Boswellia serrata, a potential antiinflammatory agent: an overview

The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and getting the resin solidified. After processing, the gum-resin is then graded according to its flavour, colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation.     

In vitro testing of drug absorption for drug 'developability' assessment: forming an interface between in vitro preclinical data and clinical outcome

Drug 'developability' assessment has become an increasingly important addition to traditional drug efficacy and toxicity evaluations, as pharmaceutical scientists strive to accelerate drug discovery and development processes in a time- and cost-effective manner. The fraction of drug absorbed and the maximum absorbable dose (MAD) can be estimated from in vivo clinical pharmacokinetics, mass balance studies or in vivo drug permeability in humans by different calculation methods. Unfortunately, in vivo data are usually unavailable at the early stages of drug discovery and development, and in vitro screening for the permeability, solubility, activity and toxicity of a drug has become a routine measurement in drug discovery and development. These in vitro data could be used to predict drug 'developability' with different calculation methods before selecting candidates for clinical evaluation. The fraction of drug absorbed in human could be predicted by in vivo human permeability or in vitro Caco2 permeability. For example, if drug permeability in Caco2 cells reaches 13.3 to 18.1 x 10(-6) cm/s, its predicted in vivo permeability in humans would reach 2 x 10(-4) cm/s, and its predicted fraction of drug absorbed would be > 90%, which is defined as highly permeable. The MAD could also be predicted with in vitro permeability, or calculated absorption rate constant. In addition, in vitro solubility and permeability data can also be used for the biopharmaceutics classification system (BCS) and, subsequently, to direct formulation optimization strategies. If drug 'developability' becomes an obstacle for drug delivery based on these in vitro data and predictions at the early stages of drug discovery and development, options such as prodrug approaches could be explored to enhance drug 'developability', in addition to different formulation methods. Therefore, in vitro absorption testing is a highly valuable tool in the decision-making process to select candidates for in vivo clinical studies at early-stage drug discovery and development.     

用临床前和体外代谢数据预测创新药物的人体药动学参数

目的:介绍采用临床前和体外代谢数据预测人体药动学参数的方法和进展.方法:对近年来有关文献进行分析、归纳.结果:应用临床前动物实验测得的药动学参数、药物的理化参数以及体外代谢数据,采用合适的方程、模型可以预测人体的主要药动学参数,包括分布容积、清除率、半衰期和生物利用度.结论:采用动物试验和体外代谢数据对人体药动学参数进行预测,将会大大提高新药筛选的效率,消除盲目性,节约时间和成本.     

Alprazolam: Review of pharmacological,pharmacokinetic, and clinical data

Alprazolam is a recently marketed triazolobenzodiazepine. The animal pharmacological data reviewed here suggest a potent anxiolytic action. But, in addition, an antidepressant activity was revealed in clinical studies and subsequently studied in animal assays. As an extension of these activities, alprazolam also displays efficacy in panic and phobic disorders. Data relating to a wide range of pharmacological activities and pharmacokinetics of alprazolam are also reviewed.     

Recent advances in pharmacokinetic extrapolation from preclinical data to humans

The early characterisation of drug metabolism and pharmacokinetic (DMPK) properties of new chemical entities plays a key role in the pharmaceutical industry's effort to reduce attrition. Specifically, a major goal of early DMPK studies is to accurately predict the behaviour of new chemical entities in humans, thus allowing likely failures to be terminated rapidly and resource to be placed on molecules most likely to succeed. The present review summarises progress over the past several years in the key technologies used in the pharmaceutical industry to achieve these goals: namely, in vivo, in vitro and in silico/computational tools. The limitations of the various assays are discussed, with attention also given to likely future directions in this field.     

In vitro preclinical cardiac assessment of tolterodine and terodiline: multiple factors predict the clinical experience

Terodiline and tolterodine are drugs used to treat urinary incontinence. Terodiline was removed from the market in 1991 for proarrhythmia, whereas tolterodine has a generally benign clinical cardiac profile. To assess differences in the electrophysiologic actions of these drugs, we evaluated their effects on hERG current (HEK cells) and cardiac Purkinje fiber repolarization. The IC50 for hERG block (37 degrees C) by tolterodine was 9.6 nM and by terodiline was 375 nM, values near or below clinical concentrations. Tolterodine elicited concentration-dependent prolongation of the action potential duration (APD90). In contrast, terodiline depressed the action potential plateau and induced triangulation without affecting APD90. The triangulation ratios (normalized ratio of APD50 over APD90) for terodiline were 0.94 and 0.59 for 1.0 and 10 microM and for tolterodine, were 0.99 and 0.97 at 7 and 70 nM. In summary, tolterodine, a potent hERG blocker, has a benign clinical cardiac profile at therapeutic concentrations that may be due to its lack of triangulation, as well as extensive plasma protein binding. However, at supratherapeutic concentrations, preclinical data predict risk of QT prolongation. These data suggest that hERG block and triangulation are among multiple factors that must be considered in preclinical cardiac safety assessments.     

