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If thisisnotpossible then flushthe linethoroughly with a compatible solution between drugs buy cipro. Inspect visually for particulate matter or discoloration prior to administration and discard if present discount 250mg cipro visa. Intermittent intravenous infusion Preparation and administration Ifusedincombinationwithanaminoglycoside(e buy cipro toronto. If thisisnotpossible then flushthe linethoroughly with a compatible solution between drugs. Withdraw the required dose and add to a suitable volume of compatible infusion fluid (usually 100mL NaCl 0. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Development of Throughout treatment * Development of severe, persistent diarrhoea may diarrhoea be suggestive of Clostridium difficile-associated diarrhoea and colitis (pseudomembranous colitis). Coagulation tests If any bleeding * More common in renal impairment and if occurs concomitant with beta-lactam antibiotics. Additional information Common and serious Immediate: Anaphylaxis and other hypersensitivity reactions have been undesirable effects reported. This assessment is based on the full range of preparation and administration options described in the monograph. Intravenous injection Preparation and administration Tenecteplase is incompatible with Gluc solutions. Select the correct vial size according to bodyweight: 8000 units for <80kg, 10000 units for 80kg and over. Screwthepre-filledsyringeontothe vial adapterandpenetrate thevial stopperinthemiddlewith the spike of the vial adapter. Immediately prior to use invert the vial with the syringestill attached, so that thesyringe is below the vial. Transfer the appropriate volume of reconstituted solution into the syringe, based on the patient’s weight (see Table T1). Inspect visually for particulate matter or discoloration prior to administration and discard if present. Technical information Incompatible with Tenecteplase is incompatible with Gluc solutions. Displacement value Negligible Stability after From a microbiological point of view, should be used immediately; however, preparation reconstituted solutions may be stored at 2--8 C and used within 24 hours. Monitoring in treatment of myocardial infarction Measure Frequency Rationale Heart rate Continuously * #Pulse may result from reperfusion. Additional information Common and serious Immediate: Anaphylaxis and other hypersensitivity reactions have been undesirable effects reported rarely. Significant * The following may "risk of haemorrhage with tenecteplase: interactions anticoagulants, heparins, antiplatelet agents, e. Stop administration and give supportive therapy as appropriate including fresh frozen plasma, fresh blood and tranexamic acid if necessary. This assessment is based on the full range of preparation and administration options described in the monograph. Terbutaline sulfate 500 micrograms/mL solution in 1-mL ampoules * Terbutaline sulfate is a direct-acting sympathomimetic with mainly beta-adrenergic activity and a selective action on beta2-receptors. Premature labour: Gluc 5% should be used to prepare the infusion to #risk of maternal pulmonary oedema. More than 10 micrograms/minute is rarely required; 20 micrograms/minute should not be exceeded. Dose in renal impairment: adjusted according to creatinine clearance:1 * CrCl >20--50mL/minute: reduce the parenteral dose by 50%. Terbutaline sulfate | 805 Continuous intravenous infusion via a syringe pump Preparation of a 100 micrograms/mL solution (other strengths may be used according to local policies) 1. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Continuous intravenous infusion (large volume infusion) Preparation of a 5 micrograms/mL solution (other strengths may be used according to local policies) 1. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with No information Compatible with Flush: NaCl 0. Stability after From a microbiological point of view, should be used immediately; however, prepared preparation infusions may be stored at 2--8 C and infused (at room temperature) within 24 hours. Additional information Common and serious Immediate: Hypersensitivity reactions have been reported. Action in case of The preferred antidote is a cardioselective beta-blocker, but use with caution in overdose patients with a history of bronchospasm. This assessment is based on the full range of preparation and administration options described in the monograph. Teriparatide | 807 Teriparatide 250 micrograms/mL solution in 3-mL pre-filled multidose pen (28 doses) * Teriparatide is a recombinant fragment of human parathyroid hormone. Pre-treatment checks * Avoid in pre-existing "Ca, severe renal impairment, metabolic bone diseases including hyperpara- thyroidism and Paget disease, skeletal malignancies or bone metastases or previous radiation therapy to the skeleton. Dose in renal impairment: no dose adjustment required in mild impairment; use with caution in moderate impairment; do not give in severe renal impairment. Technical information Incompatible with Not relevant Compatible with Not relevant pH Not relevant Sodium content Negligible Excipients Contains metacresol (may cause hypersensitivity reactions). In use: Once opened, the pen should be used for a maximum of 28 days and then discarded. Urinary calcium Periodically * In patients with suspected active urolithiasis or pre-existing hypercalciuria. Additional information Common and serious Immediate: Hypersensitivity reactions: acute dyspnoea, facial oedema, undesirable effects generalised urticaria, chest pain, oedema (mainly peripheral). Antidote: No known antidote; stop administration and give supportive therapy as appropriate. This assessment is based on the full range of preparation and administration options described in the monograph. Terlipressin | 809 Terlipressin 1-mg dry powder vial with 5mL solvent 120 micrograms/mL (1mg/8. Pre-treatment checks Caution in patients with hypertension, atherosclerosis, cardiac dysrhythmias or coronary insufficiency. Hepatorenal syndrome (unlicensed): 1mg every 4--12 hours for 7--15 days appeared to improve renal function. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with No information Compatible with Flush: NaCl 0.

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Increase to 50 mg once daily the following week generic cipro 250 mg fast delivery, then 75 mg once daily at bedtime as of the third week (max order cipro 1000 mg free shipping. Duration – Neuropathic pain: several months (3 to 6) after pain relief is obtained generic cipro 250mg, then attempt to stop treatment. Contra-indications, adverse effects, precautions – Do not administer to patients with recent myocardial infarction, arrhythmia, closed-angle glaucoma, prostate disorders. Treatment should be discontinued in the event of severe reactions (mental confusion, urinary retention, cardiac rhythm disorders); • psychic disorders: exacerbation of anxiety, possibility of a suicide attempt at the beginning of therapy, manic episode during treatment. Remarks – Sedative effect occurs following initial doses, analgesic effect is delayed for 7 to 10 days. For depression, it is necessary to wait 3 weeks before assessing therapeutic efficacy. Therapeutic action – Antimalarial Indications – Treatment of uncomplicated falciparum malaria, in combination with artesunate – Completion treatment following parenteral therapy for severe falciparum malaria, in combination with artesunate Presentation – 200 mg amodiaquine hydrochloride tablet, containing 153 mg amodiaquine base Dosage and duration – Child and adult: 10 mg base/kg once daily for 3 days Contra-indications, adverse effects, precautions – Do not administer in the event of previous severe adverse reaction to treatment with amodiaquine (e. However, given the risks associated with malaria, the combination artesunate-amodiaquine may be used during the first trimester if it is the only effective treatment available. The addition of clavulanic acid to amoxicillin extends its spectrum of activity to cover beta-lactamase producing Gram-positive and Gram-negative organisms, including some Gram-negative anaerobes. Indications – Animal bites, if antibiotic therapy or antibiotic prophylaxis is clearly indicated – Second line treatment of acute otitis media and acute bacterial sinusitis, when amoxicillin alone given at high dose failed – Acute uncomplicated cystitis (no systemic signs) in girls > 2 years – Postpartum upper genital tract infection – Severe pneumonia: parenteral to oral switch