"Generic propranolol 40 mg on line, heart disease rate per 100 000".

O. Yorik, M.A., M.D.

Associate Professor, Philadelphia College of Osteopathic Medicine

Current knowledge of the health effects of exposure to low doses of nerve agents has been reviewed and is the subject of Chapter 4 in this book (see also Sidell and Hurst, 1997; Moore, 1998a, 668 Chemical Warfare Agents: Chemistry, Pharmacology, Toxicology, and Therapeutics 1998b). To respond rapidly and effectively to a chemical incident and to respond in such a way as to save lives, first-responders must subject themselves to concentrations of the agents that may exceed current occupational exposure limits. Currently available detection technology for use at the scene of an incident may not measure chemical agents at these occupational exposure levels. In the case of sarin for example, the maximum airborne exposure concentration for an 8-hour workday is two orders of magnitude lower than the detection threshold for a hand held chemical detector (Moore and Alexander, 2001). Additionally, many of the protective ensembles that will be used by first-responders will not protect down to these levels or have not been definitively tested for their protective efficacy. Although the data appear to point to no adverse health effects from an acute, low dose of nerve agent, studies are continuing, which may provide additional support to these conclusions or may find effects that have previously gone undetected. Several recent comprehensive reviews describing the pharmacology of and general treatment principles for the major nerve agents have been prepared by Sidell (1997) and Spencer et al. Numerous recent comprehensive reviews of the health effects of low-level exposure to nerve agents are provided by Sidell (1997), Romano et al. There is information on persistent effects following symptomatic exposure to sarin from studies of victims of the 1995 Tokyo subway attack. It was suggested that a delayed effect on the vestibulo-cerebellar system was induced by acute sarin poisoning, with females possibly more sensitive than males (Yokoyama et al. Another follow-up study found visual evoked potential latencies to be significantly prolonged in sarin cases compared with the matched controls (Murata et al. One subject developed neuropathy with pathological evidence of nerve fiber degeneration at death 15 months after sarin exposure (Himuro et al. Unfortunately, all these studies were accomplished on patients who received symptomatic exposures to the agents. There are no reliable follow-up studies on people who were exposed to the agent at levels for which they experienced no effects or only mild symptoms, such as miosis. Although the data appear to point to no adverse health effects from an acute, low dose of nerve agent, studies are continuing that may provide additional support to these conclusions or may find effects that have previously gone undetected. The most sensitive marker of an observable health effect and the purported cause of early significant performance degradation is nerve agent-induced miosis. Although various exposure durations can be considered in the planning of future research, a one-time or continuous exposure lasting from minutes to several hours should be the primary target duration of exposure. The research required for this military requirement must address the development of best estimates of concentration or duration of nerve agents causing mild human incapacitation. Research needs included reliable and reproducible experimental systems to deliver and quantify very low levels of nerve agents in laboratory animals. If determining the lowest dose causing a significant performance decrement in humans is the objective, then studies conducted in nonhuman primates where accurate nerve agent inhalation dosimetry is combined with biochemical and physiological measurements, in addition to operant and behavioral testing, will be of particular benefit. A practical consideration must be to ensure that greater sensitivity will not involve a higher incidence of false positive measurements. False alarms themselves distract soldiers from combat-related tasks and may initiate the requirement for wearing personal protective gear and result in a significant decrease of combat effectiveness. Thus, emphasis on the development of highly sensitive and reliable field detection devices must go on in parallel to any toxicological studies of low-level effects. It is critical that military operational doctrine does not require implementation of maximum physical protective measures at exposure levels that are significantly below those likely to produce casualties or long-term disabilities. In order to do this, human toxicity must be estimated as accurately as possible, and appropriate toxicological data are required to minimize the uncertainty around these values. In a civilian setting, such as the terrorist nerve agent attacks in Japan, a single exposure lasting from minutes to hours should be the most realistic scenario. Rather, research on potential acute and delayed adverse health effects from low-level exposure to nerve agents should be of the highest priority. For civilian populations, the potential long-term health effects from an acute exposure to low levels of nerve agents must be studied. A source of potentially valuable perspective could be obtained from epidemiological study of pesticide-exposed workers. Likewise, follow-up assessment of patients surviving self-inflicted exposures would provide additional case-related information regarding delayed-onset and persistent, adverse clinical effects.

