2007 Week 34: Herbal Studies - Drug Interactions

ENTIRE CATALOG OF FERRET PROTEINS TO DATE



Identification of drugs that interact with herbs in drug development
School of Life Sciences, Queensland University of Technology, Brisbane, Australia.

To date, several clinically important drugs have been identified that interact with commonly used herbs. These drugs include (among others) warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). Because drug-herb interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of drugs that interact with commonly used herbal medicines has important implications in drug development. In silico, in vitro, animal and human studies are often used to identify drug interactions with herbs. We propose that drug-herb and herb-CYP interaction studies should be incorporated into drug development.
PMID: 17706549

Herb-drug interactions: a literature review
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.
PMID: 15916450

Interactions between herbal medicines and prescribed drugs: a systematic review
Department of Experimental Pharmacology, University of Naples 'Federico II', Naples, Italy.

Despite the widespread use of herbal medicines, documented herb-drug interactions are sparse. We have reviewed the literature to determine the possible interactions between the seven top-selling herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and prescribed drugs. Literature searches were performed using the following databases: Medline (via Pubmed), Cochrane Library, Embase and phytobase (all from their inception to July 2000). All data relating to herb-drug interactions were included regardless of whether they were based on case reports, case series, clinical trials or other types of investigation in humans. In vitro experiments were excluded. Data were extracted by the first author and validated by the second author. 41 case reports or case series and 17 clinical trials were identified. The results indicate that St John's wort (Hypericum perforatum) lowers blood concentrations of cyclosporin, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline; furthermore it causes intermenstrual bleeding, delirium or mild serotonin syndrome, respectively, when used concomitantly with oral contraceptives (ethinylestradiol/desogestrel), loperamide or selective serotonin-reuptake inhibitors (sertaline, paroxetine, nefazodone). Ginkgo (Ginkgo biloba) interactions include bleeding when combined with warfarin, raised blood pressure when combined with a thiazide diuretic and coma when combined with trazodone. Ginseng (Panax ginseng) lowers blood concentrations of alcohol and warfarin, and induces mania if used concomitantly with phenelzine. Garlic (Allium sativum) changes pharmacokinetic variables of paracetamol, decreases blood concentrations of warfarin and produces hypoglycaemia when taken with chlorpropamide. Kava (Piper methysticum) increases 'off' periods in Parkinson patients taking levodopa and can cause a semicomatose state when given concomitantly with alprazolam. No interactions were found for echinacea (Echinacea angustifolia, E. purpurea, E. pallida) and saw palmetto (Serenoa repens). In conclusion, interactions between herbal medicines and synthetic drugs exist and can have serious clinical consequences. Healthcare professionals should ask their patients about the use of herbal products and consider the possibility of herb-drug interactions.
PMID: 11772128



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2007 Week 34: Herbal Studies - Biotech techniques

ENTIRE CATALOG OF FERRET PROTEINS TO DATE



Applications of biotechnology techniques to the study of medicinal plants
Biotechnology Unit, University of Buea, Box 63, Buea, SW Province, Cameroon.

Medicinal plants are widely used world wide to address a variety of health problems. The major obstacles faced in the study of medicinal plants include inaccurate identification and speciation, low yield of bioactive metabolites prepared by chemical methods, variability of traditional protocols etc. In the present article we review a range of biotechnological methods that can be employed to facilitate medicinal plant studies. DNA-based techniques like PCR, RFLP, AFLP, RAPD and sequencing can be employed to resolve ambiguities in plant identification and speciation. In vitro plant organ and tissue culture methods can be employed to produce bioactive metabolites (alkaloids, flavonoids, terpenoids etc) under defined conditions. Recombinant DNA techniques can be used to manipulate metabolic pathways and produce protein pharmaceuticals such as antibodies, and protein hormones. The new disciplines of Bioinformatics and Genomics can find application in drug discovery from plant-based products. We conclude that biotechnological procedures can enhance and advance the studies of medicinal plants.
PMID: 17703560



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2007 Week 20: Proteins

ENTIRE CATALOG OF FERRET PROTEINS TO DATE



Columbia scientists determine 3-dimensional structure of cell's 'fuel gauge'
Researchers at Columbia University Medical Center have uncovered the complex structure of a protein that serves as a central energy gauge for cells, providing crucial details about the molecule necessary for developing useful new therapies for diabetes and possibly obesity. A paper published online today in the journal Science details this structure, helping to explain one of the cell's most basic and critical processes.

