By Z. Rufus. University of Massachusetts at Amherst.
Other body signs indicating that Jimson weed should be avoided include enlarged pros- tate order 10 mg norvasc mastercard hypertension treatment guidelines, urination difﬁculty generic norvasc 10mg visa hypertension care plan, ﬂuid buildup in lung tissue cheap norvasc 5 mg on line blood pressure medication making blood pressure too low, and obstruction that impedes movement of food from the stomach. The substance can raise blood pressure and body temperature while drying mucous membranes. Persons hospitalized following jimson weed ingestion have shown a ﬂushed face, ex- aggerated reﬂexes, other reﬂexes consistent with a poison acting upon the brain, and changes involving prothrombin (a factor in blood clotting). More than one report about jimson weed describes users with a saying such as this: “Blind as a bat, hot as a hare, dry as a bone, red as a beet, mad as a hatter, the bowel and bladder lose their tone, and the heart runs alone. People can become ﬁdgety and even manic, talk continuously, go into delirium (which may be combative), and fall into an exhausted sleep. Reportedly such responses to the plant inspired medical use in past times against epilepsy and psychotic behavior. Intoxicated persons can be unaware of what they are doing and unaware of what is going on around them, additional hazards on top of the drug’s sometimes dangerous physical effects. Cases are documented of agricultural workers and garden- ers being affected by apparently rubbing their eyes after contact with jimson weed or other datura plants; a case report also exists of absorption through the skin. Contamination of food is known, and unsuspecting persons have used wine and honey made from the plants. Rats on a 90-day diet including jimson weed seed experienced lower cholesterol levels, less weight gain, and increased weight of livers. Investigators running the experiment described the consequences of chronic jimson weed seed diet as undesirable, but of course humans do not eat the seeds as a regular food. Horses, cattle, and pigs react badly to jimson weed, but rabbits and sheep are relatively unaffected. Europeans were using Datura plants such as jimson weed in the 1500s; one account from that era mentions long-lasting intoxication with emotions ranging from euphoria to weeping, with people having amnesia about what they did while under the inﬂuence. The same account mentions prostitutes using Datura to make clients more pliable, and old reports speak of sexual frenzy induced by the substance. During the 1600s soldiers sent to suppress Bacon’s Rebellion in colonial Virginia partook of jimson weed, and according to an account dating from 1722, some were incapacitated for days: “One would blow up a Feather in the Air; another would dart Straws at it with much Fury; and another stark naked was sitting up in a Corner, like a Monkey, grinning and making Mows [grimaces] at them; and a Fourth would fondly kiss, and paw his Companions, and snear [sic] in their Faces. Marines at Camp Pendleton were treated for 208 Jimson Weed hallucinations from recreational jimson weed usage. A few years earlier a sur- vey of drug users in the South African military found about 3% to be using jimson weed. Some jimson weed users describe sensations of ﬂying, instant travel between one city and another, and communication with plants and inanimate objects. Although insects are a commonly reported visual hallucination from jimson weed, one uncommon sensation is a feeling of crawling insects, reminiscent of the “coke bugs” hallucination associated with cocaine. In keeping with an old but largely abandoned tradition of medicine, an articulate medical journal author engaged in Datura self- experimentation and produced a graphic account of interactions with charms of nineteenth-century Paris and with horrors of twentieth-century monsters. A witness later “told me that I fought the restraining devices so violently that he thought every blood vessel in my face and neck would explode. The Ames test, a standard laboratory procedure that screens sub- stances for carcinogenicity, indicates jimson weed seeds have potential for causing cancer. Birth defects did not become more common in children of 450 pregnant women who received the atropine component of jimson weed. The same lack of effect on congenital abnormalities was observed in a similar number of pregnancies after the women used the scopolamine component of jimson weed, a ﬁnding consistent with a rodent study. Jimson weed is botanically classiﬁed as the stra- monium species of the Datura genus. Other Datura genus plants around the world are used for similar effects, but they are not jimson weed. Johnson, “Mystical Force of the Nightshade,” International Journal of Neuro- psychiatry 3 (1967): 272. The substance was invented in the 1960s and was used as an anesthetic