Some obvious reasons include cytotoxicity and poor membrane permeability of potential inhibitors. However, other reasons are that current drug screens generally use small peptide fragments of substrates, which may have different secondary structures and often lack exosite regions (Chen and Barbieri, 2006). Complicating factors include absorption, distribution, metabolism, clearance, and systemic toxicity of inhibitor candidates. A prudent approach, therefore, is to combine high-throughput screening with cellular, isolated tissue, and in vivo assays as an iterative strategy, rather than to rely primarily on cell-free assays. Toxins were added to the muscle bath at 0 time from concentrated stock solutions; each concentration was tested on a separate hemidiaphragm muscle. Twitch tensions were elicited by supramaximal stimulation of the phrenic nerve at 30 s intervals. Tensions were 2%, 5%, 3%, 32%, and 39% of control, at the above respective time points. Current efforts are focused on examining analogs of toosendanin to shed more light on its mechanism of action. Muscles tensions were elicited by supramaximal stimulation of the phrenic nerve at 30 s intervals. The signature for designating a protein for degradation is attachment of a ubiquitin chain. Ubiquitin serves a number of cellular functions but the most widely investigated is its role in targeting to the proteasome. Ubiquitin is attached to a specific protein through the action of a cascade of enzymes designated E1, E2, and E3, which can sequentially relay ubiquitin to culminate in the covalent ligation of the ubiquitin carboxyl terminus to a lysine side chain of the target protein. The covalent attachment of ubiquitin is exquisitely regulated, and the selection of the protein target for ubiquitination resides primarily in the function of E3 ubiquitin ligases. A specific E3 may have a single or very small number of protein targets that it will recognize to bring about ubiquitination of that target (Figure 16. The E3 ubiquitin ligases are generally modular, with one domain of the E3 specifically binding and recognizing the target protein and another domain, E3 ligase catalytic domain, functioning to facilitate the attachment of ubiquitin to the target protein lysine residue (Figure 16. Such modular design allows for the generation of chimeric recombinant proteins, which contain a combination of a recognition domain for novel targets together with an E3 ligase catalytic domain to attach ubiquitin to this novel target (Figure 16. This approach of generating chimeric recombinant or ``designer' ubiquitin ligases is applied to a number of fields, including cancer therapy (Zhou et al. The specificity for selecting the target substrate protein for ubiquitin modification resides in the E3 enzyme. Botulinum Neurotoxin: Mechanism and Countermeasures 413 Development of safe and effective metalloprotease inhibitors with in vivo efficacy will no doubt be difficult. Some of the challenges involve targeting of drugs to the nerve terminal, ensuring their access to the intracellular compartment and increasing the bioavailability of the drugs to match the duration of the toxin (Goodnough et al. In addition, different inhibitors may be needed for each serotype, requiring multiple parallel efforts. Reaction of tetraethylammonium with the open and closed conformation of the acetylcholine receptor ionic channel complex. Evaluation of captopril and other potential therapeutic compounds in antagonizing botulinum toxin-induced muscle paralysis. Antagonism of botulinum toxin-induced muscle weakness by 3,4-diaminopyridine in rat phrenic nerve-hemidiaphragm preparations. Effect of 3,4-diaminopyridine on rat extensor digitorum longus muscle paralyzed by local injection of botulinum neurotoxin. Evaluation of phosphoramidon and three synthetic phosphonates for inhibition of botulinum neurotoxin B catalytic activity. Antagonism of botulinum toxin A-mediated muscle paralysis by 3,4-diaminopyridine delivered via osmotic minipumps. Structural analysis of botulinum neurotoxin serotype F light chain: implications on substrate binding and inhibitor design. A further survey of the action of Clostridium botulinum toxin upon different type of autonomic nerve fibre. Molecular characterization of murine humoral immune response to botulinum neurotoxin type A binding domain as assessed by using phage antibody libraries.