Electrons travel through proteins like urban commuters
For Duke University theoretical chemist David Beratan, the results of his 15 years of studying how electrons make their way through some important protein molecules can be summed up with an analogy: how do big city dwellers get from here to there?
In the Friday, Feb. 2, issue of the journal Science, Beratan and two co-authors use similar logic to describe their unified description of electron movements through certain "electron-transfer" proteins that lie at the heart of many processes essential for life. Such processes include harvesting light in photosynthesis in plant cells and generating energy in animal cells. "I think we have discovered the physical framework for thinking about all such protein electron-transfer chemistry," Beratan said. "Having this rule book in place will let scientists pose some hard but interesting questions about evolutionary pressures on protein structures.

Indel-based targeting of essential proteins in human pathogens that have close host orthologue(s): Discovery of selective inhibitors for Leishmania donovani elongation factor-1
We propose a novel strategy for selective targeting of essential pathogen proteins that contain sizable indels (insertions/deletions) in their sequences compared with their host orthologues. This approach has been tested on elongation factor-1[alpha] (EF-1[alpha]) from the protozoan pathogen Leishmania donovani. Leishmania EF-1[alpha] is 82% identical to the corresponding human orthologue, but possesses a 12 aminoacid sequence deletion compared with human EF-1[alpha]. We used this indel-differentiated region to design small molecules that selectively bind to leishmania EF-1[alpha] and not to the human protein. Three unrelated molecules were identified with the capacity to inhibit protein synthesis in leishmania by up to 75% while exhibiting no effect on human protein translation. These candidates may serve as prototypes for future development of antiprotozoan therapeutics. More generally, these findings provide a basis for a novel drug design platform. This platform targets essential pathogen proteins that are highly conserved across species, and consequently would not typically be considered to be conventional drug targets. We anticipate that such indel-directed targeting of essential proteins in microbial pathogens may help address the growing problem of antibiotic resistance.

Is glycine a surrogate for a D-amino acid in the collagen triple helix?
Collagen is the most abundant protein in animals. Every third residue in a collagen strand is a glycine with , = –70°, 175°. A recent computational study suggested that replacing these glycine residues with d-alanine or d-serine would stabilize the collagen triple helix. This hypothesis is of substantial importance, as the glycine residues in collagen constitute nearly 10% of the amino acid residues in humans. To test this hypothesis, we synthesized a series of collagen mimic peptides that contain one or more d-alanine or d-serine residues replacing the canonical glycine residues. Circular dichroism spectroscopy and thermal denaturation experiments indicated clearly that the substitution of glycine with d-alanine or d-serine greatly disfavors the formation of a triple helix. Host–guest studies also revealed that replacing a single glycine residue with d-alanine is more destabilizing than is its replacement with l-alanine, a substitution that results from a common mutation in patients with collagen-related diseases. These data indicate that the glycine residues in collagen are not a surrogate for a d-amino acid and support the notion that the main-chain torsion angles of a glycine residue in the native structure (especially, > 0°) are critical determinants for its beneficial substitution with a d-amino acid in a protein.

Protein-protein recognition and interaction hot spots in an antigen-antibody complex: Free energy decomposition identifies “efficient amino acids”
The molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method was applied to the study of the protein-protein complex between a camelid single chain variable domain (cAb-Lys3) and hen egg white lysozyme (HEL), and between cAb-Lys3 and turkey egg white lysozyme (TEL). The electrostatic energy was estimated by solving the linear Poisson-Boltzmann equation. A free energy decomposition scheme was developed to determine binding energy hot spots of each complex. The calculations identified amino acids of the antibody that make important contributions to the interaction with lysozyme. They further showed the influence of small structural variations on the energetics of binding and they showed that the antibody amino acids that make up the hot spots are organized in such a way as to mimic the lysozyme substrate. Through further analysis of the results, we define the concept of "efficient amino acids," which can provide an assessment of the binding potential of a particular hot spot interaction. This information, in turn, can be useful in the rational design of small molecules that mimic the antibody. The implications of using free energy decomposition to identify regions of a protein-protein complex that could be targeted by small molecules inhibitors are discussed.


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