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Combating breast cancer using combination therapy with 3 phytochemicals: Piperine, sulforaphane, and thymoquinone.
Aumeeruddy, MZ, Mahomoodally, MF
Cancer. 2019;(10):1600-1611
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Abstract
Despite the significant advances in screening methods for early diagnosis, breast cancer remains a global threat and continues to be the leading cancer diagnosed in women, requiring effective therapy. Currently, combination therapy has become the hallmark of breast cancer treatment due to the high incidence of tumor recurrence and disease progression after monotherapeutic treatments, including surgery, radiotherapy, endocrine therapy, and chemotherapy. Over the past decades, there has been considerable interest in studying the anticancer effect of bioactive phytochemicals from medicinal plants combined with these conventional therapies. The rationale for this type of therapy is to use combinations of drugs that work by different mechanisms, thereby decreasing the likelihood that cancer cells will develop resistance, and also reduce the therapeutic dose and toxicity of single treatments. Three agents have received great attention with regard to their anticancer properties: 1) piperine, a dietary phytochemical isolated from black pepper (Piper nigrum L.) and long pepper (Piper longum L.); 2) sulforaphane, an isothiocyanate mainly derived from cruciferous vegetables; and 3) thymoquinone, the active compound from black seed (Nigella sativa L.). This review focused on the combined effect of these 3 compounds on conventional cancer therapy with the objective of observing enhanced efficacy compared with single treatments. This review also highlights the importance of the nanoformulation of such bioactive phytochemicals that could enhance their bioavailability by providing an efficient targeted delivery system with a reduced systemic dose while resulting in a more efficient dosing at the target site.
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Pimavanserin: Potential Treatment For Dementia-Related Psychosis.
Cummings, J, Ballard, C, Tariot, P, Owen, R, Foff, E, Youakim, J, Norton, J, Stankovic, S
The journal of prevention of Alzheimer's disease. 2018;(4):253-258
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Abstract
Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms - Parkinson's disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer's disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS <12. The results of these studies in cognitively impaired patients with PDP provided the scientific foundation for an ongoing study of pimavanserin for treating patients with dementia-related psychosis associated with the most common neurodegenerative disorders. The study uses a relapse-prevention design with the endpoint of time-to-relapse of psychosis to evaluate the long-term efficacy and safety of pimavanserin as a potential treatment for hallucinations and delusions of dementia-related psychosis.
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The effects of black pepper on the intestinal absorption and hepatic metabolism of drugs.
Han, HK
Expert opinion on drug metabolism & toxicology. 2011;(6):721-9
Abstract
INTRODUCTION There is currently a need for a better understanding of the mechanisms of food-drug interaction as well as the clinical implication to maximize the effectiveness and applicability of black pepper or its active component, piperine, as a bioavailability enhancer in the clinical arena. AREAS COVERED This review deals with the effects of black pepper and piperine on drug metabolizing enzymes as well as on intestinal drug absorption. The review provides the reader with a comprehensive update on the potential mechanisms and pharmacokinetic interactions of black pepper and piperine with co-administered medicines. The article also provides a comprehensive update on the current known issues with black pepper and piperine. The information provided is used to assess the clinical significance of black pepper and piperine and optimize their effectiveness as a bioavailability enhancer. EXPERT OPINION For black pepper or piperine to be widely applicable in current medical practice, as a combination therapy, the clinical significance of food-drug interactions caused by concurrent use of black pepper or piperine should be carefully assessed with consideration for many compounding factors affecting the clinical outcome of pharmacokinetic interactions (e.g., dose, dosing regimen, genetic variation and species). Furthermore, the effective formulation strategy for the optimization of the pharmacokinetic characteristics of dietary components is crucial to improve their in vivo performance and ultimately maximize their effectiveness as a bioavailability enhancer.
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Published and not fully published double-blind, randomised, controlled trials with oral naratriptan in the treatment of migraine: a review based on the GSK Trial Register.
