Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) confirms that abaloparatide is a valuable addition to the armamentarium against osteoporosis

The recently published Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) assessed the efficacy and safety of abaloparatide (80 µg daily subcutaneous) (ABL) vs placebo during 18 months, in postmenopausal osteoporosis. Teriparatide (20 µg daily subcutaneous) (TPD) was used as an open label active comparator. The results of the study suggest that ABL increases bone mineral density more than TPD and reduces major osteoporotic fractures to a greater extent than TPD with a more rapid onset of action. These outcomes combined with a positive safety profile make ABL an interesting addition to the armamentarium against postmenopausal osteoporosis.     

Comparison of change in bone resorption and bone mineral density with once-weekly alendronate and daily risedronate: a randomised,placebo-controlled study

OBJECTIVE: To compare the effects of alendronate (ALN) 70 mg once weekly (OW) and risedronate (RIS) 5 mg daily between-meal dosing on biochemical markers of bone turnover and bone mineral density (BMD) in postmenopausal women with osteoporosis. Research design and methods: This was a 3-month, randomised, double-blind, placebo-controlled study with a double-blind extension to 12 months. The study enrolled 549 postmenopausal women (ALN 219, RIS 222 and placebo (PBO) 108) who were > or =60 years of age at outpatient centres. MAIN OUTCOME MEASURES: The primary endpoint was reduction in urine N-telopeptides of type 1 collagen (NTx) corrected for creatinine level at 3 months. Secondary parameters included change in BMD at the spine and hip at 6 and 12 months, NTx at 1, 6 and 12 months, and serum bone-specific alkaline phosphatase (BSAP) at 1, 3, 6 and 12 months. Adverse experiences (AEs) were recorded throughout the study for an assessment of treatment safety profiles and tolerability. RESULTS: Over 3 months, ALN produced a significantly greater mean reduction in urine NTx than did RIS (-52% vs -32%, p < 0.001), which was maintained at 12 months. ALN produced a significantly greater mean BMD increase than did RIS at 6 months, and it was maintained at 12 months at the lumbar spine (4.8% vs 2.8%, p < 0.001) and total hip (2.7% vs 0.9%, p < 0.001), as well as at the trochanter and femoral neck. Significant reductions in BSAP with ALN compared to RIS were maintained over the 12 months of treatment. Study size did not allow for meaningful assessment of differences in fracture rates. Tolerability was generally similar between ALN, RIS and PBO, and the incidence of upper GI AEs causing discontinuation and oesophageal AEs was similar in the ALN and RIS groups. CONCLUSION: In this study, ALN 70 mg OW produced a 50% greater reduction in bone resorption as measured by urine NTx and significantly greater increases in lumbar spine and hip BMD than did RIS 5 mg daily. The treatments had similar safety profiles and were generally well-tolerated. Additional studies are needed comparing OW ALN with OW RIS, which became available after the commencement of the present study.     

Comparison of change in bone resorption and bone mineral density with once-weekly alendronate and daily risedronate: a randomised,placebo-controlled study

SUMMARY

Objective: To compare the effects of alendronate (ALN) 70mg once weekly (OW) and risedronate (RIS) 5mg daily between-meal dosing on biochemical markers of bone turnover and bone mineral density (BMD) in postmenopausal women with osteoporosis.

Research design and methods: This was a 3-month, randomised, double-blind, placebo-controlled study with a double-blind extension to 12 months. The study enrolled 549 postmenopausal women (ALN 219, RIS 222 and placebo (PBO) 108) who were >60 years of age at outpatient centres.

Main outcome measures: The primary endpoint was reduction in urine N-telopeptides of type 1 collagen (NTx) corrected for creatinine level at 3 months. Secondary parameters included change in BMD at the spine and hip at 6 and 12 months, NTx at 1,6 and 12 months, and serum bone-specific alkaline phosphatase (BSAP) at 1, 3, 6 and 12 months. Adverse experiences (AEs) were recorded throughout the study for an assessment of treatment safety profiles and tolerability.

