piperidines and Hip-Fractures

The GH secretagogues (GHS) were developed by reverse pharmacology. The objective was to develop small molecules with pharmacokinetics suitable for once-daily oral administration that would rejuvenate the GH/IGF-I axis. Neither the receptor nor the ligand that controlled pulse amplitude of hormone release was known; therefore, identification of lead structures was based on function. I reasoned that GH pulse amplitude could be increased by four possible mechanisms: 1) increasing GHRH release; 2) amplifying GHRH signaling in somatotrophs of the anterior pituitary gland; 3) reducing somatostatin release; and 4) antagonizing somatostatin receptor signaling. Remarkably, the GHS act through all four mechanisms to reproduce a young adult physiological GH profile in elderly subjects that was accompanied by increased bone mineral density and lean mass, modest improvements in strength, and improved recovery from hip fracture. Furthermore, restoration of thymic function was induced in old mice. The GHS receptor (GHS-R) was subsequently identified by expression cloning and found to be a previously unknown G protein-coupled receptor expressed predominantly in brain, pituitary gland, and pancreas. Reverse pharmacology was completed when the cloned GHS-R was exploited to identify an endogenous agonist (ghrelin) and a partial agonist (adenosine); ghsr-knockout mice studies confirmed that GHS are ghrelin mimetics.

Topics: Animals; Base Sequence; Benzazepines; Ghrelin; Hip Fractures; Human Growth Hormone; Humans; Indoles; Molecular Sequence Data; Oligopeptides; Peptide Hormones; Piperidines; Secretory Rate; Spiro Compounds; Tetrazoles

To determine whether donepezil hydrochloride can reduce the prevalence and severity of delirium in older adults undergoing hip fracture repair.. Pilot double-masked randomized placebo-controlled trial.. Large academic medical center.. Sixteen individuals aged 70 and older with hip fracture.. Donepezil 5 mg or placebo was randomly allocated and initiated within 24 hours of surgery, preoperatively or postoperatively. Daily treatment was continued for 30 days or until side effects or the clinical situation required termination.. All outcomes were ascertained masked to treatment status. Information on drug tolerability and safety was obtained from the participant, nurse, and medical record. Delirium presence and severity were measured during daily hospital interviews and at 2, 4, and 6 weeks after surgery after a standardized assessment using the Confusion Assessment Method (CAM) and the Memorial Delirium Assessment Scale (MDAS).. Participants in the donepezil and placebo arms had similar baseline characteristics. Participants in the donepezil arm experienced significantly more side effects. In longitudinal models, there were no significant differences between the donepezil and placebo arms with regard to delirium presence over time (odds ratio = 0.9, 95% confidence interval (CI) = 0.4-2.3) or delirium severity over time (effect size = -0.2 on 30-point MDAS scale, 95%CI = -1.5-1.2).. Participants randomized to donepezil had no significant improvement in delirium presence or severity but experienced more side effects. Overall, sufficient evidence was not found from this pilot study to warrant a definitive Phase III trial.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Delirium; Donepezil; Double-Blind Method; Female; Hip Fractures; Humans; Indans; Male; Pilot Projects; Piperidines; Postoperative Complications; Prospective Studies

Whether pinocembrin (PCN) could be used to alleviate hip fracture-induced pain is investigated in this research. Aged rats with hip fractures were treated with vehicle or 80 mg/kg/day PCN from

Topics: Aging; Animals; Disease Models, Animal; Flavanones; Hip Fractures; Indoles; Male; Neurokinin-1 Receptor Antagonists; Nociceptive Pain; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Signal Transduction; Substance P

Recent studies have reported the presence of acetylcholine (ACh) receptor subtypes in bone tissue, and have demonstrated that inhibition of the ACh receptors has negative effects on bone mass and fracture healing capacity. However, little is known about the potential clinical effects that increased ACh signaling might have on bone. Accordingly, this study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate ACh receptors and are used to treat Alzheimer's disease (AD), is associated with a decreased risk of hip fracture in AD patients. To accomplish this objective, a case-control analysis was performed using the AD population, aged above 75 years, based in the local health area of the Carlos Haya Hospital, in Malaga, Spain. The cases were 80 AD patients that suffered a hip fracture between January 2004 and December 2008. The controls were 2178 AD patients without hip fracture followed at our health care area during the same period of time. Compared with patients who did not use AChEIs, the hip fracture adjusted odds ratio (OR) for users of AChEIs was 0.42 (95% confidence interval [CI], 0.24-0.72), for users of rivastigmine was 0.22 (95% CI, 0.10-0.45), and for users of donepezil was 0.39 (95% CI, 0.19-0.76). Data were adjusted for the following parameters: body mass index, fall risk, smoking habits, cognition, dependence, degree of AD, comorbidity score, treatment with selective serotonin reuptake inhibitors, age, and gender. Our data suggests that use of AChEIs donepezil and rivastigmine is associated with a reduced risk of fractures in AD patients. Many elderly patients with AD disease who are at risk of developing osteoporosis may potentially benefit from therapy with the AChEIs donepezil and rivastigmine.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Body Mass Index; Case-Control Studies; Cholinesterase Inhibitors; Donepezil; Female; Hip Fractures; Humans; Indans; Male; Odds Ratio; Phenylcarbamates; Piperidines; Regression Analysis; Risk; Rivastigmine

