Mark Corson

By E. Flint. Columbia Union College. 2018.

This is regrettably confusing because this receptor has now been found in the brain also (Awad and Gavish 1987) buy proscar 5 mg fast delivery androgen hormone nausea. Another difference is that these peripheral benzodiazepine receptors are located mainly intraneuronally cheap 5 mg proscar prostate natural remedies, on mitochondrial outer membranes proscar 5 mg on-line prostate cancer mortality rate, rather than on the plasma membrane. In the brain, they are associated with glial cells but in the periphery they are found in a range of tissues, including mast cells and platelets. Their function is still a matter of intense debate but one possibility is that they regulate cholesterol uptake and, secondary to this, the synthesis of neurosteroids (Do Rego et al. Other possible, albeit controversial, functions of these receptors are reviewed in Doble and Martin (1996). However, not all turned out to share the properties of the protypical benzodiazepines (anti-anxiety, anticonvulsant, etc. However, all these groups of compounds, including the benzodiazepines themselves, span the activity spectrum: from full inverse agonist to full agonist. In between these extremes are compounds which have either partial agonist or partial inverse agonist activity and some are antagonists (Fig. This spectrum of actions reflects the overall effects of these drugs on native receptors and is usually assessed in whole animals. However, the synthesis of receptors comprising different combinations of subunits has shown that the activity of these drugs depends greatly on subunit composition. Apparent effects of the antagonist in vivo could also depend on whether there is any tonic activation of the benzodiazepine receptor by an endogenous ligand. Flumazenil is available in the clinic for intravenous infusion to reverse benzodiazepine-induced sedation (e. However, because it has a half-life of only 1 h in humans, it is only of realistic benefit in reversing the actions of agonist benzodiazepines with a short half-life, such as midazolam. The potential benefits of benzodiazepine partial agonists are as non-sedative, anti- anxiety agents. Because of their low efficacy, it was predicted that a partial agonist should not induce sedation even if their receptor occupancy exceeds that normally required for an anti-anxiety effect when using a full agonist. One such compound, bretazenil, has been developed but failed to reach the clinic because it displayed some sedative activity and, more problematic, there were end-of-dose rebound effects that were undoubtedly exacerbated by its short half-life. Currently, the partial agonist, abecarnil (a b-carboline), is undergoing clinical trials. For the current status of the development of partial agonists and other promising benzodiazepine receptor ligands see Cheetham and Heal (2000). Even benzodiazepine inverse agonists might yet find some useful applications such as in the relief of cognitive deficits (which are increased by benzodiazepine full agonists) (Abe, Takeyama and Yoshimura 1998). However, three candidates have been given prominent attention, albeit for different reasons, and are worthy of mention. Although subsequently found to be an artefact of the extraction process, this compound turned out to be a ligand for the benzodiazepine receptor, nonetheless, and was the first inverse agonist to be identified. Finally, the presence in human post-mortem brain tissue of the active metabolite of diazepam, desmethyldiazepam, raised some curiosity and frank alarm (Sangameswaran et al. At the time of its discovery in the brain it was thought that there was no enzyme system capable of producing such halogenated compounds and that its presence in the brain reflected dietary intake from an environment contaminated by overuse of its parent compound. However, its discovery in stored brain tissue which had been obtained before the synthesis of the benzodiazepines allayed these fears. It is now thought possible that some benzodiazepines, including desmethyl- diazepam, occur naturally and that they are taken in as part of a normal diet (Table 19. Although, by analogy with the opioids, one would expect there to be an endogenous ligand for the widely distributed benzodiazepine receptor, its existence remains uncertain and we must be alert to the possibility that any such ligand(s) could have either agonist or inverse agonist activity. An important study, aimed at distinguishing between these possibilities, has been carried out in humans (Nutt et al. In this case, the administration of the antagonist, flumazenil, should induce anxiety in normal subjects and exacerbate anxiety in anxious patients. In this case, the administration of flumazenil should relieve anxiety in anxious patients and have no, or sedative, effects in healthy subjects. In this case, flumazenil (which normally has