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The hair follicles originate from the dermis and terminate at the surface of the skin medicine used to treat chlamydia carbidopa 125mg with mastercard. It is made up of stacks of keratin-filled corneocytes interdispersed by tightly arranged lipid bilayers (2) treatment gout generic carbidopa 110mg on line. The intercellular lipids mainly consist of free fatty acids treatment urinary incontinence buy carbidopa with paypal, ceramides, and choles- terol (2). Molecules can penetrate the skin by three main routes: (i) intracellular (across the corneocytes), (ii) intercellular lipids, and (iii) appendageal [Fig. The intercellular lipids are the major transport pathways for most drugs, in which the molecule has to pass through successive hydrophilic and hydrophobic domains in the lipid bilayers. On the other hand, the skin appendages serve as a shunt pathway for drug molecules. Since the appendages occupy only a fraction of the skin surface, they contribute very little to the drug transport. However, the appendages consti- tute a significant pathway for the iontophoretic transport of charged molecules and the penetration of particulate systems (3,4). Drugs are delivered to and through the skin for the treatment of skin diseases and systemic diseases, respectively. These include various types of formulations/ delivery systems such as powders, solutions, sprays, suspensions, emulsions, oint- ments, creams, pastes, gels, and patches. For dermatological applications, formu- lations are targeted to different layers of the skin to protect (e. In contrast, the goal in transdermal systems is to maximize drug absorption in the systemic circulation. The rate and extent of drug penetration into different layers of skin and into systemic circulation are governed by the drug properties and formulation characteristics. The concentration gradient drives the passive permeation of drug molecules through the skin, whereas the rate and extent of drug permeation are influenced by the physicochemical properties of the drug such as drug solubility in the vehicle, relative solubility of the drug in both the vehicle and the skin (partition coefficient), and molecular size, among others. Both K and Cs mainly depend on the drug property, whereas D and h mainly depend on the membrane (skin) characteristics. Different theories have been proposed to predict the transport of hydrophilic and lipophilic permeants (6). For the transport of hydrophilic molecules, the pore transport theory has been proposed by Peck et al. The pore estimates vary depending on the size of the permeant used to characterize the pores and the geometry of the measured pore (8). Chemical and physical enhancement methods are believed to increase drug permeation by increasing the effective pore radius and/or the number of pores (7,9). On the other hand, for the transport of lipophilic permeants, both porous and lipoidal pathways have been proposed (10,11). The general physicochemical properties for passive skin permeation have been widely accepted, and all the transdermal products in the market fulfill these criteria (Table 2). At the same time, the stringent requirements imposed by the skin also explains why only a handful of transdermal drugs have reached the market, in spite of intensive research over the last two decades. This has led to a number of passive and active skin per- meation enhancement strategies (13). Passive enhancement strategies include the use of chemical enhancers and prodrug approaches to improve drug partitioning and/or increase drug diffusion through the skin (13). On the other hand, active enhancement strategies use physical methods such as electric current, ultrasound, laser, or mechanical methods (12,13). All these enhancement strategies alter the drug characteristics and/or the skin barrier properties to improve skin permeation. The recent emergence of nanotechnology has opened up new opportunities to develop nanosystems for topical and transdermal applications. If not all, some of these nanosystems have been specifically developed for skin applications. The nanosystems can be classified based on the properties of the carriers as shown in Figure 2. For drug delivery applications, the nanosystems generally range in size from 1 to 1000 nm. The goal of this chapter is to provide a comprehensive overview of the formulation characteristics, mechanism of skin penetration, applications, and future prospects of nanosystems for dermal and transdermal drug delivery systems. On mixing with an aqueous medium, the phosphate groups of the phospholipids orient themselves to the hydrophilic environment spontaneously forming unilamellar or multilamellar bilayer vesicles (Fig.