Tfelt-Hansen, PC
The journal of headache and pain. 2011;(4):399-403
Abstract
Naratriptan 2.5 mg is now an over-the-counter drug in Germany. This should increase the interest in drug. The GSK Trial Register was searched for published and unpublished double-blind, randomised, controlled trials (RCTs) concerning the use of naratriptan in migraine. Only 7 of 17 RCTs are published in full. Naratriptan 2.5 mg is superior to placebo for acute migraine treatment in 6 RCTs, but inferior to sumatriptan 100 mg and rizatriptan 10 mg in one RCT each. This dose of naratriptan has no more adverse events than placebo. Naratriptan 1 mg b.i.d. has some effect in the short-term prophylactic treatment of menstruation-associated migraine in 3 RCTs. In 2 RCTs, naratriptan 2.5 mg was equivalent to naproxen sodium 375 mg for migraine-related quality of life. Naratriptan 2.5 mg (34% preference) was superior to naproxen sodium 500 mg (25% preference). Naratriptan 2.5 mg is better than placebo in the acute treatment of migraine. The adverse effect profile of naratriptan 2.5 mg is similar to that of placebo. The efficacy of naratriptan 2.5 mg versus NSAIDs is not sufficiently investigated. Naratriptan, when available OTC is a reasonable second or third choice on the step care ladder in the acute treatment of migraine.
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New drugs for Alzheimer's disease in Japan.
Takeda, M, Tanaka, T, Okochi, M
Psychiatry and clinical neurosciences. 2011;(5):399-404
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Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions.
Fong, TM, Heymsfield, SB
International journal of obesity (2005). 2009;(9):947-55
Abstract
Rimonabant and taranabant are two extensively studied cannabinoid-1 receptor (CB1R) inverse agonists. Their effects on in vivo peripheral tissue metabolism are generally well replicated. The central nervous system site of action of taranabant or rimonabant is firmly established based on brain receptor occupancy studies. At the whole-body level, the mechanism of action of CB1R inverse agonists includes a reduction in food intake and an increase in energy expenditure. At the tissue level, fat mass reduction, liver lipid reduction and improved insulin sensitivity have been shown. These effects on tissue metabolism are readily explained by CB1R inverse agonist acting on brain CB1R and indirectly influencing the tissue metabolism through the autonomic nervous system. It has also been hypothesized that rimonabant acts directly on adipocytes, hepatocytes, pancreatic islets or skeletal muscle in addition to acting on brain CB1R, although strong support for the contribution of peripherally located CB1R to in vivo efficacy is still lacking. This review will carefully examine the published literature and provide a perspective on what new tools and studies are required to address the peripheral site of action hypothesis.
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Use of cannabinoid CB1 receptor antagonists for the treatment of metabolic disorders.
Scheen, AJ, Paquot, N
Best practice & research. Clinical endocrinology & metabolism. 2009;(1):103-16
Abstract
Abdominal obesity is associated with numerous metabolic abnormalities, including insulin resistance, impaired glucose tolerance/type-2 diabetes, and atherogenic dyslipidaemia with low high-density lipoprotein (HDL) cholesterol, high triglycerides, and increased small dense low-density lipoprotein (LDL) cholesterol. A proportion of these metabolic disorders may be attributed to increased endocannabinoid activity. The selective cannabinoid 1 (CB1) receptor antagonist rimonabant has been shown to reduce body weight, waist circumference, insulin resistance, triglycerides, dense LDL, C-reactive protein (CRP), and blood pressure, and to increase HDL and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. Besides an improvement in glucose tolerance in non-diabetic subjects, a reduction of 0.5-0.7% in haemoglobin A1C (HbA(1c)) levels was consistently observed in various groups of patients with type-2 diabetes. Almost half the metabolic changes could not be explained by weight loss, supporting direct peripheral effects of rimonabant. Ongoing studies should demonstrate whether improved metabolic disorders with CB1 receptor antagonists (rimonabant, taranabant, etc.) would translate into fewer cardiovascular complications among high-risk individuals.
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Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia.
Seiki, S, Frishman, WH
Cardiology in review. 2009;(2):70-6
Abstract
Hypercholesterolemia is a major risk factor for the development of atherosclerotic vascular diseases. The most popular agents for cholesterol reduction are the statin drugs, which are competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the primary rate-limiting enzyme in the hepatic biosynthesis of cholesterol. Although relatively safe and effective, the available statins can cause elevations in liver enzymes and myopathy. Squalene synthase is another enzyme that is downstream to HMG-CoA reductase in the cholesterol synthesis pathway and modulates the first committed step of hepatic cholesterol biosynthesis at the final branch point of the cholesterol biosynthetic pathway. Squalene epoxidase and oxidosqualene cyclase are other enzymes that act distally to squalene synthase. Pharmacologic inhibitors of these downstream enzymes have been developed, which may reduce low-density lipoprotein cholesterol and reduce the myopathy side effect seen with upstream inhibition of HMG-CoA. At this juncture, one squalene synthase inhibitor, lapaquistat (TAK-475) is in active clinical trials as a monotherapy, but there have been suggestions of increased hepatotoxicity with the drug.