Mark Corson

Formation of extensive canalicular net- works by rat hepatocytes cultured in collagen-sandwich configuration buy discount rizatriptan 10 mg on-line. Correlation of biliary excretion in sandwich- cultured rat hepatocytes and in vivo in rats buy rizatriptan 10mg low price. Use of Ca modulation to evaluate biliary excretion in sandwich- cultured rat hepatocytes discount rizatriptan 10 mg. P-glycoprotein expression, localization, and function in sandwich-cultured primary rat and human hepatocytes: relevance to the hepatobiliary disposition of a model opioid peptide. Characterization of efflux transport of organic anions in a mouse brain capillary endothelial cell line. Transport studies with renal proximal tubular and small intestinal brush border and basolateral membrane vesicles: vesicle hetero- geneity, coexistence of transport system. Characterizing mechanisms of hepatic bile acid transport utilizing isolated membrane vesicles. Preparation of basolateral (sinusoidal) and canalicular plasma membrane vesicles for the study of hepatic transport processes. Mechanisms of taurocholate transport in canalicular and basolateral rat liver plasma membrane vesicles. The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. Functional involvement of rat organic anion transporter 3 (rOat3; Slc22a8) in the renal uptake of organic anions. The use of sacs of everted small intestine for the study of the transference of substances from the mucosal to serosal surface. Influence of shunt on transmural sodium transport and electrical potential differences. Uptake of the cephalosporin, cephalexin, by a dipeptide transport carrier in the human intestinal cell line, Caco-2. The human intestinal epithelial cell line Caco-2; pharmacological and pharmacokinetic applications. Molecular and functional character- ization of intestinal Na(þ)-dependent neutral amino acid transporter B0. Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2). Expression, localization, and functional character- istics of breast cancer resistance protein in Caco-2 cells. Drug absorption limited by P-glycoprotein- mediated secretory drug transport in human intestinal epithelial Caco-2 cell layer. Comparisons of P-glycoprotein expression in isolated rat brain microvessels and in primary cultures of endothelial cells derived from microvasculature of rat brain, epididymal fat pad and from aorta. Multidrug resistance-related trans- port proteins in isolated human brain microvessels and in cells cultured from these isolates. Mrp1 multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells. Contribution of sodium taurocholate co- transporting polypeptide to the uptake of its possible substrates into rat hepatocytes. Contribution of organic anion transporting polypeptide to uptake of its possible substrates into rat hepatocytes. Contribution of organic anion trans- porters to the renal uptake of anionic compounds and nucleoside derivatives in rat. Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Organic anion transporting polypeptide 2B1 and breast cancer resistance protein interact in the transepithelial transport of steroid sulfates in human placenta. The renal-specific transporter mediates facilitative transport of organic anions at the brush border membrane of mouse renal tubules. The heteromeric organic solute trans- porter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. Immunologic distribution of an organic anion transport protein in rat liver and kidney. Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter. Cloning and functional characterization of a novel rat organic anion transporter mediating basolateral uptake of methotrexate in the kid- ney. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Molecular characterization and tissue distri- bution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2. Tissue distribution and ontogeny of mouse organic anion transporting polypeptides (Oatps). Localization and function of the organic anion-transporting polypeptide Oatp2 in rat liver. Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. Organic anion-transporting poly- peptides mediate transport of opioid peptides across blood-brain barrier.

