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ConclusionIontophoresis is suitable for applications such as acetic acid (calcifictendinitis and myositis ossificans), calcium chloride and magnesium sulfate(control of musculoskeletal spasms), dexamethasone (inflammation), lidocaine(inflammation of soft tissues), zinc oxide (rheumatoid arthritis). It isalso used in cosmetic applications with devices attached to the skin and foreye treatment aimed at specific tissues of the eye, providing a treatmentoption for various eye diseases, reducing the complications secondary totraditional methods of treatment. The advantages are the significantincrease in the release and control of therapeutic agents, including drugswith high molecular weight. The disadvantages of iontophoresis are thecomplexity of the drug release system and prolonged exposure of the skin toan electrical current.Key words: Iontophoresis; Treatment; Topical applications; Electrical stimulation; Drug infusion. IntroductionIontophoresis ( ) is a noninvasive techniqueused to increase the penetration of ions through the skin layers ( ).
An electrolytic solution is infused withcontrolled voltage and/or charge ( ), with theaid of two electrodes connected to the skin, the anode (positive electrode) andcathode (negative electrode).With the advancement of microprocessor and microcontroller technology, electrotherapydevices configured for iontophoresis application decreased in size and became moreaffordable due to low production costs ( ).Iontophoresis can be used as a noninvasive intraocular drug application and can alsosimulate natural hormone secretion ( ). Theclinical application of iontophoresis may promote reaching of therapeutic indices,providing a treatment option for various eye diseases, reducing the complicationssecondary to classical methods of treatment ( ).The main advantages of iontophoresis are a significant increase in the release ofvarious types of therapeutic agents, including drugs with high molecular weight, inaddition to providing better control of the release of these agents ( ). The disadvantages are: difficultystabilizing the therapeutic agent in the application vehicle, complexity of the drugrelease system, and prolonged skin exposure to an electric current ( ).The aim of this paper is to present the state of the art on iontophoresis, rangingfrom the atomic characteristics of the ion formation to the current applications ofthe technique. First observations of matterFor a better understanding about iontophoresis, the basic structure of theionized atom is presented, merging with historical works on the use ofiontophoresis. Medical books from the sixteenth century show that the personalphysician of Queen Elizabeth I, William Gilbert (1544–1603), was one of the mostimportant authors in the field of electrotherapy (7). Gilbert is considered thefather of modern electrotherapy and wrote over 20 studies on the subject,including the book, De Magnete, in which the foundation ofelectrotherapy, including iontophoresis, was described ( ).
All existing matter in the universe is composed of mass(amount of matter) and has microscopic structures called atoms (from the Greekάτομο, ά = no; τομο = cut, split). Greek philosophers, such as Leucippus ofMiletus and Democritus of Abdera, (400 BC) stated that the atom was indivisible( ). Centuries later, John Dalton(1766–1844), took up this hypothesis and postulated theories about theindivisibility of the atom. It is currently believed that an atom has tens ofsubunits as the results of practical experiments ( ). In order to study the human being, the increasing sequence ofstructures is accepted: 1 atom, 2 molecule, 3 cell, 4 tissue, 5 organ,6 organism (, ). Atomic structures and characteristicsIn the nineteenth century, Joseph John Thomson (1856–1940), with a cathode raytube, showed that atoms were divisible.
In the same century, Eugen Goldstein(1850–1930) discovered the proton ( ).In the twentieth century, Ernest Rutherford (1871–1937) developed the atom modelthat is currently in use. Decades after Rutherford`s evidence, James Chadwick(1891–1974) suggested the existence of the neutron in the atomic structure( ). The atom has atomic subunits suchas protons, neutrons, electrons and other particles. The proton mass isapproximately 1.6 x 10 -24g, and the charge is 1.6 x 10 -19Coulombs (, ).