Cholinesterase inhibitors (ChEIs) may interact with muscle relaxants given during general anesthesia (GA), increasing the risk of postoperative complications. We evaluated the effects of ChEIs on the postoperative outcomes of older adults who underwent hip fracture surgery.. Population-based cohort study using linked administrative databases.. All individuals with dementia age 66 years or older, who underwent hip fracture surgery between April 1, 2003, and December 31, 2007, in Ontario, Canada.. Use of any ChEI (donepezil, rivastigmine, or galantamine) before surgery.. The primary composite outcome included any of the following: 30-day postoperative mortality; intensive care unit admissions; or in-hospital resuscitation. Secondary outcomes included postoperative respiratory failure and pneumonia.. We stratified the study sample on the basis of residence (community or long-term care [LTC]) and type of anesthetic (general or regional) to create four residence/anesthesia groups. We used propensity scores to match users and nonusers of ChEIs within the residence/anesthesia strata. We then calculated the relative risks (RR) and 95% confidence intervals (CI) for outcomes associated with ChEIs in the matched groups.. A total of 624 pairs of individuals from the community and 725 pairs from LTC were created among individuals who received GA. High rates of postoperative mortality and complications were observed in both ChEI users and nonusers. The RR of the primary outcome associated with ChEI use for individuals receiving GA was 0.88 (95% CI: 0.68-1.16; χ2 = 0.93; df = 1; p = 0.34) and 0.82 (95% CI: 0.63-1.04; χ2 = 2.59; df = 1; p = 0.11) in the community and LTC groups, respectively. In addition, ChEIs were not associated with any significant increased risk of postoperative respiratory complications.. ChEI use was not associated with an increased risk of postoperative complications among older adults with dementia who underwent hip fracture surgery. However, the poor postoperative outcomes overall reinforced the need to prevent fractures and improve outcomes in this population.

Topics: Aged; Aged, 80 and over; Anesthesia, General; Cholinesterase Inhibitors; Cohort Studies; Critical Care; Dementia; Donepezil; Female; Galantamine; Hip Fractures; Humans; Indans; Male; Outcome and Process Assessment, Health Care; Phenylcarbamates; Piperidines; Pneumonia; Postoperative Complications; Respiratory Insufficiency; Resuscitation; Risk; Rivastigmine

Alendronate sodium and raloxifene hydrochloride were recently approved for the prevention of postmenopausal osteoporosis, but data on their clinical efficacy are limited. We compared these drugs with hormone replacement therapy (HRT) to help women and physicians guide postmenopausal treatment decisions.. To help physicians understand how they can best help women choose the most beneficial therapy after menopause based on their individual risk profile.. We developed a decision analytic Markov model to compare the effects of alendronate therapy, raloxifene therapy, and HRT on risks of hip fracture, coronary heart disease (CHD), breast cancer, and life expectancy. Regression models linked individual risk factors to future disease risks and were modified by drug effects on bone density, lipid levels, and associated breast cancer effects.. Hormone replacement therapy, alendronate therapy, and raloxifene therapy have similar predicted efficacies in preventing hip fractures (estimated relative risk, 0.57, 0.54, and 0.58, respectively). Hormone replacement therapy should be more than 10 times more effective than raloxifene therapy in preventing CHD, but raloxifene therapy may not induce breast cancer. Women at low risk for hip fracture, CHD, and breast cancer do not benefit significantly from any treatment. Among women at average risk, HRT was preferred unless raloxifene therapy could reduce the risk of breast cancer by at least 66%, compared with a 47% increase for HRT. Women at high risk for CHD benefit most from HRT; women at high risk for breast cancer but low risk for CHD benefit most from raloxifene therapy, but only if it lowers the risk of breast cancer.. Because of significant differences in the impact of these drugs, treatment choice depends on an individual woman's risk for hip fracture, CHD, and breast cancer.

Topics: Alendronate; Bone Density; Breast Neoplasms; Coronary Disease; Decision Support Techniques; Estrogen Replacement Therapy; Estrogens; Estrogens, Conjugated (USP); Female; Hip Fractures; Humans; Life Expectancy; Lipids; Markov Chains; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Risk; Risk Factors; Sensitivity and Specificity