Precautons Ensure adequate fuid intake of 2-3 litres daily; lactaton (Appendix 7b); renal and hepatc impairment (Appendices 7d and 7a); withdraw treatment if rash occurs; reintroduce if rash is mild but discontnue immediately if it recurs; interactons (Appendix 6c symptoms 9f anxiety cheap 300 mg carbidopa overnight delivery, 6d); pregnancy (Appendix 7c) medications in carry on luggage buy carbidopa pills in toronto. Adverse Efects Rash (see precautons above); hypersensitvity reactons occur rarely treatment hiatal hernia buy discount carbidopa 125 mg on line, and include fever; lymphadenopathy; arthralgia; eosinophilia; erythema multforme (Stevens-Johnson syndrome) or toxic epidermal necrolysis; vasculits; hepatts; renal impairment. Colchicine* Pregnancy Category-C Schedule H Indicatons Acute gout; short-term prophylaxis during inital therapy with allopurinol. The drug must be stopped promptly at the frst sign of loose stools and symptomatc treatment must be given for diarrhoea. Precautons Elderly; gastrointestnal disease; cardiac impairment; hepatc impairment; renal impairment; lactaton (Appendix 7b). Adverse Efects Nausea; vomitng; abdominal pain; excessive doses may cause severe diarrhoea; gastrointestnal haemorrhage; rash; renal and hepatc damage; rarely, peripheral neurits; myopathy; alopecia; inhibiton of spermatogenesis with prolonged treatment; blood disorders. Diuretcs Diuretcs increase urinary excreton of water and electrolytes and are used to relieve oedema associated with heart failure, nephrotc syndrome or hepatc cirrhosis. Osmotc diuretcs are mainly used to treat cerebral oedema, and also to lower raised intraocular pressure. Most diuretcs increase urine volume by inhibitng the reab- sorpton of Sodium and chloride ions in the renal tubule; they also modify renal handling of potassium, calcium, magnesium and urate. Osmotc diuretcs act diferently; they cause an increase in urine volume by an osmotc efect. Although loop diuretcs are the most potent their duraton of acton is relatvely short, whilst thiazide diuretcs are moder- ately potent but produce diuresis for a longer period. Carbonic anhydrase inhibitors are weak diuretcs which are rarely, used for their diuretc efect and are principally used to lower intraocular pressure in glaucoma. Electrolyte Imbalance: The adverse efects of diuretc therapy are mainly due to the fuid and electrolyte imbalance induced by the drugs. The risk of hypoka- laemia, which may occur with both thiazide and loop diuretcs, depends more on the duraton of acton than on potency and is thus greater with thiazides than with loop diuretcs (when given in equipotent doses). Other electrolyte disturbances include hypercalcaemia (thiazides), hypocalcaemia (loop diuretcs) and hypomagnesaemia (thiazide and loop diuretcs). Symptoms of fuid and electrolyte imbalance include dry mouth, thirst, gastrointestnal disturbances (including nausea, vomitng), weakness, lethargy, drowsiness, restlessness, seizures, confusion, headache, muscle pains or cramps, hypo- tension (including postural hypotension), oliguria, arrhyth- mias. Elderly: The elderly are more susceptble to electrolyte imbalance than younger patents. Treatment should begin with a lower inital dose of the diuretc (commonly about 50% of the adult dose) and then adjusted carefully according to renal functon, plasma electrolytes and diuretc response. They produce diuresis within 1-2 h of oral administraton and most have a duraton of acton of 12-24 h. Thiazide diuretcs are used in the management of oedema associated with mild to moderate congestve heart failure, renal dysfuncton or hepatc disease; however, thiazides are not efectve in patents with poor renal functon (creatnine clear- ance of less than 30 ml per min). In hypertension, a thiazide diuretc is used at a low dose to lower blood pressure with very litle biochemical disturbance; the max. Higher doses should not be used because they do not neces- sarily increase the hypotensive response but may cause marked changes in plasma potassium, magnesium, uric acid, glucose and lipids. If a thiazide alone does not lower blood pressure adequately, it may be used in combinaton with another ant- hypertensive such as a beta-adrenoceptor antagonist. Urinary excreton of calcium is reduced by thiazide diuretcs and this property is occasionally utlized in the treatment of idiopathic hypercalciuria in patents with calcium-containing calculi. Paradoxically, thiazide diuretcs are used in the treat- ment of diabetes insipidus, since in this disease they reduce urine volume. Thiazide diuretcs, especially in high doses, produce a marked increase in potassium excreton which may cause hypoka- laemia; this is dangerous in patents with severe coronary artery disease and those being treated with cardiac glyco- sides. In hepatc failure hypokalaemia can precipitate enceph- alopathy, partcularly in alcoholic cirrhosis. Potassium-sparing diuretcs are used as a more efectve alternatve to potas- sium supplements for preventon of hypokalaemia induced by thiazide diuretcs; however supplementaton with potas- sium in any form is seldom necessary with the smaller doses of diuretcs used to treat hypertension. Loop Diuretcs: Loop diuretcs, or high-ceiling diuretcs, such as furosemide, are the most potent and rapidly produce an intense dose-de- pendent diuresis of relatvely short duraton.
