By T. Deckard. Indiana Wesleyan University.
Again buy cilostazol 50mg mastercard, vaginal administration of estradiol results in higher bioavailability than via the oral route (Figure 11 purchase cilostazol 100mg on-line. A number of different types of vaginal rings containing various progesterones and estrogens have been investigated as a steroidal contraceptive since the mid-1970s buy cilostazol 50 mg online, the most successful being a Silastic toroidal- shaped ring. This is designed for insertion into the vagina and positioned around the cervix for 21 days, in order to achieve a constant plasma progestin level and cyclic intravaginal contraception. Although the device is successful in achieving the prolonged release of levonorgestrel, irregular bleeding is a major drawback associated with its use. In postmenopausal women with symptoms of urogenital aging, the vaginal ring gives significantly better, or equal, improvements of vaginal mucosal maturation value and restoration of vaginal pH levels than estradiol—containing vaginal pessaries or conjugated estrogen vaginal creams and is significantly more acceptable. Vaginal administration of progesterone is associated with a “first-uterine-pass effect”, i. Using a human ex vivo uterine perfusion model, the vaginal administration of radioactive progesterone was shown to result in the progressive migration of [ H]3 progesterone into the uterus, where it reached high concentrations in both the endometrium and the myometrium. Furthermore, vaginal administration of micronized progesterone has been shown to enhance progesterone delivery to the uterus by about 10-fold in comparison to im injection, despite the markedly higher (about 7- fold) circulating drug concentration achieved with im injection. Uterine selectivity after vaginal 288 administration has further been observed for both danazol and the β-agonist terbutaline and the vaginal-to- uterine delivery of misoprostol is currently being investigated for the reliable termination of early pregnancy (see below). Hence considerable evidence has accumulated demonstrating that the vaginal route permits targeted drug delivery to the uterus. This phenomenon opens new therapeutic options for the administration of compounds whose primary site of action is the uterus, thereby maximizing the desired effects, while minimizing the potential for adverse systemic effects. The retrieval system comprises a Dacron polyester net which proximally surrounds the insert and has a long ribbon end. The insert is placed in the posterior fornix of the vagina; insertion is performed digitally, thereby obviating the need for speculum examination. The system is effective in producing cervical ripening at term by releasing a small amount of the drug over a prolonged period. Furthermore, the system allows the obstetrician to control the dose administered and to terminate drug delivery by removal of the device, if uterine hyperstimulation or abnormal fetal heart rate changes should occur during the ripening process. Thus the system offers particular advantages in cases where there is concern about fetal condition or a risk of uterine over-activity. Misoprostol The most widely used medical method of terminating second-trimester pregnancy for fetal malformations or previous fetal death is the intravaginal use of prostaglandins; in particular, clinical interest is growing in the use of a synthetic prostaglandin E1 analog, misoprostol. The bioavailability of vaginally administered misoprostol is 3 times higher than that of orally administered misoprostol, which may explain why intravaginal misoprostol has been reported to be more effective than oral misoprostol for medical abortion. Recently, there has been renewed interest in the possibility of delivering therapeutic peptides and proteins via the vaginal epithelium. However, in this investigation, the analog was applied selectively at the early and mid-follicular phases, when the vaginal epithelium is thick and cohesive; greater bioavailability is to be expected during the luteal phase of the cycle, when the epithelium is porous and thin. The uptake of leuprorelin via a variety of routes (iv, sc, rectal, nasal, oral, and vaginal) has been compared in diestrous rats. Insulin Rapid dose-related changes in the plasma glucose and insulin levels have been demonstrated in alloxan- induced diabetic rats and rabbits, after vaginal administration of insulin suspended in a poly(acrylate) aqueous gel (0. However, the hypoglycemic effect was less than that achieved using the rectal route in the same base, or using the ip route. Penetration enhancers may be used to promote peptide absorption across the vaginal epithelium. However, less extensive investigations on the use of penetration enhancers for the vaginal route have been carried out in comparison to other routes, such as intranasal and transdermal (see Sections 9. The mechanism of enhancement of vaginal absorption of peptides by organic acids has been attributed to their acidifying and chelating abilities. In the case of the peptide leuprorelin, it seems that the effect of lowering the pH causes self-association or conformational changes of the peptide resulting in changes in the charge of leuprorelin and the epithelial surface. Removal of Ca2+ from the tight junctions of the epithelial cells by the chelators results in opening of the junctions, thereby creating a leaky epithelium and enhancing drug delivery via the paracellular route. The chelating effects are reversible, for example changes in the vaginal epithelium produced by citric acid were rapidly reversed after the epithelium was washed with physiological saline solution. Cyclodextrins can be used to solubilize drugs and thus potentially increase the concentration gradient driving passive diffusion across membranes. New research suggests that their enhancing effect may also be partly due to the removal of fatty acids, such as palmitic and oleic acids, which are minor membrane components. Toxic effects A major disadvantage associated with the use of penetration enhancers is their potential deleterious effect on the epithelial tissue. The damaging effects of various absorption enhancers have been investigated in vaginal