Maternal weight gain was reduced by aciclovir during pregnancy purchase 10 gm fucidin free shipping antibiotic xi, but this was attributed to reduced gravid uterine weight and not to maternal toxicity purchase 10gm fucidin fast delivery virus 000. Various reproductive and developmental effects were reported in the aciclovir-treated group quality 10 gm fucidin vyrus 986 m2 for sale, including an increased rate of resorptions to implantations, skull anomalies and gross structural ano- malies of the vertebral column and tail (Chahoud et al. Dose-related reductions in embryonic growth and increased incidences of abnorma- lities were observed at the higher doses and with the larger number of doses. Maternal plasma concentrations of aciclovir > 19 mg/mL were associated with embryonic effects (Stahlmann et al. At 12 weeks, both groups of male offspring exposed in utero had reduced body weight, liver weight (high dose only) and reduced thymus weight and increased spleen weight. The only significant change in organ weights in female offspring was reduced relative (to body weight) weight of the liver. Aciclovir-exposed offspring showed an impaired immune response, as judged from host resistance to Trichinella spiratis and immunoglobulin titres (Stahlmann et al. Treatment severely reduced the weight gain of the dams throughout gestation, increased the ratio of resorptions to implantations and decreased the number of viable fetuses (Mamede et al. Five to seven samples of fetal homogenate collected on day 18 of gestation showed mean concentrations of aciclovir of 0, 0. No signs of maternal or fetal toxicity were reported in the fetuses on day 18 or in samples collected on day 29 of gestation from 15–18 additional dams (Moore et al. At evaluation on day 8 of incubation, a dose-related increase in the rate of abnormal development was reported in both series (Heinrich-Hirsch & Neubert, 1991). Retarded development of the ear anlagen was observed at 25 μmol/L aciclovir, and gross structural abnormalities, especially in the brain, were found at concentrations ≥ 50 μmol/L. Aciclovir at 100 μmol/L resulted in major deformities of the telen- cephalon and ventricles. No alterations were observed in mouse limb bud explants taken from 11-day-old mouse embryos and exposed to aciclovir at concentrations ≤ 500 μmol/L (Klug et al. It did not induce reverse mutation in Salmonella typhimurium at concentrations of 0. There was no evidence of differential or absolute killing in the Escherichia coli polA+/polA− repair assay by aciclovir at concentrations up to 10 mg per well, with or without exogenous metabolic activation. Aciclovir did not induce gene conversion in Saccharomyces cerevisiae strain D5 over the standard dose range in the presence or absence of exogenous activation. In cultured mammalian cells, aciclovir was not mutagenic at the Oua or Hprt locus of mouse lymphoma L5178Y cells or at the Oua, Hprt or Aprt locus of Chinese hamster ovary cells, but it was mutagenic in the Tk gene of lymphoma cells and this effect was unambiguous, reproducible and dose-related at concentrations ≥ 400 μg/mL. The apparent discrepancy between the two systems may be ascribed in part to the fact that the C3H cells were exposed for shorter times and few cells were used. Chinese hamster strain V79-E cells were evaluated for the frequencies of sister chromatid exchange and chromosomal aberrations after exposure to 0. This fact is important because the increase in chromosomal aberration frequency was due to chromatid gaps and chro- matid breaks [although the authors did not discuss these findings]. Exposure of cultured human lymphocytes to 250 and 500 μg/mL aciclovir in the absence of exogenous meta- bolic activation caused a linear increase in the frequency of chromosomal aberrations, due mainly to chromatid breaks. A single intravenous dose of 80 mg/kg bw resulted in a peak plasma concentration of 87 ± 16 μg/mL, however, which is lower than the concentration that caused clastogenic effects in assays for chromosomal aberrations in vitro. In groups of three female Chinese hamsters, intraperitoneal injections of ≤ 100 mg/kg bw aciclovir had no effect, while 500 mg/kg bw caused a very high frequency of chromosomal aberrations 24 h after exposure. For example, one treated hamster had chromosome breaks in 99 of 108 cells scored, and 97 of these 99 breaks occurred at the centromere of a single one of the six intermediate size metacentric chro- mosomes. Structural chromosomal aberrations were observed in cultured Chinese hamster fibroblasts and human lymphocytes and in the bone-marrow cells of Chinese hamsters dosed in vivo. In addition, an increased frequency of micronucleated cells was observed in mice dosed in vivo. It should be noted that the doses required to produce a clastogenic response were much higher than those to which people and experimental animals are exposed. Further- more, the