Role in therapy - Short-acting theophylline may be considered for relief of asthma symptoms119. Short-acting theophylline may provide no additive bronchodilator effect over adequate doses of rapid-acting 2-agonists, but it may benefit respiratory drive. Side effects - Theophylline has the potential for significant adverse effects, although these can generally be avoided by appropriate dosing and monitoring. Short-acting theophylline should not be administered to patients already on long-term treatment with sustained-release theophylline unless the serum concentration of theophylline is known to be low and/or can be monitored. Short-acting oral 2-agonists are appropriate for use in the few patients who are unable to use inhaled medication. Complementary And Alternative Medicine the roles of complementary and alternative medicine in adult asthma treatment are limited because these approaches have been insufficiently researched and their effectiveness is largely unproven. Although the psychotherapeutic role of the therapist forms part of the placebo effect of all treatments, this aspect is viewed as an integral part of the so-called holistic approach used by practitioners of complementary and alternative methods, and mitigates against performance of the large, multicenter, placebo-controlled randomized studies required to confirm efficacy. However, without these the relative efficacy of these alternative measures will remain unknown120. Although one study of the Butyeko breathing method suggested minor benefit, a later study of two physiologically-contrasting breathing techniques showed similar improvements in reliever and inhaled glucocorticosteroids use in both groups, suggesting that perceived improvement with these methods are the result of non-physiological factors122. Side effects - Acupuncture-associated hepatitis B, bilateral pneumothorax, and burns have been described. Side effects of other alternative and complementary medicines are largely unknown. However, some popular herbal medicines could potentially be dangerous, as exemplified by the occurrence of hepatic veno-occlusive disease associated with the consumption of the commercially available herb comfrey. Comfrey products are sold as herbal teas and herbal root powders, and their toxicity is due to the presence of pyrrolizidine alkaloids. Different age groups require different inhalers for effective therapy, so the choice of inhaler must be individualized. Information about the lung dose for a particular drug formulation is seldom available for children, and marked differences exist between the various inhalers. This should be considered whenever one inhaler device is substituted with another. Based on these considerations, a general strategy for choosing inhalers in children is given in Figure 3-3. Spacers retain large drug particles that would normally be deposited in the oropharynx, reducing oral and gastrointestinal absorption and thus systemic availability of the inhaled drug. Apart from those mentioned below, there have been no satisfactory studies from which conclusions about their efficacy can be drawn. A single controlled trial of chiropractic spinal manipulation failed to show benefit of this therapy in asthma121, and a systematic review of homeopathy found only three relevant **See also the "Asthma Medications: Adults" section at the beginning of this chapter for more information on the therapeutic role and side effects of various therapies. Controller Medications Controller medications for children include inhaled and systemic glucocorticosteroids, leukotriene modifiers, longacting inhaled 2-agonists, theophylline, cromones, and long-acting oral 2-agonists. Role in Therapy - Inhaled glucocorticosteroids are the most effective controller therapy, and are therefore the recommended treatment for asthma for children of all ages. Figure 3-4 lists approximately equipotent doses of different inhaled glucocorticosteroids administered via different inhalation devices. Dose-response studies and dose titration studies in children128,129 demonstrate marked and rapid clinical improvements in symptoms and lung function at low doses of inhaled glucocorticosteroids. Commercially produced spacers with well-characterized drug output characteristics are preferable. If these are not available or feasible, a homemade spacer (for example, one made from a 500 ml plastic cold drink bottle) may be used126. Nebulizers have rather imprecise dosing, are expensive, are time consuming to use and care for, and require maintenance.