absorption studies of gentamicin using ovariectomized rats. It was found that the penetration enhancers laureth-9 and lysophosphatidylcholine caused severe desquamation of the epithelium, whereas citric acid and palmitoylcarnitine were able to enhance absorption while causing only minor epithelial damage. The vaginal absorption of insulin was studied in ovariectomized rats and in the absence of any enhancer, no decrease in blood glucose was observed. Co-administration of various absorption enhancers was able to significantly increase the degree of hypoglycemia. The histological changes in the vaginal epithelium after treatment with the enhancer systems were variable and often severe: • palmitoylcarnitine chloride exhibited the greatest local toxicity including reduction of epithelial thickness and cell death. However, no conclusions can be drawn at this stage about the likely tolerability, safety and efficacy of the gel in the context of sexual intercourse. Antiviral vaginal devices Nonoxynol-9 is an approved spermicide with strong antiviral activity. The device, available as a diaphragm or a disk pessary, is fabricated from silicone elastomer matrix system. The drug release profile demonstrates square root time kinetics (M ∞ t / ) (see1 2 Section 4. While the spermicide-containing reusable diaphragms currently on the market are relatively effective when used in combination with a spermicidal formulation, they require careful fitting, insertion and maintenance. Moreover, adverse reactions, such as urinary tract infections, alterations in vaginal flora and occurrence of toxic shock syndrome, have been associated with their use. In contrast the silicone-based device described above has been reported to be stable, non-irritating and non-toxic. A vaginal sponge has also been recently developed comprising a soft poly(urethane) sponge impregnated with a gel containing 1% benzalkonium chloride, 0. The sponge therefore combines the actions of: • a physical barrier that blocks the cervix; • a material that absorbs the ejaculate; • a spermicide; • an antiviral agent. Antiviral liposomal preparations Intramuscular injection of α interferon was shown to be fairly efficacious in the treatment of genital warts; however, this route was associated with a number of side-effects including fever, myalgia, headache, nausea and fatigue. A liposomal preparation of α interferon for topical vaginal delivery has been developed, which offers the advantage of treating latent human papillomavirus infections as well as visible genital warts. The liposomal preparation can be self-administered intravaginally, without the need for multiple painful local, or im, injections. In the vagina, mucosal immune responses are initiated by the uptake of antigens from the vaginal surfaces (Figure 11. Whereas the gastrointestinal tract has identifiable aggregates of lymphoid tissue within the epithelium known as the Peyer’s patches (see Section 6.
Besides buy cheap cilostazol on line, where solids are present in solutions they may give rise to interferences and for that reason the solid content of the solutions must be below 2% wherever possible generic 100 mg cilostazol visa. Emission spectroscopy has been employed for the analysis of various alloys generic 100 mg cilostazol overnight delivery, namely : aluminium, copper, magnesium, zinc, lead, and tin. It has been used for the analysis of a number of elements, for instance : Na, K, Zn, Cu, Ca, Mg, Ni and Fe present in various tissues of human beings. Changes in trace-metal concentrations have been studied at length with regard to the ageing process. To determine the extent of elements present in ‘crude oil’ by virtue of the fact that some of these may poison the catalysts used in the cracking-process e. Substantiate your explanation based on the en- ergy-level diagrams for an ‘atom’ and a ‘molecule’. With the help of a neat-labeled circuit diagram explain the following : (a) Direct Current Arc (b) Alternating Current Arc Discuss their procedural steps, merits/demerits explicitely. Differentiate the plus and nega- tive aspects encountered in : (a) Photographic Detector ; and (b) Photomultiplier Detector, briefly. How would you identify the ‘frequencies’ and the ‘intensities’ of emission spectra by the help of : (a) Littrow type spectrograph, (b) Ebert-mounting spectrograph. Enumerate the various applications of ‘Emission Spectroscopy’ with respect to the following entities : (i) analysis of alloy, (ii) analysis of elements in tissues, (iii) analysis of elements in blood samples, (iv) analysis of Zn in pancreas tissue, and (v) elements present in ‘crude oil sample’. Quite a few such gaseous metal atoms are usually raised to a particular high energy level that enables them to allow the emission of radiation characteristics features of the metal : for example-the characteristic flame colourations of metals frequently encountered in simple organic compounds such as : Na-yellow, Ca-brick-red ; Ba-apple-green. It is quite evident that a relatively large proportion of the gaseous metal atoms shall remain in the ground state i. It has been observed that such ground-state atoms shall absorb radiant energy pertaining to their own particular resource wavelength. Therefore, when a light having the same resonance wavelength is made to pass through a flame consisting of such atoms, a portion of the light shall be absorbed accordingly. Furthermore, the extent or degree of absorption would be directly proportional to the total number of ground-state present in the flame. The emission spectrum thus obtained is made up of a number of lines that actually originate from the resulting excited atoms or ions ; and these steps may be shown diagrammatically as represented in Fig- ure 25. The resulting neutral atoms are excited by the thermal energy of the flame which are fairly unstable, and hence instantly emit photons and eventually return to the ground state (i. Boltzmann Equation : The fraction of free atoms which are excited thermally, or in other words, the relationship between the ground-state and the excited-state quantum is exclusively represented by the Boltzmann equation given below : N /N = (g /g ) e–∆E/kT......... Form equation (d) it may be observed that : • Fraction of atoms excited (N1) solely depends upon the temperature of the flame (T), and • Ratio N1/N0 is dependent upon the excitation energy (∆E). These two typical instruments shall be discussed briefly here highlighting their various components and procedural details. In general, Flame Photometers are designed and intended mainly for carrying out the assay of elements like : Sodium, Potassium, Calcium, and Lithium that possess the ability to give out an easily excited flame spectrum having sufficient intensity for rapid detection by a photocell. Procedure : The compressed and filtered air (A) is first introduced into a Nebulizer (E) which creates a negative pressure (suction) enabling the liquid sample (C) to gain entry into the atomizer (E). Thus, it mixes with the stream of air as a fine droplet (mist) which goes into the burner (G). The fuel gas (D) intro- duced into the mixing chambers (F) at a given pressure gets in touch with the air and the mixture is ignited. Consequently, the radiation from the resulting flame (H) is made to pass through a convex lens (I) and ultimately through an optical filter (J) that allows specifically the radiation characteristic of the element under examination to pass through the photocell (K). Finally, the output from the photocell is adequately amplified (L) and subsequently measured on an appropriate sensitive digital-read-out device. A = Inlet for compressed Air, B = Drain outlet (to maintain constant pressure head in the mixing Chamber), C = Liquid sample (sucked into the Nebulizer), D = Inlet for Fuel-Gas to the Laminar-Flow-Burner, E = Nebulizer to atomize the liquid sample, F = Mixing Chamber for Fuel Gas, Compressed Air, and Atomized Liquid Sample, G = Burner, H = Flame, I = Convex lens, K = Optical filter to transmit only a strong-line of the element, and L = Amplifier to amplify the feeble electrical impulse and a built-in direct read-out device. I = A calibrated potentiometer, J1 = Lines due to the ‘sample’ J2 = Lines due to the Internal Standard ‘Lithium’, and K1 & K2 = Photocells to convert light-energy to electrical impulse. The use of an internal standard flame photometer not only eliminates the visible effects of momentary fluctuations in the flame characteristics produced by variations in either the oxidant or under full pressures, but also the errors caused due to differences in surface tension and in viscosity are minimised to a great extent. Procedure : In this particular instance ‘Lithium’ is employed as an internal standard and an equal concentration is added simultaneously to the sample and the standard solutions. The sample (C) solution having the internal standard (Lithium) is sucked in by an atomizer and a fine spray is thereby introduced into the flame (D). The radiation thus emitted is subsequently passed through a filter (F) and then collected by a mirror (E). The emitted radiation reflected from the mirror is split up into two parts : the first part is caused due to the internal standard (Lithium), whereas the second part arises due to the element under examination. Both these lines J1 and J2 are passed through the respective photocells K1 and K2 whereby the light energy is transformed into the electrical impulses. These electrical impulses are usually very weak and feeble and hence, they are duly amplified by a suitable amplifier (G) individually and are subsequently introduced into the common detecting device (H) i. In short, an internal-standard flame photometer provides a direct and simultaneous result with respect to the ratio of intensities. Procedure (a) Preparation of working curves : Transfer 5 ml of the appropriate radiation buffer to each series of 100-ml volumetric flasks. Add a volume of the standard solution which will cover a concentra- tion ranging between 0 to 100 ppm. Measure the emis- sion intensity of these samples by taking at least three readings for each. Correct the average values for background lumi- nosity, and prepare a working curve from these data. If necessary, use a standard to calibrate the response of the spectrometer to the working curve. After correcting the data for background, determine the concentration by comparison with the working curve. For Emission Measurements Introduce water into the atomic vapour generator, adjust the instrument reading to zero, introduce the most concentrated solution into the generator and adjust the sensitivity to give a suitable reading ; again introduce water or the prescribed solution into the generator and when the reading is constant readjust, if necessary, to zero. Method of Standard Addition The various steps are as follows : (1) Place in each of not fewer than three similar graduated flasks equal volumes of the solutions of the substance being examined, prepared as follows : * Radiation buffers are used to minimise the effect of each ion upon the emission intensity of the others. If the generator is a flame, wash the apparatus thoroughly with water ; if a furnace is used fire it after each introduction. The distance between this point and the intersection of the axes represents the concentration of the element (e. Limits of Elements present in Calcium Acetate Sample Mg : Not more than 500 ppm of Mg ; K : Not more than 0. Discuss the following theoretical aspects of flame spectroscopy : (a) Bohr’s Equation, and (b) Boltzmann Equation.
