By N. Corwyn. Clarke College. 2019.
With oral retinoids 40 mg lasix otc blood pressure medication val, most aromatic retinoids cross the placenta; in utero exposure results in limb and craniofacial deformities purchase lasix 100 mg hypertension fundoscopic exam, as well as cardiovascular and central nervous system abnormalities lasix 40mg fast delivery prehypertension forum. Systemic absorption of topical retinoids, however, is thought to be negligible (33). A large retrospective study of birth defects in off- spring born to mothers exposed to topical tretinoin (all-trans-retinoic acid) during pregnancy has demonstrated no signiﬁcant risk (34). Even in light of this evidence, many clinicians feel strongly about avoiding topical retinoids in pregnancy (36). Reports of enhanced photocarcinogenicity in experimental mice exist (37), but no evidence exists of a comparable process with humans (38). Conversely, topical retinoids appear to have a protective effect against ultraviolet-induced premalignant and malignant lesions. However, skin treated with topical retinoids is more reactive to chemical and physical stresses (including ultraviolet light), because of the thinner horny layer and ampliﬁed vasculature. The successful trials of topical tretinoin have inspired the pursuit of other topical retinoids that could be effective in photoaging with fewer adverse effects. Undoubtedly, newer derivatives with safer adverse effect proﬁles will be forthcoming. Speciﬁcally, two new retinoids, adapalene and tazarotene, Topical Retinoids 119 licensed for the treatment of acne and psoriasis, respectively, will almost certainly be investigated for photodamage. Sus- tained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin. Topical treatment of multiple ac- tinic keratoses of the face with arotinoid methyl sulfone (Ro 14-9706) cream versus tretinoin cream: a double blind, comparative study. Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins character- istic of retinoic acid, but without measurable retinoic acid levels or irritation. Extraction of human epider- mis treated with retinol yields retro-retinoids in addition to free retinol and retinyl esters. In vitro metabolism by human skin and ﬁbroblasts of retinol, retinal and retinoic acid. Molecular mechanisms of intrinsic skin aging and retinoid-induced repair and reversal. Among such diseases, malignant tumors should be diagnosed and treated properly be- cause some of them are quick to develop, destructive, or fatal. Hyperpigmentation of the face of middle-aged women, is most common; however, it is benign, and, if diagnosed and treated early, it can be prevented in the future. Melasma is commonly observed among middle-aged women (average age of 43) (1) and is rare in men. It is a diffuse or well-circumscribed noninﬂamma- tory brown hyperpigmentation that frequently occurs around the eyes, mouth, cheeks, and forehead. An experienced old Japanese dermatologist in Kyoto City often told melasma patients, ‘‘You need not treat melasma. Just live until the age of 70 and then the melasma you suffer from will disappear. Sato (1) measured various hormones by tritium (3H) radioimmunoassay in two groups of age-matched middle-aged women (av- erage age 43) with and without melasma on the seventh days of the ovarial and 123 124 Nakayama et al. Other hormones, such as estradiol, follicle stimulating hor- mone, luteinizing hormone, prolactin, androstendione, and cortisol (Fig. The increase in plasma progesterone may be attributed to the fact that melasma is exacerbated by pregnancy where plasma progesterone is increased or by contra- ceptive pills that occasionally contained progesterone; there is gradual decline of melasma after climacterium by 70 years of age. Histopathology of melasma shows an increase in melanin pigments in the epidermal cells especially in the supranuclear region of the basal cells (Fig. The number of epidermal melanocytes has not increased and, therefore, the hyper- pigmentation of melasma is considered to be functional and reversible. Two links, however, are still missing: the connection to the increase in serum progesterone Depigmentation Agents 125 Figure 1 Serum progesterone (P4) and estradiol (E2) levels of melasma patients and matched controls in follicular and luteal phases. Melasma has been regarded as an excellent target for newly developed depigmentation agents because many middle-aged melasma patients want to re- turn their skin color to normal. Long-term therapy is necessary so that depigmen- tation occurs slowly, without provoking severe depigmentation (as with hydro- quinone monobenzyl ether) or severe hyperpigmentation of ochronosis (as with hydroquinone at 2 4% concentrations under a tropical climate) (3). Histori- cally, both disorders had been reported (4) and, therefore, both are disastrous pitfalls for those developing depigmentation agents. First, unlike hydroquinone monobenzyl ether, the depigmentation agents under development should not kill