Neutrons have a similar mass compared to the proton,with neutral electric charge. Electron have 9.1 x 10 -28g, and acharge of –1.6 x 10 -19 C (,).Niels Bohr (1885–1962), in the early twentieth century, proposed that electronswere distributed in orbits (K, L, M, N, O, P and Q) around the nucleus( ). Arnold Johannes WilhelmSommerfeld (1868–1951) inserted sublevels (s, p, d, f, g, h.) to theelectron layers (, ). Every atom has atomic subunits. Computer graphing calculator software. With the modificationof the number of structures present in an atom, there is the formation ofdifferentiated structures ( ). DimitriIvanovich Mendeleev (1834–1907) and, later (in the twentieth century), HenryGwin-Jeffreys Moseley (1887–1915) modeled the periodic table in order ofincreasing atomic number (Z) ( ). The SkinThe skin covers and protects the body, separating the internal environment of theouter environment.
It is the largest organ of the human body, representingaround 16% of body weight ( ). The humanintegumentary tissue is divided into: 1 epidermis, 2 dermis and 3hypodermis.
The surface of the epidermis is called the stratumcorneum ( ). Thestratum corneum is an important component of the skin layers, responsible forpreventing loss of body fluids, and for blocking the entry of exogenoussubstances ( ). Figure 1 The stratum corneum and the epidermis layerThe physicochemical properties of the skin enable percutaneous absorption oftopically applied medications; however, most of the medications used need toovercome the barrier imposed by the stratum corneum ( ) in order to guarantee theirpharmacological effects ( ). The threepathways that a medication uses to overcome the stratum corneumare: 1 intracellular, where medications diffuse around corneocytes, 2transcellular, where medications diffuse directly through the corneocytes, and3 via appendices, an alternative route for medications that diffuse throughthe hair follicles, sebaceous and sweat glands ( ). IontophoresisIontophoresis, also called ionophoresis, electrophoresis or cataphoresis ( ), is a technique used to enhancetransdermal penetration ( ) ofsubstances through the application of electric current (, ).In addition to constant stimulation, the main waveform used in iontophoresis isquadratic, as shown in.Applications can be made either with continuous or pulsed current ( ).
Iontophoresis is based on theprinciple enunciated by Du Fay ( ), inwhich charges with the same signal repel and charges with opposite signalsattract, facilitating the penetration of ions through the skin ( ). Figure 2 Types of quadratic waveform used in iontophoresisAnother technique similar to iontophoresis is electroporation, which is used toopen the pores of the lipid membrane for the application of transdermalmedications, similar to iontophoresis ( ). The main difference is that electroporation uses high voltage (≈ 70to 400 V) during short application periods (milliseconds) ( ), whereas iontophoresis ranges up to a few tens of volts( ).Reverse iontophoresis ( ) aims to attractsubstances out of the skin (, ), as shown in. One practical application of this technique isthe classical test for assessment of sweat conductivity in people suspected ofhaving cystic fibrosis. In this case, the procedure is calledpilocarpine ® iontophoresis ( ).
Figure 3 Illustration of reverse iontophoresis effect over ionizedsubstances. With application of a continuous current, substanceswith opposite polarities attract to each otherAccording to Chorilli et al. ( ), amedication of positive polarity should be positioned next to the positiveelectrode.
When electric current flows through the circuit, the medication willbe moved away from the electrode, causing it to penetrate through the skin intothe desired location. Other mechanisms involving iontophoresis in medicationdelivery into cells have been studied, such as electroosmosis ( ).
Electroosmosis is caused by solventflowing from the anode to the cathode. This flow occurs because the skin isnegatively charged, mainly due to the presence of amino acids in cell membranes( ). The impulse of solvent movementis transferred to the neutral molecules present in the system; thus, the solventflow, or electroosmotic flow, makes it possible to neutral molecules to beliberated by iontophoresis through the anode ( ).Samuel George Morton (1799–1851) conducted an experiment on his own arm, in whichgraphite powder was placed in contact with a positively charged electrode,followed by application of electric current.
The result was the appearance ofspots on the skin where the application was made. Morton, in the nineteenthcentury, describes that the reaction occurred due to the migration of ions fromthe positive electrode to the negative, in other words, the basic principles ofiontophoresis ( ).The use of iontophoresis is variable in length of application and electricintensity for each substance, using a predefined voltage or electrical current( ), controlling the amount oftransdermal transfer of both positive (cations) and negative (anions) ions(, ).