However, routine use of this treatment is not recommended because of the pain caused by the injections, the local side-effects and recurrence of the nail abnormalities after discontinuation of the therapy. In addition, the efficacy of intralesional steroids in nail matrix psoriasis is limited, with only 50% success in treating nail pits. Systemic treatment with methotrexate or cyclosporin can clear the nail changes, but this can be recommended only when nail psoriasis is associated with widespread disease or psoriatic arthritis. Retinoids are of little value in the treatment of nail psoriasis except for hyperkeratotic nails and pustular psoriasis. Oral administration of etretinate or acitretin can even worsen the nail changes owing to the development of nail brittleness, pyogenic granuloma-like lesions and chronic paronychia. Oral photochemotherapy can improve crumbling of the nail plate and psoriatic involvement of the proximal nail fold, but is less effective in nail pitting or subungual hyperkeratosis. Superficial radiotherapy can have a beneficial effect on psoriatic nails but is not recommended because the benefits are short-lived. Pustular psoriasis of the nail unit usually fails to respond to conventional topical treatments. Local treatment with topical anti-metabolites (mechlorethamine, 1 % fluorouracil) is an option, even though results are variable. A study of 46 patients with pustular psoriasis of the nails indicates that systemic retinoids at low dosage (less than 0. Topical calcipotriol is also useful as maintenance therapy in patients who responded to retinoids, in order to prevent recurrence. However, if lichen planus is correctly diagnosed and treated, permanent damage to the nail unit is rare, even where there is diffuse involvement of the nail matrix. Systemic steroids are effective in treating nail lichen planus: intramuscular triamcinolone acetonide 0. Intralesional injections of triamcinolone acetonide Treatment of common nail disorders 321 10mg/ml represent a possible, but painful, alternative when the disease is limited to a few finger nails. Mild relapses are frequently observed, but recurrences are usually responsive to therapy. Steroid treatment is not useful in pterygium, since the nail matrix cannot be regenerated. Although the mechanism of action of vitamin E in yellow nail syndrome is still unknown, antioxidant properties of alpha-tocopherol may account for its efficacy. A 5% solution of vitamin E in dimethyl sulphoxide produced marked clinical improvement in a double-blind controlled study. Oral itraconazole, 400 mg daily one week a month for several months, or oral flucouazole, may be beneficial in some cases. Before the ointment is applied to the nail plate surface, it is mandatory to cover the periungual skin with plastic tape in order to protect the skin from maceration. Finally, the medication is wiped off and the softened nail plate is removed using nail clippers. Chemical nail avulsion is only effective when the nail plate is partially or totally detached from the nail bed. It is not useful on normal nails, but can be successful in removing onychomycotic nails as well as thickened psoriatic nails. Patients with severe onychophagia or median nail dystrophy can be helped by daily bandaging the injured fingers with permeable adhesive tape. Fluoxetine at high dosages (60 mg/day) can be helpful in interrupting this compulsive disorder in adults. The life span of periungual warts may be such that they-and the various treatments-may exceed the patience of both patient and physician! A great variety of treatments are listed in all pharmacopoeias, reflecting their individually limited success rates. Topical treatment Topical agents include: keratolytic agents, virucidal agents and immunomodulators. Keratolytic agents Keratolytic agents are the most popular first-line treatment of warts and are particularly suitable for young children, who can apply at home creams, ointments, tapes or quickdrying acrylate lacquers containing salicylic acid in concentrations ranging from 10% to 40%.