therapy in patients treated with ceftriaxone + cloxacillin Presentation – The ratio of amoxicillin and clavulanic acid varies according to the manufacturer: Ratio 8:1 – 500 mg amoxicillin/62. Dosage (expressed in amoxicillin) – Animal bites; second line treatment of acute otitis media and acute sinusitis • Child < 40 kg: 45 to 50 mg/kg/day in 2 divided doses (if using ratio 8:1 or 7:1) or in 3 divided doses (if using ratio 4:1) Note: the dose of clavulanic acid should not exceed 12. Depending on the formulation available: Ratio 8:1: 3000 mg/day = 2 tablets of 500/62. Duration – Animal bites: 5 to 7 days; otitis media: 5 days; sinusitis: 7 to 10 days; cystitis: 3 days; upper genital tract infection: 7 days; parenteral to oral switch therapy in severe pneunonia: to complete a total of 10 to 14 days of treatment. Contra-indications, adverse effects, precautions – Do not administer to penicillin-allergic patients and patients with history of hepatic disorders during a previous treatment with co-amoxiclav. The maximum dose (expressed in amoxicillin) that can be given with these formulations is 50 mg/kg/day, without exceeding 1500 mg/day. These therapeutic combinations can be coformulated tablets (artesunate and the 2nd antimalarial combined in the same tablet, in blister-pack containing a complete course of treatment) or co-blistered tablets (tablets of artesunate and tablets of the 2nd antimalarial in the same blister-pack containing a complete course of treatment). Therapeutic action – Antimalarial Indications – Treatment of uncomplicated falciparum malaria – Completion treatment following parenteral therapy for severe falciparum malaria Presentation – 50 mg tablet Dosage and duration – Child and adult: 4 mg/kg/day once daily for 3 days Contra-indications, adverse effects, precautions – May cause: gastrointestinal disturbances, headache and dizziness. Sulfadoxine/pyrimethamine is administered as a single dose on D1, with the first dose of artesunate. If half tablets are used, remaining 1/2 tablets may be given to another patient if administered within 24 hours. Dosage and duration – Treatment Child: 150 to 200 mg/day in 3 or 4 divided doses Adult: 500 to 750 mg/day in 3 or 4 divided doses The treatment is continued until symptoms improve (1 to 2 weeks), then a preventive treatment is given as long as the situation requires. For information: – Mild to moderate persistent asthma Child: 100 to 400 micrograms/day in 2 or 4 divided doses Adult: 500 to 1000 micrograms/day in 2 or 4 divided doses – Severe persistent asthma Child: up to 800 micrograms/day in 2 or 4 divided doses Adult: up to 1500 micrograms/day in 2 or 4 divided doses Shake the inhaler. Co-ordination between the hand and inhalation is very difficult in certain patients (children under 6 years, elderly patients, etc. Duration – According to clinical response Contra-indications, adverse effects, precautions – Do not administer to patients with untreated active tuberculosis. Contra-indications, adverse effects, precautions – Do not administer to patients with closed-angle glaucoma, decompensated heart disease, prostate disorders, gastrointestinal obstruction or atony. Administer in the lowest effective dose and observe the child (risk of anticholinergic effects, e. Remarks – Biperiden is also used in Parkinson’s disease: • as monotherapy early in the course of the disease; • in combination with levodopa in the most advanced stages. Tablets must be taken daily, at night (bisacodyl is effective 6 to 12 hours after administration), until the end of the opioid treatment. Regular follow up (frequency/consistency of stools) is essential in order to adjust dosage correctly. Remarks – To prevent constipation in patients taking opioids, use lactulose if the patient’s stools are solid; use bisacodyl if the patient’s stools are soft. Dosage – When pyrimethamine is used as primary or secondary prophylaxis for toxoplasmosis Adult: 25 to 30 mg once weekly – During treatment of toxoplasmosis Adult: 10 to 25 mg once daily – During treatment of isosporiasis Adult: 5 to 15 mg once daily Duration – For the duration of the pyrimethamine treatment Contra-indications, adverse effects, precautions – Pregnancy: no contra-indication – Breast-feeding: no contra-indication Remarks – Folic acid cannot be used as an alternative to folinic acid for the treatment of toxoplasmosis: folic acid reduces the antiprotozoal activity of pyrimethamine. Do not stop treatment abruptly, even if changing treatment to another antiepileptic. Contra-indications, adverse effects, precautions – Do not administer to patients with atrioventricular block, history of bone marrow depression. However, if treatment has been started before the pregnancy, do not stop treatment and use the minimal effective dose. Due to the risk of haemorrhagic disease of the newborn, administer vitamin K to the mother and the newborn infant. The administration of folic acid during the first trimester may reduce the risk of neural tube defects. CefIxIme 1 Prescription under medical supervision Therapeutic action – Third-generation cephalosporin antibacterial Indications – Typhoid fever in children – Acute cystitis in girls over 2 years, pregnant women and lactating women – Acute pyelonephritis in adults – Cervicitis and urethritis due to Neisseria gonorrhoeae (in combination with a treatment for chlamydia) Presentation – 200 mg tablet – 100 mg/5 ml powder for oral suspension, to be reconstituted with filtered water Dosage – Typhoid fever in children Child over 3 months: 20 mg/kg/day in 2 divided doses – Acute cystitis in girls over 2 years 8 mg/kg once daily – Acute cystitis in pregnant and lactating women, acute pyelonephritis in adult 400 mg/day in 2 divided doses – Cervicitis and urethritis due to Neisseria gonorrhoeae Child: 8 mg/kg as a single dose Adult: 400 mg as a single dose Duration – Typhoid fever: 7 days; acute cystitis: 3 days for girls and 5 days for adults; acute pyelonephritis: 10 to 14 days Contra-indications, adverse effects, precautions – Do not administer to patients with allergy to cephalosporins. Contra-indications, adverse effects, precautions – Do not administer in case of poisoning by caustic or foaming products, or hydrocarbons: risk of aggravation of lesions during vomiting (caustic products), aspiration pneumonia (foaming products, hydrocarbons), and airway obstruction due to foaming when vomiting (foaming products). Therapeutic action – Phenicol antibacterial Indications – Alternative to first-line treatments of bubonic plague – Alternative to first-line treatments of typhoid fever – Completion treatment following parenteral therapy with chloramphenicol Presentation – 250 mg capsule Dosage – Child from 1 year to less than 13 years: 50 mg/kg/day in 3 to 4 divided doses; 100 mg/kg/day in severe infection (max. In these events, stop treatment immediately; • gastrointestinal disturbances, peripheral and optic neuropathies. If used during the 3rd trimester, risk of grey syndrome in the newborn infant (vomiting, hypothermia, blue-grey skin colour and cardiovascular depression). In areas where resistance to chloroquine is high, chloroquine must be replaced by another effective antimalarial suitable for prophylactic use. Contra-indications, adverse effects, precautions – Do not administer to patients with retinopathy. Dosage – Child from 1 to 2 years: 1 mg 2 times daily – Child from 2 to 6 years: 1 mg 4 to 6 times daily (max. Contra-indications, adverse effects, precautions – Administer with caution and monitor use in patients with prostate disorders or closed-angle glaucoma, patients > 60 years and children (risk of agitation, excitability). Dosage – Acute or chronic psychosis Adult: initial dose of 75 mg/day in 3 divided doses; if necessary, the dose may be gradually increased up to 300 mg/day in 3 divided doses (max. Once the patient is stable, the maintenance dose is administered once daily in the evening. Duration – Acute psychosis: minimum 3 months; chronic psychosis: minimum one year. Contra-indications, adverse effects, precautions – Do not administer to patients with closed-angle glaucoma, prostate disorders; to elderly patients with dementia (e. Dosage and duration – Adult: 200 to 400 mg as a single dose if possible one hour before anaesthetic induction Contra-indications, adverse effects, precautions – May cause: diarrhoea, headache, dizziness, skin rash, fever. Remarks – Effervescent cimetidine can be replaced by effervescent ranitidine, another H2-receptor antagonist, as a single dose of 150 mg.

