Multiple dose

Single-dose preparations intended for use in eye surgery do not contain excipient ingredients, in order to avoid tissue irritation. However, multiple-dose containers may require antioxidants (qv), antimicrobial preservatives, or buffers to maintain stabiHty and stefiHty. Such solutions are packaged in polyethylene flexible dropper units called droptainers or in glass dropper botdes. 

Elecainide is weU absorbed and 90% of the po dose is bioavailable. Binding to plasma protein is only 40% and peak plasma concentrations are attained in about 1—6 h. Three to five days may be requited to attain steady-state plasma concentrations when multiple doses are used. Therapeutic plasma concentrations are 0.2—1.0 lg/mL. Elecainide has an elimination half-life of 12—27 h, allowing twice a day dosing. The plasma half-life is increased in patients with renal failure or low cardiac outputs. About 70% of the flecainide in plasma is metabolized by the Hver to two principal metaboUtes. The antiarrhythmic potency of the meta-O-dealkylated metaboUte and the meta-O-dealkylated lactam, relative to that of flecainide is 50 and 10%, respectively. The plasma concentrations of the two metaboUtes relative to that of flecainide are 3—25%. Elecainide is mainly excreted by the kidneys, 30% unchanged, the rest as metaboUtes or conjugates about 5% is excreted in the feces (1,2). 

The two most common temporal input profiles for dmg delivery are zero order (constant release), and half order, ie, release that decreases with the square root of time. These two profiles correspond to diffusion through a membrane and desorption from a matrix, respectively (1,2). In practice, membrane systems have a period of constant release, ie, steady-state permeation, preceded by a period of either an increasing (time lag) or decreasing (burst) flux. This initial period may affect the time of appearance of a dmg in plasma on the first dose, but may become insignificant upon multiple dosing. 

Acute Toxicity The adverse effect occurring within a short time of (oral) administration of a single dose of a substance or multiple doses given within 24 hours. 

Spectinomycin. Spectinomycin may be given as a single dose, but multiple doses may be prescribed for complicated, widespread gonorrhea. The nurse warns the patient tiiat the IM injection may be uncomfortable and tiiat soreness at die injection site may be noted for abrief time. The nurse emphasizes die importance of following die primary healtii care provider s recommendations... 

Sec. 4.2, between regions placebo-controlled multiple dose. 12 placebo) primary Interim... 

Formulation(s) multiple-dose vial 1 %, 2 % single-dose vial 2 %, 3 % (as hydrochloride)... 

Pharmacodynamic tolerance to the psychomotor effects of benzodiazepines has been demonstrated after single or multiple doses (File 1985 Greenblatt and Shader 1978 Rosenberg and Chiu 1985). Pharmacodynamic tolerance to the anxiolytic effect (over a 6-month period) has not been demonstrated (Rickels et al. 1983), and clinical experience supports the view that many patients with anxiety disorders require long-term therapy with benzodiazepines or alternative antianxiety agents. An important clinical consequence of tolerance to sedative effects is observed in benzodiazepine overdoses, when patients may initially be... 

Caille G, Spenard J, Lacasse Y, et al Pharmacokinetics of two lorazepam formulations, oral and sublingual, after multiple doses. Biopharm Drug Dispos 4 31—42, 1983... 

Pharmacokinetic studies demonstrated good oral bioavailability of maraviroc and a terminal half-life of 16-23 h following multiple dosing (Abel et al. 2003 Walker et al. 2005). Single doses of up to 900 mg and multiple doses of up to 300 mg BID for 28 days were well tolerated (Abel et al. 2003 Russell et al. 2003 Walker et al. 2005). In Phase 2a studies, treatment-naive HIV-1 patients with R5 virus who received maraviroc monotherapy at doses ranging from 25 mg QD to 300 mg BID for 10 days experienced a median viral load reduction of 1.64 log jg copies/mL and... 

Russell D, Bakhtyari A, Jazrawi RP, Whitlock L, Ridgway C, McHale M, Abel S (2003) Multiple dose study to investigate the safety of UK-427,857 (100 mg or 300mg) BID for 28 days in healthy males and females. In 43rd interscience conference on antimicrobial agents and chemotherapy, Chicago, IL, USA... 

Reesink HW, Zeuzem S, Weegink CJ, Eorestier N, van Vliet A, van de Wetering de Rooij J, McNair L, Purdy S, Chu HM, Jansen PLM (2005) Final results of a phase lb multiple dose study of VX950, a hepatitis C vims protease inhibitor. Hepatology 42(1) 234A... 

