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Both processes exhibit classical saturation kinetics buy female cialis 10mg free shipping, since there are only a finite number of carrier molecules purchase 10mg female cialis overnight delivery. Thus unlike passive absorption (paracellular or transcellular) female cialis 10mg low price, where the rate of transport is directly proportional to the drug concentration (Figure 1 cheap female cialis online mastercard. At higher concentrations, the carrier mechanism becomes saturated and the rate of absorption remains constant (Figure 1. If a drug is sufficiently similar to a substance naturally transported by a carrier-mediated system, the drug may also be transported by the same system. For example, the drugs levodopa, methyldopa and 15 penicillamine are all absorbed via various amino acid transporters. Serine and threonine derivatives of nitrogen mustard, which have been investigated for antitumor activity, are also absorbed by a carrier- mediated process. Digitalis and other cardioselective glycosides also demonstrate behavior not compatible with simple partition theory, which suggests the involvement of carrier-mediated transport. Considerable attention is being focused on the identification of the structural requirements necessary for the binding and transport via the di- and tri-peptide transporters present in the gastrointestinal tract, in order to exploit this route for the oral delivery of peptides. Critical structural features that have been found to influence transport include stereoisomerism, side-chain length and net charge. Several drugs including a pGlu-L-dopa prodrug, as well as angiotensin-converting enzyme inhibitors and various thrombin inhibitors, have all demonstrated success in targeting endogenous transporters and enhancing transport across the intestinal mucosa. Endocytic processes All the above transport mechanisms are only applicable to the absorption of small molecules, less than approximately 500 Da. There is evidence that larger molecules can be absorbed with low efficiency due to endocytosis. Endocytosis is defined as the internalization of plasma membrane with concomitant engulfment of extracellular material and extracellular fluid. Pinocytosis is a non-specific process that goes on continually in all cell types, in which the plasma membrane invaginates and forms an inward channel, into which extracellular fluid flows (Figure 1. Solutes dissolved in the extracellular fluid, including large (soluble) macromolecules, may flow with the extracellular fluid into the invaginations and become internalized. Alternatively, uptake may involve: • adsorptive pinocytosis, in which macromolecules bind to non-specific membrane receptors, prior to pinocytosis; • receptor-mediated pinocytosis, in which macromolecules bind to specific membrane receptors, prior to pinocytosis. The pinocytic vesicles (endosomes) migrate inwardly and fuse with lysosomes, which contain many lyosomal enzymes, to form secondary lyosomes. The ligand is degraded by the lysosomal enzymes, the degraded products are released and the membrane is recycled back to the plasma membrane. Alternatively, the secondary lysosomes can fuse with the cell membrane, leading to exocytosis of their contents, and the membranes are recycled back to the plasma membrane. Thus pinocytosis offers a pathway through which large macromolecules, which are otherwise incapable of passing through the membrane, may be taken up by cells. In some cases, following uptake of a drug via receptor-mediated pinocytosis, the endosomes carrying the drug actually bypass the lysosomes and migrate toward the basolateral membrane, resulting in the release of the undegraded drug into the extracellular space bounded by the basolateral membrane. This process, known as transcytosis, represents a potentially useful and important pathway for the absorption of high molecular weight drugs such as peptides and proteins. Indeed, some peptides and proteins are known to enter intestinal mucosal cells through pinocytosis; furthermore, a few peptides and proteins (including immunoglobulin G, nerve growth factor and epidermal growth factor) have been reported to reach blood vessels in the lamina propria and the portal venous circulation. This process may be facilitated by serum proteins knows as opsonins, which cover the particulate and promote adsorption and ingestion. The extent and pattern of opsonization depends highly on antigen surface characteristics such as charge and hydrophilicity. When digestion is complete, the lysosomal membrane may rupture, discharging its contents into the cytoplasm. Fixed macrophages are found lining certain blood and lymph-filled spaces, such as the sinusoids of the liver (these cells are commonly referred to as Kuppfer cells), bone marrow and spleen. For the purpose of completeness, the process of phagocytosis has been described briefly here. The process of phagocytosis is of particular relevance when particulate delivery systems, such as microspheres, liposomes and other advanced delivery systems (described in Chapter 5), are used. Phagocytic processes are also finding applications in oral drug delivery and