Results: Over 3 months, ALN produced a significantly greater mean reduction in urine NTx than did RIS (?52% vs ?32%, p?<?0.001), which was maintained at 12 months. ALN produced a significantly greater mean BMD increase than did RIS at 6 months, and it was maintained at 12 months at the lumbar spine (4.8% vs 2.8%, p?<?0.001) and total hip (2.7% vs 0.9%, p?<?0.001), as well as at the trochanter and femoral neck. Significant reductions in BSAP with ALN compared to RIS were maintained over the 12 months of treatment. Study size did not allow for meaningful assessment of differences in fracture rates. Tolerability was generally similar between ALN, RIS and PBO, and the incidence of upper GIAEs causing discontinuation and oesophageal AEs was similar in the ALN and RIS groups.

Conclusion: In this study, ALN 70?mg OW produced a 50% greater reduction in bone resorption as measured by urine NTx and significantly greater increases in lumbar spine and hip BMD than did RIS 5?mg daily. The treatments had similar safety profiles and were generally well-tolerated. Additional studies are needed comparing OW ALN with OW RIS, which became available after the commencement of the present study.     

Hantzsch pre-column derivatization for simultaneous determination of alendronate sodium and its pharmacopoeial related impurity: Comparative study with synchronous fluorometry using fluorescamine

High performance liquid chromatographic (HPLC) method with a pre-column derivatization based on Hantzsch condensation reaction was applied for simultaneous determination of alendronate sodium (ALN) and its main related impurity, 4-Aminobutanoic acid (ABA) at its pharmacopeial limit. The separation of colored condensation products of ALN and ABA were achieved on Agilent Zobrax Eclipse SB-C18 analytical column (250 × 4.6 mm, 5 μm) using a mobile phase composed of acetonitrile–0.1 M acetate buffer, pH 5.0 (15:85, v/v). The flow rate was 1 mL min^?1. The detection was carried out at 340 nm using photo-diode array detector. Peak areas were used for the linear regression line in the range of 10–500 and 0.2–40 μg mL^?1 for ALN and ABA, respectively. Different conditions for the optimization of the derivatization reactions as well as for the HPLC measurement were studied. The proposed method was validated for linearity, precision, accuracy, specificity and robustness. This method was used to check the purity of ALN in the presence of ABA (related impurity) at the pharmacopeial limit (0.5%). For comparison purpose, another method was proposed which involves synchronous fluorescence measurement after ALN reaction with fluorescamine. In this method, the third derivative synchronous spectra were estimated as peak to peak measurement from 339 to 370 nm for ALN determination with LOD and LOQ of 24 and 73 ng mL^?1, respectively, showing very high sensitivity. Both methods have been applied for determination of the alendronate sodium (ALN) in bulk and pharmaceutical preparations without interference of additives in tablets or oral solution.     

Hypocalcemia induced by raloxifene

Raloxifene is an anti-resorptive agent used in postmenopausal osteoporosis. This is the first report of the occurrence of clinically significant hypocalcemia following raloxifene treatment in a patient with occult vitamin D deficiency. Since vitamin D deficiency is widely prevalent in the community, screening for vitamin D deficiency and its correction is advisable before the initiation of anti-resorptive therapy.     

Isoflavone supplementation influenced levels of triglyceride and luteunizing hormone in Korean postmenopausal women

We conducted a double-blind, randomized, placebo-controlled trial to evaluate the effects of soy-derived isoflavone on blood glucose, lipid profiles, and sex hormones related to cardiovascular disease in Korean postmenopausal women. One hundred thirteen postmenopausal women were recruited from the Seoul metropolitan area. To confirm postmenopausal and gynecologic status, the subjects were clinically examined by a gynecologist using ultra sound and X-ray. Finally, 85 postmenopausal women whose follicle-stimulating hormone (FSH) levels were higher than 40 IU/ml were enrolled. Subjects received either 70 mg isoflavone or placebo capsules daily for 12 weeks. As a result, the values of fasting glucose, insulin and HOMA-IR, as well as those of TC, LDL-C, HDL-C and FFA, were not different between the groups after supplementation. However, triglyceride (TG) levels in the treatment group decreased significantly compared with those of the placebo group (p = 0.0215). The levels of luteinizing hormone (LH) significantly decreased in the treatment group (p = 0.027); however, the levels of FSH, estrone and estradiol were not changed after intervention. In conclusion, isoflavone supplement of 70 mg/day for 12 weeks decreased blood levels of TG and LH in Korean postmenopausal women.     

