By G. Bandaro. Monmouth University, West Long Branch New Jersey.

As first shown by Kligman (10) cheap 25mg fildena with mastercard, the action of retinoids and carotenoids (11) on sun damage has led to numerous works purchase fildena 25 mg mastercard. Ascorbic acid buy cheap fildena 25 mg online, which can be found in Rosa canina (dog rose) fruits, actini- dia (kiwi fruits), or Malphigia punicifolia (West Indian cherry) is an antioxidant that is also used for many of its other properties. It is active in the synthesis of carnitin, a molecule intervening in the transfer of lipids inside the mitochondria. Ascorbic acid thus plays a role in im- proving cell resistance due to a better use of lipids. Ascorbic acid is an anti-inflammatory agent that degrades and eliminates histamine. Flavonoids, rich extracts from Gingko, Fagopyrum (buckwheat), Eucalyp- tus sambucus (European elder), or Sophora japonica are used for their antioxidant and anti-free-radical properties (13). Rosmarinus (rosemary) extracts, rich in carnosic acid, are very potent anti- oxidants, used to protect food. They favor the exchanges between the inner and the outer compartment of the cells or between cells. Some of these have excep- tional healing properties that make them of particular value in sun or antiage products: camelia (tea), argania, medicago (alfalfa), spinacia (spinach), Butyro- spermomum (shea butter), Cucurbitaceae, Pongamia (hongay or pongamia oil). Phytosterols slow down the aging process by favoring fatty acid desatura- tion, which in turn maintains membrane fluidity and catalytic activity. One can also find plant waxes (sugar cane, Camauba, Ceroxylon, Jojoba, rose) which are used to protect lips, hands, or face from dehydration. Certain plants (yeast, wheat, apple, potatoes, rice bran, Agaricus, Morus alba, or white mulberry) are rich in ceramides and glycosylceramides. These may be used for their action on skin or hair to provide hydration or reconstitute epider- mal barrier function. Other plants are rich in oils containing very long-chain fatty acids (C22, 24, 26) like Pentaclethra or ewala oil used in Africa as a massage oil, or Lim- nanthes alba or shambrilla oil. Fat Storage and Slimming We are currently using botanical extracts with very specific actions that act at various levels of adipocyte metabolism. Phytosterols from plant oils are being investigated for their potential action Botanical Extracts 103 on fat storage or degradation, on adipocyte differentation or multiplica- tion. Antiage Ascorbic acid is a key element in collagen synthesis (also in ‘‘botanical colla- gen’’). They improve microcirculation leading to a better irrigation of the tissues and thus to nutrition, hydration, hormone transport, etc. Protection of elastic fibers (collagens, elastin) is promoted by extracts hav- ing free-radical scavenging properties, activating the synthesis of these proteins or inhibiting the enzymes responsible for their degradation: streptomyces, black currant, Centella asiatica (rich in asiatic acid), Rudbeckia purpurea, Coleus, Areca,... Apigenin, extracted from Chamomile and its derivatives, and rutin from Fagopyrum have anti-inflammatory properties (by inhibiting histamine release), but they are also β-glucuronidase inhibitors. Other extracts rich in polyphenols—tanins—also have antihy- aluronidase activity (16–18). Recent studies show the importance of amino acids in protecting the skin barrier function. This hormone is very important to many biological processes and decreases rapidly with age. They con- tribute to the elimination of dead cells from the skin surface, hydration, as well as cell renewal. Selenium (Astrogalus) is said to play an important role in antiaging (immu- nity, inflammation, free radical scavenging), zinc (Taraxacum) in hair growth (action on testosterone) (24), and mother of pearl from shellfish in wound healing or tissue repair. Saponins, a huge family of compounds, whether of a steroidal or triterpenic structure, are known for their detergent activity. Constant research shows that saponins, present in botanical extracts, have tremendous pharmacological and metabolic properties. Centella asiatica (asiaticosides)—stimulates synthesis of collagen and fi- bronectin. Sterols from sabal, serenoa as well as ∆7 sterols are inhibitors of 5-α- reductase, an enzyme involved in androgenic alopecia, hyperseborrhea of the scalp or the skin, as well as acne. Glycyrrhizin from glycyrrhiza and harpagosides from harpagophytum are broadly used for their anti-inflammatory properties. Saponins have also been shown to increase stress resistance by increasing cortisol and prostaglandins, to protect membranes (Eleutherococcus), to increase metabolic efficacy (Medicago), to stimulate cells (Ginseng, bupleurum). Extracts from ganodema are immunostimulating, immunoregulating, pro- long all life in culture, and act on endocrine functions. Extracts from arctophylos uva-ursi, coactis, and adenotricha rich in arbutin and methylarbutin are used for their depigmenting effect. The main difference between the two is really the intention of the manufacturer (i. Most cosmetic products today address both the rational and the emotional aspects that characterize their need in society, while they are often still considered as a ‘‘dream in a bottle’’ (Charles Revson). Botanicals are playing an increasingly important role in the activity and safety of