They are packed at a density of 6–8 cilia per μm2 and cannot move without affecting neighbouring cilia cheap cilostazol 50mg line. In order to perform an unhindered beat cycle the movement of each cilium is slightly out of phase with that of its neighbor order cilostazol without prescription, leading to a phenomenon termed “ciliary metachrony” cilostazol 50mg discount. Metachrony results solely from hydrodynamic coupling between adjacent cilia and provides the necessary cooperation within a field of cilia to permit them to transport mucus. Each cilium is bounded by an evagination of the plasma membrane and, as shown diagrammatically (Figure 9. Each outer doublet microtubule consists of an A subfiber which is circular in cross-section, and an incomplete B subfiber, which is C-shaped in cross-section. The inner and outer dynein arms of the A subfiber project towards the B subfiber of the adjacent microtubule. Since the microtubules are constrained at the ciliary tip, it is possible to imagine how the sliding of microtubules on one side of the cilium might cause the cilium to bend. How such sliding is translated into a full beat cycle is still the subject of extensive research. A wide number of agents are able to alter the rate of ciliary beating; this can either be via a non-specific, toxic effect, e. However, data concerning the role of cyclic guanosine 5′-phosphate-dependent protein phosphorylation on ciliary beat frequency are conflicting. Increases in the intracellular concentration of Ca2+ ([Ca2+] ) increases ciliary beat frequency possibly via i protein phosphorylation induced by calcium/calmodulin kinase. Ciliated cells also respond to mechanical stimulation by increasing their beat frequency, an effect which spreads to surrounding cells (5–7 cells in all directions) and is mediated by an increase in [Ca2+]. Such intercellular signaling provides the opportunity for cooperative cellular activity which would be advantageous to the ciliated epithelium in its efforts to transport mucus. Airway cilia may be able to upregulate their beat frequency in response to an increase in the mucus load. As with most sites of drug absorption, the bioavailability of a drug is affected by the area available for absorption, the contact time between the drug and the absorption site, metabolism of the drug prior to and during absorption and the pathology of the absorbing tissue. The area available for absorption is enhanced2 by: • the convolutions of the turbinates, and • the microvilli present on the surface of the ciliated and unciliated cells of the respiratory epithelium. However, the effective surface area for absorption is influenced by the type of dosage form from which the drug is administered, as described below. Molecules (% loss) Degradation 0–15 0–5 Clearance a 0–30 20–50 Deposition (anterior loss) 10–20 10–20 Health status and environment 10–20 10–40 Membrane permeability ab 0–30 20–50 Mucus layer <1 <1 adepends on excipients bdepends on physicochemical characteristics of the drug, e. This property facilitates its physiological role in heat exchange and also potentially, drug absorption. The rich blood supply means that drugs absorbed via the nasal route have a rapid onset of action, which can be exploited for therapeutic gain. In the nasal cavity this is influenced by the rate at which the drug is cleared from the absorption site by mucociliary clearance and by metabolism. While the mucociliary clearance of deposited particles is advantageous if the particles are likely to be hazardous, the clearance of a deposited drug is clearly not beneficial if it prevents absorption. The site of deposition in the nasal cavity profoundly affects the rate of mucociliary clearance of a drug moiety: • Particles deposited on ciliated regions (for example, the turbinates) of the mucosa are immediately available for clearance. As described above, clearance of the bulk of the mucus from the nose to the nasopharynx occurs over 10–20 minutes. This is probably because most of the spray has deposited on non-ciliated regions of the nasal cavity. Deposition site; □ Turbinates; ▲ Nasopharynx ● The implications of this for drug absorption are that administration of a drug as drops may only be suitable if the drug molecule is rapidly absorbed. Those drug molecules which diffuse across the nasal epithelium more slowly will need a longer contact time and may be better administered as sprays. The absorption rate of certain drugs may be so slow that therapeutically active plasma levels are not attained. Such conditions include rhinitis, the common cold, hayfever, sinusitis, asthma, nasal polyposis, Sjogren’s and Kartagener’s syndromes. In addition, environmental factors such as humidity, temperature and pollution can also affect the rate of nasal clearance. The common cold consists of two distinct phases: mucus hypersecretion, followed by nasal congestion. It has been shown that during the former phase, less than 10% of a dose administered as a nasal spray will remain in the nasal cavity after 25 minutes. In contrast, almost all the administered dose will still be present at the site of deposition up to 90 minutes after administration during the nasal congestion phase. This would clearly lead to unpredictable absorption of an administered drug which would be unacceptable for a potent drug with a narrow therapeutic window. The inclusion of a vasoconstrictor such as oxymetazoline in the formulation might relieve such symptoms and provide more reproducible drug absorption. This would be likely to affect drug absorption but not necessarily in a reproducible manner. It has been suggested that the low bioavailabilities of some nasally administered peptides results from their enzymatic degradation in the nasal cavity. The nasal mucosa and fluids have been shown to possess a variety of exopeptidases and endopeptidases (see Section 1. The actions of intracellular enzymes will not be significant if the peptide is absorbed by the paracellular route (see Section 9. Small peptides are relatively resistant to the action of endopeptidases but their activity is significant for large peptides. Although enzymatic activity is present in the nasal cavity, this activity is generally lower than the enzymatic activity of the gastrointestinal tract, making this route an attractive alternative to the oral delivery of enzymatically labile drugs such as therapeutic peptides and proteins. These enzymes are capable of metabolizing inhaled pollutants into reactive metabolites which may induce nasal tumors. Antibodies are secreted in the nasal cavity and may be found in high concentrations in the mucus layer where they are able to neutralize antigens presented to the nasal mucosa. Foreign proteins delivered to the body are capable of eliciting an immune response and indeed antibodies have been detected in nasal secretions in response to the intranasal administration of insulin. Clearly this situation is undesirable since the therapeutic molecule will undergo degradation and the patient is likely to suffer with symptoms associated with allergic diseases such as hayfever. It is possible that pharmaceutical excipients which cause inflammation of the nasal cavity might exacerbate such reactions. One method by which mucus protects the nasal epithelium is by acting as a physical barrier and respiratory mucus has been reported to retard the diffusion of water and a range of β-lactam antibiotics used to treat respiratory infections. However, other studies have shown that antibodies (150–970 kDa) are able to diffuse through cervical mucus relatively unimpeded; these latter studies tend to suggest that the diffusion barrier presented by mucus in the nasal cavity would be insignificant.