Effects of gum resin of Boswellia serrata in patients with chronic colitis

Patients studied here suffered from chronic colitis characterized by vague lower abdominal pain, bleeding per rectum with diarrhoea and palpable tender descending and sigmoid colon. The inflammatory process in colitis is associated with increased formation of leukotrienes causing chemotaxis, chemokinesis, synthesis of superoxide radicals and release of lysosomal enzymes by phagocytes. The key enzyme for leukotriene biosynthesis is 5-lipoxygenase. Boswellic acids were found to be non-redox, non-competitive specific inhibitors of the enzyme 5-lipoxygenase. We studied the gum resin of Boswellia serrata for the treatment of this disease. Thirty patients, 17 males and 13 females in the age range of 18 to 48 years with chronic colitis were included in this study. Twenty patients were given a preparation of the gum resin of Boswellia serrata (900 mg daily divided in three doses for 6 weeks) and ten patients were given sulfasalazine (3 gm daily divided in three doses for 6 weeks) and served as controls. Out of 20 patients treated with Boswellia gum resin 18 patients showed an improvement in one or more of the parameters: including stool properties, histopathology as well as scanning electron microscopy, besides haemoglobin, serum iron, calcium, phosphorus, proteins, total leukocytes and eosinophils. In the control group 6 out of 10 patients showed similar results with the same parameters. Out of 20 patients treated with Boswellia gum resin 14 went into remission while in case of sulfasalazine remission rate was 4 out of 10. In conclusion, this study shows that a gum resin preparation from Boswellia serrata could be effective in the treatment of chronic colitis with minimal side effects.     

Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolism

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in clinical development for the treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. Herein, we describe a series of studies to assess T-DM1 absorption, distribution, metabolism, and excretion (ADME) in rats as well as to assess human exposure to T-DM1 catabolites. Following administration of unlabeled and radiolabeled T-DM1 in female Sprague Dawley rats as a single dose, plasma, urine, bile and feces were assessed for mass balance, profiling and identification of catabolites. In rats, the major circulating species in plasma was T-DM1, while DM1 concentrations were low (1.08 to 15.6 ng/mL). The major catabolites found circulating in rat plasma were DM1, [N-maleimidomethyl] cyclohexane-1- carboxylate-DM1 (MCC-DM1), and Lysine-MCC-DM1. These catabolites identified in rats were also detected in plasma samples from patients with HER2-positive metastatic breast cancer who received single-agent T-DM1 (3.6 mg/kg every 3 weeks) in a phase 2 clinical study. There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing. In rats, T-DM1 was distributed nonspecifically to the organs without accumulation. The major pathway of DM1-containing catabolite elimination in rats was the fecal/biliary route, with up to 80% of radioactivity recovered in the feces and 50% in the bile. The rat T-DM1 ADME profile is likely similar to the human profile, although there may be differences since trastuzumab does not bind the rat HER2- like receptor. Further research is necessary to more fully understand the T-DM1 ADME profile in humans.     

Effect of Boswellia serrata on intestinal motility in rodents: inhibition of diarrhoea without constipation

Clinical studies suggest that the Ayurvedic plant Boswellia serrata may be effective in reducing diarrhoea in patients with inflammatory bowel disease. In the present study, we evaluated the effect of a Boswellia serrata gum resin extract (BSE) on intestinal motility and diarrhoea in rodents. BSE depressed electrically-, acetylcholine-, and barium chloride-induced contractions in the isolated guinea-pig ileum, being more potent in inhibiting the contractions induced by acetylcholine and barium chloride. The inhibitory effect of BSE on acetylcholine-induced contractions was reduced by the L-type Ca(2+) channel blockers verapamil and nifedipine, but not by the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid, by the phosphodiesterase type IV inhibitor rolipram or by the lipoxygenase inhibitor zileuton. 3-acetyl-11-keto-beta-boswellic acid, one of the main active ingredients of B. serrata, inhibited acetylcholine-induced contractions. BSE inhibited upper gastrointestinal transit in croton oil-treated mice as well as castor oil-induced diarrhoea. However, BSE did not affect intestinal motility in control mice, both in the small and in the large intestine. It is concluded that BSE directly inhibits intestinal motility with a mechanism involving L-type Ca(2+) channels. BSE prevents diarrhoea and normalizes intestinal motility in pathophysiological states without slowing the rate of transit in control animals. These results could explain, at least in part, the clinical efficacy of this Ayurvedic remedy in reducing diarrhoea in patients with inflammatory bowel disease.     