She needs to clean this tubing with our liver cleanse order rizatriptan 10 mg on-line, which gives immediate pain relief the next day buy cheap rizatriptan 10mg on line. She also had lower back pain for which cleaning the kidney tubules of sediment is the answer cheap rizatriptan 10 mg with mastercard. She had a hysterectomy 10 years ago and a benign lump was also removed from her left breast. Summary: colon or intestinal cancer came as a surprise to Barbara as it did to me. She took the kidney herb pack with her, so she may be in the process of taking that; this should bring her relief from lower back pain. I tested her for gallstones for the persuasion value and motivation to clean her liver. Barbara had a shortened appointment to spare her financially, since she did not expect to have to purchase something like the parasite killing in- gredients. The most serious were: psoriasis in 4 locations, thyroid dis- ease, migraine headaches, irritable bowel syndrome, stomach trouble with lactose intolerance, and a severe upper and lower back pain which keeps her from sleeping at night. I explained to her that in order to get well, she would need to: 1) Cleanse her kidneys for 3 weeks; 2) Kill all her parasites; 3) Eliminate toxic elements from her body; and 4) Cleanse her liver. Does it mean that the miracidia by themselves can start ortho-phospho-tyrosine forming? Or had there been an adult in the liver recently to start it all, but then got killed somehow? Could the Sheep liver fluke also induce a cancer by starting ortho-phospho-tyrosine formation? Summary: This was certainly a happy ending for us since we had waited anxiously to hear what might have happened to her. We were not at all sure she was complying with instructions after the first visit. But her intelligence (and perhaps a little fear) saw her safely through this ordeal. She had the deadly benzene solvent in her, and it was difficult for her to believe it was in her toothpaste. He seemed to have enough determination for us to let him start his second program, the kidney herbs, on his own without visiting the office in between. But he begged for progress with his pain when sitting and lives two states away, too far away for frequent visits. The Tamoxifen was given to her to block estrogen uptake after she had a mastectomy on the right side. She will start her pet on pet parasite program and herself on the human parasite program. She will give herself a 3 day high dose program and then maintenance parasite treatment. She needs all amalgam fillings out of her mouth, all aluminum out of her kitchen, and the water softener taken out. She is dissolving her tooth fillings but instead of passing the metals through the kidney and bowel they are staying stuck in her breast. She probably has numerous kidney stones from all this which, in turn, then slow down excretion. She is full of solvents; no doubt her detoxifying mechanisms are so overtaxed that no solvent can be oxidized any more. She was given interleukin 1 and interleukin 2 plus Interferon shots for her mul- tiple kidney tumors. The other kidney was removed, full of tumors, 2 years ago, and at the same time half of her thyroid was removed for renal cell carcinoma. She was very pleased with how she felt and could not believe these simple herbs succeeded where in- terleukin and interferon had failed Hopefully, she is staying on our meat rule (beef turkey, and chicken must be cooked at home, as well done as if it were pork, never grilled And only fish or seafood in restaurants). Another possibility is that his intestinal flukes were somehow killed while the stages survived in the blood. He will stop abrasive brushing and will use strong salt water and food grade hydrogen peroxide for brushing instead. It could, of course, be in his water supply if there is galvanized piping, but we will try to emphasize the smoking first, for his sake. His lung le- sions will probably continue to enlarge, and he may not get his foot pain relieved without stopping. We may not see him again, though, since heavy emphasis on stopping addictions loses us nearly every cli- ent. He has tried every medication given by clinical doctors, as well as over-the-counter products. Also, any little sore he gets from his work (he works with lumber) does not heal for a long time. One month later He says there is some improvement but some lesions, especially on legs, are two years old! If all the people with this problem were to join hands, could they persuade authorities to protect them? Her clinical doctors found she had 80% blockage of carotid arteries and leg arteries.

Although not as clearly defined as peptidomimetic chemistry buy cheap rizatriptan 10 mg on-line, ultimately buy 10mg rizatriptan, “nucleotidomimetic” or “carbohydromimetic” chemistries may eventually emerge as new design strategies for lead compound identification purchase rizatriptan 10mg fast delivery. An alternative is to exploit molecules that are endogenous to other life forms (animal or plant) but do not naturally occur within humans. Such molecules would be classed as exogenous from the perspective of drug design for humans. Digitalis for congestive heart failure was first isolated from the foxglove plant. Various antibiotics (penicillin) and anticancer agents (taxol) are derived from natural product sources. There is good reason to be optimistic about the potential future usefulness of such exogenous compounds as a continuing source of potential lead compounds. With many thousands of years of trial-and-error by evolution on her side, Mother Nature is a vastly superior experimentalist to any mere human organic chemist. Amphibian evolution has enabled the biosynthesis of antibacterial peptides on the skins of frogs so that they can avoid infections as they swim through stagnant swamp waters; peptides