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In contrast to atropine, scopolamine produces sedation, but at higher doses it can produce excitement instead. Therapeutic uses: Although similar to atropine, therapeutic use of scopolamine is limited to prevention of motion sickness (for which it is particularly effective) and to blocking short-term memory. The amnesic action of scopolamine makes it an important adjunct drug in anesthetic procedures. Pharmacokinetics and adverse effects: these aspects are similar to those of atropine. Ipratropium is also beneficial in the management of chronic obstructive pulmonary disease. Important characteristics of the muscarinic antagonists are summarized in Figures 5. Tropicamide and cyclopentolate these agents are used as ophthalmic solutions for similar conditions as atropine (mydriasis and cyclopegia). Their duration of action is shorter than that of atropine; tropicamide produces mydriasis for 6 hours and cyclopentolate for 24 hours. Ganglionic Blockers Ganglionic blockers specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists. Thus, these drugs block the entire output of the autonomic nervous system at the nicotinic receptor. Except for nicotine, the other drugs mentioned in this category are nondepolarizing, competitive antagonists. The responses observed are complex and unpredictable, making it impossible to achieve selective actions. The drug is absorbed and is effective in reducing the craving for nicotine in people who wish to stop smoking. The stimulatory effects are complex due to effects on both sympathetic and parasympathetic ganglia. The effects include increased blood pressure and cardiac rate (due to release of transmitter from adrenergic terminals and from the adrenal medulla) and increased peristalsis and secretions. The uptake of the drug via oral absorption is good, in contrast to that of trimethaphan. As with trimethaphan, it is primarily used to lower blood pressure in emergency situations. Neuromuscular Blocking Drugs these drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end plate of skeletal muscle (see Figure 5. These neuromuscular blockers are structural analogs of acetylcholine, and they act either as antagonists (nondepolarizing type) or agonists (depolarizing type) at the receptors on the end plate of the neuromuscular junction. Neuromuscular blockers are clinically useful during surgery for producing complete muscle relaxation, without having to employ higher anesthetic doses to achieve comparable muscular relaxation. Nondepolarizing (competitive) blockers the first drug that was found to be capable of blocking the skeletal neuromuscular junction was curare, which the native hunters of the Amazon in South America used to paralyze game. Although tubocurarine is considered to be the prototype agent in this class, it has been largely replaced by other agents due to side effects (see Figure 5. The neuromuscular blocking agents have significantly increased the safety of anesthesia, because less anesthetic is required to produce muscle relaxation, allowing patients to recover quickly and completely after surgery. Note: Higher doses of anesthesia may produce respiratory paralysis and cardiac depression, increasing recovery time after surgery. At low doses: Nondepolarizing neuromuscular blocking drugs interact with the nicotinic receptors to prevent the binding of acetylcholine (Figure 5. These drugs thus prevent depolarization of the muscle cell membrane and inhibit muscular contraction. Because these agents compete with acetylcholine at the receptor without stimulating the receptor, they are called competitive blockers.
Polysaccharide Krestin (Coriolus Mushroom). Geriforte.
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Genetic alterations leading to drug resistance Acquired antibiotic resistance requires the temporary or permanent gain or alteration of bacterial genetic information. If the cell survives, it can replicate and transmit its mutated properties to progeny cells. However, mutations that produce antibiotic-resistant strains can result in organisms that may proliferate under certain selective pressures. An example is the emergence of rifampin-resistant Mycobacterium tuberculosis when rifampin is used as a single antibiotic. Resistance properties are usually encoded in extrachromosomal R factors (resistance plasmids). Plasmids may enter cells by processes such as transduction (phage mediated), transformation, or bacterial conjugation. Altered expression of proteins in drug-resistant organisms Drug resistance may be mediated by a variety of mechanisms, such as a lack of or an alteration in an antibiotic target site, lowered penetrability of the drug due to decreased permeability, increased efflux of the drug, or presence of antibiotic-inactivating enzymes (see Figure 30. Decreased accumulation: Decreased uptake or increased efflux of an antibiotic can confer resistance, because the drug is unable to attain access to the site of its action in sufficient concentrations to injure or kill the organism. For example, gram-negative organisms can limit the penetration of certain agents, including ОІ-lactam antibiotics, tetracyclines, and chloramphenicol, as a result of an alteration in the number and structure of porins (channels) in the outer membrane. Enzymic inactivation: the ability to destroy or inactivate the antimicrobial agent can also confer resistance on microorganisms. Examples of antibiotic-inactivating enzymes include 1) ОІ-lactamases (вoepenicillinasesв) that hydrolytically inactivate the ОІ-lactam ring of penicillins, cephalosporins, and related drugs; 2) acetyltransferases that transfer an acetyl group to the antibiotic, inactivating chloramphenicol or aminoglycosides; and 3) esterases that hydrolyze the lactone ring of macrolides. Prophylactic Antibiotics Certain clinical situations require the use of antibiotics for the prevention rather than the treatment of infections (Figure 30. Because the indiscriminate use of antimicrobial agents can result in bacterial resistance and superinfection, prophylactic use is restricted to clinical situations in which the benefits outweigh the potential risks. Complications of Antibiotic Therapy Because the mechanism of action of a particular antibiotic is selectively toxic to an invading organism does not insure the host against adverse effects. Hypersensitivity Hypersensitivity