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- Clinical Associate Professor, Department of Pharmacy Practice, College of Pharmacy, Purdue University, West Lafayette
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Epidemiology and pathogenesis the site of the clinical syndrome caused by an adenovirus infection is generally related to treatment 2 order rulide 150mg visa the mode of virus transmission medications kidney patients should avoid buy rulide 150mg on-line. For example treatment works generic 150 mg rulide mastercard, most adenoviruses are primarily agents of respiratory disease treatment hypothyroidism buy 150mg rulide free shipping, which are transmitted via the respiratory route. However, most adenoviruses also replicate efficiently and asymptomatically in the intestine, and can be isolated from the stool well after respiratory disease symptoms have ended, as well as from the stools of healthy persons. Similarly, ocular infections are transmitted by direct inoculation of the eye by virus-contaminated hands, ophthalmologic instruments, or bodies of water in which groups of children swim together. Structure and replication the adenovirus capsid is composed of hexon capsomers making up the triangular faces of the icosahedron, with a penton capsomer at each of the vertices (see Figure 24. Attachment to a host cell receptor occurs via knobs on the tips of the viral fibers, which is follow by entry into the cell by receptormediated endocytosis. The viral genome is then progressively uncoated while it is transported to the nucleus, where all transcription of viral genes, genome replication, and assembly occurs. Two early viral genes have the same function as the early proteins of the papovaviruses [that is, inactivating cellular regulatory proteins (including p53 and pRb) that normally prevent progression through the cell cycle (see p. Release of infectious virus from the cell occurs by slow disintegration of the dying cell. The observed disease symptoms are related primarily to the killing of these cells; systemic infections are rare. Most adenovirus infections are asymptomatic, but certain types are more commonly associated with disease than others. Respiratory tract diseases: the most common manifestation of 251 Ocular infections Follicular conjunctivitis Keratoconjunctivitis Respiratory infections Acute febrile pharyngitis Pharyngoconjunctival fever Acute respiratory disease Viral pneumonia Gastrointestinal infections adenovirus infection of infants and young children is acute febrile pharyngitis, characterized by a cough, sore throat, nasal congestion, and fever. Isolated cases may be indistinguishable from other common viral respiratory infections. Some adenovirus types tend additionally to produce conjunctivitis, in which case the syndrome is referred to as pharyngoconjunctival fever. This entity is more prevalent in school-aged children and occurs both sporadically, and in outbreaks, often within family groups or in groups using the same swimming facility ("swimming pool conjunctivitis"). The syndrome referred to as acute respiratory disease occurs primarily in epidemics among new military recruits. It is thought to reflect the lowered resistance brought on by exposure to new strains, fatigue, and crowded living conditions, promoting efficient spread of the infection. Lastly, the respiratory syndromes described above may progress to true viral pneumonia, which has a mortality rate of about ten percent in infants. Ocular diseases: In addition to the conjunctivitis that sometimes Infantile gastroenteritis Urinary tract infections Hemorrhagic cystitis Figure 24. A more serious infection is epidemic keratoconjunctivitis, which involves the corneal epithelium, and may be followed by corneal opacity lasting several years. The epidemic nature of this disease partly results from transmission via shared towels or ophthalmic solutions, person-to-person contact, or improperly sterilized ophthalmologic instruments. Adenovirus infections have been estimated to account for five to fifteen percent of all viral diarrheal disease in children. Less common diseases: Several adenovirus serotypes have been associated with an acute, self-limited, hemorrhagic cystitis, which occurs primarily in boys. Similarly, adenovirus infection of heart muscle has recently been shown to be one cause of left ventricular dysfunction in both children and adults. Other disseminated infections leading to a fatal outcome have been reported in patients with a compromised immune system or those immunosuppressed from drug therapy. Laboratory identification Isolation of virus for identification is not done on a routine basis, but may be desirable in cases of epidemic disease or nosocomial outbreak, especially in the nursery. Identification of the adenovirus serotype can be done by neutralization or hemagglutination inhibition using type-specific antisera. Treatment and prevention No antiviral agents are currently available for treating adenovirus infections.