The adverse consequences and widespread criticisms that can result from using centrally acting drugs are well illustrated by the use of the narcotic fentanyl by Russian security personnel against rebels who held citizens as hostages (Section V. Depending on the volume of fluid to be projected, dispersion devices range from small handheld pressurized canisters for use against single or small numbers of individuals, to water cannons to engage larger groups or crowds. The active material is mixed with a base such as chlorate or lactate that, on ignition, causes volatilization of the material that subsequently condenses into a cloud of solid or super cooled liquid droplets. The suspended particles or droplets then settle or aggregate into larger agglomerations. Grenades are thrown or propelled by a launcher, and cartridges can be fired from a shotgun, a riflemounted launcher, or a gas=air gun. Firing allows for greater accuracy of delivery and increased distance compared with hand-thrown grenades, but as high-velocity projectiles they can cause body injury or lethality if deployed at too close a range. The standard smoke grenade or canister produces a unifocal source of smoke that spreads with air movements from its origin. A variant on this is a grenade that, on ignition, disperses (projects) several burning subunits over a large area, and thus produces a large cloud from the scattered burning subunits, but with a reduced emission of smoke from each focal subunit. The increased internal pressure that results from ignition of the mixture causes the rubber casing to burst and scatter burning pellets over a wide area, thus producing a multifocal source of smoke (Ballantyne and Johnson, 1974a). One disadvantage of pyrotechnically generated smokes is that they contain potentially harmful combustion products formed during the burning of the mixture. Thus, one aspect of a hazard evaluation of pyrotechnically generated smokes is to conduct chemical analyses to determine the nature and relative amounts of the various combustion products (Kluchinsky et al. A biological indication of the relative contribution of combustion products to the inhalation toxicity of a smoke can be obtained by comparing the toxicity of the products resulting from igniting the burning mix alone with that resulting from igniting the burning mix containing the active agent. Because they persist in the environment, these formulations are not suitable for civilian peacekeeping operations but are used to create a persistent hazard in military operations (Blumenfeld and Meselson, 1971; Ministry of Defence, 1972). On a smaller scale, and mainly for self-defense purposes, ``tear gas pen guns' or ``tear gas pistols' are available in some countries. These devices have an explosive charge that propels a cloud of irritant material toward the assailant. They have a high physical injury potential and have caused severe local skin and eye injuries (Rengstorff, 1969). Dispersion as Vapor Pyrotechnically generated smoke, or even powder clouds, may not be acceptable as safe when based on operational circumstances; for example, situations where fires may be started, or in confined spaces with low ventilation rates where asphyxial effects could develop. Handheld irritant liquid spray devices of various types have been commercially manufactured for use by the police and other security groups. Additionally, in some countries, including the United States of America, spray canisters may be sold to the general public as self-protection devices, although they are illegal in other countries, including the United Kingdom, and civilian airlines prohibit them from being taken on to airplanes in hand luggage. These handheld devices are designed to permit the user to direct a spray of sensory irritant at the face of an assailant causing a prompt onset of temporary incapacitation from severe eye and facial skin effects, during which time the individual can be overpowered or subdued for arrest. The latter has the advantage of avoiding problems associated with potential solvent toxicity, but has the disadvantage of reduction in overall pressure resulting in a progressively weaker stream with use. Some devices now use Dymel (1,1,1,2tetrafluoroethane) as propellant, which has the advantages of being nonozone depleting, maintains canister pressurization, is compatible, and nonflammable (Olajos and Stopford, 2004). The latter factor is particularly important, because it is sometimes neglected in assessing health hazards from formulations (Holopainen et al. The toxicity and potential health hazards from the solvent and formulation should be considered in addition to those from the active constituent. In addition to causing local ocular injury, dichloromethane may also result in systemic toxicity following inhalation of the vapor and its hepatic metabolism to carbon monoxide (Horowitz, 1985; Rioux and Myers, 1988, 1989). Rappert (2003) has commented on the procedures necessary for the regulation of nonlethal weaponry to lessen uncertainties associated with claims and counterclaims associated with the medical implications of the use of nonlethal weaponry against civilian populations. A major recommendation of the Committee was that when chemical agents are used for the purposes of civilian peacekeeping, they should be studied more akin to that of a new drug rather than that of a weapon.