cosmetics; they allow for a renewal of the source of active ingredients in drugs. Oriental herbs in cosmetics: Plant extracts are reviewed for their potential as cosmetic ingredients. The effect on rhino mouse skin of agents which influ- ence keratinization and exfoliation. New raw materials and new technologies in cosmetics: Chouji and Gennoshouko extracts as a useful scavenger of reactive oxygen species for cosmetics. Prevention of second primary tumors by an acyclic retinoid, polypre- noic acid, in patients with hepatocellular carcinoma. Inhibitory effects of some natural products on the activation of hyaluronidase and their antiallergic actions. Arginine supple- mented diets inhibit endotoxin—induced bacterial translocation in mice Nutrition 1995; 11:371–374. Colloidal silicic acid for oral and topical treatment of aged skin, fragile hair and brittle nails in females. Vitamin A generically encompasses retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and retinoic acid (vitamin A acid) (Fig. In clinical use, retinoids have established their effectiveness in treating acneiform eruptions (e. Additional retinoids are currently being investigated, as are novel uses of retinoids already established in clinical practice. The main focus of retinoid usage in cosmeceuticals has been its role as the mythical ‘‘fountain of youth’’ (i. Retinoids, like all drugs, have adverse effects, the most infamous one being teratogenicity. Over 2000 derivatives have been developed in the hope of finding retinoids with increased therapeutic efficacy coupled with diminished local and systemic toxicity.

These evaluations may be performed by the investigator buy online fildena, by the subject buy fildena with visa, or by third persons comparing photographs of before and after in a randomized and blinded manner buy generic fildena 100mg line. This and similar rating scales may also be applied at baseline and follow-up to specific parameters such as wrinkles, surface roughness, mottled pigmentation, overall color, skin dryness, and texture. A 100-mm visual analogue scale has been successfully utilized to rate the overall appearance of the skin and specific parameters of fine wrinkles, discrete pigmentation, shallowness, and texture. A clinical panel evaluation technique has been described that potentially allows precise, consistent, and completely unbiased evaluations of clinical state (9). Very high-quality photographic slides are obtained, prepared in matched ca- rousels, and placed on two random-access projectors in a rear-screen projection booth. Side-by-side comparison of each patient’s time-randomized baseline and end-of-treatment photographic slides by trained, but uninvolved, evaluators is thus accomplished in a completely blinded and randomized manner. Both global response and specific parameters of overall appearance, fine wrinkles, and dis- crete pigmentation can be judged and graded on a 13-point balanced categorical Figure 2 Photoaging 21 scale with zero representing no difference between the two photographs. A score of 1to 6 is assigned when the end-of-treatment photograph is perceived to be better and a score of 1to 6 when the baseline photograph is perceived to be better. Trials of isotretinoin have successfully utilized the clinical panel and dem- onstrated the therapeutic effect compared to vehicle (10,11). Claim Substantiation If the above-described pharmaceutically oriented trials demonstrate significant effect, claim substantiation may be relatively easy and clear-cut. However, distinction may be made among the various aspects of a claim for a product. There are, in each country, very different cultural and legal perspec- tives dictating what can be stated about a product designated for photoaging. These claims are generally related to the broad perception of whether the cosmetic or skin-care aspects, the potential cosmeceutical action, or a proven pharmaceuti- cal effect is being claimed and advertised. In this regard, everything from con- sumer statements, consumer panel testing, instrumentation results, clinical testing results, to absence or presence of statements regarding alteration of structure or function of the skin must be considered in evaluating, regulating, and advertising a product. Use of Instrumentation With no other methodology is there the same potential for accurate, precise, reproducible, consistent data to used appropriately or to be nefariously manip- ulated to purport therapeutic effect as with the now-available and sophisticated instrumentation (12). Evaluation of the obtained instrumental data must take place in a clinically appropriate context for them to be truthful and meaningful (Table 5). Table 5 Instrumentation Optical profilometry Fluorescent photography Ultrasound Transepidermal water loss Skin hydration by capacitance/conductance Laser Doppler Colorimetry 22 Cunningham Optical Profilometry Profilometry is one of the most useful techniques in photodamage evaluation. A skin replica obtained with silflo dental impression material is oriented and side- illuminated to produce shadows of various widths and depths that are captured by high-resolution video interfaced to a computer containing image-analysis soft- ware (13). The width and depth of the ‘‘peaks’’ and ‘‘valleys’’ of the skin surface may correspond to roughness, wrinkling, or other surface contours or markings and can be differentiated by the