targeting. Specialized epithelial cells known as M cells, which overly lymphoid sections of the gastrointestinal tract, may be involved in the phagocytic uptake of macromolecules and microparticles from the gut (see Section 6. Pore transport A further mechanism of transcellular transport is via the aqueous pores which exist in many lipid membranes. However, most drugs are generally much larger (≥1 nm in diameter) than the pore size, and this route is therefore of minor importance for drug delivery. These properties will influence the route and mechanism of drug absorption through the mucosa. For example, it is not unreasonable to assume that: • low molecular weight hydrophilic compounds would tend to be absorbed via the paracellular route, moving between the epithelial cells; • lipid-soluble drugs would usually absorbed via transcellular passive diffusion, diffusing through the lipidic membrane barrier; • macromolecules may be absorbed via endocytic processes; • drugs bearing structural similarities to endogenous nutrients may be absorbed via carrier-mediated mechanisms. However, this is a rather simplistic view and it is important to realize that these considerations are only broad generalizations. Thus although a drug molecule may be predominantly absorbed via one particular route/mechanism, it is also likely that suboptimal transport will occur via other routes and mechanisms. In particular, drugs that are absorbed via active mechanisms are often also absorbed, to a (much) lesser extent, via passive diffusion mechanisms. A brief description of the effect of the physicochemical properties of the drug on the absorption process is given below and is discussed in more detail in the relevant chapters. A measure of the lipid solubility of a drug is given by its oil/water equilibrium partition coefficient. This is determined by adding the drug to a mixture of equal volumes of a lipophilic liquid (often octanol, but other solvents also used) and water and shaking the mixture vigorously to promote partitioning of the drug into each phase. For a given drug: if log P=0, there is equal distribution of the drug in both phases if log P>0, the drug is lipid soluble if log P<0, the drug is water soluble 19 Table 1. Thus in general, the higher the log P, the higher is the affinity for lipid membranes and thus the more rapidly the drug passes through the membrane via passive diffusion. Values of log P that are too high (>6) or too low (<3) may be associated with poor transport characteristics. Drugs with very high log P values have poor aqueous solubility, which is partly the reason for their poor absorption properties, as some degree of aqueous solubility is required for drug absorption (see Section 1. Furthermore, if a drug is too lipophilic, it will remain in the lipidic membrane and never partition out again into the underlying aqueous environment. Very polar compounds (with very low log P values) are not sufficiently lipophilic to be able to pass through lipid membrane barriers. If a drug molecule forms hydrogen bonds with water, desolvation and breaking of the hydrogen bonds is required, prior to partitioning into the apical membrane of the epithelial cell. If the number of hydrogen bonds between the drug and water is > 10, too much energy is required and there will be minimal drug transport across the membrane. The number of hydrogen bonds a drug forms with water can be estimated by inspection of the drug structure (Table 1. The lipid solubility of a drug molecule can be increased by blocking the hydrogen bonding capacity of the drug. This may be achieved by, for example, substitution, esterification or alkylation of existing groups 20 on the molecules and will decrease the drug’s aqueous solubility, favoring partitioning of the drug into the lipid membrane. The development of clindamycin, which differs from lincomycin by the single substitution of a chloride for a hydroxyl group, is such an example. Alternatively, the drug may be covalently bound to a lipid carrier, such as long-chain fatty acids. Altering the structure of the drug carries the concomitant risks of: • compromising the activity of the drug; • increasing the toxicity of the drug; • increasing the molecular weight to such an extent that the molecule will be too large to cross the membrane barrier (see Section 1. An alternative strategy, which overcomes these limitations, is to use the prodrug approach (Figure 1. This involves the chemical transformation of the active drug substance to an inactive derivative (prodrug), which is subsequently converted to the parent compound in vivo by an enzymatic or non-enzymatic process. Thus a prodrug of a drug, because of its increased lipid solubility, may demonstrate enhanced membrane permeability in comparison to the parent drug. Enzymatic or chemical transformation converts the inactive prodrug to the pharmacologically active drug, after absorption has taken place. A further important point, discussed in detail in the next section, is that lipid solubility must be considered in the context of the degree of ionization of the drug. Therefore the pH of the solution will affect the overall partition coefficient of an ionizable substance.

