, psychomotor impairment by the challenge dose of lorazepam 3 mg (LZ) was measured. In trial II, responses to LZ after pretreatment with diazepam 5 mg (DZ) (8 subjects) or alprazolam 0.25 mg (AZ) (10 subjects), both t.i.d., were compared to LZ responses measured after one-month wash-out period. In trial I no cross-tolerance between BZs was found in objective tests, and LZ induced exophoria was even increased. However, the subjects rated LZ to cause less drowsiness after pretreatment with NZ in a situation where the manifestation of cross-tolerance was facilitated by ingestion of caffeine. In trial II a clear but task-dependent development of tolerance to the challenge dose of LZ was documented. One-week pretreatment with DZ reduced subjects responses to LZ. The total serum BZ activity bioassayed by radioreceptor method after intake of LZ was significantly (P less than 0.05) higher after pretreatment with DZ than in the end of wash-out period. Thus a functional cross-tolerance was documented on complex tasks after the subjects have been continuously working under DZ burden.