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Enzyme kinetic constants are calculated by nonlinear regression analysis with computer software safe cipro 250 mg, such as GraFit (Erithacus Software Limited purchase cheap cipro on line, In Vitro Study of Drug-Metabolizing Enzymes 321 Figure 22 Examples of enzyme kinetic plots used for determination of Km and Vmax for a normal and an allosteric enzyme: Direct plot [(substrate) vs buy cipro on line amex. K0 is a con- m max stant that incorporates the interaction with the two (or more) binding sites but that is not equal to the substrate concentration that results in half-maximal velocity, and the symbol “n” (the Hill coefficient) theoretically refers to the number of binding sites. It should be noted that, at times, nonlinear regression lines represent the data points on an Eadie-Hofstee plots very poorly because the data reflect the contribution from two kinetically distinct enzymes whereas the computer software attempts to fit all data to an equation appropriate for a single enzyme. A relatively high standard error associated with the estimate of Km suggests that the nonlinear regression did not fit the data very well, and it is possible that a two enzyme model or perhaps an atypical enzyme kinetics model needs to be selected. When Km values are estimated by extrapolating data beyond the concentration range 322 Ogilvie et al. If the standard error associated with the Km value is large (>25%) and/or if the Km value falls outside the range of substrate concentrations studied, it is prudent to repeat this exper- iment with a new range of substrate concentrations that bracket the estimated Km value. When the Eadie-Hofstee plot suggests the involvement of two kinetically distinct enzymes in the formation of a particular metabolite, the data should be fitted to a dual-enzyme model according to the following equation: Vmax1 Á ½ŠS Vmax2 Á ½ŠS vtotal ¼ v1 þ v2 ¼ þ ð8Þ Km1 þ ½ŠS Km2 þ ½ŠS where vtotal is the overall rate of metabolite formation at substrate [S], Vmax1 and Vmax2 are the maximal velocities of the reaction, and Km1 and Km2 are the Michaelis-Menten constants for enzyme 1 and enzyme 2, respectively. For simplicity, the following discussion assumes that enzyme 1 is the high-affinity (low-Km) enzyme and that enzyme 2 is the low-affinity (high-Km) enzyme. It further assumes that Km1 and Km2 differ by at least an order of magnitude and that the range of substrate concentrations extended well below Km1 and up to or above Km2. Under such conditions, enzyme 2, the high-Km enzyme, contributes negligibly to vtotal at low substrate concentrations, and the range of substrate concentrations where this is largely true can be identified by visual inspection of the Eadie-Hofstee plot; (Fig. These “enzyme 1” data are plotted on an Eadie-Hofstee plot to obtain Km1 and Vmax1. Subsequently, v2 (which equals vtotal À v1) is calculated, and the data are plotted on an Eadie-Hofstee plot to obtain Km2 and Vmax2. When Km1 and Km2 differ by less than an order of magnitude, or when the range of substrate concentrations does not bracket both Km1 and Km2, it may not be possible to determine the kinetic constants of the individual enzymes. Two enzymes with similar Km values toward the same substrate have frequently been observed, and these will result in an Eadie-Hofstee plot consistent with single-enzyme kinetics. Applying the dual-enzyme model for such situations will not help; instead, reaction-phenotyping data must be used to tease out the role of the two enzymes. These result in an S-shaped curve on a (substrate) versus rate graph and a “hook”- shaped line graph on an Eadie-Hofstee plot. When allosteric interactions are In Vitro Study of Drug-Metabolizing Enzymes 323 Figure 23 Depictions of a reaction catalyzed by two kinetically distinct enzymes. The- oretical data illustrate the method used to determine the kinetic constants when two enzymes are involved in the same reaction. Note that the direct plot (left) does not effectively indicate that two enzymes might be involved in a given reaction. However, this is readily achieved by a concave-appearing Eadie-Hofstee plot (middle graph). The kinetic constants (Km and Vmax) of the high-affinity (low-Km) enzyme are determined using the initial rates observed at low substrate concentrations (solid line in the middle graph). Then, the contribution of the low-Km enzyme is subtracted and the kinetic constants for the high- Km enzyme are determined (dotted line in the middle graph). It is evident that the relative contribution of the high-Km enzyme increases (and that of the low-Km enzymes decreases) as the substrate concentration is increased. The Hill equation is: n Vmax Á ½ŠS v ¼ n ð9Þ S50 þ ½ŠS where S50 is analogous to (but not identical to) Km (i. When n is greater than 1, it indicates positive cooperativity (substrate activation); when n is less than 1, it indicates negative cooperativity (substrate inhibition) (109). A Hill coefficient of 2 implies the presence of two discrete (nonoverlapping) substrate-binding