Carlbring P buy female cialis with mastercard, Gunnarsdottir M buy generic female cialis on line, Hedensjo L buy female cialis 20mg fast delivery, Andersson G buy female cialis 20mg otc, Ekselius L, Juster H, Campeas R, Bruch M, Cloitre M, et al: Cognitive behavioral Furmark T: Treatment of social phobia: randomised trial of internet- group therapy vs phenelzine therapy for social phobia: 12-week delivered cognitive-behavioural therapy with telephone support. Titov N, Andrews G, Choi I, Schwencke G, Mahoney A: Shyness 3: comparison of the efficacy of clonazepam and cognitive-behavioral randomized controlled trial of guided versus unguided Internet-based group therapy for the treatment of social phobia. Gelernter C, Uhde T, Cimbolic P, Arnkoff D, Vittone B, Tancer M, Bartko J: online: replication and extension. Titov N, Andrews G, Schwencke G, Drobny J, Einstein D: Shyness 1: A controlled study. 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Child assessment stable purchase female cialis 20mg otc, treatment focus on concerns about cus- requires trained personnel and may be unreal- tody purchase female cialis on line, children purchase female cialis 10mg without a prescription, and parenting order discount female cialis line. A counselor who determines that Psychodynamic parenting groups take a more a patient is neglecting or abusing young children intensive approach, exploring topics such as is required to report the neglect or abuse. Counselors should incorporate appropriate assessment procedures, referrals, or treatment responses for violence. They might have to help Peer Support, or M utual-Help, patients remove themselves from dangerous situ- Program s ations. Counselors should have a broad view of domestic violence that includes female (to male) The most popular, widely used mutual-help aggression, same-sex physical and emotional models are 12-Step recovery programs, such abuse, and issues related to elder abuse. They are sources for social provide general didactic groups or seminars and support, peer identification, relapse preven- other resources addressing domestic violence. Members of sup- port groups gain strength and security from others who understand and share their con- Integrative cerns and who offer practical strategies for surviving ìone day at a time. Some patients, unable to handle rejection, have chosen not to return, others have chosen prematurely to taper from maintenance medication, and some have used this diffi- culty as justification to self-medicate. For information, contact the National Alliance of Methadone Advocates (212-595-6262 or www. Other Approaches Decreases in substance abuse among group participants have been associated with attend- In acupuncture, thin needles are inserted ing meetings frequently, obtaining a sponsor, subcutaneously at points on the body for thera- ìworkingî the 12 Steps, and leading meetings peutic purposes. Some believe that acupunc- (American Psychiatric Association 1995, 1996; ture can relieve pain, anxiety, and withdrawal Landry 1997). However, 12-Step groups are symptoms related to substance abuse, although not for everyone. Its use to treat opioid with- Patients should not be pressured to attend sup- drawal was first reported in 1973. Resistance to attendance should However, a National Institutes of Health be discussed and respected. Every effort consensus statement lists addiction as one con- should be made to help a patient find an dition for which acupuncture treatment might appropriate peer support program. Although the mechanism of acupunc- ative strategies have evolved to promote ture is not understood, some researchers have mutual-help programs, such as simulated meet- focused on the analgesic effects of opioid pep- ings to introduce patients to the language, cus- tides released during the procedure (National toms, and rules of groups. A useful manual is Relapse strategy to ensure that a severe relapse is Prevention W orkbook (Daley 2002). Relapse Prevention Strategies for M ultiple Substance Use Education about relapse is a key part of treat- Patients who abuse multiple substances may ment. Educational approaches should teach require modified relapse prevention strategies. Separate interventions drug cravings and slips to prevent full-blown may be necessary for each substance because relapses. Relapse prevention strategies often the associated risks of relapse are different for distinguish between slips and relapses, with each. For course, no level of opioid use should be con- example, a patient may associate heroin use doned, but when a relatively mild and isolated with socializing and cocaine use with alleviating episode occurs, the consensus panel recom- depression. Providing Com prehensive Care and M axim izing Patient Retention 137 Some researchers have noted that an absti- treatment for relapse prevention concluded nence violation effect may occur when a patient that these treatments, although studied for abstains from a substance but then relapses years, were ineffective (Conklin and Tiffany and possibly overuses it. W hen a slip or lapse occurs, the patientís self- Patient Follow up Strategies esteem can be lowered, which he or she may Patient followup and continuing care have been attempt to repair by continuing or