reactions to antimicrobial drugs or their metabolic products frequently occur. For example, the penicillins, despite their almost absolute selective microbial toxicity, can cause serious hypersensitivity problems, ranging from urticaria (hives) to anaphylactic shock. Direct toxicity High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host. For example, aminoglycosides can cause ototoxicity by interfering with membrane function in the hair cells of the organ of Corti. Superinfections Drug therapy, particularly with broad-spectrum antimicrobials or combinations of agents, can lead to alterations of the normal microbial flora of the upper respiratory, intestinal, and genitourinary tracts, permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. Sites of Antimicrobial Actions Antimicrobial drugs can be classified in a number of ways. These include 1) by their chemical structure (for example, ОІ-lactams or aminoglycosides), 2) by their mechanism of action (for example, cell wall synthesis inhibitors), or 3) by their activity against particular types of organisms (for example, bacteria, fungi, or viruses). Chapters 31 through 33 are organized by the mechanisms of action of the drug, and Chapters 34 through 38 are organized according to the type of organisms affected by the drug (Figure 30. Prevention of meningitis among individuals in close contact with infected patients. Overview Some antimicrobial drugs selectively interfere with synthesis of the bacterial cell wallв"a structure that mammalian cells do not possess. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms; they have little or no effect on bacteria that are not growing and dividing. The most important members of this group of drugs are the ОІ-lactam antibiotics (named after the ОІ-lactam ring that is essential to their activity) and vancomycin. Penicillins the penicillins are among the most widely effective antibiotics and also the least toxic drugs known, but increased resistance has limited their use. Members of this family differ from one another in the R substituent attached to the 6-aminopenicillanic acid residue (Figure 31.
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If this approach is unsuccessful, intradermal allergy testing to determine the degree of allergy and neutralizing dose of each allergen is recommended. Injections should be continued for at least one year to discourage reappearance of allergic reactions. Often, desensitization therapy is required for the more permeating allergens in modern society due to the difficulty of their elimination (pollen is a good example). A number of different methods exist for determining the presence of allergies to specific substances. Eliminations the oldest and simplest is the elimination of the allergen for a four-day period and then the challenge of the patient with the suspected allergen whether it be food, inhalant, or pollutant. If the patient is overweight, a fourday fast can be substituted for the elimination of a specific food. This procedure can be easily accomplished by the patient at home; however, it is qualitative and not quantitative, thus, neutralizing doses cannot be determined. However, the result is only useful if a patient has a few inhalant allergies which then can be avoided. With luck, eight or more antigens may be tested in one day from one sample of blood. Under these circumstances no more than three patients can be tested by one capable technician in one day. All of the studies are done with unstained white cells so the technician needs careful training. When a sensitive white cell comes in contact with a specific antigen, the cell may burst instantly and release all its granules. Lesser degrees of reaction are graded less and one-plus is the simple loss of movement of the white cells. Unfortunately, this test leads to an inordinate number of false positives due to the subjectivity of the tester. The absence of quantitative measures precludes the determination of neutralizing doses. Provocative Testing Some clinicians use diluted antigens given under the tongue of the patient to provoke allergic symptoms. When this neutralizing dose for each allergen or food is given twice weekly, the patient may be relieved of the annoying symptoms and can eat more foods. Once allergy testing has been completed, the neutralization dose should be checked after six months, and the injections must be continued for at least a year. The individual needs to continue using the nutritional supplements listed previously, as well as utilizing food rotation and environmental control in order to limit future allergic responses. Again, if this is unsuccessful, testing for a neutralizing dose and injection therapy may be recommended. Immunoglobulin A and E A low serum immunoglobulin A (IgA) indicates pyroluria (see separate chapter) which is frequently accompanied by food allergies, while a high serum immunoglobulin E (IgE) indicates probable inhalant allergies. Most patients with food allergies also tend to have pyroluria, a stress phenomenon associated with excess pyrroles in the urine which bind vitamin B-6 (pyridoxine) and zinc. Some allergies such as wheat are accompanied by damage to the intestinal mucosa (celiac disease), thus resulting in the malabsorption of zinc and/or pyridoxine, as well as other nutrients. Histamine is the chemical modulator of the anaphylactic reaction and is stored in the basophils of the blood. In the allergic patient who is continually being challenged with allergens, the frequent release of histamine prevents any storage of histamine in basophils. Allergic patients may react adversely when exposed to food dyes, aspirin, foods with salicylates, food additives, food preservatives, and the insecticides used to reduce spoilage of food. Organic food eating is, therefore, recommended and carefully chosen vendors become most important. In air travel, one can smell the surge of deodorant wafting through the cabin at regular intervals to the dismay and discomfort of those allergic to petrochemicals! One family was literally driven from the state of Connecticut when the government officials decided to spray the landscape for gypsy moths. Ultimately, the family broke up and we came to know the mother and her very allergic daughter named Chris. When Santa Fe got too polluted, they moved to a more rural area in New Mexico, but this was no better because it was too dry and too dusty!