Improved dosage form of the combined alendronate and calcitriol (Maxmarvil®) on the absorption of alendronate in Korean postmenopausal women

Alendronate is one of the most potent anti-osteoporotic agents for postmenopausal osteoporosis. However, high doses of alendronate cause esophageal irritation, myalgia, gastrointestinal discomfort and decrease of serum calcium level. Recently, Maxmarvil^® was developed as an enteric-coated tablet containing alendronate (5 mg) and calcitriol (0.5 μg) to minimize these side effects of alendronate. In the present study, we evaluated the pharmacokinetic profile and examined the incidence of unfavorable effects after oral administration of Maxmarvil^® in Korean healthy postmenopausal women without a previous history of fracture. In the in vitro dissolution test, alendronate was not released from Maxmarvil^® in pH 1.2 phosphate buffer solution but released in pH 6.0 and 6.8 phosphate buffer solutions and completely dissolved in 30 min. After oral administration of Maxmarvil^®, three out of 18 (16.7 %) women showed mild adverse effects; two myalgia and one upper gastrointestinal discomfort without heartburn. Most of these complaints disappeared during the study without additional treatment. The peak (U _max) and the average (U _ave) urinary excretion rate of alendronate and the time to reach U _max (T _max) were 2.94 μg/h, 0.901 μg/h and 6.77 h, respectively. The total cumulative urinary excretion of alendronate (Ae_0–24 h) was 21.6 μg (0.432 % of oral alendornate), which was similar to the reported values. Taken together, enteric-coated Maxmarvil^® is less harmful for the esophagus and gastrointestinal mucosa, shows the same pharmacokinetic profile to conventional alendronate (70 mg) and improves the tolerability of medication in clinical practice.     

Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia

Objective

The present study aimed to examine the changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia.

Methods

Sixty-two drug naïve, first-episode schizophrenia (SZ group) and 60 healthy individuals (control group) were enrolled in the study. Serum interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) levels, and body weight were measured at baseline for both groups, and repeated for the SZ group at five different time points during 6-month risperidone treatment.

Results

At baseline, serum IL-1β, IL-6, and TNF-α levels in the SZ group (53.28?±?12.62, 33.98?±?14.13, 50.08?±?12.86 pg/mL, respectively) were significantly higher than those in the control group (23.49?±?15.27, 15.53?±?7.16, 32.12?±?15.23 pg/mL, respectively) (p's?<?0.001). Within the SZ group, serum IL-1β levels decreased significantly at 2 weeks (48.02?±?16.00 pg/mL, p?<?0.01) and 1 month (44.70?±?16.63 pg/mL, p?<?0.001), but then gradually increased at 2 months (48.49?±?18.87 pg/mL), 3 months (50.59?±?18.48 pg/mL) and 6 months (53.64?±?16.22 pg/mL) to the levels comparable to baseline; serum IL-6 levels changed significantly over the course of treatment (p?=?0.001), but reached the levels comparable to baseline at 6 months (37.13?±?13.23 pg/mL); serum levels of TNF-α increased significantly at 3 months (55.02?±?16.69 pg/mL, p?<?0.01) and 6 months (58.69?±?13.57 pg/mL, p?<?0.001); steady and significant weight gain was observed at each follow-up time point (p's?<?0.001), from 56.71?±?9.25 kg at baseline to 62.72?±?9.53 kg at 6 months.

Conclusions

Risperidone treatment is associated with changes in serum pro-inflammatory cytokines levels and weight. There is an initial anti-inflammatory effect that reduces with treatment, potentially due to its weight gain side effect.     