In addition to the reduction of size and cost of electricalstimulators, currently equipment that enables iontophoresis can be adhered tothe skin in the same manner as traditional transdermal devices and nicotine patches ( ), except with a primarily cosmeticapplication ( ), as shown in. Figure 5 Iontophoresis adhesive used adhered to the skin for cosmeticpurposesIontophoresis can be applied through adhesives or electrical stimulators.
Jensenand Li ( ) developed a device thatallowed for constant iontophoretic application at frequencies up to 50kHz(quadratic waveform), with a configured work cycle of 20%, 50% and 80%. Thecurrent supplied to the electrical stimulator was 50-500 μA with variablevoltage from 0.5 to 5 V.
( ) developed a low cost electrical stimulator for the application ofiontophoresis ( ). The output currentvaried from 1–300 μA with waveforms that could be: 1 continuous (DC), 2pulsed continuous, 3 bipolar and 4 pulsed bipolar. The provided amplitudereached 36 V.The use of transdermal pathway as a gateway for medications into the body iscomfortable and efficient, providing an alternative to the classical routes ofmedication administration, such as injectable and parenteral.
It provides atreatment requiring a lower frequency of administration, proper absorption andeasy removal and promotes greater patient compliance to treatment ( ). As simple and interesting as the use oftransdermal mechanisms may seem, their development and implementation requiresextensive knowledge about the factors that affect their use, such as barriersimposed by the skin, skin penetration, site of action, medication stability anddosage ( ).In Brazil, there are some brands that work commercially with the development andsale of products that enable electrical therapy, with the options ofiontophoresis application (or Galvanic current only) and/or electroporation(, ). Showssome devices available in the national market and their basicspecifications. Iontophoresis and its applicationsSince the 1930s, the use of iontophoresis is reported as means for theapplication of various medications. Among them are: 1 acetic acid fortreatment of calcific tendinitis and myositis ossificans; 2 calcium chlorideand magnesium sulfate for control of musculoskeletal spasms; 3 dexamethasonefor inflammation; 4 lidocaine for soft tissue inflammation; 5 zinc oxidefor acute joint pain, such as damage from rheumatoid arthritis ( ).Because it is a non-invasive system for transport of molecules and because it hasno restrictions regarding the number of applications, iontophoresis is used forocular treatment by Behar-Cohen et al. Using its electromotive action, iontophoresis-based treatment,whose practice is illustrated in,has the ability to carry various types of medications to different eye tissues,without any risk to the integrity of the patient's eye ( ). Figure 6 Use of iontophoresis for ocular treatmentIn an experimental study ( ), the use ofgentamicin sulphate with iontophoresis was tested on rabbit cornea.
In thisstudy by Frucht-Pery et al. ( ), afterapplication of gentamicin sulfate associated with iontophoresis, the rate ofgentamicin penetration was influenced by the intensity of the current and/or thelength of iontophoresis application.
The major disadvantages presented in thistype of treatment (eye) are possible burns resulting from repetitive electricalcontact of electrodes near the eye ( ).Behar-Cohen et al. ( ) evaluated theapplication of iontophoresis with ocular application of dexamethasone in ratswith parenteral administration of the same drug.
The results revealed thattreatment with iontophoresis produced the same treatment efficacy as parenteralapplication, but without presenting systemic adverse effects, because it was atopical application.A study conducted by Say et al. ( ), usediontophoresis with the drug histamine bicloridate (1/10.000) as a palliativetreatment for hemophilia patients in order to promote absorption of bruises andanalgesia. It should be noted that in some cases, histamine is irritating to thepatient’s skin.
In this case, the simple application of galvanizing propertiesprovided by iontophoresis appeared amenable to treatment.Iontophoresis can also be used for clinical analysis, as in the procedure usedfor evaluating the sweat conductivity described by Mattar ( ). First, cleaning with distilled water and drying of theskin is performed, after which 2.5 cm x 2.5 cm copper electrodes are put on theskin.
Gauze soaked in a solution of pilocarpine nitrate is attached below thepositive electrode (anode) and a sulfuric acid solution of 4 mEq/L is attachedbelow the negative electrode (cathode). A current from 2 to 5 mA is then appliedfor five minutes. After application, the skin is cleaned and dried again forapplication and fixation of filter paper, which remains in place for 30 - 60minutes, then it is sent for laboratory analysis of sodium and chlorine.The technique demonstrated by Belda and Reginato ( ) used ionization with potassium iodide followed by 2% sodiumsalicylate ionization. Sixteen applications in patients with leprosy wereperformed three times a week, over a period of twenty to fifty sessions.
