By U. Gancka. Morris College.

Biochem J 277 cosmeceutical strategies to support more invasive pro- (Pt 1):277–279 cedures for patients with advanced dermal 15 discount prothiaden 75 mg without a prescription. Kerkelä E buy generic prothiaden 75 mg on line, Saarialho-Kere U (2003) M atrix metalloprotei- on transepidermal water loss buy 75 mg prothiaden amex, stratum corneum hydration, nases in tumor progression: focus on basal and squamous skin surface pH, and casual sebum content. Int J Dermatol 41(1):21–27 hairless mouse skin: possible effect on decreasing skin 21. Fagien S (1999) Botox for the treatment of dynamic and mechanical properties and appearance of wrinkles. J Invest hyperkinetic facial lines and furrows: adjunctive use in facial Dermatol 117(6):1458–1463 aesthetic surgery. Soldano S, M ontagna P, Brizzolara R, Sulli A, Parodi A, of the process and topical therapies. Expert Rev Dermatol Seriolo B, Paolino S, Villaggio B, Cutolo M (2010) Effects 2:753–761 of estrogens on extracellular matrix synthesis in cultures of 6. Coleman S, Grover R (2006) the anatomy of the aging face: human normal and scleroderma skin fbroblasts. Guinot C, M alvy D, Ambroisine L, Latreille J, M auger E, 621–625 Tenenhaus M , M orizot F, Lopez S, Le Fur I, Tschachler E 11. Australas J Dermatol 38(suppl 1):S83–S85 8 Cosmeceutical Treatment of the Aging Face 81 32. Informa Healthcare, New York, pp 311–322 Photoprotection by sunscreens with topical antioxidants and 35. Baxter R (2008) Anti-aging properties of resveratrol: review lates, the anthranilates, and physical agents. Br J Dermatol 145(4):597–601 (2005) Chemoprevention of skin cancer by grape constituent 42. Chatelain E, Gabard B (2001) Photostabilization of butyl oxidative stress in mouse skin. Int J Oncol 21(6): methoxydibenzoylmethane (avobenzone) and ethylhexyl 1213–1222 methoxycinnamate by bis-ethylhexyloxyphenol methoxy- 65. J Invest Dermatol 129(7):1805–1815 Relative assessment of oxidative stress protection capacity 71. Farris P (2007) Idebenone, green tea, and Coffeeberry® compared to commonly known antioxidants. Biochim logues investigated by pulse radiolysis: redox reaction Biophys Acta 1556(2–3):187–196 involving ergothioneine and vitamin C. Saija A, Tomaino A, Lo Cascio R, Trombetta D, Proteggente A, tions on ex vivo human skin. J Cosmet Dermatol 5(2): De Pasquale A, Uccella N, Bonina F (1999) Ferulic and caf- 150–156 feic acids as potential protective agents against photooxida- 94. Biomed Pap M ed Fac Univ Palacky Olomouc Czech M ed Rev 6(6):601–607 Repub 147(2):137–145 96. Can J Physiol Pharmacol 71(9):725–731 Evaluation of the antioxidant actions of ferulic acid and cat- 97. Free Radic Res Commun 19(4):241–253 (2007) Protective effect evaluation of free radical scaven- 81. Int J Cosmet Sci and kinetin provide ineffective photoprotection to skin when 17:91–103 compared to a topical antioxidant combination of vitamins 98. Exp Vitamin A antagonizes decreased cell growth and elevated Dermatol 15(9):678–684 collagen-degrading matrix metalloproteinases and stimu- 83. F’guyer S, Afaq F, M ukhtar H (2003) Photochemoprevention lates collagen accumulation in naturally aged human skin. Photodermatol Photo- J Invest Dermatol 114:480–486 immunol Photomed 19(2):56–72 100. Carcinogenesis 20(11): Gamma-tocotrienol inhibits nuclear factor-kB signaling 2117–2124 pathway through inhibition of receptor-interacting protein 85. J Am Podiatr M ed Assoc 79(8):395–397 lagen promotes extracellular matrix production. Barrantes E, Guinea M (2003) Inhibition of collagenase Lorimier S, Antonicelli F, Soria C, Crepin M , Hornebeck W , and metalloproteinases by aloins and aloe gel. 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Narosa M ontiel A (2002) A synthetic hexapeptide (argireline) with Publishing House, New Delhi, pp 523–524 antiwrinkle activity. In: Schueller R, Romanowski P (1997) Human genital melanocytes as androgen target (eds) Conditioning agents for hair and skin, vol 21, cells. M arshall C (2002) the use of honey in wound care: a Clin 25(3):353–362 review article. J Drugs cation of honey in the management of radiation mucosi- Dermatol 6(1):32–39 this. Fluhr J, Holleran W M , Berardesca E (2002) Clinical effects York, pp 205–218 of emollients on skin. Ando S, Suemoto Y, M ishima Y, Suemoto Y, M ishima Cosmetic science and technology series: skin moisturiza- Y (1993) Tyrosinase gene transcription and its control by mela- tion. Eaglstein W H (2001) M oist wound healing with occlu- 150s–155s sive dressings: a clinical focus. M aeda K, Fukuda M (1996) Arbutin: mechanism of its allergenic activity of lanolin. 