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Carbohydrates with an aldehyde as their carbonyl group are called aldoses, whereas those with a keto as their carbonyl group are called ketoses (Figure 7. Disaccharides contain two monosaccharide units, oligosaccharides contain three to ten monosaccharide units, and polysaccharides contain more than ten monosaccharide units and can be hundreds of sugar units in length. Isomers and epimers Compounds that have the same chemical formula but have different structures are called isomers. For example, fructose, glucose, mannose, and galactose are all isomers of each other, having the same chemical formula, C 6H12O6. Carbohydrate isomers that differ in configuration around only one specific carbon atom (with the exception of the carbonyl carbon; see "anomers" below) are defined as epimers of each other. Enantiomers A special type of isomerism is found in the pairs of structures that are mirror images of each other. These mirror images are called enantiomers, and the two members of the pair are designated as a D- and an L-sugar (Figure 7. Most enzymes are specific for either the D or the L form, but enzymes known as racemases are able to interconvert D- and L-isomers. Cyclization of monosaccharides Less than 1% of each of the monosaccharides with five or more carbons exists in the open-chain (acyclic) form in solution. Rather, they are predominantly found in a ring (cyclic) form, in which the aldehyde (or keto) group has reacted with an alcohol group on the same sugar, making the carbonyl carbon (carbon 1 for an aldose, carbon 2 for a ketose) asymmetric. Anomers: Creation of an anomeric carbon (the former carbonyl carbon), generates a new pair of isomers, the and configurations of the sugar (for example, -Dglucopyranose and -D-glucopyranose; see Figure 7. For example, glycogen is synthesized from -D-glucopyranose, whereas cellulose is synthesized from -D-glucopyranose. The cyclic and anomers of a sugar in solution spontaneously (but slowly) form an equilibrium mixture, a process known as mutarotation (see Figure 7. Reducing sugars: If the hydroxyl group on the anomeric carbon of a cyclized sugar is not linked to another compound by a glycosidic bond, the ring can open. Such sugars can react with chromogenic agents (for example, the Benedict reagent) causing the reagent to be reduced and colored, with the aldehyde group of the acyclic sugar becoming oxidized. A positive result is indicative of an underlying pathology, because sugars are not normally present in urine, and can be followed up by more specific tests to identify the reducing sugar. Joining of monosaccharides Monosaccharides can be joined to form disaccharides, oligosaccharides, and polysaccharides. Important disaccharides include lactose (galactose + glucose), sucrose (glucose + fructose), and maltose (glucose + glucose). Important polysaccharides include branched glycogen (from animal sources) and starch (plant sources) and unbranched cellulose (plant sources). These are formed by enzymes known as glycosyltransferases that use nucleotide sugars such as uridine diphosphate glucose as substrates. Naming glycosidic bonds: Glycosidic bonds between sugars are named according to the numbers of the connected carbons and with regard to the position of the anomeric hydroxyl group of the sugar involved in the bond. Lactose, for example, is synthesized by forming a glycosidic bond between carbon 1 of -galactose and carbon 4 of glucose. Complex carbohydrates Carbohydrates can be attached by glycosidic bonds to noncarbohydrate structures, including purine and pyrimidine bases (found in nucleic acids), aromatic rings (such as those found in steroids and bilirubin), proteins (found in glycoproteins and proteoglycans), and lipids (found in glycolipids), to form glycosides. This digestion is rapid and is catalyzed by enzymes known as glycoside hydrolases (glycosidases) that hydrolyze glycosidic bonds (Figure 7. Because there is little monosaccharide present in diets of mixed animal and plant origin, the enzymes are primarily endoglycosidases that hydrolyze polysaccharides and oliosaccharides, and disaccharidases that hydrolyse tri- and disaccharides into their reducing sugar components. Glycosidases are usually specific for the structure and configuration of the glycosyl residue to be removed as well as for the type of bond to be broken. The final products of carbohydrate digestion are the monosaccharides, glucose, galactose, and fructose that are absorbed by cells of the small intestine. Salivary a-amylase the major dietary polysaccharides are of plant (starch, composed of amylose and amylopectin) and animal (glycogen) origin.
