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This clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results purchase 200 mg fluconazole with mastercard fungus yeast difference. Decompression and fusion may be considered as a means to provide satisfactory long-term results for the treatment of patients with symptomatic spinal stenosis and degenerative lumbar spondylolisthesis purchase fluconazole 50mg with mastercard fungus virus. Maintained from original guideline with minor word modifcations Grade of Recommendation: C Studies obtained from updated literature search: reoperation due to complications including 2 degenerative Schaeren et al1 conducted a prospective case-series of 26 con- spondylolisthesis and 2 degenerative lumbar scoliosis patients buy cheap fluconazole 150 mg line fungus gnats kill seedlings. The preoperative percentages of slippage in patients enough stability to prevent progression of spondylolisthesis discount 200mg fluconazole fast delivery fungus vag infection. Plain and functional radiographs showed In a retrospective case-series study, Tsutsuminmoto et al3 that spondylolisthesis did not progress and the motion segments evaluated the long-term surgical outcomes of patients with lum- remained stable. At 2 year follow-up, anterior and posterior disc bar canal stenosis and Grade I degenerative spondylolisthesis height had signifcantly increased from 2. Nine patients were lost to follow-up; tion at adjacent levels was seen in 47% of patients at 4 years therefore, the fnal analysis included 42 patients. Patient satisfaction was high and 95% responded that was assessed via plain radiographs and clinical outcomes were they would undergo the same procedure again. At the f- radiographic outcomes afer 4 years in patients undergoing sur- nal follow-up, the percent recovery was greater than 3 in 69. At one and 3-year follow-up, there was no sta- clinical and radiologic outcomes in patients who underwent mi- tistically signifcant diference in the overall percent recovery crosurgical bilateral decompression using a unilateral approach. Patients better at 5-year and fnal follow up compared to that of the non- were followed for a minimum of 5 years and the mean follow-up union group (3. Regression analysis revealed that fusion sta- of reoperation, and radiographic changes afer surgery on plain tus and the presence of comorbidity were signifcant risk factors radiograph were also evaluated. Four patients required this clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results. Furthermore, this study suggests with diferent indications for posterolateral fusion. A total of that those patients who achieved solid fusion have statistically 106 patients were included in the study, including 31 with de- better long-term outcomes than those with pseudarthroses for generative spondylolisthesis (Group 1), 33 with isthmic spon- noninstrumented fusions. In addition, Recommendation #1: 28 of 31 patients reported experiencing either excellent or good Future long-term studies of the efects of surgical interventions long term results. Continued follow-up of patients already en- rolled in ongoing prospective comparative studies will yield Studies included in original guideline: higher quality data regarding the relative efcacy of surgery Booth et al5 described a presumably retrospective study of 41 compared to medical/interventional treatments. At fnal follow-up, Future long-term outcome studies, such as multicenter registry there were no new neurological defcits, no recurrent stenosis at database studies, are necessary to compare diferent surgical the level of surgery and no symptomatic pseudarthroses. Tree techniques for the treatment of patients with symptomatic spinal patients underwent surgery for adjacent level stenosis, which stenosis and degenerative lumbar spondylolisthesis. Clinical out- comes were available in 36 patients: 83% reported high satisfac- References tion, 86% reported reduced back and leg pain, and 46% had in- 1. Toyoda H, Nakamura H, Konishi S, Dohzono S, Kato M, Matsu- val, 41 were available for follow-up (8 patients died) and only 36 da H. Clinical outcome of microsurgical bilateral decompression had clinical outcomes measured. Attrition from death, however, via unilateral approach for lumbar canal stenosis: minimum fve-year follow-up. Lumbar instru- Kornblum et al6 conducted a follow-up study on 47 of 58 mented posterolateral fusion in spondylolisthetic and failed patients who had originally been part of a randomized con- back patients: a long-term follow-up study spanning 11-13 trolled trial comparing instrumented versus noninstrumented years. Minimum 5-year results of degenerative spondylolisthesis this study’s cohort consisted only of the noninstrumented cases, treated with decompression and instrumented posterior fusion. Degenerative lumbar spondylolisthesis percentage of patients had good or excellent results in patients