Tailoring the care in patients with chronic heart failure: a feasibility study on psychological support at distance

Continuity of care at home is essential for the management of patients with chronic heart failure (CHF) suffering also from anxiety/depressive symptoms. This study was aimed at evaluating the possibility of providing psychological support to CHF patients after hospital discharge. A psychodynamic model of counselling was approached by telephone by a psychotherapist and evaluated in terms of feasibility. 16 out 67 CHF patients who continue to suffer from mild to moderate anxiety/depressive disorders, which, because of location, transports or infirmity impediments, could not have access to any other care support, were enrolled in this feasibility study. At time of discharge, every 7–10 days for a pilot period of 6 months, patients were followed by a telephone call (lasting 45 min, as an in office visit) by the same psychotherapist who had previously performed in-hospital interview and tests. Evaluation of anxiety and depression and quality of life were performed by appropriate tests (Hospital Anxiety and Depression Scale and WHOQOL-Brief, respectively), questionnaires of satisfaction by patients and operator were also provided. There were 109 total contacts/6 months, with an average of 6.8 ± 3.6 calls per patient. 82 out of 109 calls (75%) were managed in the first 3-month period. Main areas of discussion were the insight and experience of disease and interaction with the health staff. At the end of the 6-month study, six patients needed further specific psychotherapist’s support and the programme was extended till 1 year (42 further calls). More than 90% patients were satisfied of the service. Operator encountered difficulties mainly due to schedule contacts during working time for worker patients. This preliminary study shows the assessment and feasibility of the psychodynamic counselling by telephone in CHF patients which needs further organizational improvement.     

Dose-dependent Effects of Ladostigil on Microglial Activation and Cognition in Aged Rats

The current study determined the effects of chronic treatment of aging rats with ladostigil, a cholinesterase (ChE) and monoamine oxidase (MAO) inhibitor, at doses of 1 and 8.5 mg/kg/day, on novel object recognition (NOR) and reference memory in the Morris water maze (MWM). A dose of (1 mg/kg/day) did not inhibit ChE or MAO but prevented the loss of NOR and reference memory in the MWM that occurs at 20.5 months of age. This anti-aging effect was associated with a reduction in the expression of CD11b, a marker of microglial activation, in the fornix and parietal cortex and restoration of microglial morphology to that in young adult rats. Ladostigil (8.5 mg/kg/day) inhibited brain ChE by ≈30 % and MAO A and B by 55–59 %, and had a similar, or greater effect than the low dose on microglia, but was less effective in preventing the decline in NOR. Ladostigil (8.5 mg/kg/day) may have caused too much cortical ChE inhibition and acetylcholine elevation at 16 months when NOR was intact. In support of this suggestion we showed that acute administration of ladostigil (8.5 mg/kg) worsened NOR at this age. However, at 20 months, when NOR was impaired and brain acetylcholine levels are 40 % below normal, ladostigil (8.5 mg/kg) reversed the memory deficit. Conclusion: Ladostigil (1 mg/kg/day) prevents the development of age-related memory deficits by a combination of immunomodulatory and antioxidant effects. A dose causing 30 % ChE inhibition is necessary in order to reverse existing memory deficits at 20 months of age.     

Urge to smoke over 52 weeks of abstinence

Rationale

Cigarette cravings are well documented during the first weeks of smoking abstinence. Treatments focus on helping smokers reduce these acute cravings. Cravings experienced later on are less well understood and may be important when considering treatment duration.

Objective

We conducted a longitudinal study of cravings over 52 weeks of smoking abstinence.

Methods

Cravings were operationalised as strength of, and time spent with, urges to smoke. These were assessed among 452 smokers quitting with behavioural support but without pharmacotherapies. Individuals maintaining abstinence were assessed at 1, 2, 3, 4, 26 and 52 weeks after quitting (n?=?197, 156, 139, 131, 66 and 38, respectively). Abstinence was validated at each assessment by expired carbon monoxide. Time courses were plotted for those abstinent for 52 weeks and for those abstinent up to earlier time points. Correlations were examined between ratings of urges at consecutive time points.

Results

Ratings of strength of urges to smoke followed an exponential decline over 52 weeks of abstinence, but 6 months after quitting 13 % of ex-smokers still reported strong urges. At 12 months, no ex-smokers reported strong urges, although 34 % reported some urges. Strength of urges to smoke after 1, 2, 3 and 4 weeks of abstinence predicted strength of urges at 6 months.

Conclusions

Strength of urges to smoke decline exponentially over time following smoking cessation, though some smokers report strong urges after 6 months of abstinence, and urges are still reported by a third of smokers after 12 months. Relapse prevention treatments may need to target prolonged craving.     