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In addition to Multiple chemical mediators of infammation derived from infammation buy prothiaden 75mg free shipping, there is pruritus and minor cellular infltra- either plasma or cells have been described purchase 75 mg prothiaden otc. Asthmatic patients may produce a delayed or secondary plasma proteins such as complement are present as precur- response following antigenic challenge order prothiaden 75 mg without a prescription, which involves the sors that require activation to become biologically active. This induces second- Mediators, such as histamine and mast cells, derived from ary degranulation of mast cells and basophils, which stim- cells are present as precursors in intracellular granules. These mediators are quickly activated by viruses, or other irritants may induce the late-phase reaction. Those that are newly synthesized include prostaglandins, leukot- the wheal and fare reaction is an immediate hyper- rienes, platelet-activating factors, cytokines, and nitric oxide. Chemical mediators in plasma include complement fragments Application of antigen by a scratch test in a hypersensitive C3a and C5a and the C5b–g sequence. Three plasma-derived individual may be followed by erythema, which is the red factors including kinins, complement, and clotting factors are fare, and edema, which is the wheal. Bradykinin is produced by acti- have a hereditary component to their allergy experience the vation of the kinin system. It induces arteriolar dilation and effects of histamine and other vasoactive amine released increased venule permeability through contraction of endothe- from mast cell granules following crosslinking of surface lial cells and extravascular smooth muscle. Acute infammation is a reaction of sudden onset marked by the classic symptoms of pain, heat, redness, swelling, and loss During clotting, fbrinopeptides produced during the con- of function. There is dilatation of arterioles, capillaries, and version of fbrinogen to fbrin increase vascular perme- venules with increased permeability and blood fow. The fbrinolytic exudation of fuids, including plasma proteins, and migration system participates in infammation through the kinin sys- of leukocytes into the infammatory site. Products produced during arachidonic acid metabolism localized protective response induced by injury or destruction also affect infammation. These include prostaglandins and 150 Atlas of Immunology, Third Edition leukotrienes, which can mediate essentially every aspect of leads to the development of a type of scar tissue at a site of acute infammation. Infammatory cells are cells of the blood and tissues that G proteins are proteins that bind guanosine triphosphate participate in acute and chronic infammatory reactions. The two types of G proteins An infammatory macrophage is found in peritoneal exu- include the trimeric (α, β, γ) receptor-associated G protein date induced by thioglycolate broth or mineral oil injection and the small G proteins including Ras and Raf which func- into the peritoneal cavity of an experimental animal. The G protein-coupled receptor family refers to receptors Bradykinin is produced through their sequential interaction. Anaphylactic shock, which employ associated trimeric G proteins for intracellular endotoxin shock, and infammation are processes in which signaling. Exudate is composed of fuid-containing cells and cellular Fatty acids and immunity: Dietary lipids exert signifcant debris that have escaped from blood vessels and have been effects on antigen-specifc and nonspecifc immunity. These deposited in tissues or on tissue surfaces as a consequence effects are related to total and fat-derived energy intake, syn- of infammation. In contrast to a transudate, an exudate is thesis of multiple eicosanoids, and alterations in cell membrane characterized by a high content of proteins, cells, or solid content. Their oversynthesis contributes to the development of chronic and acute infammatory, autoimmune, Exudation refers to the passage of blood cells and fuid con- atherosclerotic, and neoplastic diseases. The matory, and atherosclerotic disease severity by diminishing the process consists of margination and diapedesis. The increased eicosanoids found in shock and trauma can induce An infammatory mediator is a substance that participates immunosuppression in humans. Dietary fsh oil supplements also improve joint ten- N-formylmethionine is an amino acid that initiates all bac- derness in rheumatoid arthritis patients. It alerts the innate immune the mixed lymphocyte reaction, which refects graft survival. Neutrophils express spe- Linoleic acid is the only fatty acid needed to facilitate prolif- cifc receptors for N-formylmethionine-containing peptides. Cell membrane lipids play a Edema is tissue swelling as a result of fuid extravasation critical role in both primary and secondary immune responses from the intravascular space. Acute phase reactants participate in the natural or innate response to microorganisms. Pentraxins are a family of acute-phase plasma proteins interleukin-6, interferons, and tumor necrosis factor. Pentraxin fam- C-reactive protein may show a striking rise within a few ily refers to a category of glycoproteins in the blood that has a hours. Infection, infammation, tissue injury, and, very infre- cyclic pentameric symmetric structure. One of the pentraxin proteins in serum, it is 115 kDa and hematopoietic system changes include hypergamma- and is comprised of fve 206-amino acid polypeptide subunits globulinemia and leukocytosis with a shift to the left. There that are all the same and arranged in a disk conformation is diminished formation of albumin, elevated ceruloplasmin, without covalent bonds. Cellular elements may