zero efficacy) should induce anxiety in anxious patients but have no effects in healthy subjects because they have normal receptors. To distinguish between these possibilities, flumazenil was administered to panic patients and control subjects. The results of the experiment were consistent with the third possibility: flumazenil induced panic attacks in 8 of 10 patients but not in control subjects (Fig. Recent studies suggest that the binding of [11C]flumazenil is abnormally low in panic patients (Malizia et al. The receptor shift theory could also explain why benzodiazepines are ineffective in treating panic disorder but, because these drugs do effectively relieve generalised anxiety, it seems that the theory might explain the origin of the former, but not the latter disorder, and that they have different causes. He went on to stimulate the locus coeruleus of (chair- restrained) monkeys and showed that this caused behavioural changes, some of which resembled a cluster of behaviours displayed by the animals when under threat. This is an a2-adrenoceptor antagonist that increases the firing rate of, and release of noradrena- line from, noradrenergic neurons by blockade of presynaptic a2-adrenoceptors on the neuronal cell bodies and terminals, respectively. Nevertheless, the a2-adrenoceptor agonist, clonidine, which has the opposite effect to yohimbine on noradrenergic neurons, is sometimes used to relieve anxiety, especially that associated with alcohol and opiate withdrawal. However, it is not a viable long-term treatment for anxiety because of its effects on the cardio- vascular system. One complication with the above concept is that, in some brain regions, the majority of a2-adrenoceptors are postsynaptic and so a reduction in a2-adrenoceptor-mediated noradrenergic transmission, after treatment with yohimbine, cannot be ruled out as a causal factor for the anxiety induced by this drug. Measurements of noradrenaline release in animals have not helped to resolve this confusion. These observations question the role of noradrenaline as an initiator of anxiety as does the finding that the anti-anxiety drug, buspirone (see Chapter 9), increases the concentration of noradrenaline in the extracellular fluid in the frontal cortex of freely- moving rats (Done and Sharp 1994). Unfortunately, no studies have investigated the effects of chronic administration of this drug on noradrenergic transmission; this could be important because, unlike benzodiazepines, buspirone is effective therapeutically only after several weeks of treatment.

Metronidazole is also an inhibitor of aldehyde dehydrogenase generic proscar 5mg visa prostate oncology specialists reviews, causing reactions with ethanol 5mg proscar free shipping androgen hormone questionnaire, but the drug does not cause hypoprothrombinemia purchase proscar 5 mg with amex man health book. Life-threatening invasive aspergillosis, with necrotizing pneumonia, most com- monly occurs in severely immunocompromised patients. The mortality rate approaches 50%, but high intravenous doses of amphotericin B may be lifesaving. Oral itraconazole in less severe aspergillosis, but its efficacy in the invasive forms of the established. Praziquantel is the drug of choice for treatment of all fluke (trematode) infec- tions and most tapeworm (cestode) infections. Its antihelminthic action derives from an increase in membrane permeability to Ca2+, which results in contraction, followed by paralysis, of worm musculature. Mebendazole also has antihelminthic activity, but it is restricted to the nematodes. Doxycycline (or tetracycline) takes at least a 7-day course of treatment in gonor- rhea, raising the possibility of patient noncompliance. The most common pathogens implicated in bacterial meningitis in a neonate (age <1 month) are group B streptococci, followed by E. However, ampicillin is also needed to cover for Listeria monocytogenes, which occurs with an incidence of 7 to 8% in neonatal meningitis. Clindamycin has a mechanism of action similar to, if not identical with, eryth- romycin and related macrolides. Chloramphenicol also binds to the 50S subunit but interferes with the activity of peptidyltransferase. Once-daily aminoglycoside dosing regimens in the treatment of bacterial infections have similar effectiveness to the conventional dosing regimens and do not appear to increase the risk of ototoxicity. They are less likely to result in toxicity to the kidney, and the impact on cost favors once-daily dosing. There is no difference in resistance emergence rate from that of conventional dosing regimens. Ceftriaxone (1M) is a drug of choice in gonorrhea and is also highly effective in otitis media, infections in which beta-lactamase-producing strains of H. Diloxanide is a backup drug for noninvasive intestinal amebiasis, but it has minimal activity in Giardia infections. Neuraminidase is an enzyme on the