melanocytes. Second, hydroquinone itself is not cytotoxic to melanocytes; however, it degenerates dermal elastic ﬁbers under strong sunlight at high concentrations of 2–4%, which results in another disas- trous strong brown hyperpigmentation called ochronosis (5). Therefore, the best depigmentation agent inhibit tyrosinase in melanocytes, and toxicity to epidermal cells, melanocytes, dermis, and other systemic organs is negligible. Also, depig- mentation agents should not be strong sensitizers, oncogenic, or teratogenic. Hydroquinone cream changes color from white to brown after 3–4 months; therefore, it can be produced at pharmacies and hospitals on the condition that it is disposed of after the color changes. Hydroquinone cream is an excellent preparation for the treat- ment of melasma with or without mild chemical peeling (6,7). However, the color change and the production of ochronosis have inhibited its usage in cosmetics and cosmeceuticals. Mushroom tyrosinase has been commonly used, and the suppres- sion of tyrosinase could be demonstrated when dose-dependent inhibition was demonstrated with hydroquinone as an effective control. Another kind of tyrosi- nase assay is noninhibitory or nonsuppressive-type reactions of melanogenesis. According to Mishima (8), melanogenesis can also be hindered by tyrosinase production inhibition, inhibition of tyrosinase transfer, and cytotoxic inhibition (Table 3). Cultured B-16 melanoma cells have been used in this ﬁeld and are useful in demonstrating several new mechanisms of melanogenesis inhibition: glycosylation turned out to be another process of the production, along with matu- 130 Nakayama et al. Suppression of tyrosinase Kojic acid Hydroquinone Ascorbic acid Arbutin Ellagic acid 2. Its inhibition also decreased the amount of melanin, and depigmentation agents were also found. Tyrosinase activities in ribosomes and the production of premelanosomes can also be targets for melanin production inhibition (8). There are two melanins, eumelanin (black brown) and pheome- lanin (yellow or red), and eumelanin production inhibition is usually considered with depigmentation agents. Dose-dependent reactions are requested for depigmenting agents in in vitro tests, like tyrosinase inhibition or B-16 melanoma cell assay. This is needed be- cause melanogenesis inhibition increases in parallel with the concentration of the depigmentation agents in the medium. When some chemical is added to the me- dium and the inhibition of melanogenesis disappears, it means that the added substance (Fig.
Multiple-dose studies would generally be necessary to ensure that relevant metabolites can be assessed and that the relevant dose of the interacting drug is used generic lasix 40 mg without a prescription pulse pressure treatment, but special approaches may also be useful 100 mg lasix with mastercard pulse pressure medical definition. For example discount lasix 100mg online arteria jugularis interna, a loading dose of the potential inhibitor may allow relevant levels to be obtained more rapidly and selection of a one-way (fixed-sequence) crossover or a parallel design, rather than a randomized crossover study design, may also help. Using a one-way crossover design, a recent study (17) showed that multiple-dose administration of sertraline inhibited the clearance of desipramine to a considerably greater extent than did a single-dose administration. Inducers may take several days or longer to exert their effects, while inhibitors generally exert their effects more rapidly. For this reason, a more extended period of exposure to interacting drug may be necessary if induction is to be assessed. The study design should also allow assessment of how long the inhibition or induction effect will last after an interacting drug has been removed from the dosing regimen. This effect can be observed in the randomized crossover design and in the one-sequence or parallel designs by adding an additional period in which the interacting drug is withdrawn. In this case, mibefradil both increased blood levels of the dihydropyridine and inhibited the increased heart rate needed to overcome the lowered blood pressure. For an inhibitor drug that induces its own metabolism, a multiple-dose study design should be used so that the extent of interaction is not over- estimated. This inhibition may be partially explained by the lower exposure to rito- navir after multiple doses than after a single dose. When a pharmacodynamic effect is also being measured, attainment of steady state for the parent or metabolite whose pharmacodynamic effects An Integrated Approach to Assessing Drug-Drug Interactions 673 are being measured is important. In addition, inclusion of a period of the interacting drug alone in the sequence is often advisable so that its contribution to the pharmacodynamic effects can be assessed. Studies can usually be open label (unblinded), unless pharmacodynamic endpoints (e. Study Population Clinical drug-drug interaction studies