Review. Facts and fiction of phytotherapy for prostate cancer: a critical assessment of preclinical and clinical data

The objective of this work was to substantially review all preclinical and clinical data on phytochemicals, such as genistein, lycopene, curcumin, epigallocatechin-gallate, and resveratrol, in terms of their effects as a potential treatment of prostate cancer. It is known, that prostate cancer patients increasingly use complementary and alternative medicines in the hope of preventing or curing cancer. The preclinical data for the phytochemicals presented in this review show a remarkable efficacy against prostate cancer cells in vitro, with molecular targets ranging from cell cycle regulation to induction of apoptosis. In addition, well-conducted animal experiments support the belief that these substances might have a clinical activity on human cancer. However, it is impossible to make definite statements or conclusions on the clinical efficacy in cancer patients because of the great variability and differences of the study designs, small patient numbers, short treatment duration and lack of a standardised drug formulation. Although some results from these clinical studies seem encouraging, reliable or long-term data on tumor recurrence, disease progression and survival are unknown. At present, there is no convincing clinical proof or evidence that the cited phythochemicals might be used in an attempt to cure cancer of the prostate.     

The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression

Major depressive disorder (MDD) poses a significant health problem and is estimated to be the third most costly and disabling disorder in the United States. Pharmacotherapy of depression has been successful, but improvements in response rates, remission rates, side effects, compliance and faster onset of therapeutic action have become prime objectives in drug development. There is considerable support for the hypothesis that dysfunctional serotonergic or noradrenergic neurotransmission may be etiological in depressed patients. Duloxetine is a balanced and potent reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) being studied as an antidepressant medication. In this review, we highlight the preclinical pharmacology, pharmacokinetic profile, and effects of duloxetine in the pharmacotherapy of depression. Evidence for 5-HT and NE reuptake inhibition by duloxetine comes from in vitro and in vivo transporter binding and functional uptake studies. Taken together with efficacy data from in vivo microdialysis, electrophysiological and behavioral studies, it is evident that duloxetine is balanced as a dual serotonin norepinephrine uptake inhibitor in vivo. The clinical efficacy and safety of duloxetine in the treatment of MDD has been studied in 6 multicenter, randomized, double-blind, placebo-controlled trials. In these studies, duloxetine was found to be effective in the treatment of emotional/psychological and painful physical symptoms associated with depression. More importantly, duloxetine appears to have better response rates and remission from depressive symptoms, perhaps due to its ability to treat a wider range of symptoms.     

Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis

Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure.     

Complete structural assignment of serratol, a cembrane-type diterpene from Boswellia serrata, and evaluation of its antiprotozoal activity

From the dichloromethane extract obtained from the gum resin of Boswellia serrata Roxb. (Burseraceae), a well-known medicinal plant resin ("Indian Olibanum"), the cembrane-type diterpene serratol was isolated in high yield. Its structure, previously reported without clear specification of double-bond geometry and without specification of stereochemistry, was reanalysed by means of spectroscopic measurements and unambiguously assigned as S(-)-cembra-3E,7E,11E?triene-1-ol. Full assignment of all NMR data is reported for the first time. The compound was found to be identical with a cembrenol previously isolated from B. carteri. Serratolwas tested for in vitro activity against four protozoan human pathogens, namely, Trypanosoma brucei rhodesiense (East African Human Trypanosomiasis, sleeping sickness), T. cruzi (Chagas' disease), Leishmania donovani (Kala-Azar), and Plasmodium falciparum (Tropical Malaria). It was found active against T. brucei and P. falciparum. These activities were 10- to 15-fold higher than its cytotoxicity against rat skeletalmyoblasts. While some reports exist on potential anti-inflammatory activity of Boswellia diterpenes, this is the first report on antiprotozoal activity of such a compound.     