lipid envelope of influenza A and B virions that prevents their clumping together and also their binding to the surface of cells that have been already infected. Neuraminidase inhibitors interfere with this activity and reduce the availability of virions for entry into noninfected cells. Oseltamivir and zanamivir decrease the severity and duration of symptoms if given within a day or two of onset. Changes in lipid metabolism and distribution occur quite commonly, and type 2 diabetes has also been reported. Indinavir is also notable for its tendency to precipitate in the urinary tract, causing nephrolithiasis, unless the patient is maintained in a high state of hydration. Fluconazole is distinctive in terms of its ability to penetrate into the cerebro- spinal fluid, reaching levels similar to those in the blood. Conditions enhancing susceptibility to drug-induced pancreatic dysfunction include hypertriglyceridernia, hypercalcemia, and history of excessive ethanol use. Liver dysfunction including hepatitis may occur with the antitubercular drugs, isonia- zid, and pyrazinamide. Aminoglycosides (gentamicin, streptomycin) are bactericidal inhibitors of protein synthesis. They bind to the 30S ribosomal subunit to block initiation, cause misreading, and may prevent elongation. Nystatin interacts with ergosterol to form artificial membrane "pores" (azole antifungals inhibit ergosterol synthesis). Penicillins (and most cephalosporins) have minimal activity against the atypi- cal organisms associated with community-acquired pneumonia, although they may be effective against S. Erythromycin has been used, but the estolate form is contraindicated in pregnancy because of an increased risk of cholestasis. Likewise, clarithromycin and ofloxacin are both effective in community- acquired pneumonia, but neither of these drugs can be used in pregnancy because animal studies have shown detrimental effects on fetal development. Drugs that are capable of crossing the blood-brain barrier penetrate most body tissues and can appear in the milk of the lactating mother. Although concentrations of such drugs may be low in breast milk, they may cause effects in an infant who perhaps weighs just a few kilograms. Fluoroquinolones also penetrate tissues, and because they are contraindicated in children, it seems appropriate not to risk infant exposure via breast milk. The "safest" drug situation concerns nystatin, which is used only via the topical route and, as a polyene, does not cross membrane barriers. Vancomycin is usually considered to be a backup drug to metronidazole in colitis due to Clostridium difficile on the grounds that it is no more effective,is more costly, and should be reserved for treatment of resistant gram-positive coccal infections. None of the other drugs has activity in pseudomembranous colitis-indeed, they may cause it! Indications for the use of penicillin G are currently limited for a number of reasons.

It was part of a multiple drug regimen to which a fetus Alkylating agents 135 was exposed in the first trimester and it had multiple abnormalities similar to Baller–Gerald syndrome (Artlich et al order proscar 5 mg amex mens health jeans guide. An increased frequency of malformations was found in offspring of pregnant rats that were given thioguanine during embryogen- esis (Thiersch cheap 5 mg proscar with visa prostate cancer young living, 1957) proven 5 mg proscar androgen receptors in hormone-dependent and castration-resistant prostate cancer. A few reports of monotherapy with this agent during early pregnancy have been published. Wagner and associates (1980) reported a newborn with limb and ear anomalies whose mother received this agent alone. In a review of leukemia treatment during pregnancy, 46 infants (summarized from 24 case reports) were born to mothers who received cytosine arabi- noside (Ara-C) at some point during pregnancy, and several had received it during the first trimester (Caliguri and Mayer, 1989). Among exposed pregnancies, there were two spontaneous and six therapeutic abortions. Of the remaining 38 pregnancies, there were four intrauterine deaths (apparently grossly normal), one infant with polydactyly and one with adherence of the iris to the cornea; one newborn presented with neonatal pan- cytopenia (Caliguri and Mayer, 1989). Anecdotal reports seem to indicate an increased risk of birth defects following first trimester exposure to cytarabine, this kind of infor- mation cannot be used to attribute risk. However, this suspicion is bolstered by findings in experimental animal studies parallel to those in humans. In addition, it seems that treatment of leukemia during pregnancy given after the first trimester is not associated with a high frequency of congenital abnormalities. It is important to note that the folate antagonist methotrexate was a component of the polydrug therapy in several of these gravidas. When