A murine monoclonal antibody to rat transferrin was conjugated with peptides medicine vicodin buy carbidopa 110 mg free shipping, and it was demonstrated that the conjugation increased brain uptake of the peptides [59] treatment 8mm kidney stone trusted 300mg carbidopa. The use of a viral vector (virosome) with inherent capability of penetrating endothelial cells of brain capillaries has been demonstrated [61] 300 medications for nclex buy 110 mg carbidopa amex. For example, inhibition of P-gp has been investigated [65] and some P-gp inhibitors were brought up in Section 8. Needless to say, this method would most likely damage brain tissues and raises the risk for infections. The olfactory epithelium is located in the upper posterior part of the human nasal cavity with its nerve cells directly projected into the olfactory bulb of the brain. Although studies have suggested that this feat is achievable [67], actual delivery of peptide drugs or any drug by this mean has yet to be fully demonstrated. Other than vasopressin, there was no increase in peripheral blood concentrations of the peptides over the observed 30-min period. The delivery of peptide-derived antibiotic cephalexin, and permeability enhancer enzyme hyaluronidase have also been achieved by intranasal application [69]. These charge issues encompass cases in which these drugs are either readily ionized, too polar or hydrophilic to cross membranes to reach the cir- culatory system. Immunization exemplifes the delivery of protein drugs that must be administered by injection. Although the parenteral route is the most direct route into the main circulatory system and the onset of action is rapid, it is also the most dangerous because it bypasses most of the body’s natural barriers and defenses, and exposes the user to health problems such as hepatitis, abscesses, infections, and insol- uble particles. As a painful and inconvenient route that requires extreme care during injection, the parenteral route is laden with compliance and adherence problems. Some problems associated with the needle-and-syringe form of injection have been partially relieved by jet injectors. These gas- or air-powered medical injector devices use a high pressure narrow jet of the injection liquid instead of a hypodermic needle to penetrate the upper layers of the skin. Because the pressure is provided by either a portable air cartridge or a gas tank, the lack of compactness in the device and potential risk of explosion make jet injectors unlikely to be used for patient self-administration. Moreover, patients may still feel pain in the form of burning and stinging sensations because of the drug formulation. Large peptide drugs also tend to have a fair number of functional groups that can be metabolically processed, resulting in deactivation or increase clearance of the drugs. Exenatide is an analog of glucagon-like peptide-1, a gastrointestinal hormone incretin that enhances insulin secretion [70]. The 39-residue peptide drug (4187 g/mol) is approved for the treat- ment of diabetes mellitus type 2 as a twice-daily subcutaneous injection. Another example of an injectable peptide drug is 1-antitrypsin (44,325 g/mol), a human plasma-derived glycoprotein, which is injected once-a-week to manage emphysema [71]. Plasminogen activators (30,000–60,000 g/mol) are serine proteases with blood anticoagulating effects [72]. The class of plasminogen activators includes alteplase, monteplase, reteplase, tenecteplase, urokinase, streptokinase, and anistreplase. Because plasminogen activators are injected, their rapid onset of action fts their role in emergency medicine to treat such acute cases as pulmonary embolism, myocardial infarction, and stroke. Similarly, activated drotrecogin alfa (55,000 g/mol), a recombinant of activated serine protease protein C, is injected in intensive care medicine to treat sepsis by exerting anticoagulating effects [73]. Desirudin and lepirudin (∼7000 g/mol) are recombinant hirudins, which is a 65-residue protein [74]. The recombinants are bivalent direct thrombin inhibitors injected as blood anticoagulants in cases where heparin is contraindicated. In common with desirudin and lepirudin, bivaluridin is a synthetic 20-residue peptide analog (2180 g/mol) of hirudin that must be injected [75]. Large peptides used as antibiotic and antiviral agents must also be administered by the parenteral route. Being a 36-residue peptide (4492 g/mol), enfurvitide must be injected to be effective.