also be uals in only trace amounts in the plasma, with a median level produced in addition to the acute-phase proteins. Once the condition that induced its elevation has ment components, and interferons. These proteins, which migrate reacts with phosphoryl choline in the C polysaccharide of figure 2. Among by binding to C1q, agglutination of particulate ligands, and the numerous factors that contribute to natural resistance are participation of insoluble ones, as well as neutralization of the skin, mucous membranes, and other barriers to infection; biological activity. The dermis is the skin layer below the epidermis and base- Humans are confronted with a host of microorganisms with ment membrane that comprises blood vessels, lymphatic ves- the potential to induce serious or fatal infections. Yet nature sels, nerve fbers, scattered fbroblasts, macrophages, mast has provided appropriate molecules, cells, and receptors that cells, dendritic cells, and αβ T cells. Many of these defenses beneath the basement membrane and the reticular dermis is are general or nonspecifc and do not require previous expo- beneath the papillary dermis. Both the papillary and reticular sure to the offending pathogen (or closely related organism). Another important defense system is acquired immunity, which can develop after previous contact the epidermis is the upper layers of the skin that contain with the organism through infection (overt or subclinical). Early induced responses are nonadaptive host responses induced by infectious agents early in infection. Their induc- the keratin layer is an external structure of skin that pro- tive phase differentiates them from innate immunity and their tects the body from microorganisms and resists penetrating failure to involve clonal selection of antigen-specifc lympho- stimuli.

The glucuronide conjugate of Various minor metabolites of phenytoin are known (Figure 43 buy 75 mg prothiaden with mastercard. The ple m-hydroxyphenytoin (possibly an analytical artefact) 75 mg prothiaden amex, dihy- p-hydroxyphenytoin isomers neither possess known biological ac- drodiol effective prothiaden 75mg, catechol, O-methyl catechol derivatives, and a molecule tivity, nor are likely to achieve high enough concentrations in the para-hydroxylated on each aromatic ring. A possible hydantoin serum of patients with intact renal function to exert feedback inhi- ring-opened product and a N-glucuronide conjugate of the drug bition on phenytoin biotransformation. The Michaelis con- for individuals who cannot tolerate conventional phenytoin dosag- stant (Km) is in the range of 3–30 mg/L, with a mean of around es [32,33]. The problem is uncommon in Western populations but 6 mg/L (24 µmol), lower than the usual serum concentration oc- may be a signifcant issue in those of Asian extraction. The efects of Michaelis–Menten kinetics result in N-glucuronide p-hydroxyphenytoin Phenytoin Postulated epoxide metabolite Dihydrodiol 5,5´-dihydroxyphenyl metabolite O-glucuronides metabolite Catechol metabolite O-glucuronide O-methyl catechol metabolite Figure 43. Adults Substances that may decrease the oral bioavailability of phenytoin 30 Antacids Calcium sulfate (within phenytoin capsules) Charcoal (activated) Protein hydrolysates for enteric feeding 20 Sucralfate Theophylline 10 Table 43. Substances causing phenytoin displacement from plasma 0 protein binding sites 2 4 6 8 10 12 Acetazolamide Phenytoin dose (mg/kg/day) Ceftriaxone Figure 43. Oxacillin Salicylates Sulfamethoxazole Tolbutamide a non-linear relationship between drug dose and serum phenytoin Valproic acid concentration. Small phenytoin dose increments result in dispro- portionately large increases in serum concentrations. The maximum velocity of phenytoin elimination (Vmax) has been discussed here, although some of the interactions have unknown in the range 6–16 mg/kg/day, and is higher in young children than or uncertain mechanisms. The fnal outcome of a given in- can be calculated for phenytoin, but the values are not constant in teraction can be the sum of two opposing processes, each of which the individual, and vary with the phenytoin concentration range may vary from person to person, and also vary in extent depending over which the measurements have been carried out. A representative published value for the drug’s half-life over Interactions affecting phenytoin absorption the concentration range likely to be encountered in human thera- Examples of interactions afecting phenytoin absorption (Table 43. Studies in volunteers have sometimes failed to reproduce Numerous interactions between phenytoin and endogenous sub- this efect, and have also failed to elucidate its chemical mechanism. It has been found that the problem can be avoided by administer- A few of the interactions are pharmacodynamic in nature, mainly ing the drug to patients several hours before, or afer, the protein involving additional sedative efects when other drugs with sedative hydrolysate. The individual interactions that have been described salicylates, valproic acid, heparin) may displace phenytoin from are now too numerous for detailed discussion in this chapter. In most instances, outcomes of many of those