with spinal stenosis: a prospective long-term study comparing with solid fusion (86%) versus pseudarthrosis (56%). In critique of this study, the Bibliography from updated literature search authors used a less frequently implemented outcomes instru- 1. Dynamic stabilization using X-stop for high-grade childhood and adolescent isthmic spondylolis- versus transpedicular screw fxation in the treatment of lumbar thesis: long-term outcome. Adjacent segment interbody fusion in comparison with transforaminal lumbar degeneration afer lumbar interbody fusion with percutane- interbody fusion: implications for the restoration of foraminal ous pedicle screw fxation for adult low-grade isthmic spon- height, local disc angle, lumbar lordosis, and sagittal balance. Management of lumbar spine juxtafacet posterior decompression for spinal stenosis associated with cysts. Bone union rate with au- fusion through a unilateral approach and percutaneous osteo- tologous iliac bone versus local bone graf in posterior lumbar synthesis. Dysfunctional segmental motion treated with dynamic Radiographic restoration of lumbar alignment afer transforam- stabilization in the lumbar spine. Efcacy of unilat- interbody fusion using non resorbable poly-ether-ether-ketone eral laminectomy for bilateral decompression in lumbar spinal versus resorbable poly-L-lactide-co-D,L-lactide fusion devices. Radiological compari- Posterior lumbar fusion by peek rods in degenerative spine: pre- son of instrumented posterior lumbar interbody fusion with one liminary report on 30 cases. Lamberg T, Remes V, Helenius I, Schlenzka D, Seitsalo S, Poussa 58 patients treated with anterior cervical decompression and M. Decompression and inter- instrumented posterolateral fusions: report on safety and feasi- spinous dynamic stabilization using the locker for lumbar canal bility. A prospec- generative Lumbar Conditions Using a Non-Treaded Locking tive randomised study on the long-term efect of lumbar fusion Screw System With a 90-Degree Locking Cap. Two-year clinical and trans-pedicular screw fxation in the treatment of lumbar canal radiographic success of minimally invasive lateral transpsoas stenosis: Comparative study of the clinical outcome. Mini- graphic outcomes afer minimally invasive transforaminal mum 2-year follow-up result of degenerative spinal stenosis lumbar interbody fusion. World Neuro- in the adjacent segments to the fusion site afer posterolateral surg. This clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results.

The three main approaches to treatment are surgery cheap 200mg fluconazole with mastercard fungus gnats soil treatment, radiotherapy and chemotherapy order fluconazole 200 mg antifungal yeast treatment. The way in which they are combined depends on the type of cancer and its stage at diagnosis order fluconazole 200 mg overnight delivery anti fungal. New approaches to treatment now include gene therapy purchase fluconazole 150 mg line antifungal liquid soap, immunotherapy, stimulation of bone marrow, induction of differentiation in cancer cells and inhibition of angiogenesis in addition to the more standard chemotherapy. This chapter will concentrate on the drugs used in cancer chemotherapy with consid- eration of some of the other forms of therapy. This results from loss of mechanisms that normally regulate maturation and proliferation of cells. Many approaches to therapy of cancer depend on interfering with cell division, and so it is necessary to consider the normal cell cycle of dividing cells. If differentiation follows G0, cells are no longer capable of division and they leave the cycle. Cells in tumours may remain in G0 for prolonged periods and can be stimulated to divide again. A damaged cell may be repaired and if that fails, the cell would normally self-destruct by a process known as apoptosis. Apoptosis is genetically programmed cell destruction that removes old, redundant and abnormal cells. Loss or mutation of tumour sup- pressor genes allows cells to undergo malignant transformations. For example, a tumour suppressor gene known as p53 normally activates a key pathway in apoptosis. Loss or mutation of this gene allows continuous proliferation and survival of mutated cells and is seen in many types of human cancer. Cells are stimulated to divide by growth factors, which form part of the cell cycle control system. They were given this name because they can be altered by mutation, carcinogens or viruses to become oncogenes. Mutation of the ras gene leads to production of abnormal Ras, which activates cell division. It is believed that normal growth within tissues is also controlled by contact inhibition. That is, inhibition of abnormal cell division and growth by cell-to-cell contact factors called integrins and adhesion molecules. In addition, as cells are added during growth and repair, others die so overall size of a tissue or organ is maintained. In summary, cell