Eightpatients had reversal of paralysis and normalization of gait. In these cases,the duration of paralysis varied from one month to a maximum of two years.Geloid fibroedema, popularly and mistakenly called “cellulite” is a frequent andaesthetically relevant dysfunction, especially for the female population ( ).
It is described ( ) that treatment using iontophoresis and galvanization(use of electric current without pharmaceuticals) shows remarkable results inthe treatment of cellulite reduction.Research conducted by Zanin et al. ( )aimed to apply abdominal electrolipophoresis, together with iontophoresisassociated with a pharmaceutical consisting of turmeric gel. The experimentaimed to evaluate the lipid profile and levels of fat in the abdomen, before andafter applications. The study was conducted in eighteen women aged 21 to 51years old, who were sedentary and without dietary restriction. The datacollected showed satisfactory results regarding the use of electrolipophoresisalong with turmeric in decreasing the levels of the lipid profile (LDL), as wellas the effective decrease of subcutaneous adipose tissue.A new technique for administering pharmaceuticals involved in ionizedmicrocapsules ( ), iontophoresis couldcontrol the transdermal movement of these encapsulated substances as it doeswith the usual pharmaceuticals ( ).
Iontophoresis and application parametersZakzewisk et al. ( ) evaluatediontophoresis with four types of waves in the reduction of blood pressure inrabbits. Iontophoresis was administered with the pharmaceutical captopril, anangiotensin converting enzyme inhibitor. The frequency of electrical stimulationwas 10 Hz – 50 kHz, work cycle of 10% – 50%, and output current of 0 – 10 mA.The types of stimuli used were: 1 continuous, 2 pulsed continuous 3trapezoidal, 4 pulsed biphasic.
The stimulatory pattern that resulted ingreater reduction in blood pressure was the continuous pulsed wave. Pulsedbiphasic waveform on the other hand had the poorest results.The results by Kim et al.
( ), afterapplication of a mannitol solution with NaCl associated with iontophoresis onskin flaps of rats, showed that even after applications with four and eighthours duration, no significant pH changes occurred in the solution. Even insituations in which the initial pH was 7.4 (neutral) or 3.4 (acid),iontophoresis application did not destabilize the pH of the solutionsutilized.Zakzewski et al.
( ) evaluatediontophoresis with captopril for lowering blood pressure in rabbits. It wasshown that 20-minute applications had similar results to those in the group thatcontinued to receive the application of iontophoresis for two hours. Theseresults indicate that iontophoresis reaches its maximum efficiency after a fewminutes; however, after application, the effect of the iontophoresis maintains alow blood pressure for more than 90 minutes.According to data by Carvalho et al. ( ),eighteen patients with a clinical diagnosis of low back pain were randomlydivided into two groups.
The group named group 1 underwent iontophoresisapplication with dynamic Bernard currents (monophasic). Group 2 was subjectedto dynamic Bernard currents with iontophoresis associated with thepharmaceutical, hydrocortisone. Upon completion of the tests, it was found thatboth techniques significantly reduced back pain.A study conducted by Heidemann and Rosas ( ) used 1 galvanic current (continuous) and 2 diadynamic(monophasic sinusoidal) together with diclofenac sodium applied to the positive(anode) and negative (cathode) poles. The continuous current had more efficientresults when the pharmaceutical was applied to the positive pole.Yan et al. ( ) showed that theapplication of iontophoresis with alternate waveform at a frequency of 1 kHz, atintensities of electrical current tolerable to humans (2-5mA), had similarresults in transdermal ion movement when compared to a constant currentapplication at 0.2 mA.Esteves Junior et al.