for Vietnam War combat casualties; it has been routinely used for war injuries ever since. Third World physicians report the drug is safe for surgical use outside high-tech environments. Ketamine is also a veterinary anesthesia drug used with wild animals ranging from giraffes and gazelles to polar bears and arctic foxes. Two researchers reported that ketamine therapy with 42 alcoholics produced a two-year abstinence from drinking in 15 of them, an outstanding result. Other researchers report one-year abstinence in almost 66% of 111 al- coholics who received ketamine therapy (perhaps a single dose), as opposed to 24% in 100 who did not receive ketamine. Among the 111 in the original group, 81 were tracked for two years, and 40% of the 81 remained abstinent. Admittedly they are related to self-insights Ketamine 211 prompted by the substance and guided by psychotherapists, but in principle a single dose of a drug is unlikely to stop addiction to some other drug. Experiments indicate ketamine may have potential for treating migraine headache and depression, and researchers have seen evidence that ketamine may improve asthma and shrink breast cancer cells. Ketamine can reduce phantom limb pain, a strange afﬂiction in which a person senses that an am- putated limb is still present and hurting. The drug has been used in psycho- therapy to help persons face and deal with unpleasant memories, a process accompanied by what researchers described as “mind expanding effects. Researchers have described such effects as “profound” among alcoholics, and illicit ketamine users have said such effects are “intense. Users may feel like their bodies are transforming into harder or softer substances. Some users take the drug to enter the “K-hole,” a semiparalytic state described as similar to near-death experiences in which people perceive their conscious- ness as ﬂoating above their bodies, sometimes accompanied by meaningful hallucinations and by insights about the user’s life and its proper place in the cosmos. Examination of deaths among recreational ketamine users in New York City in a two-year period during the 1990s found none in which ketamine was the only substance in the person’s body. Children have accidentally been given 5 to 100 times the normal size dose and have survived with no apparent injury. Nausea and vomiting have been reported, and scientiﬁc literature contains several mentions of temporary breathing interruption caused by the drug. Increased pressure within the eye (a potential problem for glaucoma sufferers) has been measured following a ketamine dose, but not all research- ers looking for that effect have found it. The drug can interfere with a male’s physical ability to engage in sexual activity. Experiments show that ketamine can cause brain damage in rats and that simultaneous use of nitrous oxide worsens the damaging action. Ketamine can cause nervous agitation, extra salivation, blood pressure elevation, abnormal heartbeat, and muscle injury. Persons suffering from the body chemistry disorder porphyria should exercise caution about ketamine use. Tests indicate ke- tamine can alter visual perception for at least 24 hours, causing people to misjudge size and speed of objects (implying that driving skills may be im- paired). Long-term use may cause persistent difﬁculties with attention, mem- ory, and learning ability. The substance can create amnesia about what happens while a person is under the drug’s inﬂuence.
The predictive usefulness of this algorithm is then validated by being applied to the test set compounds buy norvasc 2.5 mg on-line blood pressure chart teenager. If the prediction algorithm is sufficiently robust proven 2.5 mg norvasc prehypertension facts, it can be used to direct the syntheses of optimized compounds cheap norvasc 2.5mg without prescription blood pressure kits stethoscope. This is done with alignment algorithms that rotate and translate the molecule in Cartesian coordinate space so that it aligns with another molecule. The work starts with the most rigid analogs and then progresses to conformationally flexible molecules that are aligned with the more rigid ones. The end result is that all the molecules are even- tually aligned, each on top of another. Once the molecules of the training set have been aligned, a molecular field is com- puted around each molecule, based upon a grid of points in space. Various molecular fields are composed of field descriptors that reflect properties such as steric factors or electrostatic potential. The pre- dictions from these molecular field calculations are then validated by being applied to a test set of compounds. The receptor macromolecule “recognizes” the arrangement of certain func- tional groups in three-dimensional space and their electron density. It is the recognition of these groups rather than the structure of the entire drug