sites on the enzyme, whereas a Hill coefficient of, say, 1. Correlation Analysis: Sample-to-Sample Variation in the Metabolism of the Drug Candidate Correlation analysis is one of the four basic approaches to reaction phenotyping. The experimental conditions for examining the in vitro metabolism of the drug candidate by a bank of human liver microsomes are based on the results of experiments described in Steps 2 and 3 (i. In order to obtain clinically relevant results, the metabolism of the drug candidate by human liver microsomes must be examined at pharmacologically relevant concentrations of the drug candidate, as illustrated for lansoprazole 5-hydroxylation in Figure 20. In our laboratory, reaction phenotyping is carried out with a bank of human liver microsomal samples (e. Banks of human liver microsomes intended for correlation analysis are commercially available as kits (e. The latter determination also provides a measure of the statistical significance of any correlations. Correlation analysis provides valuable information on the extent to which the metabolism of a drug candidate will potentially vary from one subject to the next (i. However, when two or more enzymes contribute to metabolite formation, corre- lation analysis may lack the statistical power to establish the identity of each enzyme. Statistically significant correlations should always be confirmed with a visual inspection of the graph because there are two situations that can produce a misleadingly high correlation coefficient: (1) the regression line does not pass through or near the origin and (2) there is an outlying data point that skews the correlation analysis, as illustrated in Figure 25. Correlation analysis works particularly well when a single enzyme dominates the formation of a particular metabolite. This approach success- fully identifies the enzymes involved when each enzyme contributes 25% or more to metabolite formation, but it will likely not identify an enzyme that contributes only approximately 10%. A graphical representation of the application of multivariate analysis to the results of a reaction phenotyping experiment is shown in Figure 26, on the basis of an examination of the sample-to-sample variation in the 1-hydroxylation of bufuralol (12 mM) by a panel of human liver microsomes. The sample-to-sample variation in bufuralol 1-hydroxylation correlates reasonably well with In Vitro Study of Drug-Metabolizing Enzymes 327 Figure 25 Common pitfalls in correlation analysis. Correlation analysis is suspected when the regression line is unduly affected by a single outlying data point, or when the regression line does not pass near the origin. When two enzymes contribute significantly to metabolite formation, their identity and relative con- tribution can be established by performing correlation analysis in the presence and absence of an inhibitor of one of the participating enzymes (preferably the major contributor). This approach works even when one of the enzymes contributes substantially less than 25% to metabolite formation, as was demonstrated by 328 Ogilvie et al. Chemical and Antibody Inhibition Chemical and antibody inhibition represent the second and third approaches to reaction phenotyping. As in the case of correlation analysis, chemical and antibody inhibition experiments must be conducted with pharmacologically relevant concentrations of the drug candidate in order to obtain clinically relevant results. Therefore, appropriate solvent and preincubation controls should be included in all chemical inhibition experiments. The lack of specificity can complicate the interpretation of chemical inhibition experiments. If a drug candidate is metabolized by a high-affinity enzyme, the con- centration of a competitive chemical inhibitor must be increased with increasing concentration of the drug candidate in order to achieve a high degree of inhi- bition. A good rule of thumb is to use multiples (generally up to 10-fold) of the lowest inhibitor concentration, which is calculated from the following equation: ½DrugŠÁKiðinhibitorÞ Lowest½InhibitorŠ¼ ð10Þ KmðDrugÞ where [Drug] is the intended final concentration of the drug candidate added to the microsomal incubation, Ki is the inhibition constant of the inhibitor for a given enzyme, and Km is the Michaelis constant of the drug candidate (as determined in Step 3). This method of calculating of the lowest concentration of inhibitor is applicable to competitive inhibitors but not to noncompetitive or metabolism-dependent inhibitors. A range of inhibitor concentrations is rec- ommended to demonstrate concentration dependence. For example, if the lowest concentration of the chemical inhibitor were calculated to be 1 mM (from the above equation), then the range of inhibitor concentration should span at least 10-fold (e. If both enzymes contribute to metabolite formation, the inhibitory effect of the chemical on one enzyme may be offset by its activating effect on the other enzyme.

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