cycle control is lost in cancer cells possibly because of mutation of tumour suppressor genes, oncogene activity, abnormal growth factor function or abnormal cell cycle control function. Characteristics of cancer include uncontrolled cell division with excessive growth of undifferentiated cells. Cancer cells invade surrounding tissues, whereas normal cells do not survive outside their normal boundaries. Cancer cells may travel to distant sites in the body via the blood and lymph to form secondary tumours that are called metastases. As cells repeatedly divide a mass forms known as a tumour, which needs a blood supply. By the time cancer has been diagnosed, cell growth and spread of malignant cells has probably occurred. A nucleotide has three components: a base, which is an organic molecule containing nitrogen; a five-carbon sugar called deoxyribose; and a phosphate group. The sequence of bases forms a set of instructions or a code for the assembly of amino acids into proteins. In human cells there are 46 chromosomes (apart from sperm and egg cells where there are 23). Each amino acid is coded for by a sequence of three bases, known as a triplet code. For the best chance of success, drugs must be used early on in a patient’s treatment along with irradiation or surgery when the cancer is most curable and the patient is most able to tolerate treatment. The general health of the patient, their nutritional status, their liver and kidney function and the viability of their bone marrow 10. Initially, growth is exponential; that is each cell divides to produce two, which then divide to produce four and so on. As a tumour gets larger growth slows down, partly because it outgrows its blood supply and partly because not all cells in the tumour divide continuously. Cells in a solid tumour can be in three different states: • those that are dividing (rapidly), possibly in continuous cell cycle; • those that are resting in the G0 phase of the cell cycle; • those that are no longer able to divide. Cells that are dividing are the best targets for chemotherapy, but they may only represent 5% of the total of tumour mass. Cells that can no longer divide do not present a problem, but cells that are resting are often resistant to cytotoxic drugs and can re-enter the cell cycle after a course of chemotherapy. Phase-specific drugs act at a particular point in the cycle, usually S phase or M phase. Phase-non-specific drugs are cytotoxic at any point in the cell cycle and may be toxic to cancer cells in the resting phase.

Chronic bronchitis and emphysema discount fluconazole 50mg visa fungus gnats peroxide, respiratory tuberculosis ‘Crack babies’ can usually be cured of their ‘addiction’ by Pulmonary heart disease abstinence over a few weeks fluconazole 50 mg overnight delivery fungus gnats worms. Currently fluconazole 150mg overnight delivery fungus key, there are no specific Aortic aneurysm drug treatments for cocaine dependence buy fluconazole 150 mg with amex baby antifungal cream. Effect of smoking on drug disposition and effects Caffeine dependence the most common effect of tobacco smoking on drug dispos- Tolerance is low grade and dependence is not clinically ition is an increase in elimination consistent with induction of important. Withdrawal can lead temically, but is of great medical importance because of its to an abstinence syndrome consisting of craving, irritability and pathological and psychological effects when used as a bever- sometimes physical features (e. Alcohol is the most important drug of dependence, and Substitution of nicotine via skin patches or nicotine gum as in Western Europe and North America the incidence of alco- part of a smoking cessation programme significantly increases holism is about 5% among the adult population. The antidepressant bupropion appears to reduce the desire to smoke and is licensed as an adjunct to motivational Pharmacokinetics support in smoking cessation. It is contraindicated in patients Ethyl alcohol is absorbed from the buccal, oesophageal, gastric with a history of seizures or of eating disorders, or who are and intestinal mucosae – approximately 80% is absorbed from experiencing acute alcohol or benzodiazepine withdrawal. Alcohol delays gastric emptying and in Varenicline, a selective nicotinic receptor partial agonist, is high doses delays its own absorption. It is started 1–2 weeks tration, alcohol can usually be detected in the blood within five before stopping smoking. Peak concentrations occur between 30 minutes and Side effects include gastro-intestinal disturbances, headache, two hours. Hepatic this group of compounds includes caffeine (present in tea oxidation to acetaldehyde is catalysed by three parallel and colas, as well as coffee), theobromine (present in choco- processes. The major effects of these com- Alcohol elimination follows Michaelis–Menten kinetics, pounds are mediated by inhibition of phosphodiesterase, with