given during embryogenesis, cytarabine was associated with an increased fre- quency of congenital anomalies in two rodent teratology studies (Chaube and Murphy, 1965; Percy, 1975). Other uses include bladder, cervix, endometrium, esophagus, head and neck, liver, lung, ovary, prostate, and skin cancers. Among 24 infants whose mothers were treated with intravenous fluorouracil in com- bination with doxorubicin and cyclophosphamide for breast cancer during the second and third trimesters of pregnancy, no congenital anomalies occurred (Berry et al. However, it must be noted that these exposures occurred outside the period of embryo- genesis, and do not indicate anything about the risk of birth defects that may be related to first trimester exposure to the drug. However, the patient had also undergone bowel resec- tion and multiple diagnostic X-ray procedures during late embryogenesis. Malformations included bilateral radial aplasia, absent thumbs, abnormal fingers, a sin- gle umbilical artery, hypoplastic aorta, and esophageal atresia, imperforate anus, and renal dysplasia. These anomalies were probably not related to fluorouracil because of the gestational timing of the exposure (i. Two normal infants were born following first-trimester maternal treatment with intravaginal 5-fluorouracil (Odom et al. Skeletal and other major anomalies (cleft palate, central nervous system) were increased in frequency among offspring of several species of pregnant nonprimate animals born to mothers exposed to this antineoplastic during pregnancy (Chaube and Murphy, 1968; Dagg, 1960; Shah and Mackay, 1978; Wilson et al. No reports regarding the use of bleomycin monotherapy during organogenesis have been published. One newborn infant had profound but transient neonatal leukopenia (resolved by day of life 13) following maternal therapy for metastatic adenocarcinoma that was initiated very early in the third trimester with bleomycin in combination with etoposide and cisplatin (Raffles et al. Limb and tail anomalies were reported in nine rat teratology studies involving bleomycin (Nishimura and Tanimura, 1976). Antibiotics 137 Dactinomycin Dactinomycin (Cosmegen), also known as actinomycin-D, is one of a group of antibi- otics produced by various species of streptomyces called the actinomycins. Primary indication for dactinomycin in obstetrics is to treat gestational trophoblastic tumors. Four normal infants (one set of twins) were born to mothers who received dactinomycin in the second and/or third trimesters of pregnancy as part of com- bination therapy in two pregnancies (Gililland and Weinstein, 1983), but there was no exposure during embryogenesis. The manufacturer of dactinomycin reported that mal- formations were increased in frequency in various animals whose mothers were given doses of the drug several times those normally used in humans, but the information is unpublished and no details were provided. It is isolated from the broth of Streptomyces caespitosus, similar to dactinomycin. No reports have been published regarding the use of mitomycin during pregnancy and infant outcome. Congenital anomalies were increased in several mouse teratology studies that employed several times the usual human therapeutic dose of the drug during preg- nancy (Friji and Nahatsuka, 1983; Gregg and Snow, 1983; Snow and Tam, 1979). In an experimental animal model, approximately 6 percent of mitomycin crossed the placenta in pregnant rats (Boike et al. Anthracycline antibiotics Anthracycline antibiotic antineoplastics (daunorubicin or Cerubidine; doxorubicin or Adriamycin, Rubex) are potent inhibitors of nucleic acid synthesis and are nonspecific cell cycle-phase agents. No studies are available of either of these agents during pregnancy, but there are a num- ber of case reports. In reviews from 18 reports of 28 pregnancies that were exposed to one of the anthracyclines at various stages of gestation, eight of the pregnancies were at 16 weeks’ gestational age or less at exposure. There were 24 normal infants (one set of twins), two spontaneous abortions, one thera- peutic abortion, and two fetal deaths (Turchi and Villasis, 1988; Wiebe and Sipila, 1994). One infant was reported with multiple 138 Antineoplastic drugs during pregnancy abnormalities, similar to Baller–Gerold syndrome; was exposed in utero at conception to combination therapy containing doxorubicin and daunorubicin (Artlich et al. Among 43 infants published in 26 reports, the frequency of birth defects was not increased, with two malformed infants (Friedman and Polifka, 2006). The cytotoxic nature of these drugs suggests that embryonic exposure may not be without risk, depending upon the timing of the exposure. The manufacturer of daunorubicin reported multiple defects in rabbits; pre- maturity and low birth weight was found in mice exposed to the drug in utero, but this infor- mation has not been published.