analysis software. The technique is reproducible and blinded, can be utilized even in large clinical trials, and has correlation with the clinical condition. Evaluation of the cheek and crows feet area of the face consistently demonstrate approximately a 10% improvement in wrinkles after treatment with tretinoin (14). It can also be useful in evaluation of skin roughness that may change after tretinoin or alpha hydroxy acid treatments. The photographs of photoaged skin may be highly dramatic in accentuating mottled and diffuse pigmentary alterations and may also be quantitative, utilizing visual counting of macules and evaluation of diffuse change compared to a 20-point gray scale (15). Polarized photography allows selective enhancement of the appearance of wrinkles, pigmentary change, or ery- thema (16). High-Resolution Facial Photography A very sophisticated research tool, high-resolution facial photography allows di- rect visualization and measurement of individual wrinkles and appears to be po- tentially highly sensitive and precise for determination of this parametner (17). Present systems are proprietary, however, and have not been commercially avail- able. Ultrasound High-frequency B-scan ultrasound consistently demonstrates an echo-poor band in the upper dermis corresponding to the location of dermal elastosis of pho- toaging (18). Refinement of ultrasound techniques may soon allow more precise definition of epidermal and dermal thickness and changes resulting from therapy. Hydration status is not specific to photo- damage but may be improved as a result of some treatments for photodamage. Cutaneous Blood Flow Blood flow through the skin can be measured by laser Doppler instrumentation and may reflect local flow as with increased capillary growth or as a result of local inflammation or overall vascular response to environmental factors such as exercise. As with many other techniques mentioned herein, interpretation of re- sults is critical to reliable conclusions about pharmacological effect of a product. The Dansyl Chloride Technique This relatively simple method allows estimation of epidermal turnover by staining stratum corneum with dansyl chloride (or other stains) and subsequently evaluat- ing the time to elimination of the stain from the skin by visual or instrumental observation. The time to elimination of the stain (in days) reflects the rate at which the desquamating stratum corneum has been replaced by underlying proliferative epidermis. Agents purporting skin ‘‘rejuvenation’’ are frequently evaluated with modifications of this technique. Skin Color by Colorimetry With the use of appropriate filter, this technique is more specific, sensitive, and reproducible than visual observation of skin color. It offers an instrumental ap- proach to enable separation of skin color effects related to melanin or heme pig- ments and is especially useful in precisely quantitating erythema. Although many techniques exist to evaluate these characteristics, in the absence of notable prod- ucts that improve these functional aspects, they are not yet of widespread pharma- ceutical testing utility. The issue of classification of any product thus becomes partly definitional and partly perceptual. As beauty is in the eye of the beholder, so the consumer, investigator, or regulator may view any objective fact in disparate fashion. There is not a single or universally defined and accepted endpoint with any of the above-elaborated techniques that determines if a product is cosmetic, cosmeceutical, or pharmaceu- tical. Most of the below products described are accepted as at least cosmetic in effect, many as pharmacologically active, and most as cosmeceutical as defined above (Table 6). Moisturizers As pointed out in a previous chapter, it is now clear that even simple occlusion of the skin, with a ‘‘moisturizer’’ such as petrolatum, has definite effects on skin Table 6 Potential Cosmeceuticals Moisturizer Retinoids Estrogens Various vitamins and minerals Alpha-hydroxy acids Beta-hydroxy acids Hydroquinones Hyaluronic acid Natural cartilage polysaccharides Photoaging 25 structure and probably on function and thus it is appropriate to begin the discus- sion of potential cosmeceuticals with this seemingly simple product (see Chap. In fact, however, the matter is far from simple, as modern moisturizers have achieved a sophistication and multiplicity of potential effects in parallel with our increasing knowledge of stratum corneum barrier function and kinetics of skin hydration and transepidermal water loss. There is no universally accepted clinical or biomechanical definition of dry skin, although photoaged skin is frequently described as dry. Instrumental measure- ments may reveal changes in skin surface topography such as irregularity of stra- tum corneum and abnormal desquamation by profilometric evaluation or sticky tape application. A decrease in moisture of the viable epidermis can be deter- mined by capacitance (Corneometer) or conductance (Skicon-100)techniques. Strictly cosmetic effects of change in perception of dryness and skin smoothness also may be noted. Retinoids Retinoids, with pleotropic biological effects including modulation of epidermal cell differentiation and sebocyte dedifferentiation, have been extensively studied and have, in a way, become the prototypic cosmeceutical by which others are judged in treatment of photoaging.