saturation occurring in the concentration range encoun- resulting in a raised intracellular cyclic adenosine monophos- tered during social drinking. Its use does not lead to Nervous system: Alcohol decreases concentration, judgement, improved intellectual performance except perhaps when discrimination, and reasoning and increases self-confidence. Progressively increasing plasma concentrations are associated Circulatory effects include direct myocardial stimulation with sensations of relaxation followed by mild euphoria, producing tachycardia, increased cardiac output, ectopic beats incoordination, ataxia and loss of consciousness. Caffeine use should be curtailed in patients concentrations, the gag reflex is impaired, vomiting may occur who suffer paroxysmal dysrhythmias. Its effect on blood pres- and death may result from aspiration of gastric contents. Cerebral vasoconstriction provides some importance of alcohol as a factor in road traffic accidents is rationale for use of caffeine in migraine. The central depressant actions of muscle relaxes and respiration is stimulated centrally. Mild alcohol greatly enhance the effects of other central depressant diuresis occurs due to an increased glomerular filtration rate drugs. In patients with organic brain damage, alcohol may subsequent to dilatation of the afferent arterioles. Chronic neurological accompaniments of persistent alcohol abuse include various forms of central Cytoplasmic and peripheral neurodegeneration, most commonly involving Catalase alcohol Microsomal the vermis of the cerebellum, and a peripheral neuropathy. Any evidence of Wernicke’s encephalopathy should be immediately treated with intravenous thiamine followed by oral thiamine for several Acetate months. Hyperuricaemia occurs (particularly, it is said, in beer drinkers) and can cause acute gout. Neutrophil dysfunction is common even when the neutrophil count is 20 normal, predisposing to bacterial infections (e. There are characteristic facial features which include microcephaly, micrognathia and a short upturned 0 20 40 60 80 100 120 140 160 180 nose. This so-called fetal alcohol syndrome is unlike that Blood alcohol concentration (mg/100 mL) reported in severely undernourished women. The patient should be nursed in a quiet environment with careful attention to fluid and electrolyte Acute effects of alcohol balance. Benzodiazepines (intravenous if necessary, Chapters • Central effects include disinhibition, impaired 18 and 22) are usually effective in terminating prolonged with- judgement, inco-ordination, trauma (falls, road traffic drawal seizures – if they are ineffective the diagnosis should accidents), violence and crime. Psychiatric assessment and social support • Convulsions, enhancement of sedative drugs. Delirium tremens occurs in less • Dependence than 10% of alcoholic patients withdrawing from • Behavioural changes alcohol. Psychological and social management: Some form of psychological and social management is important to help the patient to remain abstinent. Whatever approach is used, Medical uses of alcohol the focus has to be on abstinence from alcohol. Systemic alcohol is minority of patients may be able to take up controlled used in poisoning by methanol or ethylene glycol, since it drinking subsequently, but it is impossible to identify this competes with these for oxidation by alcohol dehydrogenase, group prospectively, and this should not be a goal of slowing the production of toxic metabolites (e. Management of alcohol withdrawal Alcohol-sensitizing drugs: these produce an unpleasant Awithdrawal syndrome develops when alcohol consumption reaction when taken with alcohol. The only drug of this type is stopped or severely reduced after prolonged heavy alcohol used to treat alcoholics is disulfiram, which inhibits aldehyde intake. Several features of acute withdrawal are due to auto- dehydrogenase, leading to acetaldehyde accumulation if nomic overactivity, including hypertension, sweating, tachy- alcohol is taken, causing flushing, sweating, nausea, cardia, tremor, anxiety, agitation, mydriasis, anorexia and headache, tachycardia and hypotension. These are most severe 12–48 hours after stopping may occur if large amounts of alcohol are consumed. Some small amounts of alcohol included in many medicines may be patients have seizures (‘rum fits’ generally 12–48 hours post sufficient to produce a reaction and it is advisable for the abstinence). A third set of symptoms consists of alcohol with- patient to carry a card warning of the danger of alcohol drawal delirium or ‘delirium tremens’ (acute disorientation, administration. Disulfiram also inhibits phenytoin severe autonomic hyperactivity, and hallucinations – which metabolism and can lead to phenytoin intoxication. Delirium tremens often follows after with- Unfortunately, there is only weak evidence that disulfiram drawal seizures and is a medical emergency.

