Limiting the use of injectable drugs Numerous patients demand treatment with injectable drugs order online paroxetine, which they imagine to be more effective buy discount paroxetine 30mg on-line. Certain prescribers also believe that injections and infusions are more technical acts and thus increase their credibility best 10mg paroxetine. When both oral and injectable drugs are equally effective cheap paroxetine 10 mg amex, parenteral administration is only justified in case of emergency, digestive intolerance or when a patient is unable to take oral medication. Oral drugs should replace injectable drugs as soon as possible during the course of treatment. Limiting the use of syrups and oral suspensions Taking liquid drugs is often easier, especially for young children and more so if they are sweetened or flavoured. It is, however, recommended to limit their use for numerous reasons: – Risk of incorrect usage Outside of hospitals, determining the correct dosage is hazardous: spoons never contain standard volumes (soup spoons, dessert spoons, tea spoons). Oral suspensions should be prepared with a specified amount of clean water, and well shaken prior to administration. Some oral suspensions must be kept refrigerated; their storage at room temperature is limited to a few days, and with syrups there is a risk of fermentation. Confusion between cough mixtures and antibacterial suspensions or syrups is common. Even using a powder for subsequent reconstitution, the costs may be 2 to 7 times higher than an equivalent dose due to the cost of the bottle itself and higher transportation costs due to weight and volume. Prescription, cost, compliance Studying the choice of treatment regimens The choice of a treatment regimen often influences compliance and cost. The shortest and least divided (1 to 2 doses per day) treatments are most often recommended. Considering non-essential medicines and placebos In developing countries as in industrialised countries, patients with psychosomatic complaints are numerous. The problems that motivate their consultations may not necessarily be remedied with a drug prescription. Is it always possible or desirable to send these patients home without a prescription for a symptomatic drugs or placebo? When national drug policy is strict and allows neither the use of placebos nor non-essential symptomatic drugs, other products are often used in an abusive manner, such as chloroquine, aspirin, and even antibacterials. This risk is real, but seems less frequent, which makes the introduction of placebos on a list of essential drugs relevant. Their composition generally corresponds to preventive treatment of vitamin deficiency and they have no contra–indications. Numerous non-prescription drug products (tonics, oral liver treatments presented in ampoules) have no therapeutic value and, due to their price, cannot be used as placebos. Antiseptics and disinfectants Antiseptics and disinfectants Definition Antiseptics are used to kill or eliminate microorganisms and/or inactivate virus on living tissues (intact or broken skin and mucous membranes). Disinfectants are used to kill or eliminate microorganisms and/or inactivate virus on inanimate objects and surfaces (medical devices, instruments, equipment, walls, floors). Certain products are used both as an antiseptic and as a disinfectant (see specific information for each product). Selection Recommended products 1) Core list No single product can meet all the needs of a medical facility with respect to cleaning, disinfection and antisepsis. However, use of a limited selection of products allows greater familiarity by users with the products in question and facilitates stock management: – ordinary soap; – a detergent and, if available, a detergent-disinfectant for instruments and a detergent- disinfectant for floors and surfaces; – a disinfectant: chlorine-releasing compound (e. Alcohol acts faster than polyvidone iodine, but its duration of action is shorter. Application to mucous membranes or broken skin is contra-indicated, however, alcohol may be used on broken skin in the event of accidental exposure to blood. For example, for antiseptic hand rub, depending on the product specifications: • Bactericidal effect may be achieved with a single application of 30 seconds duration, or 2 consecutive applications of 30 seconds each, or a single application of 60 seconds duration. Antiseptics and disinfectants Thus, when purchasing locally, it is important to verify the quality of the product and specific instructions for use (number of applications, duration of application, and volume to be used per application). For surgical activity, ensure that the product is suitable for use as a surgical hand rub. Precautions should be taken during storage and use to avoid contact with a heat source (flame, electrocautery, etc. Given the possible interactions between different groups of antiseptics, antiseptic