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This is thought to provide the principal mechanism responsible for presynaptic inhibition purchase fildena 150 mg without a prescription, whereby neurotransmitters inhibit their own release (autoinhibition) during high-frequency synaptic transmission buy 150 mg fildena with visa. This process can be replicated by applying exogenous transmitters or their analogues (see Fig buy line fildena. Records show intra- axonal recordings from (a) a regenerating sciatic nerve axon following nerve crush; (b) a normal sciatic nerve axon; and (c) a demyelinated ventral root axon after treatment with lysopho- sphatidylcholine. Currents were evoked by two successive 10 ms steps from 770 mV to 0 mV, separated by a prepulse to ‡90 mV. There are, however, a number of other ion channels, generally for K‡ or Ca2‡, that have a more subtle controlling effect on neuronal activity. Their opening may be initiated by (or dependent on) preceding changes in membrane potential and ion flux, but they can be affected indirectly by various neurotransmitters, e. The role of these channels in controlling the overall activity of neurons is clearly important and needs to be considered. However, most nerve cells possess other K‡ channels which are opened during nerve cell discharges but which stay open much longer. These do not contribute much to the repolarisation of individual action potentials but instead affect the excitability of the neuron over periods of hundreds of milliseconds or even seconds. Two principal types of channel having this effect have been identified and their properties are summarised in Table 2. This means that they are activated by the Ca2‡ influx through voltage-gated Ca2‡ channels when these are opened during a somatic or dendritic action potential, or during trains of action potentials. These are resistant to normal K‡ channel blocking agents such as tetraethylammonium or 4-aminopyridine, but can be selectively blocked (with varying affinities) by the bee-venom apamin or by certain quaternary ammonium compounds such as tubocurarine and derivatives therefrom. They were originally called M-channels because they were inhibited by activating Muscarinic acetylcholine receptors. In spite of their different structure and gating mechanisms, these channels have quite a lot in common in functional terms. This effect makes an important contri- bution to the postsynaptic action of these transmitters, and is discussed further below. The resultant Ca2‡ influx leads to a rise in intracellular [Ca2‡] that (after a delay) activates the K Ca current. Voltage responses to injecting depolarising and hyperpolarising currents from an initial resting potential of around À47 mV. However, the action potentials open Ca channels, so intracellular Ca2‡ gradually rises as shown in Fig. This current partly repolarises the cell and raises the threshold for action potential generation, so the action potential train in Fig. This allows the action potential discharge to continue throughout the length of the depolarising current injection (Fig. When the opening of M-channels is inhibited by muscarine, this adaptation is again lost. Also note that muscarine has actually depolarised the cell Ð the level of membrane potential before injecting the current pulse has changed. This is because a few M-channels are open at the resting potential and actually contribute to the resting potential. However, in practice, their effects are slightly different, depending on the pattern of stimulation, and in fact the two currents act synergistically Ð i. As Ca noted above, transmitters can also close, or open, other K‡ channels that do not directly regulate excitability but instead determine the resting potential of the neuron, and hence depolarise or hyperpolarise the neuron. These include two classes of Ca2‡ channel not involved in transmitter release Ð dihydropyridine-sensitive high-threshold L-type channels, homologous to the cardiac Ca2‡ channels responsible for ventricular contraction and some pacemaking activity; and low-threshold, rapidly-inactivating T- type Ca2‡ channels. Second, as in the ventricular muscle fibres of the heart, opening of L-type channels can generate sustained plateau potentials following the initial Na2‡-mediated action potential Ð for example, in the rhythmically firing neurons of the inferior olive (Fig. At resting potentials 4760 mV, these channels are inactivated and hence non-conducting (a voltage-sensitive closure process resembling Na‡ channel inactivation). Under these conditions, the relay neurons show sustained rhythmic firing when tonically depolarised. However, if the neurons are first hyper- polarised, T-channel inactivation is removed. The Ca2‡ entry activates K Ca channels, to produce a long-lasting (several hundred ms) after-hyperpolarisation. Hence, as the Ca2‡ is extruded and the K current declines, the low-threshold T-type Ca2‡ channels open, and the cell depolarises to Ca reach the threshold for the Na‡ channel, giving a new action potential, and so on. The burst is arrested first because the Na‡ channels inactivate, and then because the T-type Ca2‡ channels inactivate. Both inactivation processes