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For example 68w medications cheap carbidopa 300mg with amex, when treating pain it is usually desirable to use an analgesic that is rapidly absorbed (i symptoms rheumatoid arthritis carbidopa 125 mg overnight delivery. For chronic diseases medicine 2015 lyrics order cheap carbidopa on-line, such as hypertension, it is more desirable to have a product that results in a lower absorption rate and more consistent drug absorption over time, so that blood pressure does not change over the dosing interval. Typical plasma drug concentration versus time curve at steady state for a controlled-release oral formulation. Plasma drug concentrations over time with controlled-release and rapid-release products. If 500 mg of a drug is given orally and 250 mg is absorbed into the systemic circulation, what is F? A, C, B Use the following information for questions 7-8 through 7-10: A 500-mg oral dose of drug X is given, and the following plasma concentrations result: Plasma Concentration Time after Dose (hours) (mg/L) 0 0 4. If two formulations of the same drug are tested and product A has a faster absorption rate than product B, product A will take a shorter amount of time to reach peak concentration. The plasma concentrations and times observed for several points are as follows: Observed Plasma Time after Dose (hours) Concentration (mg/L) 3. You wish to begin a patient on a sustained- release preparation of drug Y and to maintain an average plasma drug concentration of - 1 20 mg/L. After 5 days (assume steady state has been reached), the mid-dose (average) plasma drug concentration is 13 mg/ L. What should the new daily dose be to result in an average plasma drug concentration of 25 mg/L? Finally, plot the residual concentration points on graph paper and use the first and last sets of time/ concentration pairs to calculate the slope of this line, which also represents Ka. You can see that this value differs considerably from Vextrap; Varea is usually a better estimate. Residual concentration = back-extrapolated concentration minus actual concentration. Residual concentration = back-extrapolated concentration minus actual concentration. Residual concentration = back-extrapolated concentration minus actual concentration. Residual concentration = back-extrapolated concentration minus actual concentration. Residual concentration = back-extrapolated concentration minus actual concentration. Describe the effects of variation in these two factors (Ka and F) on the concentration versus time curves. Look up the bioavailability for the three dosage forms of Lanoxin (tablet, elixir, and liquid filled capsule) and then plot representation concentration versus time curves for all three products at the same dose. For the example above (D-2), discuss potential advantages and disadvantages of all three dosage forms. Also, list specific situations in which one dosage form might be preferred or not preferred in a clinical dosing situation. Find bioavailability data for at least two different brands of the same drug (brand vs. Can these drugs be generically substituted and, if so, what data are used to support this claim? These transport processes are collectively referred to as drug distribution and are evidenced by the changing concentrations of drug in various body tissues and fluids. Information concerning the concentration of a drug in body tissues and fluids is limited to only a few instances in time (i. Usually, we only measure plasma concentrations of drug, recognizing that the drug can be present in many body tissues. For most drugs, distribution throughout the body occurs mainly by blood flow through organs and tissues.