Because the nucleic acid of a virus is surrounded by the capsid medicine for pink eye buy generic rulide 150mg, it is protected from environmental damage treatment xanthelasma eyelid order 150 mg rulide free shipping. Icosahedral symmetry: Capsids with icosahedral symmetry are more complex than those with helical symmetry treatment quad strain generic 150 mg rulide with visa, in that they consist of several different polypeptides grouped into structural subassemblies called capsomers treatment concussion rulide 150 mg. These, in turn, are hydrogen-bonded to each other to form an icosahedron (Figure 23. The nucleic acid genome is located within the empty space created by the rigid, icosahedral structure. Envelope An important structural feature used in defining a viral family is the presence or absence of a lipid-containing membrane surrounding the nucleocapsid. In enveloped viruses, the nucleocapsid is flexible and coiled within the envelope, resulting in most such viruses appearing to be roughly spherical (Figure 23. However, the cellular membrane proteins are replaced by virus-specific proteins, conferring virus-specific antigenicity upon the particle. In practice, this is determined by following events in a large population of infected cells in which the infection is proceeding as nearly synchronously as can be achieved by manipulating the experimental conditions. Whereas the time scale and yield of progeny virus vary greatly among virus families, the basic features of the infectious cycle are similar for all viruses. The one-step growth curve begins with the eclipse period, which is followed by a period of exponential growth (Figure 23. Introduction to the Viruses Infectious viruses per cell 1000 100 10 1 0 Eclipse period 0 10 Hours Exponential growth period Yield per cell Following initial attachment of a virus to the host cell, the ability of that virus to infect other cells disappears. This is the eclipse period, and it represents the time elapsed from initial entry and disassembly of the parental virus to the assembly of the first progeny virion. The eclipse period for most human viruses falls within a range of one to twenty hours. Exponential growth the number of progeny virus produced within the infected cell increases exponentially for a period of time, then reaches a plateau, after which no additional increase in virus yield occurs. The maximum yield per cell is characteristic for each virus-cell system, and reflects the balance between the rate at which virus components continue to be synthesized and assembled into virions, and the rate at which the cell loses the synthetic capacity and structural integrity needed to produce new virus particles. This may be from 8 to 72 hours or longer, with yields of 100 to 10,000 virions per cell. Gene expression and replication are followed by assembly and release of viral progeny. Adsorption the initial attachment of a virus particle to a host cell involves an interaction between specific molecular structures on the virion surface and receptor molecules in the host cell membrane that recognize these viral structures (Figure 23. Attachment sites on the viral surface: Some viruses have spe- Virus fails to bind to host cell receptor cialized attachment structures, such as the glycoprotein spikes found in viral envelopes (for example, rhabdoviruses, see p. In both cases, multiple copies of these molecular attachment structures are distributed around the surface of the virion. Not surprisingly, these receptors have been found to be molecular structures that usually carry out normal cell functions. Steps in the Replication Cycles of Viruses membrane receptors for compounds such as growth factors may also inadvertently serve as receptors for a particular virus. Many of the compounds that serve as virus receptors are present only on specifically differentiated cells or are unique for one animal species. Therefore, the presence or absence of host cell receptors is one important determinant of tissue specificity within a susceptible host species, and also for the susceptibility or resistance of a species to a given virus. Penetration Penetration is the passage of the virion from the surface of the cell, across the cell membrane and into the cytoplasm. There are two principal mechanisms by which viruses enter animal cells: receptormediated endocytosis and direct membrane fusion. Receptor-mediated endocytosis: this is basically the same pro- Formation of an endocytotic vesicle Endocytotic vesicle 4 Release of the virion into cytoplasm cess by which the cell internalizes compounds such as growth regulatory molecules and serum lipoproteins, except the infecting virus particle is bound to the host cell surface receptor in place of the normal ligand (Figure 23. The cell membrane invaginates, enclosing the virion in an endocytotic vesicle (endosome).