( ) applied atreatment based on iontophoresis associated with an endogenous vasodilatorypeptide (CGRP) on skin flaps of four groups of rats. Electrodes coupled to anelectrical stimulator were used, where treatment was based on the application ofa direct current amplitude of 4 mA for 20 min, with an interval of two days. Theresults showed that, on the seventh postoperative day, there was no significantdifference in the area of necrosis between the control group and the group thatreceived treatment with iontophoresis. The area of necrosis in the groupreceiving treatment came to be 20% lower than that of the control group.Iontophoresis can be used for insulin delivery through the dermis ( ). Bustelo et al. ( ) tested the interaction of subcutaneous insulindissolved in 25 mL of buffer solution with iontophoresis.
Electrodes withAg-ClAg (silver, chlorinated silver) were used with constant current at 1.2 mAfor 30 minutes in crural region (point where insulin was applied) in rabbits.During the 30 minute application, the glycemic index was attenuated compared tothe control group, but ten minutes after iontophoresis application, the level ofglucose in the experimental and control groups became equal. The results of thisresearch showed that there was viability in the application of iontophoresis oninsulin action, but studies of the effects that iontophoresis causes in thetissue with iontophoresis application should be evaluated.Iontophoresis has also been applied in a closed loop system, where the level ofpharmaceutical to be activated through the skin was controlled by feedbackobtained through the patient’s perspiration ( ).
Wascotte et al. ( )used reverse iontophoresis (extracts substance through the skin) as analternative to analysis of endogenous molecules (as for diagnosis of renalfailure) and correlated this with blood samples. The potential of iontophoresisto measure urea and potassium during hemodialysis was analyzed between 10–360minutes of application (increments of 30 in 30 minutes). Urea presented ar 2 of 0.93 at 90 minutes of application and potassiumconcentration had a r 2 of 0.91 at 120 minutes of application.
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Theseresults suggest that non-invasive monitoring of urea and potassium seems to bean alternative method for diagnosing renal failure and during hemodialysis. Withthe same technique of reverse iontophoresis, Sun et al. ( ) used reverse iontophoresis with carbon nanotubes forthe construction of a glucose biosensor.Jain et al. ( ) tested the effect ofiontophoresis with application of glibenclamide (a pharmaceutical for thetreatment of type II diabetes) in the skin of pigs. Iontophoresis had a cathodicapplication where the current density was 0.5 mA/cm 2 for eight hours.It was compared with tissues which did not have iontophoresis application, butwere only soaked with the solution so that there was passive transport of thesubstance through the membrane. The results showed a correlation of 0.99 betweenthe application to the skin and the concentration applied to the skin, with asuperiority of the latter in the group that received iontophoresis applicationcompared to the group that was only exposed to glibenclamide.Iontophoresis is used with other substances to evaluate a possible increase inblood perfusion ( ).
Agarwal et al.( ) showed that iontophoreticapplication of acetylcholine in ten healthy volunteers increases bloodperfusion. In another study, Kigasawa et al. ( ) studied the effectiveness of iontophoresis with the use ofribonucleic acid (small interference RNA) in a mouse model for atopic dermatitis(endogenous eczema). The cathodic application was 0.3 mA/cm 2 for onehour. The distinguishing factor of the study was application of RNA restrictedto the epidermis (target site) without going into the dermis, therebydemonstrating the effectiveness of therapy for atopic dermatitis.Prasad et al.
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( ) evaluated the use ofiontophoresis with methotrexate (folic acid antagonist) used for treatment ofcancer, psoriasis and rheumatoid arthritis, also in rats. The applicationintensity was 0.2 mA/cm 2 for one hour in excised abdominal tissue.The results showed that the tissues with application of iontophoresis had a 32%increase in the concentration of methotrexate as compared with the group thathad only passive drug application. ConclusionsIontophoresis is a means of applying pharmaceuticals to the organism based onphysicochemical principles of attraction or repulsion of charges. The materialconsulted in this study allowed the understanding of how this technique has beenemployed for diagnostic and therapeutic procedures. Given the advantages observed inthe use of iontophoresis such as transdermal topical application, its clinical andrehabilitative use is recommended. However, similar to other therapeutic modalities,its use should be preceded by a proper study of its possibilities and limitations.With research and development of new technologies, such as pharmaceuticals appliedwith microcapsules, the use of iontophoresis is more precise and controlled,increasing its treatment effectiveness.
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Currently the use in the field of physicaltherapy has a practical application and good results, especially since it isnoninvasive and enables topical application of pharmaceuticals.
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