molecule that results in an interaction, normally consisting of noncovalent binding. The collection of relevant groups responsible for the effect is the pharmacophore, and their geometric arrange- ment is called the pharmacophoric pattern, whereas the position of their complemen- tary structures on the receptor is the receptor map. Over the years, many attempts have been made to define the pharmacophores and their pattern on many drugs. If the minimum number of descriptors that differentiate activity from inactivity is known, it is possible to deduce the bioactive face of the molecule — that part of the molecule around which all of the relevant descriptors are focused. This bioactive face logically defines the pharmacophoric pattern of the bioactive molecules. If in vivo activities are used, the bioactivities will be influenced by pharmacokinetic and pharmaceutical factors. If a drug molecule cannot withstand the trip from the gut to the receptor microenvironment, it makes no difference whether the drug actually binds to the receptor. Many factors must be taken into consideration when optimizing for the pharmacoki- netic and pharmaceutical phases. If the drug is destined for a brain- based receptor, can the drug cross the blood–brain barrier? This can be a daunting task, since the body inflicts many metabolic chemical reactions upon the drug molecule during the processes of absorp- tion and distribution. Understanding these metabolic reactions is crucial to the contin- uing optimization of the drug molecule. Oxidation at the terminal carbon atom of an alkyl substituent is ω-oxidation; oxidation of the carbon atom located second from the end is ω-1 oxidation. Unless specifically catalyzed by an enzyme, ω-1 oxidation tends to occur more frequently. The anticonvulsant drug ethosuximide is metabolized at both the ω and ω-1 position. Alkenes may react to produce epoxides (alterna- tively, sometimes, the alkenes do not react and are metabolically stable). The anticonvulsant drug carbamazepine is metabolized via epoxidation to yield carbamazepine-10,11- epoxide; in turn, this is rapidly opened to yield carbamazepine-10,11-diol. Carbon atoms that are situated adjacent to imine, carbonyl, or aromatic groups are frequently oxidized. Typically, a hydroxyl group is attached to the carbon as part of the oxidation process. Since many drugs contain aromatic rings, this is a very common metabolic transformation. The process tends to be species specific, with human showing a strong tendency to hydroxylation in the para position. The anticonvulsant drug phenytoin is metabolized by being para-hydroxylated in its aromatic rings. Primary amines may be hydroxylated at the nitrogen atom (N-oxidation) to yield the corresponding hydroxylamine. Alternatively, primary alkyl or arylalkyl amines may undergo hydroxylation at the α-carbon to give a carbinolamine that decomposes to an aldehyde and ammonia (through the process of oxidative deamination). Secondary aliphatic amines may lose an alkyl group first (N-dealkylation) prior to oxidative deamination. In this process, the carbon atom located α to the oxygen atom is hydroxylated, followed by cleavage of the C-O bond. The oxidation of alcohols to aldehydes and of aldehydes to carboxylic acids is routine, and is catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, respectively. A large number of aromatic and aliphatic ketones are reduced to the corresponding alco- hols; these reductions are frequently stereospecific. The metabolic con- version of the nitro group in clonazepam to an amine is a representative example. The plasma, liver, kidney, and intestines contain a wide variety of nonspecific amidases and esterases. These catalyze the metabolism of esters and amides, ultimately leading to the formation of amines, alcohols, and car- boxylic acids. The enzymes that catalyze conjugations are transferases such as glucuronosyltransferase, sulfotransferase, glycine N-acyltransferase, and glutathione S-transferase. The conjugation reactions normally target hydroxyl, carboxyl, amino, or thiol groups. There are four classes of glucuronide metabolites: O-, N-, S-, and C-glucuronides. It is important that the vulnerability of each of these building blocks to metabolic attack be appreciated during the drug design process. This section lists the major molecular building blocks and briefly outlines their susceptibility to metabolism. Alkyl functional groups tend to be metabolically nonreactive and to be excreted unchanged. Therefore, alkanes can be used to build the framework of a mole- cule or as lipophilic functional groups. Rarely, a linear alkyl group will be oxidized in a process that is catalyzed by a mixed-function oxidase enzyme. When this occurs, it does so either at the end of the hydrocarbon chain or adjacent to the final carbon (the “omega-minus-one carbon”). While cyclopropane may be reactive, due to ring strain, cyclopentane and cyclohexane are metabolically inert. The majority of alkene- containing drugs do not exhibit significant rapid metabolism at the double bond. There are some isolated examples of alkene-containing compounds that undergo epoxidation, catalyzed by mixed-function oxidase, or that add water across the double bond to give an alcohol. Halogenated hydrocarbons are not easily metabolized and show significant stability in vivo.
