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Clinically important drug interactions • Drugs that increase effects/toxicity of α blockers: β blockers womens health blog cheap raloxifene 60 mg buy, diuretics menstruation vs pregnancy 60 mg raloxifene order mastercard, verapamil womens health questions generic 60 mg raloxifene fast delivery. Editorial comments: This drug appears to cause dizziness less frequently than doxazosin women's health boutique houston memorial buy raloxifene 60 mg with mastercard. Mechanism of action: Relaxes smooth muscles of the bronchi- oles by stimulating β2-adrenergic receptors menstruation occurs when generic raloxifene 60 mg buy line. Contraindications: Hypersensitivity to adrenergic compounds, tachycardia (idiopathic or from digitalis). Editorial comments: Seizures, liver enzyme elevations, and hyper- sensitivity reactions have rarely been reported with terbutaline use. Mechanism of action: Stimulates receptors in androgen-respon- sive organs, thereby promoting growth and development of male sex organs. Drug should be administered only by physician who is aware of possible adverse effects of drug on bone maturation. Contraindications: Hypersensitivity, males with carcinoma of the breast, known or suspected carcinoma of the prostate, seri- ous cardiac, renal or hepatic decompensation. This drug is listed without detail in Physician’s Desk Reference, 54th edition, 2000. Mechanism of action: Stimulates receptors in androgen-respon-sive organs, thereby promoting growth and development of male sex organs. Adjustment of dosage • Kidney disease: No experience with use in renal insufficiency. Contraindications: Hypersensitivity to testosterone, males with carcinoma of the breast, known or suspected carcinoma of the prostate, serious cardiac, renal or hepatic decompensation. Editorial comments • If desired results are not achieved in 6–8 weeks, another form of testosterone replacement should be considered. Mechanism of action: Reversibly inhibits initiation and conduc- tion of nerve impulses near site of injection. Contraindications: Hypersensitivity for ester-type local anes- thetic (eg, procaine). Warnings/precautions: Use with caution in patients with severe liver disease, spinal deformities, existing neurologic disease, severe uncontrolled hypotension, septicemia, infection at site of injection, abnormal or reduced levels of serum cholinest- erase. Editorial comments: If an oxytocic drug has been administered along with tetracaine, extreme care must be used when a vaso- pressor agent is used to treat the hypotension that frequently accompanies spinal anesthesia. Mechanism of action: Inhibits bacterial protein synthesis after specific ribosomal binding. Susceptible organisms in vivo: Borrelia burgdorferi, Borrelia recurrentis, Brucella sp, Calymmatobacterium granulomatis, Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia tra- chomatis, Ehrlichia sp, Helicobacter pylori, Rickettsia (Q fever), Rickettsia sp, Vibrio sp. Thereafter, continue tetra- cycline orally to complete at least 14 days of therapy. Contraindications: Hypersensitivity to any tetracycline, patients with esophageal obstruction, children ≤8 years. Warnings/precautions • Use with caution in patients with impaired kidney function. Clinically important drug interactions • Drugs that decrease effects/toxicity of tetracyclines: aluminum antacids, iron preparations, calcium salts, magnesium salts, sodium bicarbonate, zinc salts, bismuth salts, cimetidine. Editorial comments • Uses for tetracyclines include treatment of early Lyme disease, Vibrio infections such as cholera, and rickettsial infections including typhus, Q fever, and Rocky Mountain spotted fever. They are also used to treat genital infections (granuloma ing- uinale, nongonococcal urethritis, pelvic inflammatory disease, and other infections caused by C. Theophylline Brand names: Aerolate, Aminophyllin, Marax, Respbid, Slo- Phyllin, Theo-Dur, Theolair (also many other name brands). Increase dose to 400 mg/d after 3 days and again up to 600 mg/d after 3 more days. Food: Patient should take limited amounts of xanthine-containing foods or beverages (caffeine-containing coffees, colas, choco- lates, teas). Contraindications: Hypersensitivity to xanthine compounds (caffeine, theobromine), uncontrolled seizures, uncontrolled arrh- ythmias. Clinically important drug interactions • Drugs that increase effects/toxicity of theophylline: sympa- thomimetic drugs, erythromycin and other macrolide antibiotics, cimetidine, glucocorticoids, interferon, oral contraceptives, β blockers, tetracycline, mexiletine, ciprofloxacin and other quinolones, allopurinol, thyroid hormone, halothane, trolean- domycin, calcium channel blockers, disulfiram, thiabendazole. Editorial comments • Status asthmaticus is not rapidly responsive to usual doses of conventional bronchodilators. An oral pre- paration of theophylline is not used for treating status asth- maticus. Contraindications: Hypersensitivity to thiabendazole, use for pinworm infestation. Warnings/precautions: Use with caution in patients with kidney or liver disease, anemia, severe malnutrition, vomiting. Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Adverse reactions • Common: drowsiness, headache, hypotension, anorexia, nausea, vomiting, rash. Clinically important drug interactions: Thiabendazole increases effects/toxicity of aminophylline, theophylline. Editorial comments: This drug is not to be used as a prophylac- tic therapy for pinworm infestation. Editorial comments • This drug is not listed in the Physicians’Desk Reference, 54th edition, 2000. Contraindications: Hypersensitivity, severe bone marrow depres- sion, liver disease (relative contraindicated), kidney disease (relat- ive contraindicated). Warnings/precautions • Use with caution in patients with kidney or liver disease, bone marrow suppression. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Clinically important drug interactions • Drugs that increase effects/toxicity of thiotepa: antineoplastic agents, radiation therapy. Discontinue therapy or reduce dose at the first sign of a sudden large decrease in leukocyte or platelet count. Therapy should be resumed when leukocyte count and thrombocyte count increase to >2000 mm3 and 50,000 mm3, respectively. Editorial comments • Following bladder installation, patient should retain the drug for 2 hours. Patient should be repositioned every 15 minutes to obtain maximum bladder area contact. Adjustment of dosage • Kidney disease: Creatinine clearance >60 mL/min: 3 g q4h; creatinine clearance 30–60 mL/min: 2gq8h; creatinine clear- ance 10–30 mL/min: 2 g q12h; creatinine clearance <10 mL/min: 2 g q24h. Editorial comments: Ticarcillin has poor efficacy against Enter- ococcus faecalis (which is susceptible to piperacillin and mez- locillin). Mechanism of action: Inhibits platelet function, resulting in incre- ased bleeding time. Contraindications: Hypersensitivity to ticlopidine, neutropenia, history of thrombocytopenia, active bleeding from peptic ulcer, active intracranial bleeding, other active bleeding diatheses, severe liver disease. Warnings/precautions • Use with caution in patients with risk of bleeding (surgery, his- tory of ulcer disease), kidney or severe liver disease, gout, asthma, angina, hemodynamic instability, biliary obstruction. If a patient’s neutrophil count declines consistently and is only 30% less than baseline count, more frequent monitoring is necessary. Such medications should not be used without first consulting the treating physician. Such medications should not be used without first consulting the treating physician. Editorial comments • The drug of choice for male patients after a completed stroke is aspirin. There are some studies suggesting that ticlopidine may be slightly more effective in female patients. Mechanism of action: Competitive blocker of β-adrenergic receptors in heart, blood vessels, and eyes. Susceptible organisms in vivo: Staphylococci (penicillinase and nonpenicillinase), Staphylococcus epidermidis, Acinetobacter sp, Citrobacter sp, Enterobacter sp, Escherichia coli, Klebsiella sp, Proteus sp, Providencia sp, Pseudomonas sp, Serratia sp. Warnings/precautions • Use with caution in patients with renal disease, neuromuscular disorders (eg, myasthenia gravis, parkinsonism), hearing disor- ders. Clinically important drug interactions • Drugs that decrease effects/toxicity of aminoglycosides: peni- cillins (high dose), cephalosporins. Parameters to monitor • Monitor peak and trough serum levels 48 hours after beginning therapy and every 3–4 days thereafter as well as after chang- ing doses. If serum creatinine increases by more than 50% over baseline value, it may be advisable to dis- continue drug treatment and use a less nephrotoxic agent, eg, a quinolone or cephalosporin. Blocks myocardial excitability by reducing membrane conductance of sodium and potassium ions. Adjustment of dosage • Kidney disease: Creatinine clearance <30 mL/min: 50% of normal dose should be administered. Warnings/precautions • Use with caution in patients with heart failure, kidney or liver disease. Advice to patient • Take missed drug as soon as remembered if within 4 hours of previous drug. Clinically important drug interactions: Drugs that increase effects/ toxicity of tocainide: lidocaine, metoprolol, rifampin. Editorial comments • Tocainide is not often used because its side effects overshadow its efficacy as an antiarrhythmic. If the patient develops any signs of infection or excessive bruising or bleeding, complete blood counts should be performed promptly. If a hematologic disorder has been identified as being responsible, tocainide should be discontinued. Mechanism of action: Stimulates release of insulin from pancre- atic beta cells; decreases glucose production in liver; increases sensitivity of receptors for insulin, thereby enhancing effective- ness of insulin. Dose is best administered before breakfast or, if taken twice a day, before the evening meal. Contraindications: Hypersensitivity to the drug, diabetes com- plicated by ketoacidosis. Editorial comments • This drug is listed without details in the Physician’s Desk Reference, 54th edition, 2000. Mechanism of action: Stimulates release of insulin from pancre- atic beta cells; decreases glucose production in liver; increases sensitivity of receptors for insulin, thereby enhancing effec- tiveness of insulin. Dose is best administered before breakfast or, if taken twice a day, before the evening meal. Contraindications: Hypersensitivity to the drug, diabetes com- plicated by ketoacidosis. Editorial comments • This drug is listed without details in the Physician’s Desk Reference, 54th edition, 2000. Mechanism of action: Inhibits cyclooxygenase, resulting in inhi- bition of synthesis of prostaglandins and other inflammatory mediators. Indications/dosage/route • Rheumatoid arthritis, osteoarthritis Ð Adults: 400 mg t. Mechanism of action: Inhibits sodium and chloride reabsorp- tion in proximal part of ascending loop of Henle. Contraindications: Hypersensitivity to sulfonamides, anuria, hepa- tic coma, severe electrolyte depletion. Editorial comments • Torsemide has the advantage of a safer pregnancy category than other loop diuretics. Mechanism of action: Most likely produces analgesia by binding to opioid receptors. Adjustment of dosage • Kidney disease: Creatinine clearance <30 mL/min: 50–100 mg q12h. Contraindications: Hypersensitivity to tramadol or opioids; acute intoxication with alcohol; other analgesics, opioids, hypnotics, or psychotropic agents. There is an increased risk in patients with conditions that predispose to seizures, eg, head injury. Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Sit at the edge of the bed for several minutes before standing, and lie down if feeling faint or dizzy. Adverse reactions • Common: dizziness, vertigo, headache, nausea, constipation, somnolence. In some clinical trials, tramadol was comparable or superior to adult dosages of codeine with/without acetaminophen. Use caution if administering to individuals with a prior history of opioid dependence or abuse of other drugs. Chronic dosage should be at lowest effective dose; downward titration is suggested. American Aca- demy of Pediatrics expresses concern regarding use of trazadone while breastfeeding. Warnings/precautions: Use with caution in patients with car- diac disease, risk of suicide. Adverse reactions • Common: dry mouth, dizziness, drowsiness, fatigue, insomnia, anxiety, nausea. Clinically important drug interactions: Trazodone increases effects/ toxicity of digoxin, phenytoin. Mechanism of action: Acts on distal renal tubules to inhibit sodium– potassium exchange. Adjustment of dosage • Kidney disease: Contraindicated in patients with anuria, acute and chronic renal insufficiency, or significant renal dysfunction. Contraindications: Anuria, hyperkalemia, severe renal insuffi- ciency, serum potassium level >5 mEq/L, patients receiving other potassium-sparing diuretics or potassium supplements, hypersensitivity to triamterine, significant renal dysfunction.