Investigational drugs for fracture healing: preclinical & clinical data

Introduction: The need for fracture healing enhancement for the management of fracture complications such as non-union and for the achievement of early function in fracture patients is constantly increasing. Therefore, the development and evaluation of novel pharmaceutical agents is mandatory in order to accelerate the process and increase bone union rates.

Areas covered: This review summarizes the most recent knowledge on the pharmacological enhancement of fracture repair. It provides a synopsis of the most important preclinical and clinical studies published over the past five years on long bone fracture healing.

Expert opinion: To date, limited drugs seem to have the potential for clinical use in fracture healing enhancement and the field is progressing very slowly. Among anti-osteoporotic drugs, only PTH and anti-sclerostin antibodies have such a potential but further research is needed before clinical use. The same applies also to BMPs, the use of which still carries major drawbacks that should be overcome before their widespread clinical utilization. Other drugs and growth factors, such as statins, VEGF, FGF, EPO, could be future key players in fracture healing but evidence is still lacking. Further in depth understanding of the healing process is essential in order to identify novel effective pharmacological agents.     

A method for estimating pharmacokinetic risks of concentration-dependent drug interactions from preclinical data.

This article evaluates a novel approach for estimating the pharmacokinetic risks associated with drug interactions in populations. Preclinical pharmacokinetic and metabolism data are analyzed with a stochastic differential equation-based pharmacokinetic model that recognizes that the risks associated with known drug interactions involve deterministic and stochastic components. Specifically, a Bernoulli jump-diffusion pharmacokinetic model that accounts for the pharmacokinetics, the variability inherent in the pharmacokinetics, and the idiosyncratic nature of the possibility of drug interactions is proposed. In addition, the variability inherent in the extent of drug interaction is explicitly accounted for. The approach provides useful mechanistic insights into the stochastic processes that "drive" drug interactions in populations because it yields analytical results. The validity of the model predictions was tested with experimental data from two previously investigated systems: N-1 and N-3 caffeine demethylation in populations with smokers and in the terfenadine-ketoconazole system.     

Bactericidal activity of cefadroxil, cephalexin, and cephradine in an in vitro pharmacokinetic model

Cefadroxil (Duricef, Mead Johnson and Company), resembles cephalexin and cephradine in spectrum of antibacterial activity but differs in human pharmacokinetic properties. Whether the latter are likely to affect activity in vivo was assessed by determining bactericidal activity against clinical isolates under conditions simulating the variation of drug concentration in the blood stream after an oral dose of 500 mg to adults. In this kinetic model, cefadroxil was more active than cephalexin or cephradine against Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae and one of two strains of Escherichia coli. The other strain of E. coli was virtually unaffected by the cephalosporins. S. pyogenes was equally susceptible to all three cephalosporins. Analysis of the results suggest that the pharmocokinetic properties of an antibiotic affect its activity in the blood stream, provided the susceptibility of the infecting organism is concentration-dependent within the range of drug concentration occurring in serum.     

Lack of pharmacokinetic interaction between omeprazole or lansoprazole and ivabradine in healthy volunteers: an open-label, randomized, crossover, pharmacokinetic interaction clinical trial

The effects of omeprazole and lansoprazole (CYP3A4 inhibitors) on the pharmacokinetics of a single dose of ivabradine (metabolized via CYP3A4) and its active metabolite (S18982) were assessed. Pharmacodynamics and safety were secondary objectives. An open-label, randomized, crossover, phase I, pharmacokinetic interaction design was used. Volunteers received a single oral dose of ivabradine (10 mg), were randomized to receive either omeprazole (40 mg) or lansoprazole (60 mg) for 5 days, and were administered an ivabradine dose on the sixth day. Crossover was performed after washout. Pharmacokinetic parameters for ivabradine did not vary significantly after omeprazole (C(max): 45.0 +/- 36.6 vs 42.7 +/- 27.6 ng/mL, P = .98; AUC: 128 +/- 87 vs 126 +/- 63 ng/mL, P = .82) or lansoprazole administration (C(max): 45.0 +/- 36.6 vs 41.3 +/- 29.4 ng/mL, P = .70; AUC: 128 +/- 87 vs 123 +/- 50, P = .73). Analyses of S18982 pharmacokinetic parameters showed similar results. Coadministration of either omeprazole or lansoprazole did not significantly affect the pharmacokinetics of a single dose of ivabradine. No pharmacodynamic interaction or safety concerns were evidenced.