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Readers are thus encouraged to replicate and fill out this form themselves and those readers of this volume who are school counselors, psychologists, clinicians or public servants of any sort with the ability to test this questionnaire on populations of the indicated age level are encouraged to do so if possible. Please return the form to Keith Jordan, c/o Princeton Brain-Bio Center, with any information that may be useful in evaluating the results. Our hope is that one day this test will be used to screen populations of young people in school systems, clinics, prisons and other agencies so that those suffering from dangerous mental disorders can be isolated, investigated and administered adequate treatment as indicated by the nature of their difficulties. Scale 1 Depression this scale checks for symptoms of clinical depression, including disturbance of mood, depressive cognition and biological symptoms. Scale 2 Impulsivity this scale measures your degree of self-control and how well you make judgements before following your impulses and entering or initiating a situation. Scale 3 Paranoia this scale measures abnormal reactions to others such as undue suspicion and ideas of reference. Scale 4 Disperceptions this scale measures your senses such as vision and hearing; normally these are in good balance and free from aberrations such as hallucinations. This scale also measures delusions or bizarre interpretations of life experiences. Scale 6 Histadelia this scale measures traits of the histadelic or high histamine biotype. Scale 7 Copper Excess this scale measures symptoms of having too much copper-from plumbing, containers, commercial vitamins, birth-control pills and other sources-in the body. Scale 8 Vitamin C Deficiency this scale measures symptoms of a deficiency of this important nutrient. During the course of evolution, man lost his ability to manufacture his own Vitamin C, and is now dependent on external sources. Scale 9 B-6 Deficiency this scale measures symptoms of deficiency in this vitamin, which is part of the biological deficit in Pyroluria. Upon giving an account of the symptoms and current state, the person seeking help learns from the practitioner that either a physical disorder exists, or does not. In the former case, the doctor will elect to postpone discussion of other problems until the physical one is under control. In the later case, the problems in happy, fruitful and useful living will remain the prime concern. The clinically oriented "medical model" which basically treats schizophrenia as a symptom of some underlying disease or disorder, and the "psychoanalytical model" which means to correct some basic misunderstandings in the minds of schizophrenics, are only two of the eight models presented by authors Miriam Siegler and Humphrey Osmond in Models of Madness. Such fundamentally different beliefs can be seen in how various people (including the professionals) treat "sick" patients and their families. The Clinically Oriented Medical Model of Schizophrenia We have all frequently experienced the affects of illnesses on our mental or emotional state-making us groggy, or irritable, or depressed, or forgetful. Even the common cold has a profound effect upon our mental abilities and on our mood. In this model, schizophrenic patients are considered to be physically ill in a way that not only affects their brains, but also their behavior. Whenever we are in fact ill, most of us would like the advantages of competent medical advice preferably given in the clear, familiar doctor/patient relationship. A clinically oriented medical model of schizophrenia is designed for this purpose. As a clinical medical model, it focuses on biologically relevant information about patients, which leads to diagnosing the appropriate illness, and planning the best possible treatment approach available. Because the true function of the clinical medical model is not only to treat the ill, but also to ensure that, within the realm of medicine, no one is blamed for the illness, all schizophrenics and their families are granted freedom from illness-related blame and guilt. Only the clinical medical model can perform both treatment and absolution of blame functions and it can do so only through the proper use of its two main components: "Aesculapian authority" and the "the sick role. Schweninger at last imposed moderation on the genius who had imposed it on others, but never on himself. Patterson in 1957 to be a unique combination of wise, moral, and charismatic authority, through which the doctor, having agreed to do all he can to help the patient get well, proceeds to give his orders. According to Patterson, the doctor with Aesculapian authority has been granted the right to be heard by reason of knowledge and expertise, and the right to control and direct stemming from the goodness of his goal to better the health of the patient (as expressed in the Hippocratic Oath) and by means of his powerful and mysterious abilities in the face of illness and death. Without such authority few, including Bismarck, would be willing to submit to most medical treatments since they may be too frightening, disgusting, painful, expensive, life-threatening, or simply unpleasant.