can generally be performed in healthy volunteers unless safety considerations preclude their participation. Sometimes, use of subjects/patients for whom the substrate drug is intended offers advan- tages, including the opportunity to study pharmacodynamic endpoints not present in healthy subjects. Improved understanding of the metabolic basis of drug-drug interactions allows the use of more informative approaches to choosing substrates and potential interacting drugs. Figure 1 describes a decision-making process (20) for the conduct of in vivo drug interaction studies once a new drug is characterized as a substrate for a particular metabolic pathway or an inhibitor of that pathway. In contrast to earlier approaches that focused mainly on a specific group of approved drugs (e. In studying an investigational drug as the interacting (inhibiting or inducing) drug, the choice of substrates (approved drugs) for initial 674 Huang et al. In testing inhibition, the substrate selected should generally be one whose phar- macokinetics are markedly altered by coadministration of known specific inhibitors of the enzyme systems to assess the impact of the interacting inves- tigational drug. If the initial study shows that an investigation drug either inhibits or induces metabolism, further studies using less sensitive substrates, based on the likelihood of coadministration, may be useful. In testing an inves- tigational drug for the possibility that its metabolism is inhibited or induced (i. The choice of interacting drug can then be based on known, important inhibitors of the pathway under investigation. If the study results are negative, then absence of a clinically important drug-drug interaction for the metabolic path- way would have been demonstrated. If the clinical study of the strong, specific inhibitor/inducer is positive, it should generally be determined in further clinical studies whether there is an interaction between the test drug and less potent specific inhibitors or inducers. Use of the drug with grapefruit juice may call for caution depending on the drug’s exposure-response relationship (23). John’s wort may be listed in the labeling along with other known inducers, such as rifampin, rifabutin, rifapentin, dexamethasone, phenytoin, carbamazepine, or phenobarbital, as possibly decreasing plasma levels. When the above study shows significant interaction, further evaluation with weaker inhibitors may be necessary. In testing an investigational drug for the possibility that it may be an inhibitor/ inducer of P-gp in vivo, digoxin or other known substrates of P-gp should be used. In testing an investigational drug for the possibility that its transport may be inhibited or induced in vivo (as a substrate of P-gp), an inhibitor of P-gp should be studied. In testing an investigational drug for the possibility that its disposition may be inhibited or induced (i. Route of Administration For an investigational agent used as either an interacting drug or substrate, the route of administration should generally be the one being studied in trials. If only oral dosage forms will be marketed, studies with an intravenous formulation are not usually necessary, although information from oral and intravenous dosings may be useful in discerning the relative contributions of alterations in absorption and/or presystemic clearance to the overall effect observed for a drug interaction. For example, the interaction studies of clarithromycin and intravenous or oral doses of midazolam enabled Gorski et al. Sometimes the use of certain routes of administration may reduce the utility of information from a study. Dose Selection For both substrate and interacting drug, testing should maximize the possibility of finding an interaction. Doses smaller than those to be used clinically may be needed for substrates on safety grounds and should provide an adequate assessment of an interaction. The differential effects of different doses of ritonavir on the plasma levels of saquinavir (18) demonstrate the dose effect of an interacting drug. In some cases, these measures may be of interest for the inhibitor or inducer as well, notably where the study is intended to assess possible interactions between both study drugs. In certain instances, an understanding of the relationship between dose, blood levels, and response may lead to a special interest in particular pharmacokinetic measures/parameters. For example, if a clinical outcome is most closely related to peak concentration (e. In certain instances, reliance on endpoints in addition to pharma- cokinetic measures/parameters may be useful. Increasingly, also, these factors can affect the regulatory decision to approve such a drug and/or how it is labeled. Section 505 of the Food Drug and Cosmetic Act requires that, for approval, a drug must be demonstrated to be both effective and safe when used as labeled. Safety is not an absolute measure but rather reflects a conclusion that the drug’s benefits outweigh its risks. Among the risks that must be considered is the presence of individuals who are at particular risk because of individual characteristics (e. It is striking that several important drugs—terfenadine, mibefradil, astemizole, and cisapride—have been removed from the market, at least partly, because of drug-drug interaction problems (28–31). The importance of both mean and between- and within- individual variability must be assessed in light of many factors. These include the toxicity of the drug (wide therapeutic range drugs may not be harmful even if their pharmacokinetics are very variable, e.