Reversibility of renal cortical lesions induced in rats by high doses of nitrilotriacetate in chronic feeding studies

The effects in the renal cortex of the male rat of continuous administration of a high dose of nitrilotriacetate (NTA) for 24 months were compared with those of the administration of a similar dose for 18 months followed by a 6-month recovery period on the control diet. The results suggest that discontinuation of treatment interrupts the sequence of events leading to tumour formation. This study indicates that all stages in the proposed pathogenesis of renal tubular tumour formation by NTA, up to the occurrence of adenomalous hyperplasia and neoplasia, are reversible. Apparently, tumour development is dependent on the continuous administration of high doses of NTA in the presence of toxic injury to the majority of nephrons.     

Serum ibuprofen levels of extremely preterm infants treated prophylactically with oral ibuprofen to prevent patent ductus arteriosus

Aim

The aim of this study was to explore the effects of early oral ibuprofen administration on the incidence of hemodynamically significant patent ductus arteriosus (hsPDA) and define the association between serum ibuprofen levels and ductal closure.

Method

Preterm infants with a gestational age of <28 weeks and/or birth weight of <1,000 g were randomized either to the intervention (ibuprofen prophylaxis) or control group. The intervention group received oral ibuprofen 10 mg/kg within 12–24 h after birth followed by 5 mg/kg at 24 and 48 h. Serum ibuprofen levels after the treatment were analyzed in the intervention group, and the incidence of hsPDA and complication rates were compared between two groups.

Results

Nineteen infants who received one course (three doses) of prophylactic ibuprofen in the intervention group and 17 infants in the control group who underwent an echocardiographic examination on the fourth day of life were analyzed. hsPDA was observed in five (26 %) infants in the intervention group and ten (58 %) infants in the control group (p?=?0.09). In the intervention group two infants experienced gastrointestinal bleeding two infants had spontaneous intestinal perforation, and two infants developed acute kidney failure. Mean serum ibuprofen level was 28.7?±?16.9 mg/L in the intervention group, and there was no correlation between ibuprofen level obtained on the fourth day and ductal closure.

Conclusion

Oral ibuprofen prophylaxis reduces the rates of hsPDA even it is not statistically significant. The ductal closure rate did not correlate with serum ibuprofen levels. Due to high prevalence of adverse events observed, our data do not support the use of oral ibuprofen for prophylaxis of hsPDA.     

Chronic Pharmacological and Safety Evaluation of Hematide™, a PEGylated Peptidic Erythropoiesis‐Stimulating Agent,in Rodents

Abstract: Hematide? is a synthetic peptide‐based, PEGylated erythropoiesis‐stimulating agent, which is being developed for the chronic treatment of anaemia associated with chronic renal failure. To support the safety of long‐term dosing of chronic renal failure patients, a comprehensive toxicology programme was implemented including rat subchronic and chronic studies. Rats were administered 0, 0.1, 1 and 10 mg/kg of Hematide every 3 weeks for 3 months via subcutaneous injection or for 6 months via intravenous injection. The dosing period was followed by a 6‐week follow‐up period. The primary pharmacology of Hematide resulted in erythroid polycythemia as measured by elevated haemoglobin levels that were time‐ and dose‐dependent. The pharmacology profiles were similar regardless of administration route. For example, for male rats at Day 90, subcutaneous dosing resulted in haemoglobin increases of 2.7, 4.5 and 6.9 g/dl for 0.1, 1 and 10 mg Hematide/kg respectively, compared to 2.8, 5.7 and 7.4 g/dl increases for intravenous dosing. Histopathological changes were related to the prolonged severe polycythemia induced in normocythemic animals administered an erythropoiesis‐stimulating agent. The findings included extramedullary haematopoiesis in the spleen and liver, bone marrow hypercellularity and organ congestion. Microscopic findings were reversible, demonstrating a return towards control findings within 6 weeks following cessation of dosing. Systemic exposures, based on both area under the curve (AUC) and maximum concentration (C_max), were substantially greater for intravenous than subcutaneous administration. No Hematide‐specific antibodies were detected. In conclusion, Hematide is a potent erythropoiesis‐stimulating agent, and the studies provide support for the safety of clinical development, including chronic dosing, for the treatment of anaemia associated with chronic renal failure.     