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The scopolamine patch is able to maintain plasma levels in the therapeutic window for extended periods of time women's health clinic markham discount raloxifene 60 mg buy, delivering 0 women's health center bismarck nd buy discount raloxifene 60 mg on-line. Nitroglycerin This drug has been used to treat angina pectoris for over 100 years womens health queensbury ny purchase raloxifene 60 mg overnight delivery. It is a potent compound with a high clearance (266 L/hr) women's health clinic omaha ne 60 mg raloxifene order mastercard, short half-life (1–4 minutes) and extremely low oral bioavailability (<1%) women's health problems brown discharge discount raloxifene 60 mg without prescription. Percutaneous transport of mtroglycerin is relatively efficient, and conventional ointment formulations were the first modern-day transdermal formulations available. In the early 1980s, however, three patches appeared more or less simultaneously (Transderm-Nitro NitroDisc, and NitroDur), and transdermal delivery became widely recognized as an alternative route of administration for appropriate drugs. Since that time, numerous new and modified patches have been approved which differ considerably in design, composition, drug loading and release mechanism. Nevertheless, it is possible to demonstrate a bioequivalence between these patches, in terms of the resulting plasma concentration versus time profiles (Figure 8. When nitroglycerin is delivered via the skin, a sustained concentration can be achieved over an extended period of time. This profile contrasts sharply with those obtained following administration of sublingual and ointment 205 Figure 8. Despite this apparently clear pharmacokinetic advantage, however, it turns out that zero- order delivery of nitroglycerin for 24 hours, on a chronic basis, poses a pharmacodynamic problem: namely, tolerance. That is, even though the delivered amount of drug per unit time remains constant, the pharmacological effect of the drug decreases progressively, to the point that there is essentially no benefit to the patient. The problem is resolved by imposing a drug-free period during each dosing interval of 24 hours. Thus, presently, the patches are applied in the morning, after showering, and worn for 12–16 hours, with a “resting” or wash-out period overnight when patients are less susceptible (although not immune) to angina attacks. The drug has a relatively long half-life (6–20 h) and a modest clearance (13 L h−1). The rationale for the development of transdermal clonidine was to reduce side-effects and to improve patient compliance. The control of drug delivery over 7 days is impressive, and avoids the “peaks and valleys” of2 conventional (twice-a-day) oral administration (Figure 8. However, this system has not achieved as wide a success as first seemed likely because of skin sensitization. Clonidine itself, when administered transdermally on a chronic, repetitive basis, induces in a significant fraction of patients a classic immunologic skin reaction, and this has severely attenuated its use. Estmdiol Transdermal estradiol is indicated for postmenopausal hormone replacement therapy. Estradiol is a potent, high clearance (600– 800 L/hr) and short half-life (1 hr) drug. Due to the very high hepatic first-pass effect, conventional oral hormone replacement therapy results in an artificially elevated and, in the long 206 Figure 8. Transdermal delivery of estradiol, however, results in sustained plasma concentrations over several days (Figure 8. Pharmacologically, beneficial effects on the frequency of hot flushes, sleep disturbance, irritability and mental accuity have been documented. More recently, other simpler, and more elegant, monolithic systems have reached the market, and perform as well as, if not better than, the original system. Because the postmenopausal woman is usually treated concomitantly with an oral progestin (i. One of the first of these systems containing estradiol and levonorgestrel has recently been approved for marketing. Fentanyl This very powerful analgesic had been limited to parenteral use during and after surgery. Accurate dose titration is necessary because of the drug’s very narrow therapeutic window (1–2 ng mL−1). The potential of fentanyl, however, to significantly improve the treatment of acute post-operative pain and chronic cancer pain provoked the development of the now-approved Duragesic transdermal system. This reservoir system can be used for up to 3 days and is available in four “doses” (10, 20, 30 and 40 cm delivering, respectively, 25,2 50, 75 and 100 µg hr−1). Nicotine 207 Nicotine is generally believed to be the principal addictive component in tobacco. Patches containing nicotine are targeted at smoking cessation and compete with other nicotine-based systems, including chewing gum, lozenges and a nasal spray. Nicotine has a relatively short half-life (2 hr) and high clearance (78 L hr−1), which means that nicotine replacement via the gum, for example, requires almost constant chewing of about 10 pieces per day to match the bioavailability of the “drug” achieved by smoking one cigarette per hour. Transdermal delivery, therefore, was designed to provide sustained input over the course of 24 hours (or, in the case of one system, for ~16 hours—the argument being that not even the heaviest smoker lights up when asleep! Several patches reached the market (such as Nicotrol, Nicoderm, Prostep and Habitrol) representing examples of each of the basic system designs, and all of which are pharmacokinetically bioequivalent. There are differences, though, in the degree of irritation induced by the different patches and this seems to be related to the relative thermodynamic activity of nicotine in the different systems. Drug loading also varies appreciably between the different patches, as does the efficiency of drug usage. Short- term efficacy has been established by showing that the use of the patches reduces tobacco withdrawal symptoms and increases abstinence. Longer-term studies reveal that the patches can be effective but require supplemental pyschological and motivational aid and counseling to minimize the chances that a subject returns to smoking. Recently, in many countries, nicotine patches have become available “over the counter” without a prescription. Testosterone These patches (Testoderm, Testoderm with Adhesive, and Androderm) are approved for the treatment of hormonal insufficiency in diseases such as primary hypogonadism and hypogonadotropic hypogonadism. The systems are applied daily to mimic the endogenous profile of serum testosterone in the normal male. Testoderm (4 mg and 6 mg) and Testoderm with Adhesive (6 mg) release controlled amounts of testosterone upon daily application to scrotal skin. These systems have contact areas of 40 or 60 cm , and2 contain 10 and 15 mg of testosterone, respectively. The matrix system, Androderm, also provides continuous delivery of testosterone for 24 hours, but is applied to non-scrotal skin. Permeation enhancers are essential for this patch to ensure the efficient delivery of drug through skin sites which are less permeable than scrotal skin. The Androderm systems have a central drug delivery reservoir surrounded by a peripheral adhesive and are available in doses of 2. These testosterone systems illustrate two different approaches to solve the problem of inadequate percutaneous absorption rate. In the former case, the patch must be applied to the body’s most permeable skin site, the scrotum (which has been shown to be at least five times more permeable than any other site). In the latter, the difficulty is resolved by creating a transdermal formulation which includes excipients to reduce barrier function. Neither solution is ideal: scrotal application is clearly not preferred from a patient compliance standpoint; on the other hand, permeation enhancers, by their very nature, tend to be irritating (and the more effective they are, the greater the irritation they provoke). This general problem, which presently limits the application of transdermal delivery, is now discussed in more detail. The effective steady-state concentration of the drug is Css (mg cm−3) and its systemic clearance is Cl (cm hr3 −1). Ideally, A is relatively small (say 50 cm or less) and k is determined by the device and is less2 o than the maximum drug flux (Jmax) possible across intact stratum corneum. Their clearance values and target steady-state plasma concentrations have been taken from the literature, and it has been assumed that, for each compound, a steady-state delivery rate (k ) intoo the body of 25 µg cm−2 hr−1 can be achieved. Of course, for many compounds, such a high flux (which is typical only for such rapidly permeating drugs as nitroglycerin and nicotine) is completely unrealistic. As can be seen by the resulting estimations of the minimum patch area (Amin) necessary to arrive at the target blood concentration (determined using Equations 8. Consequently, considerable effort is being directed at approaches to increase Jmax, i. Possibilities include: 209 • increasing the amount of drug in the vehicle and hence increasing the total delivered dose from a single application (but this does not necessarily mean that the rate of absorption is enhanced); • increasing drug solubility in the stratum corneum, i. It should: • elicit no pharmacological effect; • be specific in its action; • act quickly, with a predictable duration, and its action should be reversible; • be chemically and physically stable, and be compatible with all components of the drug delivery system; • be odorless and colorless; • be non-toxic, non-allergenic and non-irritating. It remains to be seen to what extent the limitations can be relaxed for a chemical promoter to be acceptable (to patients and to the regulatory authorities). Enhancers include a wide range of chemical entities that increase skin permeability (Figure 8. Outstanding issues which need to be resolved include questions about the mechanism of action of the different enhancers in use at present, and the reversibility of their effects in vivo. Regulatory approval within the United States for an enhancer known as Azone proved to be extremely difficult because, as a new chemical developed specifically for skin permeation enhancement, it was subjected to an examination almost as detailed as that customary for a new therapeutic agent. Needless to say, this is an expensive path to follow for what is essentially a low-concentration excipient in a formulation and, as a result, the strategy now is to identify already-known and in-use materials (or combinations thereof) which have enhancing capabilities. These “generally regarded as safe” components offer a much easier regulatory path than that reserved for a new chemical entity. Practically speaking, the potential difference across the skin provides a force in addition to the passive flow of solute induced by the concentration gradient (Figure 8. The isoelectric point of human skin is around pH 4 which implies that skin, under normal physiological conditions, supports a net negative charge. Hence, the skin is permselective to the passage of positive ions and, as a result, more momentum is transferred to the solvent in the direction of cation flow. Thus, iontophoresis also induces a convective flow (called electroosmosis) whereby the flux of both charged and uncharged species can be significantly enhanced over passive levels. Thus, all things being equal, positively charged compounds are delivered more efficiently from the anode than negatively charged compounds from the cathode than neutral substances from the anode. Predictably, there appears to be an inverse dependence of iontophoretic permeability on molecular weight. Whether there is an “upper limit” has not been determined, although delivery of quite large molecules (e. In practical terms, this means that the viability of delivery as a function of increasing molecular weight is dependent upon a concomitant increase in pharmacological potency (i. It should also be noted that, with respect to peptide transport, amino acid sequence and conformation are potentially important variables that can dramatically impact upon iontophoretic delivery. From a practical standpoint, iontophoresis offers, under ideal circumstances, the singular advantage that it is an enhancement procedure which acts on the drug rather than on the skin (as is the case with chemical enhancers, for example). Typically, a constant or pulsed direct current is applied between the two electrodes placed on the skin surface. The current determines the charge flowing in the circuit, and hence the number of ions moving across the skin—if the current is doubled, the number of ions transferred across the skin is increased by a factor of two; if the current is turned off, ion flow through the membrane should return to the passive (i. Even though the drug may only carry a fraction of the total charge flowing (or may even be primarily transported by electroosmosis), its flux will be directly proportional to the applied current density, and hence highly controlled and controllable. Ag/AgCl), which do not lead to the hydrolysis of water at the potentials used, are preferred. Acceptable levels of current density and total current are dependent upon the treatment area and duration of current passage. The ionic composition of the delivery system should be selected so that there is minimum competition with the drug to carry charge across the skin (i. However, there must be sufficient electrolyte present to sustain current passage and to satisfy the electrochemical requirements of the electrodes. And, as mentioned above, in the case of larger compounds, for which electroosmosis may be the major mechanism of transport, different formulation strategies may be required. Other, integrated products are known to be moving through the development pipeline; those furthest along are one containing fentanyl for analgesia, and another which is a more sophisticated device also containing lidocaine. Conservatively, one can expect these systems to reach the marketplace at the beginning of the 212 21st century. In particular, it has been possible to create molecules with much better skin permeation properties from which the active species is subsequently “released”, either enzymatically, or by simple hydrolysis, at the level of the viable epidermis. At the transdermal level, on the other hand, an equivalent strategy has not (at least, consciously) been used. That is, redesigning a molecule with good pharmacological effect when, for example, injected to enable its facile transdermal permeation and delivery. The answer is simply financial—such an approach creates in effect (insofar as the regulatory agencies are concerned) a new chemical entity which must be subjected to the same indepth scrutiny as the “parent” compound. Under these circumstances, most pharmaceutical companies would prefer to invest in the search for a different, orally active analog. The microparticulate species employed include liposomes, niosomes and microemulsions (see chapter 5). Usually, the aim of this strategy is to improve, somehow, the delivery of lipophilic drugs, which have low inherent solubilities in most of the classical formulation excipients. While numerous and expensive liposomal and niosomal-based cosmetic products can be found on sale in every large department store, the use of this technology in pharmaceutical preparations has yet to make a significant impact. These systems are difficult to stabilize, use ingredients which are not cheap, and remain difficult to justify in terms of therapeutic benefit (relative to simpler, cheaper vehicles). Although progress of such formulaics for the parenteral route are showing considerable promise (see chapter 5), their efficient release into and through the skin is not guaranteed. Claims that such colloidal carriers can transport their “pay loads” intact across the stratum corneum have not been substantiated. Given that the space between the corneocytes of the stratum corneum is on the order of 0. Targeting of vesicles to specific appendageal structures, such as the hair follicle, has been discussed and illustrated qualitatively, but the practical utility (and efficiency) of such an effort is still a matter for investigation more than development. In this approach, saturated solutions of drug in miscible cosolvent mixtures of different composition are combined to create a resulting formulation in which the drug is present at n-fold its saturation concentration.