A toxic drug reaction can occur when an excessive dose is taken order cilostazol australia, either intentionally or by accident discount cilostazol 50 mg with mastercard. The result is an exaggerated re- sponse to the drug that can lead to transient changes or more seri- ous reactions purchase cilostazol 100 mg with amex, such as respiratory depression, cardiovascular col- lapse, and even death. To avoid toxic reactions, chronically ill or elderly patients often receive lower drug doses. Iatrogenic issues Some adverse drug reactions, known as iatrogenic effects, can mimic pathologic disorders. Other examples of iatrogenic ef- fects include induced asthma with propranolol, induced nephritis with methicillin, and induced deafness with gentamicin. You’re so sensitive Patient sensitivity–related adverse reactions aren’t as common as dose-related reactions. Sensitivity-related reactions result from a patient’s unusual and extreme sensitivity to a drug. These adverse reactions arise from a unique tissue response rather than from an exaggerated pharmacologic action. Extreme patient sensitivity can occur as a drug allergy or an idiosyncratic response. Previous ex- posure to the drug or to one with similar chemical characteristics For an allergic sensitizes the patient’s immune system, and subsequent exposure reaction to occur, the patient must have causes an allergic reaction (hypersensitivity). The allergic reaction can vary in intensity from an immediate, life-threatening anaphylactic reaction with circulatory col- lapse and swelling of the larynx and bronchioles to a mild reaction with a rash and itching. Idiosyncratic response Some sensitivity-related adverse reactions don’t result from pharmacologic properties of a drug or from an allergy but are specific to the individual patient. While teaching a patient about drug therapy for diabetes, you review the absorption, distribution, metabolism, and excretion of insulin and oral antidiabetic agents. Pharmacokinetics discusses the movement of drugs through the body and involves absorption, distribution, metabo- lism, and excretion. Which type of drug therapy is used for a patient who has a chronic condition that can’t be cured? Maintenance therapy seeks to maintain a certain lev- el of health in patients who have chronic conditions. Pharmacodynamics studies the mechanisms of ac- tion of drugs and seeks to understand how drugs work in the body. Sometimes food enhances absorption—so grab a quick snack and come back for a review. Cholinergic drugs enhance the action of acetylcholine, stimulating the parasympathetic nervous system. Cholinergic drugs Cholinergic drugs promote the action of the neurotransmitter acetylcholine. These drugs are also called parasympathomimetic drugs because they produce effects that imitate parasympathetic nerve stimulation. Mimickers and inhibitors There are two major classes of cholinergic drugs: Cholinergic agonists mimic the action of the neurotransmit- ter acetylcholine. Anticholinesterase drugs work by inhibiting the destruction of acetylcholine at the cholinergic receptor sites. How cholinergic drugs work Cholinergic drugs fall into one of two major classes: cholinergic agonists and anticholinesterase drugs. Cholinergic agonists Anticholinesterase drugs When a neuron in the parasympathetic nervous system is stim- After acetylcholine stimulates the cholinergic receptor, it’s de- ulated, the neurotransmitter acetylcholine is released. Anticholinester- choline crosses the synapse and interacts with receptors in an ase drugs inhibit acetylcholinesterase. Cholinergic agonists stimulate cholinergic re- line isn’t broken down and begins to accumulate, leading to ceptors, mimicking the action of acetylcholine. Pharmacokinetics (how drugs circulate) The action and metabolism of cholinergic agonists vary widely and depend on the affinity of the individual drug for muscarinic or nicotinic receptors. Metabolism and excretion All cholinergic agonists are metabolized by cholinesterases: • at the muscarinic and nicotinic receptor sites • in the plasma (the liquid portion of the blood) • in the liver. Pharmacodynamics (how drugs act) Cholinergic agonists work by mimicking the action of acetylcho- line on the neurons in certain organs of the body called target or- gans. Examples include the following: • Other cholinergic drugs, particularly anticholinesterase drugs (such as ambenonium, edrophonium, neostigmine, physostigmine, Adverse and pyridostigmine), boost the effects of cholinergic agonists and reactions to increase the risk of toxicity. Because they bind with • Quinidine also reduces the effectiveness of cholinergic agonists. As acetylcholine builds up, it continues to stimu- fects can include: late the cholinergic receptors. One day at a time: Recognizing a toxic response It’s difficult to predict adverse reactions to an- Enter edrophonium ticholinesterase drugs in a patient with myas- Deciding whether a patient is experiencing a thenia gravis because the therapeutic dose toxic drug response (too much drug) or a my- varies from day to day. Increased muscle asthenic crisis (extreme muscle weakness and weakness can result from: severe respiratory difficulties) can be difficult. When edrophonium is used, suction, oxygen, mechanical ventilation, and emer- gency drugs, such as atropine, must be readily available in case a cholinergic crisis occurs. Pharmacokinetics Here’s a brief rundown of how anticholinesterase drugs move through the body. Because the duration of action for an oral dose is longer, however, the