cleansing and antisepsis should only be carried out using products from the same class. Instructions for glutaraldehyde use must be followed scrupulously: 1) two preliminary washes of the equipment through immersion in a detergent-disinfectant solution for instruments, followed each time by rinsing; 2) complete immersion of the equipment in a 2% glutataldehyde solution for 20 minutes; 3) thorough final rinsing, with filtered water (or sterile water for endoscopes introduced into a sterile cavity) to eliminate any residue; 4) thorough drying with a sterile towel; 5) sterile wrapping and use within 24 hours. Glutaraldehyde solution is irritating to skin and mucous membranes, and releases toxic vapours. Personnel exposed to glutaraldehyde should take precautions to protect skin and eyes and avoid inhalation of vapours (risk of nausea, headache, breathing disorders, rhinitis, eye irritation, dermatitis). Precautions should be taken during storage and use to avoid contact with a heat source. Non-recommended products – Hydrogen peroxide (3% or 10 volumes) has limited efficacy as antiseptic agent but can be useful to clean contaminated wounds. Updated: February 2017 Antiseptics and disinfectants Preparation and use of antiseptic solutions Preparation Aqueous solutions of many antiseptics can be contaminated by pathogens (especially Pseudomonas aeruginosa) during handling. To avoid this, the following precautions must be taken: – Prepare all aqueous antiseptic solutions with clean water that has been boiled for a few minutes and cooled. Every medical facility should define a clear policy concerning the renewal of antiseptic solutions. Use – Do not use antiseptic solutions belonging to different classes for the same procedure: incompatibilities between different compounds exist. No evidence exists that antiseptics reduce the risk of transmission, however, their use – after thorough cleaning – is not contraindicated. If an antiseptic is used despite this recommendation, it must be allowed to dry before vaccine injection. Preparation and use of disinfectant solutions The effectiveness of disinfection can be impaired by error in preparation (concentration, temperature), failure to follow recommended contact times, or deterioration of the product due to poor storages conditions. Personnel carrying out disinfection should wear protective clothing when preparing or using disinfectant solutions: gown, rubber apron, gloves with long cuffs, goggles and mask. Preparation Solutions should be prepared with clean water (chlorine solutions should be prepared with cold water only, in non-metal containers). Antiseptics and disinfectants – Solution for disinfecting floors and surfaces: prepare just before use, and discard any unused solution. The solution may be used for a maximum of 24 hours; if visibly soiled, discard and replace with fresh soaking solution before 24 hours are up. Disinfection of floors and surfaces – Apply detergent-disinfectant intended for floors and surfacesa, without rinsing. Follow manufacturer’s instructions for dilution and specific preparation procedures. Or – After cleaning with a detergent (cleaning product without an antimicrobial agent) and rinsing with water, apply a 0. Preliminary washing and rinsing are essential: the activity of chlorine is reduced in the presence of organic material (sputum, vomit, faeces, blood and other body fluids), and the detergent used may be incompatible with chlorine. Stainless steel surfaces should be rinsed with water after disinfection with chlorine solution. The use of detergent-disinfectant products reduces workload (cleaning and disinfection are carried out as a single procedure), but they have the disadvantage of being weak detergents and leaving a film, which causes dirt to build up on the floors. Disinfection of linen After hand washing, followed by rinsing: soak the clean linen in a solution of 0. Pre-disinfection of reusable medical devices/instruments – After use, soak medical devices (disassembled, forceps and scissors opened): • In a detergent-disinfectant solution intended for medical devices and instrumentsa. For correct dilution and soak times, follow manufacturer ’s instructions; use a timer. Comply with recommended soaking times and concentrations (risk of corrosion of metal instruments). Soaking for too long (> 15 minutes) and/or in a solution that is too concentrated will increase the risk of corrosion. Antiseptics and disinfectants Cleaning-disinfection of reusable medical devices/instruments After the pre-disinfection step: – Immerse the material in a detergent-disinfectant solution intended for medical devices and instrumentsb (for correct dilution and soak times, follow manufacturer’s directions). Comply with recommended soak times and concentrations (risk of corrosion of metal instruments). Injection for spinal anaesthesia: 5% (hydrochloride) in  lidocaine 2‐ mL ampoule to be mixed with 7.