We have hosted Ascaris from our early beginnings as humans order norvasc 2.5 mg without a prescription arteria tapada del corazon, although having household pets is probably a new life- style cheap 2.5mg norvasc with visa hypertension vs preeclampsia. I don’t know the answer discount norvasc 5 mg visa 160 over 100 blood pressure, but obviously eliminating As- caris infestation is a most important task. I believe it can be safely concluded that tapeworm stages and Ascaris together with their associated bacteria, initiate our tumor disease. Later, Clostridium bacteria and various toxins and “carcinogens” make their deadly contribution. There is no tumor, benign or malignant that does not have inorganic (toxic) copper, that is detected with the Syncrometer. On blood tests, it is easily seen that non-food copper depresses the serum iron level. Ultimately copper is lethal because with- out sufficient iron (in a properly reduced state, kept that way by vitamin C) our detoxification systems fail, red blood cell for- mation fails, energy metabolism fails, we fail. Metallic copper comes into our bodies with water that has run through copper pipes, from metal tooth fillings, and from plastic tooth fillings polluted with copper. Copper has a great affinity for sulfur and uses up our chief sulfur compounds: glu- tathione, cysteine, taurine, and methionine. And eventually the sulfur that must stay combined with iron in our most vital or- gans is used up. Fortunately it is easy to eliminate toxic copper from our bodies by removing it from your water pipes and your mouth. Copper accumulation in cancer patients has been noted for a long time, but it was thought to be due to the cancer itself. And in fact, the accumulation, far from being due to the cancer patient’s genetic tendency, can be easily stopped just by changing the water pipes and getting copper-containing tooth fillings removed. And as copper levels continue to go down, the in- vasive fungus growths also decline. Quite a few fungi and their toxic products, called mycotox- ins, have been studied in connection with cancer. The Syn- crometer routinely detects aflatoxin and patulin, which are mycotoxins, at the tumor site. Other foods, especially fermented foods, could be contaminated with it, too, because the mycotoxin is not alive and is not dam- aged by cooking. I routinely detect it at a tumor site, but its pre- ferred organ is the parathyroid. No sooner is it back in the parathyroids but it shows up at the tumor sites, too, doing its best to shrink the tumors there. Our habit of eating rotten fruit (not right off the tree) and letting fungus germinate in the intestine (constipation) keeps us inundated with patulin. Stopping eating bruised fruit and clearing the bowel of fungus with Black Walnut Hull Tincture Extra Strength (two 18 Horubala, A. Cobalt, vanadium, malonic acid, several bacteria varieties, and assorted carcinogens. Inorganic cobalt blocked oxygen utili- zation so that the body was fooled into believing it was at the top of a tall mountain, where the air is very thin (poor in oxy- gen). But blocking oxygen utilization has the same effect as being anemic, so nothing was gained. A steady trickle of cobalt to your tumor could be expected to support tumor growth. Another toxic effect of inorganic cobalt is in the liver where the two main blood proteins are made: albumin and globulin. These two must be carefully regulated since they control the osmotic pressure in the blood vessels. The total may get much too high, such as 10 gm/dl in multiple myeloma, or much too low (below 6) when terminal illness has progressed. The toxicity of cobalt to the heart has been known for dec- ades; it was made illegal in nearly all uses then. But by replacing the metal with plastic, we have frequently not removed the cobalt! It is usually present, either as a component or contaminant of the plastic restoration. When both metal and plastics are meticulously removed, blood albumin and globulin levels correct themselves—often in just three days! Vanadium is asserting its toxicity in other organs, too; in the liver, and in the tumorous organ. Since globulin is less effective than albumin as an osmotic water attractant, water is allowed to leave the circulation and simply seep into the surrounding tis- sue. Vanadium is also the cause of the frequent mutations seen in tumors—in the p53 gene. A healthy p53 gene is necessary