doses of up to 450 mg/kg bw per day that were given to mice and rats by gavage during the two-year tests for carcinogenicity, in which treatment-related tumours did not develop, are unlikely to have produced peak plasma concentrations sufficient to precipitate a clastogenic response. The lowest clastogenic doses were 250 μg/mL in cultured human lymphocytes and 540 μmol/kg bw in mouse bone marrow after intravenous administration. The peak plasma concentration in humans receiving a typical dosing regime is about 2 μmol/L, or 0. It is used in the treatment of herpes simplex, varicella and herpes zoster viral infections. Oral and topical forms of aciclovir are very widely used for mucocutaneous infections. Intravenous preparations are widely used for some infections including encephalitis associated with herpes simplex viral infection and neonatal herpesvirus infection. It is widely distributed, can cross the placenta and is, relative to many other antiviral drugs, slowly removed from plasma. More than half the administered drug is excreted unchanged, while the metabolite 9-carboxymethoxymethylguanine consti- tutes 8–14% of the dose. Urinary excretion can be markedly reduced in patients with impaired renal function. The pharmacokinetics of aciclovir in dogs is similar to that in humans, but the drug is removed more rapidly from the plasma of rats. Adverse effects of aciclovir have been reported extremely rarely in people who have received oral or topical formulations. Higher doses are given intravenously in cases of serious illness, and most of the side-effects have been reported after such usage. Insufficient human data were available on the reproductive and prenatal effects of aciclovir. No developmental toxicity was reported in mice, rats or rabbits given doses over several days during gestation. There is inadequate evidence in experimental animals for the carcinogenicity of aciclovir. Overall evaluation Aciclovir is not classifiable as to its carcinogenicity to humans (Group 3). An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. The tablets may also contain macrogol, magnesium stearate, microcrystalline cellulose, povidone, sodium carboxymethyl starch and tita- nium dioxide. The syrup may also contain anhydrous citric acid, flavourings, glycerol, maltitol solution, saccharin sodium, sodium benzoate, sodium hydroxide and sucrose. The oral solution containing 50 mg/5 mL zidovudine is colourless to pale yellow and has a pH of 3–4; the oral solution contains sodium benzoate as a preservative and may contain sodium hydroxide to adjust the pH.
For a uniform cheap fucidin 10 gm amex antibiotic prophylaxis dental, rectangular cross-section order fucidin 10gm without prescription bacteria blood, the cantilever’s spring constant is given by k = Ewt3/4l3 purchase 10 gm fucidin otc do antibiotics for acne cause weight gain, where w is the width of the cantilever, l is its length, t is its c thickness, and E is the elastic modulus. Most cantilever probes are rectangular or triangular with a “two-beam” geometry connecting at the tip. From the deﬂection of the cantilever, we calculate tip-sample force data by using Hooke’s law F = kcz, where F is the magnitude of the force acting between the tip and sample, kc is the cantilever spring constant, and z is the cantilever deﬂection at its free end. In most imaging modes, a feedback 316 Dobrokhotov system senses instantaneous cantilever deﬂection and adjusts scanner elements to maintain a constant interaction between the tip and sample. For example, selective chemical functional groups may be attached to the probe, generating force data reﬂecting sample composition. The image produced will thus be a convolution map of chemical makeup, not merely surface topogra- phy. Force spectroscopy generates a force–distance curve for a single location on the sample. This is a plot of the magnitude of the force acting between tip and sample versus the position of the scanner in the direction normal to the substrate. Force–distance curves hold a wealth of information about the sample’s mechanical properties. Points of dis- continuity, the slopes of the approach, and retract curves, as well as any observed hystereses all cede hints to surface behavior. Hysteresis, for example, is the result of adhesion, surface deformation, and/or nonlinear performance of the instrument, such as piezoelectric or other transducers for scanning and the probe detection sen- sor (e. Rather, it controls and/or measures the vertical scanner position, the cantilever deﬂection, and the sample deformation. We often collect an array of force–distance curves at discrete sites over an area of the sample surface to determine effects of sample heterogeneity. In these cases, force, adhe- sion, and stiffness data are readily collected and made available for ofﬂine inter- pretation and analysis. Other physical interactions between the probe and sample may