The highest concentration examined in vitro should be at least 10-times higher than the maximum in vivo plasma concentration purchase generic paroxetine canada, and it is not uncommon to use a maximum in vitro concentration that is 100-fold higher purchase paroxetine in india. When such in vivo concentrations are not known trusted paroxetine 30mg, it is typical to use in vitro concentrations ranging from 0 buy paroxetine 30 mg overnight delivery. Many drug candidates (and even some marker substrates) tend to have poor aqueous solubility at physiological pH. Regardless of the assay, each experiment should include a no-vehicle control (no-solvent control) and a vehicle (solvent) control to assess the effect of the solvent under the conditions of a given exper- iment. The effect of the drug candidate is compared against the appropriate vehicle (solvent) control. Intra-assay Controls It is important to incorporate within each assay certain controls that prove that the test system is performing as expected. To verify that each assay is performed under initial rate conditions, incubations should be performed in the absence of the drug candidate at approximately half and twice the normal protein concen- tration and for approximately half and twice the normal incubation period. Intra- assay controls as well as analytical controls are also included on the same plate. The analytical controls are intended to determine if the drug candidate causes ion suppression or chromatographic interference. Because the autosampler injects samples proceeding down the microtiter plate columns from left to right, the 0- and 30-minute preincubated samples are arranged so that they alternate, rather than placing all 30-minute preincubated samples at the end of the analytical run. This method minimizes bias that might result from slight changes in analytical response during the course of the analytical run. It is also for this reason that one set of standard curve samples is placed at the beginning and the other at the end of the analytical run. However, if deuterated forms of the metabolite standard are used as internal standard, changes in analytical response should affect the metabolite and internal standard to the same extent and therefore be corrected. For direct inhibition, Ki determinations can be conducted for the most potently inhibited enzymes. Because Ki determinations provide information on the mechanism of inhibition (competitive, noncompetitive, etc. If there is an indication of significant time-dependent inhibition, it may be necessary to perform addi- tional experiments to further characterize this type of inhibition. The following sections will outline the rationale for choosing to perform follow-up studies and their experimental design. Instead, it is recommended that the cut-off point take the plasma concentration of the drug candidate into account. However, cimetidine can be administered in doses of up to 2400 mg/day and can reach plasma Cmax values approaching 10 mM. Because Ki determi- nations are conducted at substrate concentrations from Km/3 to 10Km,itis important to target an appropriate analytical range during development and validation of the analytical method. Ideally, the lower limit of quantitation should represent >90% inhibition at Km/3 and the upper limit should normally represent the rate at 10Km in the absence of inhibitor. A wide analytical range allows for a thorough characterization of inhibition to provide a more accurate Ki determination. The use of a well-characterized pool of several individual human liver microsomal samples (as discussed earlier) can obviate the need to change analytical ranges from one batch or lot to the next. A typical design for the first part of this experiment includes evaluating the drug candidate at the same concentration that provided the maximal change in percent inhibition from 0- to 30-minute preincubation in the initial experiment. It is recommended that at least a 10-fold, and preferably a 25- or even a 50-fold dilution be used, which necessitates preincubating the drug candidate with a 10- to 50-fold higher protein concentration than used in the initial incubation. At the end of the preincubation period with this higher con- centration of microsomal protein, an aliquot is removed and added to a normal incubation mixture, including the marker substrate, so that the 10- to 50-fold dilution produces the “normal” concentration of microsomal protein (typically 0. The dilution method outlined above has some important limitations when examining mechanism-based inhibitors that are potent and highly pro- tein-bound because in order to perform a dilution experiment, the microsomal protein concentration must first be increased during the preincubation. In this case, increasing the con- centration of 8-methoxypsoralen by 25-fold, to 1. Consequently, enzyme inactivation by the inhibitor still occurs during the substrate incubation period (in fact, it’s virtually unavoidable), and it is especially pronounced for potent metabolism-dependent inhibitors like 280 Ogilvie et al. To avoid over-metabolism of coumarin, the substrate concentration was increased to 50 mM. For studies with potent inactivators that are also highly bound to protein, dialysis, rather