are removed when the cell hyperpolarises back again, so becoming available for another burst. As a result, the cells change their firing pattern from tonic firing to burst-firing simply dependent on membrane potential. This is thought to explain the switch between tonic firing in awake animals to burst-firing during slow-wave sleep. In the awake state, the neurons are maintained in a tonic state of depolarisation due to the release of neurotransmitters such as histamine and acetylcholine, which inhibit K‡ currents (see above), but hyperpolarise during slow-wave sleep when transmitter release diminishes Ð or when the receptors for the transmitters are blocked by anti-histamines or anti-cholinergic drugs. However, it should be emphasised that T-channels are quite widely distributed and their burst-inducing properties may also be important in some forms of epilepsy since they can be blocked by certain anti-epileptic drugs, such as ethosuximide. Finally, entry of Ca2‡ through somatic and dendritic Ca2‡ channels activates calmodulin-dependent protein kinases to modulate transcription, and thereby plays a crucial role in certain components of neural development and plasticity. Neither L nor T channels appear susceptible to the form of G-protein-mediated inhibition characteristic of N or P/Q channels. This leads to a slow depolarisation until the threshold for the T-type Ca2‡ channels open, leading to a rapid depolarisation and spiking (Fig. The h-channels then switch off (because the cell is depolarised) and reopen during the subsequent hyperpolarisation. In this way sustained oscillations of membrane potential, leading to a steady rhythmic action potential discharge, can be maintained. The h-channels are blocked by low concentrations of Cs‡ ions, or by agents which block the cardiac current and slow the heart: such agents inhibit the neural membrane potential oscillations and discharges. Conversely, transmitters or mediators that inhibit adenylate cyclase, like enkephalins and adenosine, shift the activation curve to more negative potentials and slow rhythmic discharges. The amplifier also incorporates a device for applying a potential to the pipette, so that the potential across the cell membrane at the tip of the pipette can be varied. By convention, the direction of current flow always refers to the direction in which ‡ve ions move. Thus, outward current is generated by ‡ve ions flowing out of the cell into the pipette (or 7ve ions going the other way).

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The drug is metabolizedinthe liver quality 100mg fildena, and the elimination half-life isapproximately 3 order discount fildena line. Diltiazemis also available for intravenous infusion and isoccasionally usedinthis form to control heart rate during atrial fibrillation or atrial flutter order fildena with a visa. Dosage The usual dosage of verapamil is 240–360 mg/day in divideddoses given every 8 hours. Both drugs are also available in long-acting forms that can be given onceortwiceaday. Five to 10 mg is administered over a period of 2 minutes; an additional 10 mg can be given after 10 minutes. Infusion rates can be titrated to as muchas15mg/h, depending on the response of the heart rate. Continuing diltiazeminfusions for longer than24hours is not rec- ommended because longer infusionperiods have not been studied. Accordingly, the major electrophysiologic effects of calcium-channel blockers are limited to these two struc- tures. As a general rule, calcium blockers have minimal or no electro- physiologic effecton the atrial or ventricular myocardium. However, the slowcalcium channel has beeninvoked as a necessary com- ponent in the development of both early afterdepolarizationsand delayed afterdepolarizations. Accordingly, calcium-channel blockers can occasionally ameliorate afterdepolarizationsand the arrhyth- mias they cause. Further, it isapparent that the calcium channels might be re- sponsible, on occasion, for localized areas of slowconductioninthe ventricles. Thus, in relatively rare circumstances, calcium-channel blockers can be used to treat ventricular arrhythmias (see below, and Chapter 12) Like Class I antiarrhythmic drugs, calcium blockers exhibit use dependence—theirbinding and blocking of the calcium channels increases at more rapid heart rates. Clinical use of calcium-blocking agents Supraventricular tachyarrhythmias Verapamiland diltiazemcan be very useful in the management of manysupraventricular tachyarrhythmias either by affecting the 104 Chapter 6 mechanism of the arrhythmia itself and thus terminating or pre- venting it, or in slowing the ventricular response to the arrhythmia. Atrial tachyarrhythmias All these arrhythmias are localized to the atrial myocardium,socal- cium blockers have very little direct effecton them. Ingeneral, it is easier to control ventricular response during atrial fibrillation thanit is during atrial flutter or atrial tachycar- dia. On the other hand, controlling the ventricular response during chronic atrial fibrillationis often quite achievable, thoughacombination of drugs may be required (calcium blockers plus beta blockers and/or digoxin). In the acute setting, intravenous