for the gene’s tumor suppresser action, which is to 20 produce a substance that prevents tumors from forming. By removing vanadium from your dentalware (both metal and plastic), the vanadyl complexes disappear and p53 gene muta- tions disappear, too. And as the disease became terminal the additional toxic effects of vanadium were easily spotted: much too low albumin and high globulin, and an exceptionally high red blood cell count. The children’s vanadium came from 1) chronic exposure to car exhaust (a source that constantly invaded their home), 2) a household gas leak, or 3) leaking refrigerant (I suspect fossil 19 One might expect that having both toxins would cancel the toxicity. Indeed, the blood proteins are often in normal range for can- cer patients, the problem being masked by this dual toxicity. But in other ways they do not cancel their toxicity, and each takes its toll on your health. Vanadium leaves the body, even from the vital organs, in a week after clean air is supplied and artificial materials are taken out of the mouth. Malonic acid was found to inhibit the use of oxygen by animals (respiration) as early as 1900! By 1930, Otto War- burg had found that anything that inhibited respiration could cause tumor formation. But it was never suspected that tape- worm stages release malonic acid, or that plastic teeth seep it, or that we even eat it in certain common foods. We have seen that some of these common denominators of tumors suppress our oxygen use. And from there, when low immunity allows, they travel to the young tumor and colonize it. This is because bacteria can themselves be infected 21 Geoffrey Zubay, Biochemistry, Addison Wesley Publishing Co. So when the bacteria manage to invade your cell by penetrating the membrane (not an easy job), the virus gets a free ride. Scientists have studied transformation to determine when and how it causes tumor growth but don’t have all the answers.
Mupirocin was not teratogenic in several animal studies generic 5 mg norvasc with visa arteria iliaca externa, but no human studies of this drug have been published purchase norvasc 2.5 mg free shipping arteria supraorbitalis. No studies are published of the use of this drug during human or animal pregnancy purchase norvasc 5mg online heart attack exo lyrics. According to its manu- facturer, silver sulfadiazine was not teratogenic in animal studies (unpublished). Some systemic preparations are also used for vaginitis: amphotericin B, griseofulvin, and ketoconazole. Systemic antifungals are not associated with an increased risk of birth defects, except for griseofulvin (conjoined twinning is hypothesized with griseoful- vin; see Chapter 2). Topical application of these agents on parts of the body is not asso- ciated with an increased frequency of congenital anomalies or other medical complica- tions. Ciclopirox, haloprogin, naftifine, and tolnaftate are antifungals used to treat tinea corpus, cruris, pedis, and versicolor. No human studies of these drugs during pregnancy have been published, but their manufacturers report that these antifungal agents were not teratogenic in several animal studies. Applied topically, it is used to treat tinea captis, corporis, cruris, versicolor, pedis, and barbae. No human reproduction studies for any of these agents have been published and the same is true for animal data. Benzoyl peroxide, resorcinol, and salicylic acid have significant potential for systemic absorption, but no cases of adverse fetal effects are documented related to the topical route of delivery. Manufacturer data on salicylic acid was reported to be ter- atogenic in animals when used in large doses, several times that used in humans. It is very unlikely that these agents have any effect on prenatal development because they are not absorbed systemically. Coal tar and sali- cylic acid are often used in combination with other agents, such as sulfa, and in combi- nation with one another to treat seborrhea and seborrheic dermatitis. According to the manufacturer, however, several of these agents may be teratogenic in laboratory animals. Topical steroids are very unlikely to be associated with significant risk to the human fetus, except triamcinolone (see below). Systemic adrenocorticosteroids are sometimes indicated to treat dermatologic diseases and there is a small collection of these agents (Box 13. The frequency of con- genital anomalies was not increased among 43 infants born to women who took pred- nisone during early pregnancy (Heinonen et al. Perinatal deaths were increased in frequency among infants born to women who took this steroid throughout preg- nancy, but the disease being treated (e. Fetal growth retardation was associated with prednisone use during gestation by one research group (Reinisch et al. Prednisone and prednisolone Prednisone and prednisolone are active adrenoglucocorticoids. Numerous