than dilution, may be the preferred approach to investigate the irreversibility of metabolism- dependent inhibition. Thekinact value is analogous to the Michaelis-Menten Vmax and simply represents the maximal rate of enzyme inactivation at saturating concentrations of inhibitor. At a basic level, the design consists of choosing concentrations of drug candidate and preincubation times so that the percentage inhibition will range from 10% to 90% after preincubation, when possible. These assumptions are: (1) there is negligible metabolism of the inhibitor during the preincubation stage, and (2) there is insignificant enzyme inactivation or direct inhibition during the substrate incubation stage. In fact, however, unless the inhibitor (drug candidate) is removed by dialysis prior to the substrate incubation, there is invariably some metabolism of the inhibitor during the substrate incubation period, and direct inhibition of the enzyme inevitably occurs to some extent because a mechanism-based inhibitor of an enzyme is, by In Vitro Study of Drug-Metabolizing Enzymes 283 definition, a substrate for that enzyme. The ratio of the preincubation time with inhibitor to the incubation time with maker substrate 2. Normalization of data for the spontaneous time-dependent loss in enzyme activity in the absence of inhibitor 5. The substrate incubation time should be short relative to the preincubation time to minimize further inactivation of the enzyme after the preincubation stage. Therefore to maximize the ratio of substrate incubation time to pre- incubation time, the substrate incubation time should be as short as possible (e. In the case of metabolism-dependent inhibitors, the use of a long substrate incubation time can lead to an artifactual overestimation of direct inhibition and a corre- sponding underestimation of mechanism-based inhibition potential because there will be appreciable enzyme inactivation even in the zero-minute preincubation samples. In this case, mibefradil appears to have nearly fourfold greater potency as a direct inhibitor when a long substrate incubation period is used (i. For some metabolism-dependent inhibitors, the blunting effect of long substrate incubation times could be even more pronounced, possibly leading to the erro- neous conclusion that no metabolism-dependent inhibition occurs. After the preincubation stage, the samples should be diluted at least 10-fold (and preferably 25- to 50-fold) prior to the substrate incubation stage to reduce the concentration of inhibitor and thereby minimize its direct inhibitory effects. These very high protein concentrations can dramatically decrease the free (unbound) concentration of drug candidate. Consequently, a correction for protein binding during the preincubation stage is warranted, especially for basic lipophilic 284 Ogilvie et al. However, there are two caveats to this rule: (1) the substrate must be soluble at this concentration and (2) the substrate must remain selective for the enzyme in question. If either solubility or selec- tivity is problematic at a high substrate concentration, then a lower substrate concentration must be used. The use of high substrate concentrations achieves two objectives: (1) it helps to diminish any competitive inhibition that might be In Vitro Study of Drug-Metabolizing Enzymes 285 caused by the remaining drug candidate and (2) it helps to decrease any further inactivation of the enzyme by diminishing the metabolism of the remaining drug candidate. The spontaneous, time-dependent loss in enzyme activity in the absence of inhibitor must be taken into account when analyzing the data from mechanism- based inhibition studies (Fig. To account for this loss, vehicle-control samples should be included and they should match all of the time points for the drug candidate. Normalization of the data can be accomplished by first calculating the decrease in activity over time for each concentration of drug candidate, including 0 mM (i. Further data analysis initially consists of performing linear regression for each line defined by the natural log transformed data at each concentration of drug candidate. If a large dilution factor and saturating concentrations of marker 286 Ogilvie et al. Figure 14 Design and graphical representation of irreversible or quasi-irreversible metabolism-dependent inhibition—determination of kinact and Ki values. The negative slope of the line is equal to kobs, which represents the inactivation rate constant for that particular inhibitor concentration. In this approach, the control activity in the above equation is always the zero-minute control for the solvent, rather than the solvent control at each time point. The incubations were then continued for two minutes to allow for conversion of paclitaxel to 6a-hydroxypaclitaxel. The data are plotted with incubation time on the x axis and enzymatic rates on the y axis. Subsequently, for each inhibitor concentration, the pre- incubation time (x axis) was plotted against the natural log of the percentage of remaining enzyme activity (y axis) (middle graph). The inhibitor concentration was then plotted against the initial rates of inactivation of the enzyme (negative slope of the lines in the middle graph).