The more acetyl- example 200mg fluconazole overnight delivery fungus gnats leaf damage, evidence was found for the existence of en- choline the end-plate region contains cheap fluconazole 50 mg on-line fungus dog vomit, the more recep- dogenous peptides with morphinelike activity fluconazole 50mg otc kaufmann antifungal diet. When of these peptides have since been identified and are col- the number of open channels reaches a critical value order 50 mg fluconazole with amex antifungal diet plan, lectively termed endorphins and enkephalins (see sodium enters rapidly enough to disturb the ionic bal- Chapter 26). It is now clear that drugs such as morphine ance of the membrane, resulting in local depolarization. The sequence never lose sight of the fact that receptors are in actuality of events can be shown diagrammatically as follows: 10 2 Mechanisms of Drug Action 11 Ach receptor → Na influx → action potential ion channel. The binding sites for acetylcholine (see → increased free Ca → contraction Chapter 12) and other agonists that mimic it are on one of the subunits that project extracellularly from the cell membrane. The precise chain of events changes the conformation of the glycoprotein so that following drug–receptor interaction depends on the the side chains move away from the center of the chan- particular receptor and the particular type of cell. The nel, allowing sodium ions to enter the cell through the important concept at this stage of the discussion is that channel. The glycoproteins that make up the nicotinic specific receptive substances serve as triggers of cellular receptor for acetylcholine serve as both the walls and reactions. This arrangement repre- If we consider the sequence of events by which sents one of the simpler mechanisms by which a recep- acetylcholine brings about muscle contraction through tor may be coupled to a biological response. Many receptors are capable of initiating a chain of Chemicals that interact with a receptor and thereby initi- events involving second messengers. Thus, acetyl- many of these second-messenger systems are proteins choline itself, as well as the drugs nicotine and car- termed G proteins, short for guanine nucleotide– bamylcholine, are agonists for the receptors in the binding proteins. In ber of instances, the next step involves the enzyme this instance the chemical does not cause contraction, adenylyl cyclase. Many neurotransmitters, hormones, but because it occupies the receptor site, it prevents the and drugs can either stimulate or inhibit adenylyl cy- interaction of acetylcholine with its receptor. Such a clase through their interaction with different receptors; drug is termed an antagonist. Each kinase phosphorylates a specific protein or exogenously administered drugs, neurotransmitters, or proteins. Such phosphorylation reactions are known to hormones exert their pharmacological effects. By apply- be involved in the opening of some calcium channels as ing mathematical principles to dose–response relation- well as in the activation of other enzymes. In this system, ships, it became possible to estimate dissociation con- the receptor is in the membrane with its binding site on stants for the interaction between specific receptors and the outer surface. Subsequently, meth- membrane while the adenylyl cyclase is within the mem- ods were developed to measure the specific binding of brane but projects into the interior of the cell. The nicotinic re- ture of the response depends on these factors: ceptor on skeletal muscle, for example, is known to be composed of five subunits, each a glycoprotein weighing • Which G protein couples with the receptor 40,000 to 65,000 daltons. T S G A S S R S L R A Y E P P Although most drug–receptor interactions are read- P R R L G P P S S A L ily reversible, some compounds, such as the anticancer P T A G P T S W S R T R A A G R P R G G A P L R R G G R R R A G A E G G A G G A D G G A G P G A A G nitrogen mustards (see Chapter 56) and other alkylat- ing agents form relatively irreversible complexes. The tineoplastic or antibiotic drug, since long-lasting inhibi- amino acid sequence is represented by the one-letter code. The formation of an ionic bond results from the electrostatic attraction that occurs between oppositely charged ions. The strength of this bond is considerably the variety of possible responses is further in- less (5 kcal/mole) than that of the covalent bond and di- creased by the fact that receptor-coupled G proteins minishes in proportion to the square of the distance be- can either activate enzymes other than adenylate cy- tween the ionic species. Most macromolecular receptors clase or can directly influence ion channel functions. All members of this family of G as nitrogen or oxygen, and thereby form a bridge (hy- protein–coupled receptors are characterized by having drogen bond) between these two donor atoms. The seven membrane-enclosed domains plus extracellular formation of several such bonds between two mole- and