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Once candidate genes are selected, they are cloned, expressed and purified and used for immunological studies. By using robotics and highthroughput screening techniques, in 6 months it is possible to screen over 500 proteins for their suitability for use in vaccines (Grandi 2001). Attempts to develop a vaccine for group B Neisseria meningitidis using the conventional approach had failed and there were two reasons for this. First, the capsular polysaccharide of group B meningococci is a poor immunogen and has the potential to cause autoimmunity. Secondly, the surface-exposed proteins that had been tested were able to induce protective immunity but only offered protection against a limited number of isolates because of high sequence variability. Of these, 61% were expressed successfully and the purified proteins were used to immunize mice. Immune sera were then screened for bactericidal activity and for the ability to bind to the surface of meningococci. Seven representative proteins were selected for further study and were evaluated for their degree of sequence variability among multiple isolates of the bacteria. The eventual outcome was the identification of two highly conserved proteins with good potential as vaccine candidates. The second approach to identifying candidate proteins for vaccines is to identify those proteins that are specifically induced during infection. Both these technologies were developed before the genomics era and neither is dependent on sequence information. Microarrays are used to identify virulence genes by growing the pathogens in appropriate in vivo models and then determining which genes are newly expressed compared with cells grown in vitro. The proteins that are most likely to produce a protective immune response are localized on the cell surface. Although there are algorithms for predicting protein localization from genome sequence data, they give no indication of the protein composition of the cell surface in qualitative and quantitative terms. However, this information can be obtained by using a variety of protein analysis techniques to elucidate the protein composition of the cell surface after growth in vitro. It is used to generate a peptide-mass fingerprint which is then compared with theoretical fingerprints of all the proteins predicted from analysis of the genome sequence. By using automated procedures, which include excision of protein spots from two-dimensional gels, enzymatic digestion, mass spectrometry and database searching (p. The development of new types of markers has allowed dense marker frameworks to be assembled for many species. For a single gene trait, biological or environmental limitation accounts for penetrance, but in a multigenic trait the genetic context is important. Hence, the consequences of inheriting one gene rely heavily on the co-inheritance of others. Populations are typically generated by crosses between inbred strains, usually the first generation backcross (N2) or intercross (F2). They define which alleles are inherited in individuals, so that chromosomal associations can be made, and provide genetic recombination information so that location within a chromosome can be deduced. F1 hybrids are genetically identical to each other but individuals in subsequent generations are not. Backcross progeny reveal recombination events on only one homologue, the one inherited from the F1 parent, but intercross progeny reveal themselves on Theme 4: Getting to grips with quantitative traits Quantitative trait loci As noted in theme 1, the term complex trait refers to any phenotype that does not exhibit classic Mendelian recessive or dominant inheritance attributable to a single gene locus. Polygenic traits may be classified (Lander & Schork 1994) as discrete traits, measured by a specific outcome. Many important biological characteristics are inherited quantitatively but, because these effects have not generally been resolvable individually, quantitative geneticists have used biometrical procedures to characterize them (Falconer & McKay 1996). A congenic strain has only one chromosomal region that distinguishes it from a parental strain. All involve arranging a cross between two inbred strains differing substantially in a quantitative trait. If there is a statistically significant association between the trait performance and the marker locus genotypes. Lander and Botstein (1989) have ·· 220 Chapter 12 (a) P A1A1 Ч A2A2 (b) F1 A1A2 F2 A1A1 A1A2 A2A2 A1A1 A1A2 A2A2.
- Breast biopsy, using methods such as needle aspiration, ultrasound-guided, stereotactic, or open
- Inability to continue playing sports or other activities
- A blood test to be sure it is not a form of syphilis, which can cause a similar rash
- Shallow breathing
- Nasal polyps, sac-like growths of inflamed tissue lining the nose or sinuses
- Act normally in social situations
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Fructokinase provides the primary mechanism for fructose phosphorylation (see Figure 12. The enzyme has a low Km for fructose and a high Vmax (or, maximal velocity; see p. Cleavage of fructose 1-phosphate Fructose 1-phosphate is not phosphorylated to fructose 1,6-bisphos-phate as is fructose 6-phosphate (see p. Kinetics of fructose metabolism the rate of fructose metabolism is more rapid than that of glucose because the trioses formed from fructose 1-phosphate bypass phosphofructokinase-1, the major ratelimiting step in glycolysis (see p. Conversion of mannose to fructose 6-phosphate Mannose, the C-2 epimer of glucose (see p. Hexokinase phosphorylates mannose, producing mannose 6-phosphate, which, in turn, is reversibly isomerized to fructose 6-phosphate by phosphomannose isomerase. Most intracellular mannose is synthesized from fructose or is preexisting mannose produced by the degradation of structural carbohydrates and salvaged by hexokinase. Conversion of glucose to fructose via sorbitol Most sugars are rapidly phosphorylated following their entry into cells. Therefore, they are trapped within the cells, because organic phosphates cannot freely cross membranes without specific transporters. An alternate mechanism for metabolizing a monosaccharide is to convert it to a polyol (sugar alcohol) by the reduction of an aldehyde group, thereby producing an additional hydroxyl group. Synthesis of sorbitol: Aldose reductase reduces glucose, producing sorbitol (glucitol; Figure 12. This enzyme is found in many tissues, including the lens, retina, Schwann cells of peripheral nerves, liver, kidney, placenta, red blood