pa- tient doesn’t need to take it as frequently. Distribution Physostigmine can cross the blood-brain barrier (a protective bar- rier between the capillaries and brain tissue that prevents harmful substances from entering the brain). Donepezil is highly bound to plasma proteins, tacrine is about 55% bound, rivastigmine is 40% bound, and galantamine is 18% bound. Depending on the dosage, anticholinesterase Pharmacodynamics drugs can produce a Anticholinesterase drugs promote the action of acetylcholine at stimulant or receptor sites. From minutes to weeks Reversible anticholinesterase drugs block the breakdown of acetylcholine for minutes to hours; irreversible anti- cholinesterase drugs do so for days or weeks. Drug interactions These interactions can occur with anticholinesterase drugs: • Other cholinergic drugs, particularly cholinergic agonists (such as bethanechol, carbachol, and pilocarpine), increase the risk of a toxic reaction when taken with anticholinesterase drugs. Most of the adverse re- actions caused by anti- cholinesterase drugs re- Cholinergic blocking drugs sult from increased ac- tion of acetylcholine at Cholinergic blocking drugs interrupt parasympathetic nerve im- receptor sites. These drugs Adverse reactions are also referred to as anticholinergic drugs because they prevent acetylcholine from stimulating cholinergic receptors. Muscarinic receptors are • diarrhea cholinergic receptors that are stimulated by the alkaloid mus- • shortness of breath, carine and blocked by atropine. Next come their synthetic sisters Synthetic derivatives of these drugs (the quaternary ammonium drugs) include: • glycopyrrolate • propantheline. Atropine may also be used as an antidote for nerve agents (See the appendix, Vaccines and antidotes for biological and chemical weapons.
A highly specific interaction between glucose and concanavalin A (Con A) was used to form physical cross-links between glucose-containing polymer chains discount cilostazol 50 mg without prescription. Since Con A exists as a tetramer at physiological pH and each subunit has a glucose binding site discount 50mg cilostazol, Con A can function as a cross-linking agent for glucose- containing polymer chains buy cilostazol 50 mg lowest price. Because of the non-covalent interaction between glucose and Con A, the formed cross-links are reversible (Figure 16. Individual free glucose molecules can compete with the polymer- attached glucose molecules. Thus, the maintenance of the cross-links depends on the relative concentration of free glucose in the environment. The gel is formed by mixing glucose-containing polymers with Con A in the absence of external glucose. In the presence of elevated glucose levels in solution, however, the gel becomes a sol (i. As the environmental glucose level decreases again, the competition of free glucose against the polymer-bound glucose decreases and thus the gel is formed again. It has been shown that diffusion of insulin is much slower in the gel state than in the sol state, and insulin release can be controlled as a function of the glucose concentration in the environment. Glucose-sensitive phase-reversible hydrogels can also be prepared without using Con A. Glucose, having pendant hydroxyl groups, competes with polyol polymers for the borate groups. Thus, as the glucose concentration increases, the cross-linking density of the gel decreases and the gel swells to release more insulin. The glucose exchange reaction is reversible, and borate-polyol cross-linking is re-formed at a lower glucose concentration. Instead of long chain polyol polymers, shorter molecules, such as diglucosylhexanediamine, can be used as a cross-linking agent. Since the phenylboronic acid gel is sensitive to glucose only at alkaline conditions (pH ≥ 9), various copolymers containing phenylboronic acid were synthesized to provide glucose sensitivity at physiological pH. All the components of the system in the sol state are essentially in the dissolved state, and thus they can be released to the environment in the absence of protecting membranes. During the process of gel to sol transition by the addition of glucose, the incorporated insulin can be released as a function of glucose concentration. There are of course other polymeric systems which can be used in glucose-sensitive erodible insulin delivery. Small closed and open circles represent a polymer-attached glucose and a free glucose, respectively. Diffusion of insulin through the solution (sol) can be an order of magnitude faster than that through the hydrogel (gel) As discussed in Section 16. The uniqueness of poly (N,N′- dimethylaminoethyl methacrylate and ethylacrylamide) is that the critical transition temperature increases as the polymer becomes ionized (i. Thus, the insoluble polymer matrix at a certain temperature becomes water-soluble as the pH of the environment becomes lower. This unique property has been used for glucose-controlled insulin release as illustrated in Figure 16. In the presence of glucose, gluconic acid generated by glucose oxidase protonates dimethylamino groups of the polymer. This induces shift of the critical transition temperature to a higher temperature for the polymers at the surface of the insulin-loaded polymer matrix. This leads to the dissolution of the polymer from the surface and thus the release of insulin. An erodible matrix system based on the shift of the critical transition temperature can also be made using polymers containing phenylboronic acid groups. Poly(N,N-dimethylacrylamide-co-3- (acrylamido)phenylboronic acid) shifts its critical transition temperature in response to changes in glucose concentration. Addition of glucose to such a polymer system can increase the critical transition temperature by 15° around the body temperature. Thus, the system can be designed to become water-soluble in the presence of glucose at the body temperature. Insulin which is loaded inside the polymer can be released as a function of glucose concentration in the environment. The decrease in pH by gluconic acid results in ionization of the polymer, which in turn increases the lower critical solution temperature. This makes the polymer water-soluble, and erosion of the polymer matrix