increasing found to be critical to preventing relapse and substance use. The consensus panel by repeated exposures to an experience that believes that these discharges are, in many previously triggered drug use (Childress et al. Zanis and W oody many substance abuse (1998) found substantial increases in death treatment programs, fairly and rates among those involuntarily discharged for lends itself to such continued drug use. W hen discharge is unavoidable, it should complete abstinence be handled fairly and humanely, following pro- was not achieved (e. Treatment for other substance use and addiction should be offered to patients coping Reasons for Adm inistrative with dual addictions (see chapter 11). If all lence should be taken seriously, and interven- of these avenues are exhausted and a patient tions should be rapid. Staff should document must be discharged for inability to pay fees, problem behavior. To ensure that patients are and consistently enforce guidelines for patient not cut off abruptly from medication, some behavior. However, this may pre- tant factors in preventing administrative sent serious obstacles for many patients, espe- discharge. Training in interpersonal techniques 2003, the American Association for the to handle aggressive or upset patients in non- Treatment of Opioid Dependence released new provocative ways should be part of training for guidelines for addressing involuntary with- all staff. These problem should be to identify it, review the guidelines can be found at www. Preventing and Finding Dosing should not be a behavioral tooló patients should not be disciplined by having Alternatives to Adm inistrative their medication dosage decreased or withheld, Discharge nor should they be rewarded for good conduct by having their dosage increased. Programs Com m unicating program are encouraged to develop nonpunitive ways to rules clearly set limits and contain disruptive behavior. However, in some cases, involuntary discharge Including program rules in patient orientation becomes necessary. Involuntary dis- should include escalating warnings and specified charge should be done with the understanding consequences including referral. Some States have devel- schedules require medical determination (see oped regulations to guide this process. Staff members not directly involved with a dis- ciplinary action should conduct a review of Members of the consensus panel agree that that action. Participation the National Alliance of Methadone Advocates in these organizations helps empower patients (www. Advancement of Addiction Treatment Other benefits include practice in group inter- (www. Because patients should be educated about their treat- accreditation agencies are concerned with input ment and encouraged to participate in it. In from patients, such involvement by patients general, these advocacy groups are made up usually is viewed favorably by these agencies. Administrators use drug test results in response to quality assurance Development of requirements. Ball and Ross (1991) found that the most effective programs had Other less than 10-percent positive tests. Drug use patterns routinely for alcohol and marijuana or only as have changed markedly in recent decades; for needed. Lim itations of Until new, commercially available tests are Drug Tests developed, drug testing of patients receiving buprenorphine primarily should be to detect The consensus panel cautions that drug test substances of abuse. Training and assuming that its availability continues (see educating staff members about the benefits and chapter 3). Staff members should understand, for example, that certain prescribed and over- Testing for Substances of the-counter medications and foods might gener- ate false positive and false negative results for Abuse different substances. As other drug-testing methods and has well-established cutoff levels and other are developed and attain Federal and State laboratory guidelines (Cone and Preston 2002). Concerns usually Alternatives to urine and oral-fluid testing have relate to the specimen collection process or the benefits and limitations. However, blood testing is A patientís physical condition can affect test impractical, costly, sensitivity and specificity. Urine testing is not and difficult, and feasible for patients with renal failure (e. George and Braithwaite (1999) urine drug testing is found that variations in metabolism and excre- testing is dominant likely to be the domi- tion could affect urine concentrations of nant method in methadone or its metabolites. Two studies evaluated patientsí self-reports of drug Just as some patients metabolize methadone or use and concluded that they are at least as reli- other treatment medications at different rates able as urine drug tests (Zanis et al. In addition, the technique urine drug test results regardless of whether is well studied, has been in use for a long time, 146 Chapter 9 patients were notified of tests in advance. Some drugs remain detectable that study, some patients stated that unan- longer in urine than in saliva. Drug residue in nounced urine tests deterred them from sub- the oral or nasal cavity was found to contami- stance use, but 53 percent said it did not.

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