As a rule of thumb 40 mg lasix with mastercard arteria lusoria definition, drugs pass through membranes in an undissociated form 100 mg lasix amex blood pressure pulse 90, but act as ions (if ionization is a possibility) generic lasix 40mg without prescription heart attack yahoo answers. A pKa in the range of 6–8 would therefore seem to be most advantageous, because the nonionized species that passes through lipid membranes has a good probability of becoming ionized and active within this pKa range. This consid- eration does not relate to compounds that are actively transported through such membranes. A high degree of ionization can prevent drugs from being absorbed from the gastroin- testinal tract and thus decrease their systemic toxicity. This is an advantage in the case of externally applied disinfectants or antibacterial sulfanilamides, which are meant to remain in the intestinal tract to fight infection. Also, some antibacterial aminoacridine derivatives are active only when fully ionized. Ionization can also play a role in the electrostatic interaction between ionic drugs and the ionized protein side chains of drug receptors. Therefore, when conducting experiments on drug–receptor binding, it is advis- able to regulate protein dissociation by using a buffer. The degree of ionization of any compound can be easily calculated from the Henderson–Hasselbach equation: % ionized = 100/(1 + antilog [pH − pKa]) (1. The latter method provides very accurate electron-density maps, but only of molecules in the solid state; it cannot be used to pro- vide maps of the nonequilibrium conformers of a molecule in a physiological solution. To provide easily obtained yet rigorous assessments of electron distribution properties, quantum mechanics calculations are now employed (see section 1. Molecular quantum mechanics calculations provide several methods for calculating the orbital energies of atoms, combining the individual atomic orbitals into molecular orbitals, and deriving from the latter the probability of finding an electron at any atom in the molecule— which is tantamount to determining the electron density at any atom. There are several methods for doing this, with varying degrees of sophistication, accuracy, and reliability. These calculations permit quantification of the charge density on any atom in a drug molecule. Such atomic electron density values may be used when correlating molecu- lar structure with biological activity during the drug molecular optimization process. In addition to providing values for charge densities on individual atoms, quantum mechanics calculations may also be used to determine the energies of delocalized orbitals; such energy values may also be used when correlating molecular structure with pharmacologic activity. They are expressed in β units (a quantum-chemical energy parameter whose value varies from 150 to 300 U/mol). In addition to providing insights concerning correlation of molecular structure with pharmacologic bioactivity, quantum mechanics calculations of electron distribution may also be employed to understand the molecular basis of drug toxicity. For instance, overall p-electron density of polycyclic hydrocarbons has traditionally been assumed to correlate with the carcinogenicity of these compounds. According to this hypothesis, defined reac- tive regions on the molecule undergo metabolism to form reactive intermediates such as epoxides, which react with cell constituents such as the basic nitrogen atoms in nucleic acids. Although this model has been widely cited in the literature, it is appropriate to warn the reader that, however attractive, it is seriously questioned. However, p-electron density is very important in the chemical reactivity of aromatic rings. The synthetic preparation of new molecules is challenging, time consuming, and expensive. Theoretical chemistry, combined with modern compu- tational methods, offers a powerful solution to this prediction dilemma. The docking of a drug with its receptor site is a precise interaction between two mole- cules. The success of this interaction is dependent upon the geometry, conformation and electronic properties of the two molecules. Designing drugs requires techniques for deter- mining and predicting the geometry, conformation, and electronic properties of both small molecules (i. Molecular modeling is the evaluation of