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Their spectrums of activity order genuine paroxetine online, clinical uses buy paroxetine with visa, biodisposition buy discount paroxetine 40 mg, and side effects are considered discount 20 mg paroxetine with mastercard. The methods bacteria use to develop resistance to the sulfonamides, their activity and clinical uses, biodisposition, and side effects are considered. The simultaneous inhibition of the tetrahydrofolate synthesis pathway at two steps has a synergistic effect and prevents the rapid generation of resistance. Their clinical use, the relevant drugs in this class, their biodisposition, and side effects are reported. Its use as an antiprotozoal and antibacterial drug is discussed, as are its side effects. Antitubercular Drugs Infections caused by Mycobacterium tuberculosis are treated with combination therapy. Backup drugs include streptomycin, fluoroquinolones, capreomycin, and cycloserine. Table V-1-4 summarizes the actions, resistance, and side effects of the antitubercular drugs. Thus, most bacterial antibiotics are ineffective, and many otherwise potentially effective drugs are also toxic to their human hosts. A difference between fungi and humans susceptible to exploitation by antibiotics is the high concentration of ergosterol in their membranes. The polyenes amphotericin (amp B) are amphoteric compounds that bind to ergosterol, forming pores, which results in the leakage of intracellular contents. The activity, clinical uses, biodisposition, and side effects of these polyenes are discussed. The azoles (ketoconazole, fluconazole, c1otrimazole, miconazole, and itraconazole) kill fungi by interfering with ergosterol synthesis. The mechanisms of action, clinical uses, biodisposition, and side effects are considered. Griseofulvin interferes with microtubule function; terbinafine blocks ergosterol synthesis. Antimetabolites are usually prodrugs requiring metabolic activation by host-cell or viral enzymes-eommonly, such bioactivation involves phosphorylation reactions catalyzed by kinases. Saquinavir, one of the least toxic, has very low (and variable) oral bioavailability that predisposes to resistance development. The steps in viral replication and the main sites of action of such antiviral drugs are illustrated in Figure V-3-1. The mechanisms of action, activities, clinical uses, and adverse effects are discussed. Other Antivirals Amantadine blocks the attachment, penetration, and uncoating of influenza virus A; zanamivir and oseltamivir inhibit influenza viruses A and B neuraminidase, promoting viral clumping and decreasing the chance of penetration. It is used to treat respiratory syncytial virus, influenza A and B, Lassafever, Hantavirus, and as an adjunct to alpha-interferons in hepatitis C. TableV-4-2 lists the drugs of choice used against the various forms of malaria, and information is given about treatment and prophylaxis of malaria. The drugs used to treat helminthic infections are listed, and their mechanisms of action are noted. An 82-year-old hospitalized patient with creatinine clearance of 25 mL/min has a micro- bial infection requiring treatment with antibiotics. Which of the following drugs is least likely to require a dosage adjustment, either a smaller dose than usual or an increased inter- val between doses? Past history includes a severe allergic reaction to amoxicillin when used for an ear infection. The physician needs to treat this infection, but prefers not to use a drug that needs parenteral administration. Which one of the following agents is most likely to be appropriate in terms of both effectiveness and safety? A woman has pelvic inflammatory disease, and the decision is made to treat her with anti- biotics as an outpatient. One of the drugs to be used is a cell-wall synthesis inhibitor with activity against anaerobic gram-negative rods, including Bacteroides fragilis. She is warned that unpleasant reactions may occur if she consumes alcoholic beverages while taking this drug. If the antibiotic may cause hypoprothrombinemia, it can be identified as which of the following? What is the drug most likely to be effective in diseases caused by cestodes and trematodes? Several antibiotics are effective in single doses for the treatment of uncomplicated gon- orrhea. Which one of the following drugs necessitates a 7-day course of treatment to be effective? In bacterial meningitis, third-generation cephalosporins are commonly drugs of choice. However, in neonatal meningitis they would not provide coverage if the infection was due to which of the following organisms? Which one of the following drugs inhibits bacterial protein synthesis, preventing the translocation step via its interaction with the 50S ribosomal subunit? Despite its short elimination half-life, gentamicin may be administered once daily (at high dose) in the treatment of hospitalized patients with infections caused by