such as these could be a good starting point for the peptidomimetic design of novel antibacterial agents. Reptile evolution has culminated in the biosynthesis of neuroactive venoms for pur- poses of hunting and defense; these molecules have been fine-tuned by evolution as agents specific for neurotransmitter receptors. Plant evolution has culminated in a wide variety of biomolecules that affect any animal that may choose to eat them: it is bio- logically advantageous for some plants to be eaten so that their seeds can be dispersed in the stool of the animal that ate them; conversely, it is biologically advantageous for other plants to produce noxious chemicals to decrease the likelihood of their being eaten. Because of these diverse biological activities, any of these non-human biosyn- thetic molecules could, in principle, be a lead compound for human drug discovery. Another promising feature of animal- or plant-based natural products is that they are a superb source of molecular diversity. As a synthetic chemist, Nature is much more creative and is not constrained to the same finite number of synthetic reactions typically employed by human synthetic organic chemists. Furthermore, when developing compound libraries for high throughput screening (see section 3. Although ethnopharmacology, the scientific investigation of natural products, folk medicine, and traditional remedies, has led to some bona fide drugs (e. However, natural products have always been and still are an inexhaustible source of drug leads as well as drugs. From each of these sources, extracts conducted with solvents with different polar- ities will yield different natural products. This complex extraction system ensures the identifica- tion of all possible candidate molecules from a plant source. Several research institutes and well-established groups (notably the Scripps Institute of Oceanography and the University of Hawaii) are producing some very promis- ing results in this field. The isolation of prostaglandins from a coral was one of the more startling recent discoveries in marine pharmacology. An extension of natural products chemistry is the biochemical information derived from the study of metabolic pathways, enzyme mechanisms, and cell physiological phenomena; this research has revealed exploitable differences between host and para- site (including malignant cells), and between normal and pathological function in terms of these parameters. The large and fertile area of antimetabolite (metabolic inhibitors) and parametabolite (metabolic substitutes) chemistry is based on such stratagems, and has found use in the field of enzyme inhibition and in conjunction with nucleic acid metabolism. The design of drugs based on biochemical leads remains a highly sophis- ticated endeavor, light-years removed from the random screening of sulfonamide dyes in which it has its origin. However, of the approximately 10200 “small” organic molecules that could theoretically exist in our world (1052 of which are drug- like molecules), many would be purely synthetic substances that do not occur naturally. The concept of rational drug design (in contrast to its logical counterpart, irrational drug design) implies that the disease under consideration is understood at some funda- mental molecular level and that this understanding can be exploited for purposes of drug design. Such an understanding would facilitate the design of purely synthetic mol- ecules as putative drugs. Although this ideal of rational drug design has been pursued for many years (see section 3. Recognizing its chemical similarity to iodine, French physicians immediately exploited it as an iodine alternative for the treat- ment of numerous conditions, including syphilis and thyroid goitre. Although no bene- ficial effects were reported for either bromine or its potassium salt, their widespread use persisted and eventually the depressant effect of potassium bromide on the nervous system, so-called ivresse bromurique, was recognized. However, it was a report in the German literature concerning bromide’s ability to induce impotence and hyposexuality, rather than ivresse bromurique, which lead to its discovery as an anticonvulsant. In 1857, Sir Charles Locock, the physician accoucheur to Queen Victoria, ascrib- ing to the then prevalent view that epilepsy arose from excessive sexuality, introduced bromide as an anaphrodisiac to suppress the supposed hypersexuality of epileptics. Although side effects had been considerable (and included psychoses and serious skin rashes), bromides were successful in 13 of the 14 patients treated. On 11 May 1857, at a meeting of the Royal Medical and Chirurgical Society, Locock proudly reported his success in treating “hypersexual” epilepsies with bromides. He argued that logical and rational drug development had finally been achieved for the time: epilepsy arises from excessive sexuality; potassium bromide suppresses sexual- ity; therefore, potassium bromide successfully treats epilepsy. In reality, it was little more than yet another serendipitous discovery, since hypersexuality has absolutely nothing to do with epilepsy. Regardless of the flawed reasoning, bromides were a major step forward in the treatment of epilepsy and their use persisted until the introduction of phenobarbital in 1912. Rational drug design is an iterative process, dependent upon feedback loops and new information. When the drug designer makes the first prototype molecule, this molecule becomes a probe with which to test the drug design hypotheses. The molecule can then be further designed and refined to better improve its ability to dock with the receptor site and elicit a biological response. This cycle of “design–test–redesign–retest” can go on for several iterations until the optimized molecule is achieved.