animal studies reported an increase in the fre- quency of cleft palate with prednisolone (as well as other steroids) when given in large doses (e. The association between oral clefts and prednisone exposure was assessed among humans using data from well-regarded case–control studies (Carmichael and Shaw, 1999; Rodriguez-Pinilla and Martinez-Frias, 1998) and it was concluded that the risk of nonsyndromic cleft palate may be associated with prednisone/prednisolone and other glucocorticoid exposure during embryogenesis. Note that most oral clefts can be surgically corrected and this isolated defect is not associated with other physical or mental abnor- malities. Hydrocortisone Hydrocortisone, another glucocorticoid, is the main steroid produced by the adrenal glands. The frequency of congenital anomalies was not increased among infants whose mothers took hydrocortisone during early pregnancy, including the first trimester (Heinonen et al. As with prednisone/prednisolone, an increased frequency of cleft palate was found among the offspring of experimental animals whose mothers were given hydrocortisone during embryogenesis (Chaudhry and Shah, 1973; Harris et al. It is possible that a small risk for cleft palate in humans exists with hydrocortisone use during embryogenesis, but it is likely that the risk is small at less than 1 percent (Shepard et al. Adrenocorticosteroids 247 Dexamethasone and betamethasone These agents (dexamethasone and betamethasone) are glucocorticoids that are closely related to prednisone (see Prednisone and prednisolone above). No human teratology studies of dexamethasone or betamethasone have been published. These drugs are com- monly used in the late second and early third trimesters to promote fetal lung maturity, preventing respiratory distress syndrome (Collaborative Group on Antenatal Steroid Therapy, 1984; Liggins, 1976; Liggins and Howie, 1974). Consistent with other corti- costeroids, dexamethasone and betamethasone are reported to be associated with an increased frequency of cleft palate in the offspring of pregnant animals that received these agents during embryogenesis (Mosier et al. Fetal body and organ weight were decreased in several animal studies with exposure to these glucocorticoids during pregnancy (Barrada et al. As with other glucocorticoids, it is possible that a small risk for cleft palate in humans exists with dexamethasone and betametha- sone use during early pregnancy. Triamcinolone No human epidemiological studies of triamcinolone use during early pregnancy have been published. The published case–control studies are confounded and it is not possi- ble to interpret them for triamcinolone exposures. The cause of concern for triamci- nolone exposure during embryogenesis is an increased frequency of congenital anom- alies found in offspring of three species of nonhuman primates that received this corti- costeroid during embryogenesis (Bacher and Michejda, 1988; Hendrickx and Tarara, 1990; Hendrickx et al. The collection of congenital anomalies included neural tube defects, craniofacial malformations, and skeletal anomalies. Therefore, triamcinolone should be avoided dur- ing pregnancy, especially during the first trimester (Friedman and Polifka, 2006). Triamcinolone will most probably be associated with an increased risk of birth defects in humans when these studies are reported. This warning is issued to attempt a reduc- tion of the number of infants who will be damaged, i. Cortisone The risk of congenital anomalies among women who used cortisone during pregnancy and its possible adverse fetal effects cannot be assessed with the available published data. Among only 34 infants exposed to cortisone during early pregnancy, the frequency of congenital anomalies was not increased (Heinonen et al. Cortisone is in the drug class (glucocorticoids) noted above to be associated with an increased frequency of cleft palate in several animal models, including nonhuman primates (Biddle and Fraser, 1976; Walker, 1971). The nonhuman primate association, even with small sample sizes, is an ominous indicator. Based mostly on primate data, these agents will predictably be shown to be associated with an increased frequency of isolated cleft palate in human 248 Use of dermatologics during pregnancy infants exposed to glucocorticoids during embryogenesis. Glucocorticoids summary In summary, limited human data are published of adrenocorticosteroid use during early human pregnancy and possible association with congenital anomalies or other possible adverse fetal effects. Although these agents were used for many years in pregnant women without apparent adverse effects, no systematic studies are available. Recent analyses based upon reputable case–control studies indicate that a low risk (< 1 percent) for cleft palate may be associated with glucocorticoid exposure during the first trimester.