aerobic gram- negative rods. In the treatment of a urinary tract infection in a patient known to have a deficiency of glucose-e-phosphate dehydrogenase, it would not be advisable to prescribe which of the following? Which one of the following drugs is most likely to be effective against all strains of the above-mentioned organisms? Oseltamivir and zanamivir are available for treatment of infections due to influenza A and B. If these changes are related to his drug treatment, which of the following is the most likely cause? Which one of the following drugs is most suitable in an immunocompromised patient for prophylaxis against infection due to Cryptococcus neoformans? Which one of the following drugs is most likely to be associated with elevations of pan- creatic enzymes, including amylase and lipase? In community-acquired pneumonia, pathogens responsible for infection include pneu- mococci, gram-negative rods, and atypicals, such as M. Which one of the following drugs used as monotherapy is most likely to be both effective and safe if your patient is pregnant? Which one of the following drug situ- ations involving the mother is unlikely to cause effects in the nursing infant? In a patient who has an established hypersensitivity to metronidazole, what is the most appropriate drug to use for the management of pseudomembranous colitis? Microbial resistance to fluoroquinolones is increasing, and some strains of Streptococcus pneumoniae are now resistant to ciprofloxacin. The other mechanisms listed underlie microbial resistance to other antibiotics as follows: sulfonamides (choice B), macrolides (choice C), extended-spectrum penicillins (choice D), and beta-lactams (choice E). Erythromycin is eliminated largely via biliary excretion, and decreases in renal function do not usually require a dose reduction, unless creatinine clearance is <10 mUmin. All of the other antimicrobial drugs listed are eliminated by the kidney, at rates proportional to creatinine clearance, so major dose reductions would be needed in patients with renal dysfunction to avoid toxicity. Azithromycin is highly effective as an oral agent in the management of phar- yngitis caused by gram-positive cocci and may necessitate only a short course of therapy. In patients who have marked hypersensitivity to penicillins, it is inappropriate to use a cephalosporin, even though cefaclor is active against common oropharyngeal pathogens. One must assume that complete cross- allergenicity exists between different members of the penicillin class of antibiotics, and, in any case, penicillin G is not usually given orally because of its lability in gastric acid. Vancomycin would need parenteral administration, and this antibiotic should be reserved for more serious bacterial infections. Low-level resistance occurs via mutations in the inh A gene, which codes for an enzyme involved in synthesis of mycolic acids. Effective treatment often requires hospitalization, but some patients are treated on an outpatient basis. Several cephalospo- rins, including cefotetan (but not ceftriaxone), have a chemical structure that results in a disulfiram-like effect on aldehyde dehydrogenase and also causes inhibition of prothrombin synthesis. Metronidazole is also an inhibitor of aldehyde dehydrogenase, causing reactions with ethanol, but the drug does not cause hypoprothrombinemia.

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Malformations observed included facial anomalies similar to those observed in human newborns deliv- ered to women with epilepsy who received anticonvulsants during gestation cheap paroxetine on line. A decrease in the number of specific brain cells and changes in neonatal behavior have been observed in animal studies of gestational exposure to the drug (Bergman et al purchase 20mg paroxetine otc. The relevance of these observations to the clinical use of phenobarbital in humans is unknown purchase cheap paroxetine. Transient neonatal sedation or withdrawal symptoms that include hyperactivity generic paroxetine 40 mg online, irri- tability, and tremors have been observed among newborns exposed to phenobarbital during pregnancy (Desmond et al. Hemorrhagic disease of the newborn has been associated with phenobarbital use during pregnancy and typically begins within the first 24 h of life (Gimovsky and Petrie, 1986; Mountain et al. In con- trast, maternal phenobarbital therapy immediately before delivery has been used to pre- vent intraventricular hemorrhage in premature newborns (Morales and Koerten, 1986; Shankaran et al. The fre- quency of major and minor congenital anomalies was not increased among 298 infants born to women treated with amobarbital exposure during the first trimester (Heinonen et al. Amobarbital use during the first trimester was possibly associated with car- diovascular defects (seven cases), inguinal hernia (nine cases), clubfoot (four cases), gen- itourinary anomalies (three cases), and