infusionsofdiltiazem have proven to be very effective in controlling the ventricular rate during atrial tachycardias. Multifocal atrial tachycardia Multifocal atrial tachycardia isalmost exclusively seenduring acute illness, most oftenduring acute respiratory decompensation. Both verapamiland diltiazem are moder- ately effective in preventing recurrences of these reentrant arrhyth- mias. Ventricular tachyarrhythmias As noted, the slowcalcium channel has very little to do with depolar- ization of the typical myocardial cell. Accordingly, neither verapamil nor diltiazem are efficacious in treating typical reentrantventricular tachyarrhythmias. Two clinical syndromes have beendescribed,however, in which verapamil has been effective in treating ventricular tachycardia— repetitive monomorphic ventricular tachycardia(which seemstobe duetoachannelopathy) and idiopathic left ventricular tachycardia (which may be a form of reentranttachycardia involving abnormal, verapamil-sensitive Purkinje fibers). Toxicity and drug interactions Verapamil has significant negative inotropic properties and can precipitate congestive heart failure in patients with impaired ventricular function. Like any calcium blocker (manyofwhich are marketed solely for the treatmentofhypertension), verapamil can producesignificanthypotension. Other side effects include consti- pation, dizziness, nausea, headache, edema, and bradyarrhythmias. Negative inotropic effects can be additive when verapamil is given with flecainide, disopyramide, or beta blockers. Verapamil canin- crease drug levels of carbamazepine,cyclosporine, and theophylline. Vera- pamil can reduce serum lithium levels in patients taking lithium; on the other hand, verapamil can increase sensitivity to lithium. Diltiazem also has negative inotropic properties but clinically sig- nificant impairmentofventricular functioncaused by diltiazem has been rare. Since these agents do not fit the Vaughan-Williams classification system (see Chapter 2), they are considered separately in this chapter. Digoxin, the preparation of digitalis nowmost commonly used, is well absorbed, isexcreted by the kidneys, and has an elimi- nation half-life of 1. First, it increases intracel- lular calcium during muscle contraction,thus increasing inotropy. Second, it increases parasympathetic tone, which makes it useful for treating supraventricular arrhythmias. Digoxin can also be of benefit in treating bypass-tract-mediated tachycardias, butbecause the drug can have a direct effecton the bypass tract itself (resulting in a shortening of refractoriness and thus potentially making the bypass tract more dangerous), it is rarely used for these arrhythmias. The cardiac arrhythmias associated with digoxin toxicity are potentially life threatening. Digoxin toxic- ity appears to increase the risk of developing refractory ventricular arrhythmias or bradyarrhythmias after direct-current cardioversion; cardioversion should be avoidedif digoxin levels are high. The man- ifestationsofdigoxin toxicity are exacerbated by hypokalemia, and maintaining normal serum potassium levels in patients taking this drug is important. Managementofdigoxin toxicity consists of stopping the drug, cor- recting electrolyte disturbances (especially, hypokalemiaand hypo- magnesemia), pacing (ifsignificant bradyarrhythmias are present), and using phenytoin or lidocaine for ventricular arrhythmias. If life- threatening arrhythmias are present, use of digoxin-specific anti- bodies can be rapidly effective and should be considered. Digoxin levels can be elevated by concomitant use of quinidine, amiodarone, verapamil, erythromycin,and tetracycline. The drug isremoved from the circulation very quickly;its half-life is less than 10 seconds. In ad- dition to its electrophysiologic effects, adenosine can have a potent vasodilatory effect, butthis effect is also fleeting. The drug is given asarapid intravenous bolus, usually beginning with 6 mg intravenously for 1–2 seconds. Flushing, headache, sweating,and dizziness are also relatively common,but these symptoms last for less than 1 minute. Magnesium Magnesium has not received as much attention as other elec- trolytes, which reflects a general, recurrent themeand shortcom- ing in science—ifsomething is difficult to measure, ittendstobe ignoreddespite its potential importance. Not only is the metabolism of magnesium complicated (absorption from the gut ishighly vari- able and dependson the level of magnesium in the diet, and the Table 7. Recently, however, there has beengrowing interest in the use of intravenous magnesium to treat a variety of medical conditions (in addition to its traditional place in the treatmentofpreeclamp- sia): asthma, ischemic heart disease, and cardiac arrhythmias. The precise mechanism by which magnesium can ameliorate ar- rhythmias has not been established. That magnesium might have an effectoncardiac electrophysiology is not surprising,however, when one considers that among the manyenzyme systems in which mag- nesium plays a crucial role is the sodium–potassium pump. Magne- sium can thus have an important influenceon sodium and potassium transport across the cell membraneand therefore oncardiac action potential.