involving drug metabolism are listed in these potential interactions are unlikely to be of clinical impor- Table 43. The possible mechanisms of the interactions are all result of the interaction is usually to decrease the total drug Phenytoin 579 Table 43. This concentration range is usually con- metabolic basis of many of the reported interactions involving al- sidered the ‘therapeutic’ or ‘target’ range for the drug. Because of the Michaelis–Menten elimina- fully controlled once serum phenytoin levels exceed 6–8 mg/L, but tion kinetics of phenytoin, a small degree of inhibition of the drug’s much higher levels may be needed for control of focal seizures. The therapeutic likely to go unnoticed, unless serum phenytoin concentrations are range values for the drug in plasma water (unbound plasma con- monitored, or seizure control deteriorates. Serum phenytoin levels centration) or saliva are approximately one-tenth of those in whole ofen decrease when primidone, vigabatrin, carbamazepine or phe- plasma (serum). In theory, it would always be better to measure the nobarbital is added as co-medication, although sometimes the op- drug’s concentration in plasma water rather than in whole plasma posite efect occurs when carbamazepine or phenobarbital is added. In practice, the unbound (free) drug concen- trations are more expensive to measure, and the measurements are Phenytoin affecting other substances less accurate. Tey are rarely needed unless there is good reason to Phenytoin can alter the body’s elimination of other substances by (i) suspect altered plasma protein binding of the drug. At steady-state, the peak-to-trough fuctuation in not yet known what contribution other interaction mechanisms serum phenytoin concentration in adults is likely to be of the order may make. Both enzyme induction and inhibition can occur simul- of ± 10% over a 12-h dosage interval. Greater inter-dosage fuctu- taneously, with clinical consequences that are difcult to predict in ations occur in children. As a result, the concentrations of carbamazepine, cloba- Tere are wide inter-individual variations in steady-state serum zam, clonazepam, felbamate, lacosamide, lamotrigine, primidone, phenytoin concentrations at conventional doses of the drug (300 or tiagabine, topiramate, valproic acid, ethosuximide, perampanel and 400 mg/day), and an appreciable proportion of the values fall out- zonisamide can fall when phenytoin is added as co-medication. The correlation between dose and level efect of phenytoin on phenobarbital concentrations varies, with is better if phenytoin dosage is expressed relative to body weight. By causing enzyme induction, phenytoin can The maximum velocity of phenytoin biotransformation (or the also decrease the serum levels and clinical efectiveness of many clearance value) is higher in children than in adults [23]. A pheny- cardiovascular agents, chemotherapeutic agents, hormonal agents, toin dose of 5 mg/kg/day will yield a mean mid-therapeutic range psychotropic agents and many other substances. However, prepubertal children will need a and co-administered drugs are listed in Tables 43. Be- mean phenytoin dose of 11 mg/kg/day to achieve a similar mean cause a signifcant proportion of patients with epilepsy are treat- serum drug concentration. It also tends to comes of simultaneous administration of phenytoin and another be slightly lower in the elderly than in younger adults. Tere may be a temporary fall in serum phenytoin drug dose return to prepregnancy values over a few weeks afer levels in the 24 h afer craniotomy but the reason for this is unclear. This sequence of changes needs to be kept in mind if it is considered desirable to maintain serum phenytoin concen- trations at their pre-pregnancy values throughout pregnancy, and Effcacy aferwards. However, if this is done, the reduced serum protein Merritt and Putnam [49] frst demonstrated in 1938 the efcacy of binding of the drug in the third trimester of pregnancy should phenytoin against major seizures in the more common epileptic be taken into consideration. Tey gave the drug for 2–11 months to 142 patients during pregnancy appears to be a consequence of increased drug with seizure disorders not controlled by phenobarbital and bro- metabolism. Bromides were withdrawn but phenobarbital was continued during pregnancy were determined afer intravenous adminis- when phenytoin was commenced. In 118 patients with frequent tration of stable isotope-labelled drug, and compared with those ‘grand mal’ seizures, ‘complete relief’ was obtained in 58%, with a determined afer parturition in the same women, Dickinson et al. The corresponding [47] found that mean Vmax was signifcantly higher during preg- fgures for 74 patients with ‘petit mal’ (some of whom would now nancy than post partum (1170 ± 600 mg/day versus 780 ± 470 mg/ probably be classifed as having complex partial seizures) were 35% day). Likewise, Km was also higher during pregnancy than post and 49% respectively, and for the six with ‘psychomotor seizures’, partum, for values calculated both in whole plasma (18. Tere may also be a premenstrual and menstrual fall in and seizure disorder classifcation sometimes appeared uncertain.