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In this regard pregnancy knee pain buy raloxifene 60 mg low price, hair follicles can be used as a reservoir for drug delivery to localize the drug to the hair follicles or deliver the drug to the surround- ing epidermal cells (4) pregnancy zumba dvd best buy raloxifene. This was found tape-stripping studies in human volunteers by using fluorescent-labeled poly(lactide-co-glycolide) nanoparticles (300–400 nm) menstrual xex order raloxifene 60 mg on line. The nanoparticles are slowly cleared from the hair follicles by sebum secretions and the migration of par- ticles to nearby cells and through the lymphatic system (4) menstruation hygiene discount 60 mg raloxifene mastercard. The surface charge on the polymeric nanoparticles also influences their permeation through the skin women's health clinic chico ca cheap raloxifene 60 mg online. The authors attributed the higher penetration to the charge repulsion between the negatively charged skin lipids and the carboxylate groups in the negatively charged nanoparticles (66). The larger surface of the smaller 50-nm particles and the high charge density in 500-nm particles were attributed to their higher skin penetration (65). One of the distinct features of dendrimers is their large number of surface functional groups that can carry a high drug payload and also undergo multivalent interactions with the biological membranes (67). Due to their unique architecture, drugs can be encapsulated inside the core (nanocontainers), com- plexed, or conjugated to the surface functional groups (nanoshells). The surface functional groups in the dendrimers can be tailored for various drug delivery applications (67,68). The number of branches and surface functional groups increases with each dendrimer generation. Many studies have been reported with dendrimers in cell cultures and other routes of administration (68), but very few studies have explored dendrimers for skin mediated drug delivery. Cationic den- drimers were found to penetrate deeper (40–60 m) in the skin compared to other dendrimers (Fig. It has been found to increase the skin penetration of both hydrophilic and lipophilic drug molecules (70–73). The possible mechanisms include increased drug solubil- ity, increased skin partitioning, and the penetration-enhancing effect through their interaction with the skin lipids (70–73). However, further studies are required to clarify their mechanism of skin penetration. In particular, liposomes and lipid nanopar- ticles are widely used in cosmetic products for their moisturizing and smoothen- ing effect on the skin (37,74). Furthermore, they can be used to deliver skin pro- tectants, antioxidants, and skin-whitening agents. Vesicular systems can be used to deliver hydrophilic and hydrophobic cosmetic agents and improve their skin retention and sustain the release of these agents. Table 4 provides a representative list of cosmetic agents delivered using various nanosystems. Inorganic sunscreens, such as titanium dioxide and zinc oxide, derive their sunscreen functionality from their particulate nature. The functionality of organic sunscreens can be improved by encap- sulating them in various nanosystems (79) in which the nano-encapsulated sun- screen can function as both particulate and organic sunscreens. Furthermore, the encapsulation improves skin retention and reduces systemic absorption of sun- screens. In addition, the nanosystem can protect the organic sunscreen from pho- toxidation and enhance sun protection factor by sustaining the release from the nanosystem (79). Polymeric nanoparticles, made of poly(vinyl alcohol) substituted with various satu- rated fatty acids, including myristic, palmitic, stearic, and behenic acids, were used to limit the skin penetration of benzophenone-3 (61). In a similar manner, nanocapsules made of poly(E-caprolactone) were used to protect octyl methoxycinnamate (82). In such cases, the active agent has to penetrate to a depth of 20 to 200 m in the skin (83). Therefore, deformable liposomes, ethosomes, and niosomes have been widely explored for topical and transdermal applications. The concentration of estradiol was significantly increased in the epidermis by using transfersomes compared with an aqueous solution (85). Transfersomes pro- duced a threefold increase in methotrexate penetration across excised pig skin com- pared with an aqueous solution and conventional liposomes (86). Similarly, ethosomes resulted in 30-fold higher testosterone levels in 24 hours compared with commercial testosterone patch (29). Acyclovir delivered from etho- somes was significantly higher than commercial cream formulation (87). The estradiol flux was in the following order: Tween 20 > Span 60 > Span 85 > Span 40. Of the various systems, transfersomes are promis- ing for topical/transdermal delivery of small molecules, with several of them in early or advanced clinical trials. As a result, ketoprofen transfersomes was found to have much lower systemic exposure (90). Protein Delivery Among the various nanosystems, transfersomes and ethosomes appear to be promising for systemic delivery of proteins (Table 6). Several preclinical and clin- ical studies have shown the feasibility of transdermal delivery of insulin by using transfersomes (Transferulin r ) (91). Insulin in transfersomes produced a compar- ative pharmacokinetic profile to subcutaneously injected insulin (91). The normo- glycemia lasted for 16 hours, with a single application of Transferulin. However, transfersomes may not be suitable for producing peak insulin concentrations (due to their relatively long lag time of 6 hours) but can be used as a sustained insulin delivery system. Alternatively, biphasic vesicles have been developed for the systemic delivery of proteins through the skin (92). The protein is entrapped in a w/o microemulsion, which is, in turn, encapsulated in a lipid vesicle. Biphasic vesicles of insulin have been shown to reach steady state glucose levels within 6 to 8 hours and the effect of insulin lasted for 75 hours in diabetic rats (92). The biphasic vesicles dissociate in the skin and release the insulin, which is then taken up into the systemic circulation through lymph. One of the advantages of the biphasic vesicles is that drugs can be loaded in both the microemulsion and the vesicle (92). Although the Langerhans cells form only 1% of keratinocytes, they cover 25% of the total skin area (93). When these cells are activated, they migrate to the draining lymph nodes and induce strong antigen-specific responses by B and T lymphocytes (94). Gap junction protein loaded in transfer- somes elicited antigen-specific antibody titers that were equivalent to subcutaneous injection (96). In a similar manner, ethosomes were used to immunize the mice with hepatitis B surface antigen (97). Results showed that the ethosomal system produced more robust immune response compared to intramuscular injection of hepatitis B surface antigen suspension or topically applied hydroalcohilic solution. Gene Delivery An attractive alternative to protein is to deliver the gene of interest to the