intracellular loops. Such bonds serve action with G proteins occurs with the intracellular por- to maintain the tertiary structure of proteins and nu- tions of the receptor. The general term for any chain of cleic acids and are thought to play a significant role in events initiated by receptor activation is signal trans- establishing the selectivity and specificity of drug– duction. Like the hydrogen bonds, sev- drugs in a number of ways, and the forces that attract eral van der Waals bonds may be established between the drug to its receptor must be sufficiently strong and two molecules, especially if the drug molecule and a re- long-lasting to permit the initiation of the sequence of ceptor have complementary three-dimensional confor- events that ends with the biological response. The closer the forces are chemical bonds, and a number of types of drug comes to the receptor, the stronger the possible bonds participate in the formation of the initial binding forces that can be established. The drug molecule, following its administration and the principles derived from dose–response curves passage to the area immediately adjacent to the recep- are the same in animals and humans. However, obtain- tor surface (sometimes called the biophase), must bond ing the data for complete dose–response curves in hu- with the receptor before it can initiate a response. We shall there- Resisting this bond formation is a random thermal agi- fore use animal data to illustrate these principles. Under normal circumstances, the electrostatic attraction of the ionic Quantal Relationships bond, which can be exerted over longer distances than In addition to the responsiveness of a given patient, one can the attraction of either the hydrogen or van der may be interested in the relationship between dose and Waals bond, is the first force that draws the ionized mol- some specified quantum of response among all individ- ecule toward the oppositely charged receptor surface. Such information is obtained by this is a reasonably strong bond and will lend some sta- evaluating data obtained from a quantal dose–response bility to the drug–receptor complex. Generally, the ionic bond must be reinforced by a Anticonvulsants can be suitably studied by use of hydrogen or van der Waals bond or both before signifi- quantal dose–response curves. This is true because the potential of new anticonvulsants to control epileptic unreinforced bonds are too easily and quickly broken seizures in humans, these drugs are initially tested for by the energy of thermal agitation to permit sufficient their ability to protect animals against experimentally time for adequate drug–receptor interaction to take induced seizures. This type of response, in contrast to a graded re- valent bond formation has occurred, the drug–receptor sponse, must be described in a noncontinuous manner. Once dissociation has oc- the construction of a quantal dose–response curve curred, drug action is terminated. The frequencies of association and dis- will not respond to a given dose, a comparison of indi- sociation are a function of the affinity between the drug viduals within a population shows that members of that and the receptor, the density of receptors, and the con- population are not identical in their ability to respond centration of drug in the biophase.

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Methyl ergonovine domethacin may increase the risk of neonatal intra- is an -agonist that causes direct smooth muscle con- ventricular hemorrhage 150mg fluconazole free shipping fungus gnats soil drench. Carboprost tromethamine is a methylated nor cardiac arrest has been demonstrated in the fe- analogue of prostaglandin F2 buy discount fluconazole 50mg online antifungal drops. Prostaglandins and mechanisms of these medications are contraindicated for labor in- preterm birth cheap fluconazole 150mg with amex fungus gnats coffee grounds. Prostaglandins are involved in the pyretic response cheap fluconazole 50 mg line antifungal nail polish walmart, Tocolytics for preterm labor: A systematic review. She reports no pain, no their due date are classified as having postterm or labor contractions, no vaginal bleeding, no leaking postdate pregnancy. She carry the increased risk of fetal death (2 to 6 times reports that her fetus is moving. On further history, as high as for women who are at 40 weeks’ gesta- you find that the patient reports no other com- tion). Women who are postterm have a higher risk plaints, and her medical, surgical, social, and family of cesarean section, trauma from delivery, prolonged histories are all negative. The physical examination bleeding after delivery, and prolonged hospitaliza- you perform produces normal findings. Newborns who are born postterm have an in- uterine fundal size measurement is 40 cm. Her creased risk of being pathologically large (macroso- pelvic examination reveals that her cervix is 3 cm mia), birth trauma, intolerance to labor, meconium dilated, 50% effaced, soft