molecular properties and structures using computational chemistry and molecular graphics to provide three-dimensional visu- alization and representation of molecules. Quantum pharmacology is the application of the methods of modern computational chemistry to understanding drug action at the molecular and atomic level of structural refinement. A review of drug design papers in the Journal of Medicinal Chemistry and of pharmaceutically relevant papers in the Journal of the American Chemical Society, covering the year 2000, reveals that 43% of these papers included computational chemistry techniques in their design and analyses of drug molecule action. Clearly the dawn of the 21st century has emphasized the exponentially growing importance of molecular modeling and quantum pharmacology in drug design. Accordingly, a basic understanding of medicinal chemistry in the modern era requires an appreciation of the fundamentals of quantum mechanics, molecular mechanics, and the other techniques of computational chemistry as applied to drug design. The medicinal chemist who uses com- mercially available computer programs to design drugs should not treat them as merely “black boxes,” and should have some insight into their conceptual basis. This is best achieved by using a “mechanics” method that permits the geometry of a molecule to be expressed as a function of energy. By minimizing this energy function, one can ascertain the optimal geometry of the molecule. Quantum mechanics and molecular mechanics are the dominant “mechanics” methods in quantum pharmacology (see figure 1. Once the wavefunction is known for a particular system, then any physical property may in principle be determined for that system. However, ψ is just a normal mathematical function; it has no special mathematical properties. If the system being studied is a simple hydrogen atom with a single electron outside of a positively charged nucleus, the Schrödinger equation may be solved exactly. The wavefunctions which satisfy the Schrödinger equation for this simple hydrogen atom are called orbitals; a hydrogenic atomic orbital is therefore the three-dimensional mathe- matical function from which one may calculate the energy and other properties of a single electron. For single atoms that contain multiple electrons (polyelectronic mono-atomic systems), the wavefunction for the atom (ψ) is a product of one-electron wavefunctions (χi), one for each electron. Drug molecules may have their properties ascertained by either experimental or theoretical methods. Although experimental meth- ods, especially X-ray crystallography, are the “gold standard” methods, calculational approaches tend to be faster and do provide high quality information. Nonempirical techniques, such as ab initio quantum mechanics calculations, provide accurate geometries and electron distribution properties for drug molecules. In quantum pharmacology, the goal is to determine the wavefunction Ψ for the drug molecule so that the energy and properties of the drug may be calculated. It is not possible to provide an exact mathematical solution for the wavefunction of an entire molecule. Accordingly, quantum mechanics calculations that provide approximate, but not exact, solutions for the drug molecule wavefunction are employed; these approxi- mate methods are called molecular orbital calculations. In molecular orbital calculations, the molecular orbitals φ are represented as a linear combination of atomic orbital functions (χi). A variety of different mathematical func- tions may be used to represent these atomic orbital functions.
Amiodarone This drug is used primarily to treat life-threatening ventricular arrhythmias (e buy lasix 100mg low price hypertension over the counter medication. Amiodarone has limited ability to cross the placenta purchase lasix cheap online 5 htp and hypertension, with newborn concentrations reaching only 10–25 percent of maternal serum levels (Rotmensch et al buy lasix mastercard blood pressure normal child. Of six pregnancies exposed to amiodarone after 10 weeks ges- tation, hypothyroidism (n = 2) and small size for gestational age (n = 4) was observed (Magee et al. Learning disabilities were unusually frequent in two small series of children exposed to amiodarone during gestation (Bartalena et al. When administered chronically during pregnancy, fetal goiter is a major risk after 10 weeks gestation. Fetal death is consistently reported in animal studies of the drug dur- ing pregnancy. A possible association between fetal cretinism has also been suggested, especially from direct fetal injection (Pinsky et al. Otherwise, the frequency of congenital anomalies was not increased among 30 infants exposed to amiodarone dur- ing the first trimester (Bartalena et al. Mexiletine Similar in action to lidocaine, mexiletine is a local anesthetic type of antiarrhythmic agent (Zipes and Troup, 1978). Mexiletine is used primarily to treat ventricular arrhyth- mias (ventricular tachycardia, premature