polydactyly in Black infants (two cases). In a sur- vey including over 1300 women exposed to multiple agents, of whom 175 infants were exposed to amobarbital during the first trimester, the frequency of congenital anomalies was increased (Nelson and Forfar, 1971). Authorities in the field generally believe that this drug is not likely to be a teratogen and that the significant associations may be due to chance and conducting multiple statistical comparisons (Friedman and Polifka, 2006). Furthermore, no studies in animals evaluating the teratogenic effects of aprobarbital have been published. Among 112 infants whose mothers took butalbital during the first trimester, no increased frequency of congenital anomalies was found among the offspring (Heinonen et al. Transient neonatal withdrawal was reported in association with butalbital use late in gestation (Ostrea, 1982). No animal studies of possible teratogenic effects of butalbital have been published. Among 250 infants whose mothers took pento- barbital during the first trimester, the frequency of congenital malformations was not increased (Heinonen et al. Similarly, among more than 50 newborns born to women exposed to pentobarbital during the first trimester of gestation, the frequency of birth defects was no greater than expected (Jick et al. Skeletal and craniofacial defects, as well as fetal loss, were increased among the off- spring of pregnant mice, golden hamsters, and rabbits given pentobarbital many times the doses that are used in humans (Hilbelink, 1982; Johnson, 1971; Setala and Nyyssonen, 1964). Changes in behavior and decreased brain–body weight ratios were reported among the offspring of pregnant rats administered 20–40 times the human dose of pentobarbital during embryogenesis (Martin et al. The relevance of these findings in animals to the clinical use of this barbiturate in humans is unknown. Results in a Japanese multi- institutional study that included the frequency of congenital anomalies in a cohort of 111 infants born to pregnant epileptics who used mephobarbital during the first trimester, were similar to those for the infants of pregnant epileptics treated with other medications (Nakane et al. In a small case series, the frequency of congenital malformations was no greater among the newborns of 17 epileptic mothers exposed to mephobarbital during the first trimester of pregnancy than among the newborns of epileptic mothers who received no treatment (Annegers et al. Among 378 infants born to women who took secobarbital during the first trimester, the fre- quency of congenital anomalies was not increased (Heinonen et al. One report of an infant with neonatal withdrawal symptoms of hyperirritability and seizures associated 198 Psychotropic use during pregnancy with maternal use of large doses of secobarbital throughout gestation has been published (Bleyer and Marshall, 1972). Benzodiazepines Benzodiazepines are minor tranquilizers with mild anticonvulsant and sedation proper- ties (Box 10. These agents differ in potency and duration of effect, and indications for their use are based upon these features. Diazepam is also used to treat alcohol withdrawal and as an adjunct to anticonvulsants in the treatment of seizure disorders. Inconsistencies in the currently available epidemiological data on the risk of congeni- tal anomalies among newborns of women who were exposed to diazepam during gesta- tion, confound the issue. Diazepam use during the first trimester was not associated with an increased frequency of malformations among the newborns of more than 150 women in two cohorts, or among 60 newborns of women who used the drug in the first trimester (Aselton et al. In contrast, first-trimester diazepam use was increased almost threefold among 1427 infants with congenital malformations compared to controls in one study (Bracken and Holford, 1981), but not in another case–control study that included 417 newborns with multiple congenital malformations (Czeizel, 1988). A hypothesized ‘benzodiazepine embryofetopathy’ (typical facial features, neurological dysfunction, and other anomalies) (Laegreid et al. Some early evidence suggested that maternal use of diazepam or other benzodi- azepines during the first trimester of gestation was associated with facial clefts in the infants (Aarskog, 1975; Safra and Oakley, 1975; Saxén, 1975; Saxén and Saxén, 1975); more extensive studies have not confirmed this association. Among the infants of women who had first-trimester exposure to antineurotics (mainly diazepam) the fre- quency of congenital anomalies was not increased (Crombie et al. On balance, the possible risk of cleft lip or palate in the infant of a women exposed to diazepam during the first trimester, if increased at all, is less than 1 percent. Notably, family history of congenital anomalies is a confounder in at least two of these studies. Maternal use of diazepam or related compounds during the first trimester