Inflammatory activity and anticardiolipin antibodies during tibolone treatment of healthy postmenopausal women

The aim of the study was to investigate the inflammatory activity and anticardiolipin antibodies (Acl) during tibolone administration. Twenty seven clinically healthy postmenopausal women were included in the study and were divided into two groups: 16 women (mean age 56.4 +/- 4.6 years) who received tibolone at a dose of 2.5 mg/day for 6 months and an untreated control group (n = 11, mean age 54.8 +/- 4.0 years). Acl of IgG and IgM isotype, and C-reactive protein (CRP) were determined at baseline, 1, 3, and 6 months after treatment. Acl did not change during tibolone treatment, while CRP increased significantly at the 1st, 3rd, and 6th month compared with that at the baseline values. These preliminary data indicate that tibolone administration does not induce increase in Acl. This may counterbalance the adverse influence on CRP.     

Impact of extended ginsenoside Rb1 on early chronic kidney disease: a randomized,placebo-controlled study

Ginsenoside Rb1 (GS-Rb1) is a well-known antioxidant derived from traditionally used herbal medicine ginseng. It has been suggested that reactive oxygen species (ROS) is involved in chronic kidney disease (CKD) in which GS-Rb1 may play a protective role. The aim of this study was to evaluate prospectively the effects of GS-Rb1 in patients with early chronic kidney disease. 197 patients who have been diagnosed with early CKD (stage 2 or 3) were recruited and randomly assigned to receive GS-Rb1 (500 mg daily oral administration, n = 103) or placebo (n = 94) for consecutive 6 months. Analytical procedures performed at baseline, the end of the treatments, and 6 months after the treatments included renal function evaluation (creatinine and urea clearance), oxidative stress measurement, inflammation assessment, and lipid profile. Of 177 patients completing the study, the GS-Rb1 group (n = 91) showed a positive response in significantly alleviating renal function impairments compared to the placebo group (n = 86). In addition, GS-Rb1 treatment was effective in reducing the extent of oxidative stress and inflammation in CKD patients, whereas continued deterioration was observed in the placebo group. Thus, extended treatment of patients using GS-Rb1 may present an antioxidant-based approach to slow the progression of CKD at the early stages.     

Brief Substance Abuse Treatment with Urban Adolescents: A Translational Research Study

The purpose of this translational research study was to test a brief, manualized adolescent substance abuse treatment protocol's effects in an urban community setting compared to a sample in an experimental study from which the treatment was first employed. One hundred two adolescents who were treated with a manualized protocol of five sessions of Motivational Enhancement Therapy/Cognitive Behavioral Therapy (MET/CBT-5) were followed for six months and outcomes were analyzed against a comparison sample (n = 102). Both groups were treated with (MET/CBT-5). The community setting group showed reduced alcohol use relative to the comparison group at six months using unadjusted measures and at three and six months using propensity score analyses to adjust for the differences in baseline characteristics of the two groups. These findings support using brief, manualized treatments for diverse, urban adolescents in outpatient community settings.     

Simple and sensitive liquid chromatography–tandem mass spectrometry methods for quantification of tadalafil in rat plasma: application to pharmacokinetic study in rats

A simple and sensitive liquid chromatography–tandem mass spectrometry method was developed and validated in rat plasma for quantification of tadalafil, a novel therapeutic agent for erectile dysfunction. Tadalafil and acebutolol (internal standard) were extracted by liquid–liquid extraction with tert-butyl methyl ether. The chromatographic separation was performed on a reverse phase C₁₈ column with a mobile phase consisting of 0.1 % formic acid and acetonitrile (45:55, v/v) at a flow rate of 0.3 mL/min. The protonated analyte was quantitated by multiple reaction monitoring with a Waters Quattro micro? API mass spectrometer. The calibration curve was linear over a concentration range of 2–2000 ng/mL, and the lower limit of quantification was 2 ng/mL with a precision (CV %) of 10.9 %. Acceptable intra-day and inter-day precision and accuracy were obtained at 3 concentration levels (3, 200, and 1500 ng/mL). Tadalafil was found to be stable in a battery of studies, including bench top, freeze–thaw, and autosampler conditions. The validated method was successfully used to determine tadalafil concentration in rat plasma samples after oral administration at a dose of 1 mg/kg.