also be mapped with more difﬁculty, such as energy loss or long-range forces. It is primarily the stiffness data that are of interest to nanomechanical studies. Some nanowires exhibit surprisingly high tensile strength, possibly due to the presence of fewer mechanical defects per unit length than in their macroscopic analog. Deforma- tion tests for determining the mechanical properties of edge-supported ﬁlms are similar to bending nanowires and are plagued with similar difﬁculties of exper- imental setup and data interpretation at the nanoscale. Edge-supported ﬁlm deﬂections may be interpreted from expressions derived for the classic centrally loaded plate deforma- tions or from extended models for membranes and shape memory materials. We expect to observe discrepancies between actual deformations and predicted values based only on global bending model predictions at this stage in development for both suspended ﬁlms and nanowires. Perhaps the most striking effect is the opportunity to associate high ﬂexibility and high strength with high stiffness, a property that is absent in graphite ﬁbers. The mechanical properties are strongly dependent on the structure of the nanotubes, which is due to the high anisotropy of graphene (2). Knowledge of the Young’s modulus (E) of a material is the ﬁrst step towards its use as a structural element for various applications. The Young’s modulus is directly related to the cohesion of the solid and, therefore, to the chemical bonding of the constituent atoms. For a thin rod of isotropic material of length l0 and cross- sectional area A0, the Young’s modulus is then E = stress/strain = (F/A0)/( l/l0). Moreover, in each class of solids (deﬁned by the nature of the bonding), experiments show that elastic constants follow a simple inverse fourth power law with the lattice param- eter. Small variations of the lattice parameter of a crystal may induce important variations of its elastic constants. For example, C33 of graphite (corresponding to the Young’s modulus parallel to the hexagonal c-axis) depends strongly on the tem- perature due to interlayer thermal expansion. It is interesting to compare the different theoretical results concerning the Young’s modulus and its dependence on the nanotube diameter and helicity. The results are found to vary with the type of method and the potentials used to describe the interatomic bonding. The Young’s modulus can be written as the second deriva- tive of the strain energy divided by the equilibrium volume. Continuum elastic the- ory predicts a 1/R2 variation of the strain energy, with an elastic constant equal to C11 of graphite (which corresponds to the Young’s modulus parallel to the basal plane), independent of the tube diameter. Therefore, in the classical approximation, 318 Dobrokhotov the Young’s modulus is not expected to vary when wrapping a graphene sheet into a cylinder. This is not surprising, as the atomic structure is not taken into account, so the elastic constants are the same as in a planar geometry. The question now is what happens in very small diameter tubes for which the atomic structure and bonding arrangement must be included in a realistic model. Both ab initio and empirical potential-based methods have been used to calculate the strain energy as a func- tion of the tube diameter (and helicity). They all agree that only small corrections to the 1/R2 behavior are to be expected. As a consequence, only small deviations of the elastic constant along the axis (C33 in standard notation) are observed. It is worth noting that the dependence of the elastic constants on the nanotube diam- eter is found to be different for each model. For example, two different empirical potentials give different values for the elastic constant and show a different trend as a function of diameter. A decrease of C33 when the radius decreases is sometimes predicted; in other cases, the inverse behavior is observed (2). The aver- age value of the Young’s modulus derived from this technique for 11 tubes was 1. Given these uncertainties in the method, it was not possible to state whether single-walled tubes are stiffer than multiwalled tubes. All measured values of E for nanotubes indicate that it may be higher than the currently accepted value of the in-plane modulus of graphite. The authors point out that either the cylindrical structure of the tubes imparts greater strength or the modulus of graphite has been underestimated. The latter statement is less likely considering the high precision of macroscopic methods and the vari- ety of concordant experiments on single-crystal graphite and ﬁbers. On such a substrate, nanotubes occa- sionally lie over the pores, either with most of the tube in contact with the mem- brane surface or with the tube suspended over a succession of pores (Fig. Attractive interactions between the nanotubes and the membrane clamp the tubes to the substrate.