of pregnancy and an increased risk for cardiovascular anomalies was observed in two case–control studies involving 773 infants (Bracken and Holford, 1981; Rothman et al. In a follow-up study of 298 infants with congenital heart defects, no association with first-trimester diazepam was found (Zierler and Rothman, 1985). The risk for congeni- tal heart disease among the infants of women who have first-trimester exposure to diazepam, is probably not increased, but if it is increased the magnitude is small (< 1–2 percent). Sedatives, hypnotics, and tranquilizers 199 Diazepam is readily transferred across the placenta to the human fetus and becomes concentrated in the fetal compartment with a 2:1 ratio (Erkkola et al. Apnea, hypotonia, and hypothermia were observed in newborns of women who took diazepam during the third trimester of pregnancy or peripartum (Cree et al. Tremors, irritability, and hypertonia similar to neonatal narcotic withdrawal was observed in some infants chronically exposed in utero during the third trimester to diazepam (Rementeria and Bhatt, 1977). Loss of beat-to- beat fetal heart rate variability was associated with diazepam exposure during late preg- nancy (Scher et al. The effect of prenatal exposure to this drug and any untoward central nervous system function in later life is unknown. A few reports of normal infants born to women who took toxic doses of diazepam during gestation, with the majority of cases occurring after the first trimester have been published (Cerqueira et al. Animal studies indicate that diazepam is a teratogen in mice and hamsters, but only when doses hundreds of times greater than those used in humans are administered (Kellogg, 1988; Weber, 1985). It also has less anticonvulsant, muscle relaxant and sedative properties, but is effective in treating alcohol withdrawal. In several cohort studies, the frequency of congenital defects was not increased among more than 480 newborns whose mothers had first-trimester exposure to chlordiazepoxide (Crombie et al. Two case–control studies reported no association between maternal use of this benzodiazepine in the first trimester and congenital defects (Bracken and Holford, 1981; Rothman et al. In contrast, in a small cohort study an association was reported between congenital malformations in 35 infants and maternal use of chlordiazepoxide in the first 42 days of gestation (Milkovich and van den Berg, 1974). Maternal chlordiazepoxide was associated with neonatal withdrawal beginning on day 26 of life (Athinarayanan et al. Chlordiazepoxide given to pregnant hamsters in doses greater than those used in humans during embryogenesis resulted in an increased frequency (dose-dependent) of central nervous system anomalies and maternal toxicity (Guram et al. The fre- quency of congenital anomalies was not increased among the offspring of pregnant rats given benzodiazepine, but fetal loss, growth retardation, and skeletal variants were increased in frequency with higher doses (Buttar, 1980; Saito et al. In a case–control study, a significant association between first-trimester exposure to lorazepam and anal atresia was published (Bonnot et al. Placental transfer of lorazepam was reported by several investigators (de Groot et al. Intravenously administered maternal lorazepam in hypertensive gravidas was associated with low Apgar scores, hypothermia, poor feeding, and a requirement for assisted ventilation in the infant. No congenital anomalies were reported among the offspring of pregnant rats and mice given up to 4 mg/kg. The rate of malformations was approxi- mately 5 percent in over 400 births reported to the manufacturer (St Clair and Schirmer, 1992). In a case–control study from Hungary, the association between alprazolam expo- sure and congenital anomalies was slightly elevated, but not significantly so (Eros et al. Several series containing more than 300 pregnancies followed through teratogen information services found no apparent increase in congenital anomalies (Friedman and Polifka, 2006) This agent, as other benzodiazepines, may cause hypotonia and hypothermia in the newborn (Yonkers and Cunningham, 1993). Among 89 infants born to women who used oxazepam during the first trimester, there were no congenital anom- alies (Ornoy et al. Small numbers of first-trimester exposure to clonazepam are published in clinical case series, but they are confounded by concomitant use of other known teratogens (anticonvulsants), as well as small sample sizes and sample selection bias (Friedman and Polifka, 2006). Congenital anomalies were not increased in frequency among the offspring of preg- nant rabbits or rats administered oxazepam in doses greater than those used in humans (Owen et al. Changes in behavior were observed among the offspring of pregnant mice given oxazepam in doses four to 42 times those used clini- cally (Alleva and Bignami, 1986).

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