Lundberg rizatriptan 10 mg with mastercard, “The Effect of Benzodiazepines on the Fetus and the Newborn order rizatriptan 10 mg amex,” Neuropediatrics 23 (1992): 18–23 order rizatriptan 10 mg without a prescription. Lundberg, “Neurodevelopment in Late Infancy after Prenatal Exposure to Benzodiazepines—A Prospective Study,” Neuropediatrics 23 (1992): 60–67. Laegreid, “Clinical Observations in Children after Prenatal Benzodiazepine Exposure,” Developmental Pharmacology and Therapeutics 15 (1990): 186–88. Viggedal, “Mental Development in Late Infancy after Prenatal Exposure to Benzodi- azepines—A Prospective Study,” Journal of Child Psychology and Psychiatry, and Allied Disciplines 34 (1993): 295–305. Silberstein, “Headaches and Women: Treatment of the Pregnant and Lactating Migraineur,” Headache 33 (1993): 536. McElhatton, “The Effects of Benzodiazepine Use during Pregnancy and Lac- tation,” Reproductive Toxicology 8 (1994): 461–75. Czeizel, “Lack of Evidence of Teratogenicity of Benzodiazepine Drugs in Hun- gary,” Reproductive Toxicology 1 (1987–1988): 183–88. McElhatton, “The Effects of Benzodiazepine Use during Pregnancy and Lactation,” Reproductive Toxicology 8 (1994): 461–75; U. Bergman, “Pharmacoepi- demiological Perspectives on the Suspected Teratogenic Effects of Benzodiazepines,” Bratislavske Lekarske Listy 92 (1991): 560–63 (abstract in English). Jick, “Addiction Rare in Patients Treated with Narcotics,” New England Journal of Medicine 302 (1980): 123. Heath, “Anabolic-Steroid Use, Strength Training, and Multiple Drug Use among Adolescents in the United States,” Pediatrics 96 (1995, pt. Massengale, “Glue-Sniffing in Children: Deliberate Inha- lation of Vaporized Plastic Cements,” Journal of the American Medical Association 181 (1962): 300–304. Patterson, “Acute and Chronic Effects of the Voluntary Inhalation of Certain Commercial Volatile Solvents by Juveniles,” Journal of Drug Issues 4 (1974): 167. A lphabetical Listings of rugs All substances listed here have been declared a public concern by government officials, medical caregivers, or news media. If a listing mentions another drug’s name in bold type, that drug has an entry of its own in this section of the book. For example, most anabolic steroids pro- mote development of male characteristics when used by females. If an indi- vidual anabolic steroid is known to have that effect, that information is given in the individual listing. Such a style might make some entries seem repetitive if someone is looking up one anabolic steroid after another, but this approach improves the odds of important information being communicated. A cross- reference style that expects readers to flip back and forth among pages to “see this” or “see that” in order to avoid repetition might work for scientists, but for readers of this book, ease of usage is more important. Although many drugs of abuse are described in this section, many others exist that are not included here. The choice of which to include and which to leave out was based on several factors. Another factor was whether a drug is abused even though it is not a controlled substance. Still another factor was whether enough data exist in the scientific literature to provide solid information. With some drugs described here, scientific infor- mation is scanty concerning particular aspects of a given drug, such as poten- tial for causing cancer; that lack is specifically noted where relevant in drug descriptions. Listings are arranged in the fol- lowing manner: Pronunciation: The proper way to pronounce a substance’s name is given here. Formal Names: Entries in this section are a partial list of brand names and ge- neric names. The lists are not necessarily complete, but they do include typical informal names. Type: The type of drug and its class are given so a reader can refer to pages elsewhere in this book having background information about that substance. Federal Schedule Listing: The status line gives the drug’s legal standing (see page 6 for explanations of “schedules”) and the U. Drug Enforcement Ad- ministration Controlled Substances Code Number if the drug is a controlled substance. Normally Schedule V substances are prescription, but can be nonprescription in some state jurisdictions. A substance may be legally available but may become illegal if used in prohibited ways. Pregnancy Category: Not all drugs have an official pregnancy category desig- nation. For example, such a rating does not exist for substances lacking official approval for therapeutic use. Occasionally information in one of the above listings could not be verified despite diligent search. The detailed descriptions of each drug are arranged to cover: • uses • drawbacks • abuse factors • (some but not all) drug interactions • cancer (risks) • pregnancy (effects) • (in some cases) additional information Reliable sources of additional scientific information are suggested at the end of each individual substance entry. At the back of this book is a list of general information sources, some of which may have additional data about the sub- stance covered in the alphabetical entry. Many drugs have been studied for decades, and some references reflect the venerable history of such studies. Alphabetical Listings of Drugs 33 Drug descriptions occasionally mention the following concepts: One drug may be stronger than another, but such a comparison depends not only on the effect being measured but on the animal species being tested. Frogs, chickens, and rats may react very differently than humans would to an equivalent dose of various drugs.