In order to reduce exposure at the edges medicine 503 300 mg carbidopa amex, the bilayers self-close into one or more concentric compartments around a central discrete aqueous phase symptoms graves disease cheap 110mg carbidopa free shipping. Dependent on the preparation protocol used medications in checked baggage cheap 125 mg carbidopa mastercard, liposome diameters can vary between 0. Depending on the physico-chemical nature of the drug, it can either: • be captured in the encapsulated aqueous phase (i. Thus liposomes can serve as carriers for both water-soluble and lipid-soluble drugs. The liposomal encapsulation of a wide variety of drugs, including antitumor and antimicrobial agents, chelating agents, peptides, proteins and genetic material have all been described. Bilayer composition can be almost infinitely varied by choice of the constituent lipids. Liposomal bilayers may also accommodate sterols, glycolipids, organic acids and bases, hydrophilic polymers, antibodies and other agents, depending on the type of vesicle required. The rigidity and permeability of the bilayer strongly depend on the type and quality of lipids used. The alkyl-chain length and degree of unsaturation play a major role For example, a C18 saturated alkyl chain produces rigid bilayers with low permeability at room temperature. Such systems are more stable and can retain the entrapped drug for relatively longer periods, whereas more “fluid” bilayer systems can be prepared if a more rapid release is required. As phospholipid bilayers form spontaneously when water is added, the important challenge in liposome preparation is not the assembly of simple bilayers (which happens automatically), but in causing the bilayers to form stable vesicles of the desired size, structure and physicochemical properties, with a high drug encapsulation efficiency. There are many different approaches to the preparation of liposomes; however, they all have in common that they are based on the hydration of lipids: Liposomes represent highly versatile drug carriers, offering almost infinite possibilities to alter structural and physicochemical characteristics. This feature of versatility enables the formulation scientist to modify liposomal behaviour in vivo and to tailor liposomal formulations to specific therapeutic needs. It has taken two decades to develop the liposome carrier concept to a pharmaceutical product level, but commercial preparations are now available in important disease areas and many more formulations are currently undergoing clinical trials. Examples of the different applications and commercial products of various types of liposomal systems are given below. Most of the early work on liposomes as a drug-carrier system employed this liposomal type. Conventional liposomes have also been used for antigen delivery and a liposomal hepatitis-A vaccine has received marketing approval in Switzerland. A commercial product based on conventional liposomes has been introduced for the parenteral delivery of the anti-fungal drug, amphotericin B, which is poorly tolerated in conventional formulations. Two other lipid-based formulations of amphotericin B have also recently been commercially introduced: • Abelcet consists of ribbon-like structures having a diameter in the 2–5 µm range. In spite of the large differences in structural features (a further example of “liposomal” versatility), all formulations have been shown to greatly reduce the toxicity of amphotericin B, allowing higher doses to be given and thereby improving clinical efficacy. DaunoXome liposomes are also long circulating liposomes, in this case encapsulating the cytostatic daunorubicin. Although a non-stealth system, long circulation times are attained by using a particularly rigid bilayer composition, in combination with a relatively small liposome size. The encapsulation of these anthracycline cytostatics in liposomes effects a modified biodistribution of the drug; the drug is distributed away from the heart, where it can exert considerable toxic effects, and is preferentially taken up by solid tumor tissue. The primary focus of their use has been in the targeted delivery of anticancer agents. The stability of these micelles depends on the nature of the hydrophilic and hydrophobic effects. Micellar systems based on amphipathic block-copolymers have gained most attention as intravenously administered drug carrier systems over the years. These block-copolymers form micelles in aqueous solution with spherical core/shell structures and diameters around 20–40 nm (Figure 5. The hydrophobic core of these micelles can be loaded with a hydrophobic drug such as doxorubicin.