cells, and cells of the ovaries and seminal vesicles. In cells of the liver, ovaries, and seminal vesicles, there is a second enzyme, sorbitol dehydrogenase, which can oxidize the sorbitol to produce fructose (see Figure 12. The two-reaction pathway from glucose to fructose in the seminal vesicles benefits sperm cells, which use fructose as a major carbohydrate energy source. The pathway from sorbitol to fructose in the liver provides a mechanism by which any available sorbitol is converted into a substrate that can enter glycolysis or gluconeogenesis. Effect of hyperglycemia on sorbitol metabolism: Because insulin is not required for the entry of glucose into the cells listed in the previous paragraph, large amounts of glucose may enter these cells during times of hyperglycemia (for example, in uncontrolled diabetes). This is exacerbated when sorbitol dehydrogenase is low or absent (for example, in retina, lens, kidney, and nerve cells). As a result, sorbitol accumulates in these cells, causing strong osmotic effects and, therefore, cell swelling as a result of water retention. Some of the pathologic alterations associated with diabetes can be attributed, in part, to this phenomenon, including cataract formation, peripheral neuropathy, and microvascular problems leading to nephropathy and retinopathy. Phosphorylation of galactose Like fructose, galactose must be phosphorylated before it can be further metabolized. Most tissues have a specific enzyme for this purpose, galactokinase, which produces galactose 1-phosphate (Figure 12. Physiologic consequences are similar to those found in hereditary fructose intolerance (see p. The accumulated galactose is shunted into side pathways such as that of galactitol production. This reaction is catalyzed by aldose reductase, the same enzyme that converts glucose to sorbitol (see p. Lactose, known as "milk sugar," is made by lactating (milk-producing) mammary glands. It is -lactalbumin, and its synthesis is stimulated by the peptide hormone prolactin. Protein B forms a complex with the enzyme, protein A, changing the specificity of that transferase so that lactose, rather than Nacetyllactosamine, is produced (see Figure 12. Fructose is first phosphorylated to fructose 1-phosphate b y fructokinase and then cleaved by aldolase B to dihydroxyacetone phosphate and glyceraldehyde.
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Gabapentin and pregabalin are specific for highvoltage-gated P/Q type calcium channels, whereas ethosuximide is specific for low-voltage-gated T-type calcium channels. Other drugs such as lamotrigine, valproate and topiramate block calcium channels as just one of many cellular actions. Carbamazepine is effective for partial seizures with or without secondary generalisation. It is not recommended for primary generalised seizures (especially myoclonic epilepsy), which can be worsened by it. Rashes, including serious reactions such as StevensJohnson syndrome, tend to be more of a problem for this drug than other anticonvulsants. A further set of issues arise from the hepatic induction property of carbamazepine: both osteomalacia and folic acid deficiency may occur due to enhanced metabolism of vitamin D and folic acid, respectively. Other unwanted effects can include gastrointestinal symptoms, headache, blood disorders. Phenytoin Phenytoin (diphenylhydantoin, Epanutin, Dilantin) acts principally by blocking neuronal voltage-dependent sodium ion channels; this action is described as membrane stabilising, and discourages the spread (rather than the initiation) of seizure discharges. Phenytoin provides a good example Oxcarbazepine Oxcarbazepine, like its analogue carbamazepine, acts by blocking voltage-sensitive sodium channels. It is rapidly and extensively metabolised in the liver; the tЅ of the parent drug is 2 h, but that of its principal metabolite (which also has therapeutic activity) is 11 h. Unlike carbamazepine, it does not form an epoxide, which may explain its lower frequency of unwanted effects; these include dizziness, headache and hyponatraemia, and selective cytochrome enzyme induction (potentially causing failure of oestrogen contraception). Monitoring of plasma sodium may be necessary in the elderly and patients on diuretics. Oxcarbazepine is used either as monotherapy or as addon therapy for partial seizures. The speed with which the dose can be escalated is generally quicker than that for carbamazepine. Eslicarbazepine this drug is an enantiomer of a hydroxyl derivative of oxcarbazepine, and has an efficacy spectrum similar to carbamazepine and oxcarbazepine, i. It appears to have fewer of the unwanted effects of its parent drugs, and its dose can be raised to an effective range more quickly (within 12 weeks); only two dose are available. Phenytoin is hydroxylated extensively in the liver, a process that becomes saturated at about the doses needed for therapeutic effect. Thus phenytoin at low doses exhibits first-order kinetics but saturation or zero-order kinetics develop as the therapeutic plasma concentration range (1020 mg/L) is approached, i. Thus dose increments should become smaller as the dose increases (which is why there is a 25 mg capsule), and plasma concentration monitoring is advisable. Phenytoin given orally is well absorbed, allowing for achievement of therapeutic range concentrations within 24 h (as may be required in patients with frequent seizures). Phenytoin is a potent inducer of hepatic enzymes that metabolise other drugs (carbamazepine, warfarin), dietary and endogenous substances (including vitamin D and folate), and phenytoin itself. This latter causes a slight fall in steady-state phenytoin concentration over the first few weeks of therapy, though this may not be noticeable with progressive dose increments. Drugs that inhibit phenytoin metabolism (causing its plasma concentration to rise) include sodium valproate, isoniazid and certain non-steroidal anti-inflammatory drugs. The main role of phenytoin in modern practice is in the emergency control of seizures, including status epilepticus, because of its reliable antiepileptic effect, and because an effective treatment dose can be loaded rapidly. It may also be used to prevent partial seizures with or without secondary generalisation, but is not generally used first line in this regard because of its adverse effect profile (see below). It may worsen primary generalised epilepsies, such as absence or myoclonic seizures, and so is not used for these conditions unless status epilepticus occurs. The membrane-stabilising effect of phenytoin finds use in cardiac arrhythmias, trigeminal neuralgia and myotonic dystrophy (an inherited disorder in which skeletal muscle becomes over-excitable). Adverse effects of phenytoin are multitudinous, especially with years of therapy, which fact, together with its narrow therapeutic range, is why phenytoin is not favoured for long-term therapy. Unwanted effects related to the nervous system include cognitive impairment, cerebellar ataxia, dyskinesias, tremor and peripheral neuropathy. Haematological effects include: macrocytic anaemia due to increased folate metabolism (treatable with folate supplementation), IgA hypergammaglobulinaemia, lymphadenopathy and pseudolymphoma. Osteomalacia due to increased metabolism of vitamin D occurs after years of therapy and calls for bone-density scanning. It causes rash in about 10% of patients, including, rarely, serious reactions such as StevensJohnson syndrome and toxic epidermal necrolysis (potentially fatal).