Proteins and drugs with molecular weights above 1 medicine 8 capital rocka buy generic rulide 150 mg on-line,000 become more restricted (Mirkin 1975) treatment zamrud buy rulide 150 mg otc. Lipid solubility may also be measured by retention times on reversed-phase liquid chromatography columns (Abemethy and Greenblatt 1984) medicine while pregnant buy cheap rulide 150mg line. The in vitro perfused placental preparation medicine emoji generic 150mg rulide mastercard, using guinea pig or human tissue, may be used to estimate the participation of the placenta in drug clearance, whether metabolites are formed, and the ease with which drugs may pass the placenta. In drug development, the in vitro perfused human placenta has the advantage of being able to screen for drugs that exhibit a large first-pass metabolism by the placenta. Although there are enzyme systems in the placenta capable of metabolizing drugs, a first-pass metabolism by the placenta does not appear to be a mechanism to extensively protect the fetus from drug exposure. The basic allometric equation is of the form Y = a Mb (equation 1), which relates some physiological variable Y to body mass M raised to a fractional power b. In the logarithmic form, the equation is written log Y = log a + b log M (equation 2) where b is the slope of a straight-line plot and a is the Y-intercept. Allometric equations are derived by taking the antilog of empirically observed relationships in the form of equation 2 (Dedrick 1973; Mordenti 1986). Despite large differences in mass among animals, most mammals have similar anatomy, physiology, and biochemistry. Adolph (1949) compiled 33 equations that related quantitative physiological properties in various animals to body weight. Examples include ventilation rate, clearance of creatinine, heartbeat duration, and nitrogen output. Since renal blood flow is approximately 25 percent of cardiac output regardless of mammalian species, it could be expected that allometric relationships might exist among different animals in the ability to eliminate drugs. Boxenbaum (1984) demonstrated that the intrinsic clearance of antipyrine could be scaled across species with the exception of man. Various pharmacokinetic parameters have been successfully scaled among different species with a variety of drugs. The application of interspecies scaling has not been widespread in the field of drug abuse. An example of the goodness of fit of data from this study is presented in figure 4. These include the ability to produce more meaningful data from animal experiments and to interpolate drug doses between animals and humans. The steadystate unbound methadone concentration in the fetal plasma is approximately one-third of that in the maternal plasma. This suggests an instability exists in pharmacokinetic parameters and pharmacodynamic response. Thus, treatment of the pregnant addict must rely on principles of good clinical observation and care in addition to pharmacokinetic and dynamic studies conducted in animals to predict potential benefits and adverse effects. The value of conducting concentration-controlled clinical trials in drug development programs for treating the pregnant addict can be increased. Nevertheless, it may be important to monitor plasma drug concentration to assess any relationship to side effects or toxicity and to assess the degree of intersubject variability. Animal models remain useful in screening for physiological and behavioral teratogenic effects during the drug development process. Nevertheless, the goal is to use enough of the drug to be therapeutic without being toxic. Therefore, for adequate dosage regimen design, knowledge of some fundamental pharmacokinetic parameters is critical. Interspecies scaling using allometric principles to predict pharmacokinetics in pregnant animals may be an attractive alternative to human studies, but should complement studies conducted in nonpregnant women. Human placental tissues were found to be able to metabolize drugs via each of the major drug metabolic reactions, although at a very slow rate (Juchau 1985). However, the significance of the placental metabolism to the fetal drug exposure remains to be investigated. Fetal metabolism has been demonstrated in fetal liver tissue preparations and in utero in animal models. In the pregnant ewe model, the fetus was found to be capable of metabolizing drugs such as 126 methadone and acetaminophen; this resulted in an overall reduced fetal exposure to the drugs. The metabolic rate in the fetus in general is a fraction of the maternal rate on a body weight basis, and therefore is inconsequential to the overall total body metabolism (including the maternal and the fetal clearance) of a drug in pregnancy. However, the degree to which the fetus participates in drug elimination will reduce the overall exposure of the unchanged drug but may result in accumulation of the metabolites.