at the surface releases the loaded insulin 16. Addition of glucose leads to the lowering of pH, which in turn results in ionization and thus swelling of the membrane (Figure 16. When a membrane swells, it tends to release more drugs than the membrane in the non- swellable state. As glucose enters the membrane, glucose oxidase entrapped inside the membrane transforms glucose into gluconic acid, which in turn reduces the pH of the hydrogel membrane. This causes swelling of the membrane followed by more release of insulin through the membrane concentration increases. A glucose-sensitive hydraulic flow controller can be designed using a porous membrane system consisting of a porous filter grafted with a polyanion (e. The grafted polyanion chains are expanded at pH 7 due to electrostatic repulsion among charges on polymer chains. Glucose oxidase converts glucose to gluconic acid which lowers the pH and protonates the carboxyl groups of the polymer. Due to the reduced electrostatic repulsion, the polyanion chains then collapse (i. In one approach insulin was chemically modified to introduce glucose, which has a specific binding site for the Con A lectin. The glycosylated insulin-Con A system exploits complementary and competitive binding behavior of Con A with glucose and glycosylated insulin. The free glucose molecules complete with glucose-insulin conjugates bound to Con A, and thus, the glycosylated insulin is desorbed from the Con A in the presence of free glucose (Figure 16. As the pH decreases as a result of gluconic acid formation, the carboxylate groups are protonated and the electrostatic repulsion is reduced. This in turn causes shrinkage of the polymer chains to open pores for insulin release conjugates are released to the surrounding tissue and the studies have shown that the glucose-insulin conjugates are bioactive. In another approach, insulin was modified to introduce hydroxyl groups so that the hydroxylated insulin can be immobilized by forming a complex with phenylboronic acid groups on the support (Fig. The support can be hydrogel beads made of polymers containing phenylboronic acid, e. The hydroxylated insulin can be displaced by the added glucose and the displaced insulin can be released. While the approaches taken in the immobilized insulin systems are highly elegant, there is an inherent drawback of this approach. The approach requires modification of insulin to create a new chemical entity which would require full regulatory approval. The Massachusetts Institute of Technology has recently developed a 17 mm by 17 mm by 310 μm device containing 34 reservoirs.
The main advantage of phase-separation method is that it protects active drugs from partitioning out into the dispersed phase cheap cilostazol amex. However order 100 mg cilostazol with visa, the residual solvent content is a major concern generic cilostazol 50mg amex, especially when organic solvents are used as the hardening agent (54). Emulsion-Solvent Evaporation/Extraction In this method, the polymer is ﬁrst dissolved in a water-immiscible, volatile, organic solvent such as chloroform, dichloromethane, or ethyl acetate (55). To harden the nanoemulsion droplets into solid nanoparticles, the organic solvent is evapo- rated or extracted from the system after it diffuses into the external aqueous phase. For the removal of solvent, the stirring process may be continued for several hours at Polymeric Nanoparticles for Small-Molecule Drugs 23 high-temperature/low-pressure conditions; a quicker option to harden the parti- cles may be to pour the emulsion into water, causing the solvent to phase toward the surfactants in the interface and eventually diffuse out into the aqueous phase. Normally, the rate of solvent extraction or evaporation has signiﬁcant effects on the porosity of the nanoparticles, which, in turn, signiﬁcantly affects the drug release from the nanoparticles. Since the solvent extraction is normally faster than the evap- oration rate (the latter depends on the boiling point of the solvent), the resultant porosity of the nanoparticle matrix prepared by the solvent extraction method is usually greater than the nanoparticles prepared by using the evaporation process (56). Nanoparticles may be harvested by centrifugation or ﬁltration, washed, and freeze-dried to produce free-ﬂowing nanoparticles. One of the challenges encoun- tered in this method is the poor entrapment and burst release effect of moderately – water-soluble and hydrophilic drugs. The encapsulation efﬁciencies of the water- soluble drugs can be increased by using a w/o emulsiﬁcation method in which the solution of the drug and polymer of interest are dissolved in a water-miscible organic solvent, such as acetonitrile or acetone, and emulsiﬁed in an oil, such as light mineral oil containing an oil-soluble surfactant. Finally, the emulsion is sub- jected to solvent removal processes and the oil is removed from the particles by washing with hexane (56,57). A diagrammatic representation of o/w single emul- sion solvent evaporation method is depicted in Figure 1. A modiﬁcation of the single-emulsion method is made by the preparation of a water-in-oil-in-water (w/o/w) type multiple emulsion, which allows for the better incorporation of hydrophilic drugs; this process is termed as the double- or multiple-emulsion method. The process consists of adding the aqueous solution of the drug to the polymer solution in an organic solvent with vigorous stirring to form the ﬁrst o/w emulsion. On the other hand, the evaporation process assumes the predominant step if the polymer solvent (e. Early reports on the multiple emulsion (w/o/w) solvent evaporation method for the preparation of poly(d,l-lactide)- and poly(lactide-co-glycolide)–biodegradable nanoparticles by Bodmeier and McGinity (58,59) and Ogawa et al. This method was subsequently modiﬁed and applied toward the delivery of proteins and other small-molecule drugs by a number of different research groups (61,62). The major existing challenges of this method for the production of nanoparticles are the parameters that control the particle size and the outcome of uniform size dis- tribution for small particles. Moreover, the common solvent used to