Theoretically 10 gm fucidin overnight delivery antibiotics for uti birth control pills, if the dose is greater than Vmax order fucidin on line antimicrobial door handles, steady state will never be reached buy cheap fucidin 10gm online infection signs. The Michaelis-Menten equation can be rearranged to provide an equation that estimates the time required (in days) for 90% of the steady-state concentration to be reached (t90%), as shown below (where the dose equals the daily dose): 10-4 From the previous example, when dose = 300 mg/day, Vmax = 700 mg/day, Km = 12 mg/L, and the volume of distribution (V) is estimated to be 50 L: When the dose is increased to 400 mg/day: We can see that as the dose is increased, it takes a longer time to reach steady state, drug continues to accumulate, and the plasma drug concentration continues to rise. Clinical Correlate The t90% equation will only provide a rough estimate of when 90% of steady state has been reached, and its accuracy is dependent on the Km value used. Other ways to check to see if a patient is at steady state are to examine two levels drawn approximately a week apart. Additionally, it is safe to wait at least 2 weeks (and preferably 4 weeks) after beginning or changing a dose before obtaining new steady-state levels. Linear pharmacokinetics means that the plot of plasma drug concentration versus time after a dose is a straight line. When hepatic metabolism becomes saturated, any increase in drug dose will lead to a proportionate increase in the plasma concentration achieved. When the rate of drug elimination proceeds at half the maximum rate, the drug concentration is known as: A. Which of the equations below describes the form of the Michaelis-Menten equation that relates daily drug dose to Vmax, Km, and the steady-state plasma drug concentration? The phenytoin dose is then changed to 400 mg/ day, and 2 months after the dose change the plasma concentration determined just before a dose is 18 mg/L. After the dose of 400 mg/day is begun, how long will it take to reach 90% of the steady-state plasma concentration? Drugs with linear pharmacokinetics may exhibit plasma concentrations versus time plots that are not straight lines, as with multiple-compartment drugs. There will be a disproportionate increase in the plasma concentration achieved because the amount of drug that can be eliminated over time cannot increase. At very low concentrations, drugs are more likely to exhibit first-order kinetics because hepatic enzymes are usually not yet saturated, whereas at higher concentrations, enzymes saturate, making zero-order kinetics more likely. Use dose pairs of 300 and 400 and concentration pairs of 10 and 18 to calculate Km. The steady-state plasma concentration resulting from a daily dose of 500 mg would be estimated from the line equation as follows: Rearranging gives: C, D. When using the t90% equation, examine what happens to t90% when dose greatly exceeds Vmax. Discuss several practical methods to determine when a nonlinear drug has reached steady state. Examine the "time to 90% equation" and note the value of Km that is used in this equation. Substitute several different phenytoin Km values based on a range of population values (i. Based on this observation, what value of Km would you use when trying to approximate the t90% for a newly begun dose of phenytoin? Discuss the patient variables that can affect the pharmacokinetic calculation of a nonlinear drug when using two plasma drug concentrations obtained from two different doses. Write a pharmacy protocol describing an appropriate phenytoin dosing and monitoring service. Explain how the various sources of pharmacokinetic variation affect pharmacokinetic parameters. Describe ways to avoid or minimize errors in the collection and assay of drug samples. These differences in drug effect are sometimes related to differences in pharmacokinetics. However, irrespective of pharmacokinetics, drug effects may vary among individuals because of differences in drug sensitivity. Age At extremes of age, major organ functions may be considerably reduced compared with those of healthy young adults. In neonates (particularly if premature) and the elderly, renal function and the capacity for renal drug excretion may be greatly reduced. Renal function declines at a rate of approximately 1 mL/minute/year after the age of 40 years. In the neonate, renal function rapidly progresses in infancy to equal or exceed that of adults. When dosing a drug for a child, the drug may need to be administered more frequently. Compared with adults, the neonate has a higher proportion of body mass made up of water and a lower proportion of body fat. The elderly are likely to have a lower proportion of body water and lean tissue (Figure 11-1) Both of these changes, organ function and body makeup, affect the disposition of drugs and how they are used. Reduced function of the organs of drug elimination generally requires that doses of drugs eliminated by the affected organ be given less frequently. With alterations in body water or fat content, the dose of drugs that distribute into those tissues must be altered. For drugs that distribute into body water, the neonatal dose may be larger per kilogram of body weight than in an adult. Disease States Drug disposition is altered in many disease states, but the most common examples involve the kidneys and liver, as they are the major organs of drug elimination. In patients with major organ dysfunction, drug clearance decreases and, subsequently, drug half-life lengthens. Some diseases, such as renal failure or cirrhosis, may even result in fluid retention and an increased volume of drug distribution. Alterations in drug clearance and volume of distribution require adjustments in the dose administered and/or the dosing interval. For most drugs, when clearance is decreased but the volume of distribution is relatively unchanged, the dose administered may be similar to that in a healthy person but the dosing interval may need to be increased. Alternatively, smaller doses could be administered over a shorter dosing interval. When the volume of distribution is altered, the dosing interval can often remain the same but the dose administered should change in proportion to the change in volume of distribution. Effect of Volume of Distribution and Impaired Renal/Hepatic Function on Drug Dose Clinical Correlate When adjusting a dose of a drug that follows first-order elimination, if you do not change the dosing interval, then the new dose can be calculated using various simple ratio and proportion techniques. For example, if gentamicin peak and trough serum drug concentrations, in a patient receiving 120 mg Q 12 hours), were 9 and 2. Likewise, one can check to see if this trough would be acceptable with this new dose: "if 120 mg gives a trough of 2. A 23-year-old male experienced a major traumatic injury from a motor vehicle accident. On the third day after injury, his renal function is determined to be good (creatinine clearance = 120 mL/minute), and his weight has increased from 63 kg on admission to 83 kg. Note that fluid accumulation (as evidenced by weight gain) is an expected result of traumatic injury.
By W. Jaffar. The Pennsylvania State University. 2019.