Meat purchased from a grocery store fildena 50 mg mastercard, fresh or frozen buy fildena with amex, pro- vides you with a variety of organ specimens cheap fildena 50 mg with amex. To make a du- rable unfrozen sample, cut a small piece, the size of a pea, and place it in an amber glass bottle (½ oz. Pork brains from the grocery store may be dissected to give you the different parts of the brain. Chicken livers often have an attached gallbladder or piece of bile duct, giving you that extra organ. I use ½ oz amber glass bottles with bakelite caps (see Sources) to hold specimens. To make a specimen of skin, use hangnail bits and skin peeled from a callous, not a wart. As it thawed, different organs were cut away and small pieces placed in bottles for preserving in cold tap water and grain alcohol. The piece of intestine closest to the anus corresponds to our colon, the part closest to the stomach corresponds to our duodenum. The 2 layers of the stomach and different layers of the eye, the optic nerve and spinal cord were obtained this way. Another complete set of tissue samples were obtained from a freshly killed steer at a slaughter house. In this way the 4 chambers of the heart were obtained, the lung, trachea, aorta, vein, pancreas, and so forth. Purchasing a Complete Set of Tissue Samples Slides of tissues, unstained or stained in a variety of ways for microscope study give identical results to the preparations made by yourself in the ways already described. You also have a set of test substances, whether chemical compounds, or elements, or products. Your goal is to search in your own organs and body tissues for the substances that may be robbing you of health. Then you will only hear resonance with substances that are ac- tually in the body fluid. Since this cannot be proved with certainty, obtain several urine samples from different persons whom you believe to be healthy and make several test specimens in order to compare results. Label your specimens Urine A (child), Urine B (woman), Urine C (mine), and so forth. Electronically, a dead specimen is equivalent to a live specimen, so that pasteurization of the milk does not help. Use your own, if you have deparasitized yourself and test negative to various fluke stages. When you test with a substance on one plate and nothing on the other, you are searching your entire body for that substance. By putting a tissue sample on the other plate you are testing for the substance specifically in that tissue in your body, and this is much more sensitive. To find mercury in your kidneys you would use a mercury sample on one plate, and a kidney sample on the other. If you put a substance on each plate, a resonating circuit means the two samples have something in common. For exam- ple, if you have mercury on one plate and some dental floss on the other, a positive result indicates mercury in the floss. Test your skin for the presence of brown sugar, using the newly made sample bottle and your skin specimen. Prepare a paper applicator by tearing the corner from a white unfragranced paper towel. Dip the paper wick in the pint of sugar water and apply it to the skin of your inner arm where you can rub freely. Leave the shredded wick on the skin and tape it down with a piece of clear tape about 4 inches long (this increases the time you have to work). Place your skin tissue specimen on one plate and the sugar specimen bottle on the other plate. As soon as you hear resonance, implying that the skin has absorbed the sugar solution (which may take a full minute), replace the skin specimen with one of liver and listen for resonance again. After five to ten minutes the sugar will be gone from all of these tissues and your experiment is ended. Notice that you have only a few minutes to get all your testing done after the skin has absorbed the test substances. Assemble the products named in the isopropyl alco- hol list (page 45) and benzene list (page 163)... Place the isopropyl alcohol test substance on one plate and your products, in turn, on the other. This is such a global tragedy that people must protect themselves by using their own tests. Rather than assur- ances, regulatory agencies should provide the consumer with cheap and simple tests (dip sticks and papers so we need not lug our Syncrometers around). Even if some test should fail, not all tests would fail to find an important pollutant like benzene. If your aluminum specimen actually has cadmium or cop- per in it, you are also testing for these in your brain. Leave your purest aluminum test substance on one plate, and replace the brain sample with these items, testing them one at a time. Choose tissues like kid- ney, nerves, brain, liver, in addition to white blood cells. I have never dissected human tissues and subjected them to confirmatory laboratory tests. It seems reasonable that because skin and tongue are directly provable, that other tissues work similarly. Testing Someone Else Seat the person comfortably with their hand resting near you. Since you are touching this person, you are putting yourself in the circuit with the subject. A coil of about 10 microhenrys, worn next to the skin, works well and is easily made. Obtain insulated wire and wrap 24 turns around a ball point pen (or something about that size), closely spaced. Nevertheless, ortho-phospho-tyrosine, Salmonella, mercury in your kidneys, aluminum in the brain all show up in the saliva, too. This test is not as sensitive as having the person present in the circuit, though.