solubilize the polymer, dichloromethane, is a class 2 solvent that poses problems in use in pharma- ceutical preparations due to its potential toxicity (63). The common class 3 solvent, acetone, produces highly porous particles that eventually adversely facilitate the drug release, especially for hydrophilic small-molecule drugs (64). Moreover, pro- cessing with acetone must be done very carefully because of its high ﬂammability. In another modiﬁcation of the solvent evaporation method (66), the oil phase consists of water-miscible organic solvents such as methanol or acetone together with water-immiscible chlorinated organic solvents. During the formation of an o/w emulsion, acetone/methanol rapidly diffuses into the outer water phase and causes an interfacial turbulence between the two phases, thus resulting in the for- mation of smaller particles. Poly- meric nanoparticles can be prepared by using an emulsion technique that avoids surfactants and chlorinated solvents and involves a salting-out process between two miscible solvents to separate the phases (67). The saturated aqueous solution prevents complete miscibility of both the phases by virtue of the high salt content. After the preparation of the initial water- in-oil emulsion (w/o), water is immediately added in sufﬁcient quantity to cause a phase inversion from water-in-oil (w/o) to oil-in-water (o/w) type emulsion; this induces complete diffusion of acetone from the internal nonaqueous phase into the continuous external aqueous phase, thus leading to the formation of nanoparti- cles. The ﬁnal emulsion is then stirred overnight at room temperature to allow for the complete removal of acetone. Emulsiﬁcation Solvent Diffusion Method In the technique developed by Quintanar-Guerrero et al. Water is subsequently added under constant stirring to the o/w emulsion system, thus causing phase transformation and outward diffusion of the solvent from the inter- nal phase, leading to the nanoprecipitation of the polymer and the formation of col- loidal nanoparticles. Finally, the solvent can be eliminated by vacuum steam distil- lation or evaporation. A schematic diagram of the emulsiﬁcation-solvent diffusion method is presented in Figure 2. Emulsion Polymerization This method has been used to prepare poly(alkyl cyanoacrylate) nanoparticles with an approximate diameter of 200 nm (69). A schematic diagram for preparation of Poly(alkyl-cyanoacrylate) nanoparticles by anionic polymerization is presented in Figure 3. The alkyl cyanoacrylate monomer is dispersed in an aqueous acidic medium containing stabilizers such as dextrans and poloxamers (70). The low pH favors the formation of sta- ble and high molecular mass nanoparticles. The nonpolar ends within the interior of the surfactant micelles help solubilize the monomer. When the monomer in the inte- rior of the micelle gets depleted, more monomer droplets from the exterior aqueous phase enter inside; thus, the polymerization reaction proceeds inward and contin- ues until it is terminated by the free radicals. The drug can be solubilized in the poly- merization medium either before the monomer is added or later when the reaction has ended. Finally, the nanoparticulate suspension is puriﬁed either by ultracen- trifugation or by redispersing the nanoparticles in an isotonic medium. The various factors affecting the formation of particles, their size, and molecular mass include monomer concentration, stirring speed, surfactant/stabilizer type and concentra- tion, and the pH of the polymerization medium (71). Polymeric Nanoparticles for Small-Molecule Drugs 27 Phase Separation in Nonaqueous System Unlike the single o/w and double w/o/w emulsion techniques, this process can be used to encapsulate both hydrophilic and lipophilic drugs, offering distinct advantages in terms of the entrapment efﬁciency over the application of predomi- nantly aqueous systems that wash away highly hydrophilic drugs. In this method, hydrophilic drugs are solubilized in water and added to an organic solution of the polymer (w/o emulsion), whereas lipophilic drugs can be dissolved/dispersed in the polymer solution (51). With the loss of the solvent, there is a reduction in the polymer solubility, and the coating polymer in the solu- tion undergoes phase separation, with the coacervate phase containing the polymer coacervate droplets. The polymer coacervate adsorbs on to the drug particle surface, resulting in the encapsulation of the drug by the precipitated polymer. It was noted that the o/w emul- sion template produced smaller particle size and higher entrapment efﬁciency for the hydrophobic drug than the nonaqueous o/o template used for the same drug. On the other hand, the entrapment of a highly water-soluble agent, a Bowman-Birk inhibitor, was signiﬁcantly increased by using the nonaqueous o/o template (73). Large-Scale Pilot Production of Drug-Loaded Nanoparticles Spray Drying Some of the challenges faced by this technique include the production of small-sized nanoparticles and the need for innovative methods to increase the drug-entrapment efﬁciency. However, when compared with other methods, it provides a relatively rapid and convenient production technique that is easy to scale up, involves mild processing conditions, and has relatively less dependence on the solubility char- acteristics of the drug and the polymer. In this method, a solution or dispersion (w/o) of a drug in an organic solvent containing the polymer is sprayed from the sonicating nozzle of a spray dryer and subsequently dried to yield nanoparticles. The process parameters that can be varied include the inlet and outlet air temper- atures, spray ﬂow, and compressed spray air ﬂow (represented as the volume of the air input). In a novel, low-temperature, freeze–spray-drying method (74), the solution or dispersion of the drug in an organic solvent containing the dissolved polymer is sprayed or atomized through an ultrasonic nozzle into a vessel contain- ing liquid nitrogen overlaying frozen ethanol and frozen at −80◦C and lyophilized. The liquid nitrogen is evaporated, whereupon the melting liqueﬁed ethanol extracts the organic solvent from the frozen droplets causing the particles to harden.