epider- mal cells, which can then express the protein. Cutaneous gene therapy is particularly attractive owing to the multitude of potential disease states in the skin, such as infectious (herpes), proliferative (psoriasis), and invasive (carcinoma) diseases (99). Topical gene therapy can be easily confined to the affected area, thus reducing the likelihood of systemic toxicity. Moreover, the assessment of efficacy by visual inspection or biopsy is immeasurably more practical for the skin than any other organ. However, there are several key physical and enzymatic barriers that gene-based medicines have to overcome before producing a therapeutic effect (99). The physiochemical properties of the lipoplexes such as particle size, charge density, and stability of the complex influence the skin transport and subsequent cell uptake. Lipoplexes have been found to mainly localize to the follicular regions in the skin and hence can be used to treat perifollicular diseases such as alopecia (100). A new class of cationic Gemini surfactants has been explored for topical gene delivery (103). These surfactants are composed of two ionic head groups which are attached to their hydrocarbon tails [e. No skin irritation was observed, unlike the conventional cationic liposomes (104). The higher transfection of nanoemulsions was attributed to their small size (∼30 nm) and the penetration-enhancing effect of nonionic sur- factants in the emulsions. Thus, dendriplexes offer the additional advantage of gene transfection in the solid state unlike liposomes, which can be used to transfect only from a liquid matrix. Topical adminis- tration of this formulation produced specific immune response in the lymph nodes. Nanoparticles were prepared using microemulsion method, with emulsifying wax as the oil phase and hexadecyltrimethyl ammonium bromide as a cationic surfactant. This was designed based on the fact that pathogens enter the cell membranes through the mannose receptor. It was taken up by lipid carriers and drained to the lymph nodes to Nanosystems for Dermal and Transdermal Drug Delivery 145 produce an immune response. In spite of an increas- ing number of reports on the use of various nanosystems for the skin, there is no clear consensus on the optimal size for skin penetration. The difference in the skin type and experimental conditions makes it difficult to compare the results. How- ever, based on the studies so far, it is fairly accurate to state that the influence of particle size on skin penetration is a complex interplay of physicochemical prop- erties of the drug, physicochemical properties of the carrier including the shape and the formulation matrix in which the carrier is incorporated. A close look at the molecular size of the marketed passive transdermal drugs reveals that they all have a very small hydrodynamic radius of 0. This suggests that the pas- sive permeation can be expected for particles in the similar size range. However, as discussed earlier, the estimate of the skin pore size varies from 2 to 30 nm (8). Furthermore, the presence of appendages provides an additional transport path- way that is not available in other biological membranes. The diameter of the pilosebaceous opening varies from 10 to 75 m, whereas the diameter of the hair follicle varies from 0. Studies using excised skin obtained from different anatomical sites showed that the highest penetration was found with particles that are comparable to the thickness of the hair shaft (0. In general, smaller particles were found to penetrate deeper into the follicles from the pumping action caused by the hair movement that continuously occurs in living tissues. In addition to serving as a site for localized drug delivery for the treat- ment of perifollicular diseases, the follicles can also serve as a long-term reservoir for delivery to surrounding cells in the skin (4). On the other hand, the intercorneocyte penetration of particles is dictated by the flexibility of the carriers and their interaction with the intercellular lipids. Most of these soft colloidal particles seem to collapse at the surface of the skin, and the components then interact and enhance the skin permeation of drugs (18). On the other hand, ultradeformable liposomes appear to be a unique carrier, in which the remarkable deformability of the vesicles results in the penetration of intact vesicles deep into the skin under osmotic gradi- ent (24). Arguably, newer methods are required to understand the skin penetration of ultradeformable vesicles. The surface charge on the nanosystems also plays a sig- nificant role in skin penetration. It is known that the skin carries a negative charge at the physiological pH due to the carboxyl residues from skin proteins and lipids (113). Surprisingly, even negatively charged liposomes and polymeric nanoparticles have been found to penetrate the skin very well. This is attributed to the charge repulsion with the carboxyl groups of the lipids in the pores (66). On the other hand, in case of dendrimers, the positively charged dendrimers penetrated better than the negatively charged or neutral dendrimers (Fig. The difference may be due to the other skin–carrier interactions, in addition to the charge interactions. The vehicle used for the nanosystems can also have a significant influence on the skin 146 Venuganti and Perumal penetration. In general, lipid carriers have been found to produce higher penetration enhancement for hydrophilic drugs than for lipophilic drugs (18). The optimal par- ticle size differs for the skin penetration of lipophilic and hydrophilic solutes. In a comparative study (27) using lipophilic and hydrophilic dyes in liposomes of vary- ing sizes (73–810 nm), the highest skin penetration was seen with 71 nm particles for the lipophilic dye and 120 nm particles for the hydrophilic dye. This differ- ence is also partly attributed to the difference in the skin penetration pathways for hydrophilic and lipophilic molecules. The authors used a novel, in vitro human skin sandwich model to study the role of shunt pathway (115). The skin sandwich model is a useful technique to characterize the transport pathways of other nanosys- tems. Furthermore, comparative studies between different nanosystems in a single skin model can clarify the role of size, charge, shape, and other properties on the skin penetration of nanocarriers. The data generated from animal skin should be carefully extrapolated to human skin since the animal skin differs in their composition and follicular den- sity (77). In general, the rank-order correlation for skin permeation is rabbit skin > rat skin > pig skin > monkey skin > human skin. The commonly used rodent skin is at least nine times more permeable than human skin, whereas pig skin is four times more permeable than human skin (116). It is also important to note that the skin diseases can alter the barrier integrity vis-a-vis the skin penetration of nanosystems. The skin has received a lot of attention from the toxicological perspective as a potential route for the systemic exposure of nanomaterials, particularly with respect to sunscreen agents (77).