For example proscar 5 mg prostate nutrition, by administering reserpine (which causes noradrenaline to leak out of the vesicles into the cytoplasm)together with an inhibitor of the enzyme monoamine oxidase (which will prevent metabolism of cytoplasmic noradrenaline) purchase 5 mg proscar overnight delivery androgen hormone replacement, it is possible to redistribute the noradrenaline stored within nerve terminals because it leaks from the vesicles but is preserved within the neuronal cytoplasm purchase 5 mg proscar otc prostate exam. Under these conditions, the total amount of transmitter in the terminals is unchanged but impulse-evoked release rapidly diminishes. Different evidence, mainly based on histological studies, suggested that acetylcholine is also released by vesicular exocytosis. It is then possible to fracture axolemma membranes in a way that separates their lipid bilayer. Electron microscopy reveals numerous pits in the membranes which are thought to reflect the vesicle/axolemma fusion pore of vesicles in the process of exocytosis. Subsequent studies, combining immunocytochemistry with electron microscopy, showed that proteins in the membranes of vesicles become incorporated into the axolemma during transmitter release. Furthermore, when neurons are stimulated in a medium containing an electron-dense marker, that does not penetrate the neuronal membrane, the marker later appears in vesicles inside the nerve terminals (Basbaum and Heuser 1979). This suggests that such markers are incorporated into the vesicles when they come into contact with the extracellular fluid during exocytosis. For instance, impulse-evoked release of this transmitter is prevented by the drug, vesamicol, which blocks uptake of acetylcholine from the cytoplasm into the terminal vesicles (Searl, Prior and Marshall 1991). Although most evidence supports vesicular exocytosis of acetylcholine (see Ceccarelli and Hurlbut 1980), some researchers contest this view. According to this scheme, opening of the pore is triggered by an increase in the concentration of intracellular Ca2‡ and allows gated release of aliquots of cytoplasmic acetylcholine. The vesicles are thought to serve merely as a reserve pool of transmitter and for sequestration of intracellular Ca2‡ (Dunant 1994). They are delivered to the terminals by fast axoplasmic transport and are the only type of vesicle to be found in axons (see Calakos and Scheller 1996). This suggests that they have different functions and regulatory processes which, since they contain peptides, agrees with the finding that their release requires higher frequencies of nerve stimulation than does that of the classical neurotransmitters. Electron microscopy certainly shows that their membranes are recovered after fusion with the axolemma but precisely how this occurs is unresolved. One possibility is that they are retrieved intact from the active zone, immediately after release has taken place. Alternatively, they could become incorporated into, and mix with, the components of the axolemma but are reformed after sorting of the different membrane elements (see Kelly and Grote 1993). Recent studies of exocytosis from retinula cells of the Drosophila fly suggest that both these processes for membrane retrieval can be found within individual cells. These studies have shown that there is rapid recovery of vesicular membrane from the active zone. However, a second slower process exists which takes place at sites remote from the active zone and involves the formation of invaginations in the axolemma. This process is thought to precede endocytosis because the formation of these invaginations is followed by the appearance of tubular cisternae within the nerve terminal from which new vesicles bud-off (Koenig and Ikeda 1996). This finding raises the interesting question of whether these different processes lead to the formation of two different populations of synaptic vesicles with different release characteristics. The reserve pool would then comprise vesicles which are docked, more remotely, on the neuronal cytoskeleton. It is thought that vesicles move from one pool to the other as a result of the actions of protein kinases which effect cycles of phosphorylation/dephosphorylation of proteins, known as synapsins, which are embedded in the vesicle membranes. Although they account for only about 9% of the total vesicular membrane protein they probably cover a large proportion of their surface. Recent evidence suggests that, while synapsins might have a role in synaptogenesis, they also regulate the supply of vesicles to the release pool (Hilfiker et al. Experiments in vitro have shown that dephosphorylated synapsin I causes growth and bundling of actin filaments which are a major component of neuronal microfilaments. Such findings form the basis of the hypothesis that synapsin I forms a ternary complex with transmitter storage vesicles and the neuronal cytoskeleton, thereby confining vesicles to a reserve pool (Fig. Phosphorylated synapsin dissociates from the vesicles and F-actin, reduces the number of vesicle anchoring sites, and so frees the vesicles to the release pool. This process would enable synapsin to act as a regulator of the balance between the releasable and reserve pools of vesicles. By contrast, injection of dephosphorylated synapsin I into either the squid giant axon or goldfish Mauthner neurons inhibits transmitter release. It has also been suggested that synapsin promotes vesicle clustering by a process which is not dependent on phosphorylation. It achieves this by forming cross-bridges between vesicles and by stabilising the membranes of the aggregated vesicles, thereby enabling them to cluster in the active zone without fusing with each other or the axolemma. When synapsin dissociates from the vesicles, as occurs during neuronal excitation, this membrane-stabilising action is lost. This would enable fusion of the membranes of vesicles, clustered near the active zone, with the axolemma. This scheme is supported by evidence that vesicles near the active zone have much lower con- centrations of synapsin than those located more remotely (Pieribone et al. For instance, it has been suggested that they might also regulate the kinetics of release, downstream of the docking process. An increase in intracellular Ca2‡ triggers phosphorylation of synapsin I which dissociates from the vesicular membrane. This frees the vesicles from the fibrin microfilaments and makes them available for transmitter release at the active zone of the nerve terminal and Scheller 1996). The following sections will deal with those factors about which most is known and which are thought to have a prominent role in exocytosis. The extent to which this scheme explains release from large dense-cored vesicles is unclear, not least because these vesicles are not found near the active zone.