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They also rest on the claim that drugs have not changed expectation of life or mortality (as measured by national mortality statistics), or at least it is very difficult to show that they have, and that drugs indisputably can cause illness (adverse reactions). Overall mortality figures are an extremely crude and often an irrelevant measure of the effects of drugs whose major benefits are so often on quality of life rather than on its quantity. In the case of many infections it is not disputed few survived beyond 3 years16 after diagnosis; they died for lack of insulin. It is unjustified to assert that a treatment is worthless just because its mention on death certificates (whether as a prime or as a contributory cause) has not declined. The relevant criteria for juvenile-onset diabetes are change in the age at which the subjects die and the quality of life between diagnosis and death, and both of these have changed enormously. Negligence and strict and no-fault liability All civilised legal systems provide for compensation to be paid to a person injured as a result of using a product of any kind that is defective due to negligence (fault: failure to exercise reasonable care). The question why a person who has suffered injury due to the biological accident of disease should have to depend on social security payments while an identical injury due to a drug (in the absence of fault) should attract special added compensation receives no persuasive answer except that this is what society seems to want. But this does not mean that environmental improvements alone are sufficient in the fight against infections. When comparisons of illnesses in the pre- and postantimicrobial eras are made, like is not compared with like. Environmental changes achieved their results when mortality from infections was high and antimicrobials were not available; antimicrobials were introduced later against a background of low mortality as well as of environmental change; decades separate the two parts of the comparison, and observers, diagnostic criteria and data recording changed during this long period. It is evident that determining the value of antimicrobials is not simply a matter of looking at mortality rates. This is no surprise because all must die and insulin is no cure15 for this lifelong disease. Most, if not all, life insurance companies now accept young people with diabetes with no or only modest financial penalty, the premium of a person 510 years older. Before insulin replacement therapy was available 15 A cure eliminates a disease and may be withdrawn when this is achieved. A manufacturing defect would be dealt with in a way no different from manufacturing errors in other products. Standard drugs in day-to-day therapeutics: there should be a no-fault scheme, operated by or with the assent of government that has authority, through tribunals, to decide cases quickly and to make awards. This body would have authority to reimburse itself from others manufacturer, supplier, prescriber wherever that was appropriate. An award must not have to wait on the outcome of prolonged, vexatious, adversarial, expensive court proceedings. Should compensation be reduced in smokers and drinkers where there is evidence that these pleasure drugs increase liability to adverse reactions to therapeutic drugs? This comprises a mass of practices varying from the worthless to highly effective remedies, such as digitalis (England), quinine (South America), reserpine (India), atropine (various countries). It is the task of science to find the gems and to discard the dross,24 and at the same time to leave intact socially valuable supportive aspects of traditional medicine. This is not because there has been too little thought, it is because the subject is so difficult. New unlicensed drugs undergoing extensive trials in patients who may reasonably expect benefit: the producer should be strictly liable for any serious effect. New drugs after licensing by an official body: the manufacturer and the community should share liability for serious injury, as new drugs provide general benefit. Although the Commission considered compensation for death and personal injury suffered by any person through manufacture, supply or use of products, i. For this reason, governments are supporting traditional medicine and at the same time initiating scientific clinical evaluations of the numerous plants and other items employed, many of which contain biologically active substances. It is difficult to resist the conclusion that when scientific medicine neither guarantees happiness nor wholly eliminates the disabilities of degenerative diseases in long-lived populations, and when drugs used in modern medicine cause serious harm, public disappointment naturally leads to a revival of interest in alternatives that alluringly promise efficacy with complete safety. These range from a revival of traditional medicine to adoption of the more modern cults. Lack of understanding of how therapeutic effects may be measured is also a prominent feature. A proposition belongs to science if we can say what kind of event we would accept as refutation (and this is easy in therapeutics). A proposition (or theory) that cannot clash with any possible or even conceivable event (evidence) is outside science, and this in general applies to cults where everything is interpreted in terms of the theory of the cult; the possibility that the basis of the cult is false is not entertained. This appears to be the case with medical cults, which join freudianism, and indeed religions, as outside science (after Karl Popper).