in consistency, and midpo- staining, meconium aspiration, and possible subse- sition in the vagina. What would be a good course In appropriate patients, it nearly always leads to of action? Pelvic Scoring for decide who are appropriate patients for labor induc- Elective Induction. The following table defines the scoring weeks (when using the woman’s menstrual period to system. Cervical Cervical Score Dilation (cm) Effacement (%) Station Consistency Position 0 Closed 0–30 3 Firm Posterior 1 1–2 40–50 2 Medium Midposition 2 3–4 60–70 1,0 Soft Anterior 3 5 80 1 Androgens, Antiandrogens, 6363 and Anabolic Steroids Frank L. Its primary function is to regulate In males, testosterone is the principal circulating andro- the differentiation and secretory function of male sex gen, and the testes are the principal source. Androgens also possess protein ana- the adrenals are capable of androgen synthesis, less bolic activity that is manifested in skeletal muscle, bone, than 10% of the circulating androgens in men are pro- and kidneys. Testosterone is synthesized by drugs, having limited and relatively predictable side ef- Leydig cells of the testes at the rate of about 8 mg/24 fects. Plasma androgen concentrations also vary greatly interstitial cells of Leydig found between the seminifer- in women through the menstrual cycle, with peak levels ous tubules. Acetate is converted Circulating testosterone is reversibly bound to two major to cholesterol through numerous reactions in or on plasma proteins, albumin and gamma globulin. Cholesterol, once to albumin is a relatively nonspecific low-affinity and formed, is stored in lipid droplets in an esterified form. Free testosterone reflects the amount turned to the cytoplasm, where it serves as the principal that is biologically active and available for interaction precursor of testosterone. Leydig cell origin and serves as a hormone reservoir Plasma testosterone levels also exhibit age-associated and transport protein for the androgen. Urinary 17-ketosteroid excre- the regulation of plasma testosterone is accomplished tion declines slowly as a result of a concomitant through a dynamic feedback interaction among the hy- decrease in the metabolic clearance rate of testos- pothalamus, pituitary, and testis (Fig. Inhibin has been isolated primarily from testicular extracts but also may be found in the antral fluid of ovarian follicles in females. The catabolism of plasma testosterone and other androgens occurs primarily in the liver (Fig. The currently accepted hypothesis of androgen action in Androgen-binding male sex accessory organs is depicted in Fig. Non-sex accessory tissues also are targets for the testes, where they regulate testosterone synthesis and protein anabolic actions of androgens. The resultant increases in possess lower levels of endogenous hormone, minimal serum testosterone levels exert a negative feedback at 5 -reductase activity, and lower concentrations of spe- both the hypothalamic and the pituitary levels. Androgens and estrogens can modulate go- nadotropin release at both the hypothalamus and pitu- Androgens produce both virilizing and protein anabolic itary levels. In addi- and lengthening of the vocal cords, and a significant tion to the effects on male reproductive function, an- (30%) increase in the rate of long bone growth. The degree of virilization clude the growth of male-pattern facial, pubic, and body and timing of puberty also affect peak bone density and hair, the lower vocal pitch resulting from a thickening risk of osteoporosis in males. The protein anabolic actions of androgens on bone and skeletal muscle are responsible for the larger stature of males than females. They also have several of Androgens other actions, not necessarily associated with maleness, Virilizing effects such as lymphoid tissue regression during puberty. Although re- 63 Androgens, Antiandrogens, and Anabolic Steroids 729 placement therapy is the primary use of androgen ad- of puberty. The eunuchoid phenotype is caused by ministration, these hormones also are used and abused absent or deficient androgenic induction of the undif- for their protein anabolic effects. Androgen tence, or decreased libido in otherwise fully virilized replacement therapy is effective only when the end or- males. The source of hypogonadism can be testicular, as gans are sensitive to androgens, so certain forms of occurs in primary hypogonadism, or it may result from pseudohermaphroditism are unresponsive to androgen abnormalities of the hypothalamic–pituitary axis, as in replacement. The compounds most effective in bringing about masculinization are the long-acting enanthate, cypionate, Prepuberal Hypogonadism or propionate esters of testosterone; these preparations Prepuberal hypogonadism is often unsuspected until a require intramuscular injection. Recently effective cuta- delay in male sexual development is noticed at the time neous forms of androgens have become available and may be equally effective.