Solicited injection site and systemic reactions were recorded in a diary card for 7 consecutive days after each vaccination medications list purchase rulide 150 mg without prescription. Participants were monitored for 28 days (30 days for infants and toddlers) for unsolicited adverse events and for 6 months post-vaccination for visits to symptoms gestational diabetes buy discount rulide 150mg on-line an emergency room medications in pregnancy generic 150 mg rulide with amex, unexpected visits to symptoms inner ear infection best rulide 150 mg an office physician, and serious adverse events. Unsolicited adverse event information was obtained either by telephone interview or at an interim clinic visit. Information regarding adverse events that occurred in the 6-month post-vaccination time period was obtained via a scripted telephone interview. Solicited Adverse Events in the Primary Safety Studies the most frequently reported solicited injection site and systemic adverse reactions within 7 days following vaccination in children 9 months and 12 months of age (Table 1) were injection site tenderness and irritability. The most commonly reported solicited injection site and systemic adverse reactions in adolescents, ages 11-18 years (Table 3), and adults, ages 18-55 years (Table 4), after a single dose Confidential/Proprietary Information Page 8 of 43 Sanofi Pasteur Inc. Except for redness in adults, injection site reactions were more frequently reported after Menactra vaccination than after Menomune A/C/Y/W-135 vaccination. Grade 2: cries and protests when injection site is touched, Grade 3: cries when injected limb is moved, or the movement of the injected limb is reduced. Grade 2: not interested in surroundings or did not wake up for a feed/meal, Grade 3: sleeping most of the time or difficult to wake up. Grade 2: 2 to 5 episodes per 24 hours, Grade 3: 6 episodes per 24 hours or requiring parenteral hydration. Grade 2: interferes with normal activities, Grade 3: disabling, unwilling to engage in play or interact with others. Grade 2: interferes with or limits usual arm movement, Grade 3: disabling, unable to move arm. The p-values were calculated for each category and severity using Chi Square test. Solicited Adverse Events in a Booster Vaccination Study For a description of the study design and number of participants, [see Clinical Trials Experience, Booster Vaccination Study (6. The most common solicited injection site and systemic reactions within 7 days of vaccination were pain (60. Overall rates of solicited injection site reactions and solicited systemic reactions were similar to those observed in adolescents and adults after a single Menactra dose. Adverse Events in Concomitant Vaccine Studies Solicited Injection Site and Systemic Reactions when Given with Routine Pediatric Vaccines For a description of the study design and number of participants, [see Clinical Trials Experience (6. Participants who received Menactra and the concomitant Confidential/Proprietary Information Page 17 of 43 Sanofi Pasteur Inc. Irritability was the most frequent systemic reaction, reported in 62% of recipients of Menactra plus concomitant vaccines, and 65% of the control group. For all study groups, the most frequently reported solicited local reaction at the Menactra site was pain: 52. For all study groups, the most frequently reported systemic reaction following the administration of Menactra alone or with the respective concomitant vaccines was myalgia: 24. Injection site pain was reported more frequently after Td vaccination than after Menactra vaccination (71% versus 53%). The overall rate of systemic adverse events was higher when Menactra and Td vaccines were given concomitantly than when Menactra was administered 28 days after Td vaccine (59% versus 36%). In both groups, the most common reactions were headache (Menactra + Td vaccine, 36%; Td vaccine + Placebo, 34%; Menactra alone, 22%) and fatigue (Menactra + Td vaccine, 32%; Td vaccine + Placebo, 29%; Menactra alone, 17%). More participants experienced pain after Typhoid vaccination than after Menactra vaccination (Typhoid + Placebo, 76% versus Menactra + Typhoid, 47%). The majority (70%-77%) of injection site solicited reactions for both groups at either injection site were reported as Grade 1 and resolved within 3 days post-vaccination. In both groups, the most common systemic reaction was headache (Menactra + Confidential/Proprietary Information Page 19 of 43 Sanofi Pasteur Inc. Post-Marketing Experience In addition to reports in clinical trials, worldwide voluntary adverse events reports received since market introduction of Menactra are listed below.
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