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The blue staining that is common in psychedelic mushrooms is evidence of oxidation—meaning that the active ingredients (psilocin and psilocybin) are being oxidized menstrual rage purchase discount raloxifene on-line, too—rendering the ‘shrooms inactive menstruation 6 weeks after giving birth buy raloxifene 60 mg with mastercard. While refrigeration is recommended menstruation 9 days after ovulation order discount raloxifene online, freezing fresh mushrooms should be avoided menstruation knee pain purchase cheap raloxifene on-line, since the expansion of the freezing water in the cells ruptures the cell walls and thus opens them up for oxidation menopause excessive bleeding 60 mg raloxifene order otc. Mushrooms that were frozen while fresh may be an attractive blue color, but they are inactive.... Storage of fresh mushrooms should be in a breathable container such as a paper bag stored in a refrigerator, avoid putting fresh ‘shrooms in a ziploc bag, as they may become slimy or moldy—ugh! One way to dry them is by placing them on a cookie sheet in an oven on the lowest temp. My main problem with dried shrooms is that in my experience they are not any-where near as potent as fresh ‘shrooms. I believe the reason for this is that the two psychoactive ingredients (psilocin and psilocybin) are present in equal amounts in fresh shrooms. My current favorite method is to blend 3-4 fresh ones in a blender with orange juice—the effects are fantastic and the taste is tolerable. I believe this is due in part to the fact that the shrooms are almost completely liquified by the blending process, releasing the “good stuff” into the orange juice and making it more readily absorbed by the stomach. Remember though, that dairy products may delay/block the absorption of certain substances. Another method of ingestion is to boil the shrooms, fresh or dried (or a rice cake) in a couple cups of water for about 5 minutes (until they have sunk), and then either add a tea bag for hot tea, or make Kool-Aid with the cooled water (straining out the shrooms, of course). Sprinkling fresh or dried shrooms (chopped) onto pizza, or into spaghetti sauce is another treat—fun for a “shroom party”. Since psilocin and psilocybin are soluble in both water and alcohol, soaking shrooms in any liquor will release these active ingredients into the liquor, making for a powerfully intoxicating liquor mix. I should mention again that once shroom production has really tapered off (and you’ll be able to tell) after 2 - 3 months, the rice cake can be eaten/used, if you closely examine it and decide that there is no green or black mold contaminant present. I should note that the rice cake will probably be all kinds of funky colors—a mix of white, steel blue, gray, maybe even purple in places from spores falling on it! A single rice cake is enough for 2 - 4 people to trip on, although 2 is probably the better figure. Some of my best trips were on half a rice cake chopped up and cooked in an omelete! That’s what I love about the rice-cake method—when the shrooms stop growing there’s no waste! Speaking of no waste, if I ever had a rice cake that I didn’t want to risk eating I might use it to innoculate a compost pile or a pasture full of cow shit by inserting a small piece into each cow-pie or into the compost pile. Use a spatula to mix in enough distilled water to make the vermiclulite about as damp as it can be without feeling soggy. The idea is to coat the wet vermiculite particles with the dry powder as you stir the mix with the spatula. Ingredients : 1/4 cup brown rice flour 1/2 teaspoon dextrose 500mg glycine 1/2 teaspoon oyster shell powder 1/2 teaspoon trace minerals (gypsum powder may work) Where do you get this stuff? Dextrose is also available from wine making / beer brewing stores, or diabetic supply companies. After the mix is made lightly tamp it down and cover this layer with ½” to 1” dry vermiculite. Either one will work but mycelium water is much faster and has less chance of contamination. A large innoculation around the edges and several squirts in the middle (5-15cc) will get things going in a hurry. Wrap the outside of the container to the level of the top of the vermiculite with aluminum foil. Dried I usually chop them up, then let them set for a month or two for the entheogenic goodies to disperse throughout the honey. This means you can take it anywhere, especially paired with a likely-looking bagel. Fresh shroomies seem to go into a state of suspended animation when dunked in honey, though some of the sparkles still end up in the honey itself. Some people have mentioned a concern that commercially produced dry ice may leave a small amount of acetone residue when evaporated. Alternately you could put the mushrooms in a plastic bag inside the jar so they don’t touch the dry ice. Set the lid lightly on top without sealing it and wait until the dry ice evaporates. The carbon dioxide which is released during the evaporation process is heavier than air, so it will stay in the jar while displacing the air. How to grow Psychoactive Cacti (Peyote and San Pedro): They take a while, something between a fruit tree and a 30 year government bond. In the Texas desert with infrequent rain, a peyote button 1 inch across may be ten years old. Therefore a 5 year old button under prime cultivation conditions would be eating size. And yes, once the carrot like root is established new buttons rapidly form from the sliced portion, if cut at ground level or just above. Grafting is a way of cutting small seedlings and growing them on faster growing rootstock. Using this method, we are going from raisin size babies to 3 inch buttons in 4 or 5 months, a huge increase. However these spoiled little critters have had almost no time to produce alkaloids, so the best thing to do with this technique is to re-cut the grown graft and allow it to re-establish its own roots. The beauty of this method lies in the ability to increase one’s stock plant supply considerably within one growing season. Starting from seed, one can graft the babies a year later, grow for a year on graft, then another on its own roots, or about 3 yrs total until dinner. When grafting seedlings, the crown is grafted first, then (tip of the day) the tiny roots can be grafted onto another graft stock, upside down, and will also shoot forth several new heads in a season, thus making several buttons from each seed. Getting your hands on Cuttings and Seeds: The easiest way to start growing cactus is from cuttings. When you find it, dug it up and transplant it and then use it’s cuttings and seeds to grow more. Growing Tips for our Spiny Friends: Cacti are part of a larger group of plants called succulents. Through natural selection most Cacti species lost their leaves, which allowed too much evaporation in the desert. To protect themselves from the Sun and predators many species developed spines and hair, waxy skin, along with bitter alkaloids. Most Cacti do fairly well as house plants, but however they are quite slow growing. Be sure and save the sunniest spots in your house for your Cactus plants as they need lots of light. If you are going to grow some of your Cacti to flower, or for seeds, then don’t move them while in bloom. Don’t be in a hurry to scorch them under a hot July Sun, give them a month or more to get gradually get used to it. If after you put it outside your cactus starts to acquire a lighter green or tan tint, it is probably sunburned, move it to some shade. Watering: As a rule water your Cacti seldom, and be very careful not to over water. Cacti and other succulents prefer hot and dry conditions and a soil that affords good drainage and aeration. Let the soil dry out completely between waterings during the growing season, and water even less during the winter. When watering your Cactus don’t forget to use lukewarm water, cold water can shock the roots. A good way to test if your cactus needs water is to poke a small, clean redwood stake in the soil. Different Soil Types: A good soil mix is essential if you expect good growth and health for your Cactus. There are several good brands of commercially available Cactus soils that come prepackaged. For those of you who want to do it yourself, here are a few recommended soil formulas. Also add one Tablespoon each of ground bone meal and ground limestone per gallon of mix. If you are making your own soil it would be a good idea to sterilize the mixture by baking in an oven at 400 degrees F for 60 minutes. Fertilizing your Cactus: All mature actively growing cacti need to be fed occasionally. A commercial formula such as miracle grow or rapid grow can be used, but should be diluted to half strength. Regular Bone Meal, available at most Garden Centers, makes an excellent organic fertilizer. Don’t forget the macro-nutrients like Iron (Fe), Calcium (Ca), Sulfur (S), and Magnesium (Mg). Also important are the micro-nutrients Copper (Cu), Zinc (Zn), and Manganese (Mn). A location where the plant gets at least 4 hours a day of bright, direct sunlight is ideal. The best possible situation would be a South facing sliding glass door, and a reflective screen placed behind the Cactus to redirect and concentrate the light. Many Cacti have beautiful and fragrant flowers, but they can be quite hard to get to bloom. The optimal conditions to induce flowering are, a cooler temperature (especially at night), reduced day length (12 hours or less), and variations in nutrients (lower nitrogen levels). Try putting your Cactus in a dark, unheated garage (not below freezing) for a few weeks. Forcing can also be done inside, but you need a place next to lots of glass that stays cooler than the rest of the house. Planting/Transplanting: Cacti prefer to be in unglazed clay pots with a layer of course gravel and charcoal in the bottom. Most Cacti have far ranging lateral roots so a shallow, wide clay pot is preferred. Be sure not to put your cactus in too large a pot because that can lead to later problems. Avoid transplanting too many times as this can also shock the plant, pick one size and stick with it a while. When handling small Cacti, use a pair of tongs, and for larger ones, use a rolled up newspaper. Cactus spines can be very sharp and can penetrate gloves, as you may well become aware of. During dormancy water is not taken in as rapidly by the plants roots, nor does it evaporate as quickly, and the result might be root rot. If possible bring your cactus inside the house and place it by a sunny window so it can continue to grow (slowly) through the winter. Cacti are well suited to being packaged for extended periods without light or water, they will almost always arrive at your house in good condition. Since Cacti are tough and hardy, they don’t have to be shipped by an overnight service, like most tropicals. About a couple weeks before the first hard frost (see Farmer’s Almanac for dates) I make sure that the soil dries up completely (shielding the plants from rain if required). Then I just move the containers inside my garage to protect the cacti from freezing. The temperature in the attached, but unheated garage drops to about 38 degrees during the coldest part of Winter. The cacti remain sheltered in the garage, in total darkness, all Winter until I bring them out in the Spring after all danger of frost is past. I usually keep them under a shaded patio for a week or so, and slowly move them to partial direct sun, then full sun over the course of two weeks (they are subject to sunburn if exposed to direct sun immediately after emergence from the dark. I use Miracle Grow plant food (as directed for container plants, even though they are exposed to the rain outdoors. By July there is usually some good new growth which is very explosive in August and continues (slower) into late September. By late October the cycle continues and they are again placed in the dark shelter of a garage. Do this by making one slice 1/3 of the way from the growing tip, and another slice 1/3 of the way from the base of the plant. When rooting a Trichocereus species, take a cutting that is at least 15 cm (6 inch) in length. I have heard that cuttings as small as 2 cm (1 inch) thick can be rooted, but I advise a larger section. Set it in a cool dark place until the bottom becomes dry and hard to the touch (somewhat like cork). The section is now ready for planting after being dipped in a rooting hormone like Root Tone (use per instructions).

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