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Digoxin-specific antibody fragments | Dihydrocodeine tartrate | 253 Additional information Common and serious Injection-related: Too rapid administration: Although rare generic 50mg fildena, allergic undesirable effects reactions are thought to be more likely with rapid dosing buy cheap fildena 100mg on line. Signs and symptoms of digitalis intoxication should begin to improve within 30 minutes of administration discount fildena 100 mg without a prescription. This assessment is based on the full range of preparation and administration options described in the monograph. Dihydrocodeine tartrate 50mg/mL solution in 1-mL ampoules * Dihydrocodeine is an opioid analgesic. Pre-treatment checks * Do not use in acute respiratory depression, where there is a risk of paralytic ileus, in raised intracranial pressure and in head injury, in comatose patients and phaeochromocytoma. Close monitoring of respiratory rate and consciousness is recommended for 30 minutes in patients receiving an initial dose, especially elderly patients or those of low bodyweight. Close monitoring of respiratory rate and consciousness is recommended for 30 minutes in patients receiving an initial dose, especially elderly patients or those of low bodyweight. Technical information Incompatible with Not relevant Compatible with Not relevant pH 3--4. Dihydrocodeine tartrate | 255 Monitoring Close monitoring of respiratory rate and consciousness is recommended for 30 minutes in patients receiving an initial dose, especially elderly patients or those of low bodyweight. Measure Frequency Rationale Pain score At regular intervals * To ensure therapeutic response. Monitor for side- * Can cause side-effects such constipation, which effects and toxicity may need treatment. Additional information Common and serious Common: Nausea and vomiting (particularly initially), constipation, dry mouth, undesirable effects urticaria, pruritus, biliary spasm, " or #pulse, hallucinations, euphoria, drowsiness, histamine release (caution in asthmatics). Counselling May cause drowsiness; if affected do not drive or operate machinery, avoid alcoholic drinks (the effects of alcohol are enhanced). This assessment is based on the full range of preparation and administration options described in the monograph. It has also been used with sodium calcium edetate in acute lead poisoning particularly acute lead encephalopathy. The aim of treatment is to provide an excess of dimercaprol in body fluids until the excretion of the metal is complete. Do not use in iron, cadmium or selenium poisoning as the dimercaprol--metal complexes formed are more toxic than the metals themselves. Pre-treatment checks * Do not use in patients with peanut allergy as the injection contains arachis oil. Intramuscular injection Contains arachis oil -- should not be given in peanut allergy. Dimercaprol | 257 Technical information Incompatible with Not relevant Compatible with Not relevant pH Not relevant Sodium content Nil Excipients Contains arachis oil. Special handling For disposal: React with weak aqueous solution (up to 15%) of calcium hypochlorite. Monitoring Measure Frequency Rationale Temperature After the initial * Any abnormal reaction (e. Renal function Daily during therapy * Discontinue or continue with extreme caution if acute renal failure develops during therapy. It is rapidly metabolised and the metabolites and dimercaprol--metal chelates are excreted in the urine and bile. Action in case of Antidote: Treatment with a parenteral antihistamine or ephedrine 30mg may overdose reduce symptoms. This assessment is based on the full range of preparation and administration options described in the monograph. Dipyridam ole 5mg/mL solution in 2-mL ampoules * Dipyridamole is a coronary vasodilator and inhibits platelet aggregation. Thallium-201 should be injected within 3--5 minutes following the 4-minute infusion. Dose calculation: 567 Â bodyweight ðkgÞ Total dose in mL ¼ 5000 Intravenous infusion via a syringe pump Preparation and administration 1. Dilute to at least 3 times the original volume of dipyridamole injection with NaCl 0. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with No information Compatible with Flush: NaCl 0. This will allow initial thallium perfusion imaging to be performed before reversal of the pharmacological effects of dipyridamole. Also abdominal pain, vomiting, diarrhoea, nausea, dizziness, headache, paraesthesia, myalgia. Significant * The following may #dipyridamole levels or effect: interactions caffeine (avoid for 24 hours before test), theophylline (avoid for 24 hours before test). Action in case of Antidote: No known antidote; stop administration and give supportive therapy overdose as appropriate. This assessment is based on the full range of preparation and administration options described in the monograph. Disodium folinate (sodium folinate) 50mg/mL solution in 2-mL, 8-mL and 18-mL vials * Disodium folinate is a derivative of tetrahydrofolic acid, the active form of folic acid. Pre-treatment checks * Do not give if the patient is anaemic owing to vitamin B12 deficiency. Consult specialist literature as regimens vary greatly depending on the indication. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Technical information Incompatible with No information Compatible with Flush: NaCl 0. Stability after From a microbiological point of view, should be used immediately; however, preparation prepared infusions may be stored at 2--8 C and infused (at room temperature) within 24 hours. Monitoring Measure Frequency Rationale Creatinine and methotrexate At least daily in folinic acid * The dose of disodium folinate levels rescue is dependent on these parameters in “rescue”. Disodium folinate | Disodium levofolinate | 263 Additional information Common and serious Immediate: Pyrexial reactions, anaphylaxis and urticaria have been reported undesirable effects rarely. Significant * Folinate may #levels or effect of the following drugs: interactions possible #efficacy of folic acid antagonists, e. This assessment is based on the full range of preparation and administration options described in the monograph.