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Pentazocine is one sixth as potent as morphine, nalbuphine is slightly less potent than morphine and butorphanol is five to nine times as potent. Adverse effects include nausea, vomiting, dizziness, sweating, hypertension, palpitations, tachycardia and central nervous system disturbance (euphoria, dysphoria, psychotomimesis). Pentazocine has effects on the cardiovascular system, raising systolic blood pressure and pulmonary artery pressure, and should be avoided in myocardial infarction. Papaveretum Papaveretum is a mixture of opium alkaloids, the principal constituents being morphine (50%), codeine, papaverine and noscapine. Partial agonist opioid analgesics Buprenorphine Buprenorphine is a partial agonist at the m receptor. The partial agonist activity, however, is thought to occur at a higher dose than would be normally used therapeutically and is, therefore, rarely clinically significant. It is 30 times more potent than morphine and its receptor affinity (tenacity of binding) is high. Thus, its peak effect may occur up to 3 h after administration, and its duration of action as long as 10 h. In theory, a partial agonist has less potential for respiratory depression and abuse. Respiratory depression can occur with buprenorphine overdose and, because of its affinity with the m receptor, may only be partially reversed by Opioids with action on other systems Pethidine (meperidine) Pethidine (meperidine) was discovered in 1939 during a search for atropine-like compounds. Its use as a treatment for asthma was abandoned when its opioid agonist properties were appreciated. Close monitoring of the patient and repeated doses of naloxone may therefore be necessary. A common starting dosage in an opioid-naive patient with Ё acute opioid overdosage is 0. For patients receiving long-term opioid therapy, it should be used only to reverse respiratory depression and must be administered more cautiously to avoid precipitating withdrawal or severe pain. Despite its structural dissimilarity to morphine, pethidine shares many similar properties, including antagonism by naloxone. It is extensively metabolised in the liver and the parent drug and metabolites are excreted in the urine. It can cause central excitation and, eventually, convulsions, if it accumulates after prolonged intravenous administration or in renal impairment. Pethidine has atropine-like effects, including dry mouth and blurred vision (cycloplegia and sometimes mydriasis, though usually miosis). Its use as an analgesia in obstetric practice was based on early clinical research which showed that, unlike morphine, pethidine did not appear to delay labour. However, the doses of pethidine used in these early studies were low and it is now established that pethidine confers no added advantage over other opioids at higher equi-analgesic doses. Pethidine is eight to ten times less potent than morphine, has poor and variable oral absorption, with a short duration of action in the range of 23 h. For all these reasons, it is recommended that pethidine should be avoided if alternatives are available. Opioids with a short half-life (morphine and diamorphine) should be used as first-line agents for acute pain but may be replaced with longer-acting drugs if pain persists. Knowledge of equi-analgesic doses of opioids is essential when changing drugs or routes of administration (Tables 18. Cross-tolerance between drugs is incomplete, so when one drug is substituted for another, the equi-analgesic dose should be reduced by 50%. Opioid rotation is commonly used in cancer-related and chronic non-malignant pain as a means of reducing side-effects and limiting the development of tolerance. It is a centrally acting analgesic with relatively weak m-opioid receptor activity. However, it also inhibits neuronal reuptake of noradrenaline/norepinephrine and enhances serotonin release, and this is thought to account for some of its analgesic action. Roughly 20% of an oral dose undergoes first-pass metabolism and less than 30% of a dose is excreted unchanged in the urine. This metabolite is an active m agonist with a greater receptor affinity than tramadol.