ventricular contractions). No studies of con- genital anomalies in infants exposed to mexiltene have been published. A few anecdotal case reports suggest no adverse effects on the fetus or on labor, but the importance of such observations is not clear. Mexiletine was not teratogenic in various laboratory ani- mals (data from the manufacturer’s insert). Cord blood concentrations of this drug were similar to maternal levels, and therapeutic levels may be found in breast milk (Timmis et al. However, breastfeeding is not contraindicated when the mother is using mexiletine (American Academy of Pediatrics, 1994). Verapamil is used to transplacentally treat fetal supraventricular tachycardia (Klein and Repke, 1984; Rey et al. Verapamil should be used with caution in pregnant patients because it might reduce uterine blood flow by 25 percent or more (Murad et al. Importantly, 10–20 percent of neonates who received this drug intraveneously for supraventricular tachycardia and congestive heart failure devel- oped cardiac depression and cardiac arrest (Kleinman and Copel, 1991). Therefore, ver- apamil is not recommended for use in infants of less than 1 year (Garson, 1987). Verapamil might have adverse effects in the fetal heart, especially in the presence of heart failure and hydrops (Shen et al. Among 33 infants exposed to verapamil in the first trimester, no increase in congenital anomalies was reported (Magee et al. Verapamil is not contraindicated in breastfeeding mothers (American Academy of Pediatrics, 1994). Propranolol Propranolol is a beta-adrenergic blocker used to treat supraventricular and ventricular tachycardias, hypertension, hyperthyroidism, and migraine headaches. It is also used in the intrauterine treatment of fetal arrhythmias (Bhagwat and Engel, 1995; Eibeschitz, 1975). The major- ity of this information is derived from the treatment of hypertension during pregnancy. Nonetheless, no controlled human teratology studies of propranolol have been published. The drug was not teratogenic in at least two animal studies (Fuji and Nishimura, 1974; Speiser et al. Adverse fetal effects have been reported with the use of propranolol during pregnancy. Intrauterine growth retardation and use of propranolol were associated in one study (Pruyn et al. Importantly, it is also possible that the maternal hypertension, and not propranolol therapy per se, is responsible for decrease in fetal growth. Several other beta-adrenergic blocking agents are available but are used primarily for the treatment of hypertension. It was successfully used for the intrauterine treatment of fetal tachycardias (Spinnato et al. Quinidine was also used to treat fetal hydrops from reciprocat- ing tachycardia that did not convert with maternal digitalization (Guntheroth et al. Among fewer than 20 pregnancies, quinidine exposure during the first trimester was not associated with an increased frequency of congenital anomalies (Rosa, personal communication, cited in Briggs et al. It has also been reported to be effective in the treatment of supraventricular tachycardia in pregnant women (Afridi et al. There are no published studies regarding the teratogenic effects of this adenosine. Cardiac glycosides are effective because of their inotropic effects on the heart and antiarrhythmic effects. Various digitalis preparations cross the placenta readily, resulting in significant fetal levels with cord levels that are 50–80 percent of maternal levels (Chan et al. No scientific studies regarding the safety of cardiac glycosides in pregnant women have been published. Fetal digitalis toxicity has occurred, but this was secondary to maternal overdose (Sherman and Locke, 1960). Available information supports the view that car- diac glycosides are probably safe for use during pregnancy. Low-molecular-weight heparin is also used to treat thromboembolism in pregnancy, and does not cross the pla- centa (Feijgin and Lourwood, 1994; Macklon et al. Warfarin derivatives are contraindicated for use during pregnancy Coumarin derivatives, including warfarin, are contraindicated for use during pregnancy. Use after the first trimester includes brain and eye defects, and other anomalies associated with vascular disruption. However, in a review of 172 pregnant women from published reports, Turrentine and associates (1995) found no increase in congenital anomalies and a pregnancy loss rate of 5. Among more than 140 infants exposed to heparin during the first trimester, the frequency of congenital anomalies was not increased (Chan et al. Similarly, in a literature review among more than 440 infants exposed to low molecular weight heparins during pregnancy, including nearly 200 infants whose mothers were treated during the first trimester, no congenital anom- alies were noted (Sanson et al. Seven to 10 infant defects would have been expected to occur in the absence of any drug exposure. Therefore, ascertainment bias may confound the detection of birth defects in their study.