Jarvinen KM, Sicherer SH, Sampson HA, Nowak-Wegrzyn A Use of multiple doses of epinephrine in food-induced anaphylaxis in children. J Allergy Clin Immunol 2008 122 133-138. 

It is important to stress that these three eriteria must be met before neurotoxicity can be established. Similar effeets upon 5-HT levels, reuptake sites, and morphology must also be observed before it ean be concluded that 5-HT neurotoxicity has occurred. In this regard, multiple doses of METH have been shown to produee long-lasting reduetions in tryptophan hydroxylase activity (Hotchkiss et al. 1979) as well as 5-HT content and uptake sites (Rieaurte et al. 1980) in the rat brain. 

Hotchkiss, A.J. Morgan, M.E. and Gibb, J.W. The long-term effects of multiple doses of methamphetamine on neostriatal tryptophan hydroxylase, tyrosine hydroxylase, choline acetyltransferase and glutamate decarboxylase activities. Life Sci 25 1373-1378. 1979. 

Multiple doses of MDMA or MDA resulted in a further decline in TPH activity (figure 4). In contrast to METH, however, neither MDA nor MDMA altered neostriatal TH activity. The decrease in TPH activity was accompanied by a dramatic decrease in 5-HT and 5-HIAA concentrations these changes in TPH activity and in 5-hydroxyindole content also occurred in other serotonergic terminal areas such as the hippocampus and cerebral cortex. Both neostriatal DA and homovanillic acid (HVA) were initially elevated 3 hours after a single dose of MDMA, but had returned to normal... 

FIGURE 4. Effect of multiple-dose drug treatment on neostriatal TH and... 

The possible role of DA in the MDMA-indueed alterations of the serotonergie system was then examined. Teehniques previously used in studying the role of DA in the METH-indueed neuroehemieal effeets were employed. When DA synthesis was inhibited with MT, the effeet of multiple doses of MDMA on TPH activity (figure 6) and eoneentrations of 5-HT and 5-HIAA was attenuated. The degree of proteetion with MT seemed to be a funetion of the size and number of doses of MDMA used as well as a funetion of the serotonergie parameter that was measured. 

Moreover, the early transient response to a single dose of MDMA was less attenuated by MT than was the persisting response that oeeurred after multiple doses of MDMA. 

NOTE Rats were administered multiple doses of MDMA (2.5, 5, or 10 mg/kg, SC, five doses, one every 6 hr). Concurrent with each MDMA dose, MT (60 mg/kg) or saline vehicle was administered IP. Rats were killed 18 hours after the last dole. Results are the means of SEM (n=6 to 8). expressed as a percent of control (vehicle-saline). 

A second study compared the effeets of single versus multiple doses. One group of monkeys reeeived a single 5 mg/kg dose of MDMA orally another group reeeived the same dose by the same route, but on a twine daily basis for 4 days. As before, the multiple dose regimen produeed a... 

TABLE 5. Effect of single vi multiple doses of MDMA on regional brain serotonin in the primate 2 weeks later... 

Although the optimal duration of systemic corticosteroids is unknown, therapy should be continued until PEF is greater than or equal to 80% of predicted or personal best. According to the NAEPP, the usual regimen is to continue frequent multiple doses until the patient s FEVi or PEF improves to 50% of predicted and then decrease the frequency to twice daily. In general, the duration of therapy ranges from 3 days for mild exacerbations to 14 days for severe exacerbations. It is not necessary to taper the systemic steroid dose in patients receiving short bursts of systemic corticosteroid therapy, as the adrenal suppression that occurs is transient and rapidly reversible.18... 

Ti me to reach peak serum concentrations Distribution 0.5-3 hours (regular-release) 4-12 hours (extended-release) 0.25-1 hours (oral solution) 4.5 hours (regular-release) 1.5 hours (suspension) 3-12 hours (extended-release tablets) 4.1-7.7 hours (extended-release capsules) higher peak concentrations with chewable tablets 4.5 hours (range of 3-13 hours) 1 -4 hours (VPA) 3-5 hours (DVPX single dose) 7-14 hours (DVPX extended-release multiple dosing) 1 -4 hours... 

Half-life (t1/2) 18-27 hours (adult) greater than 36 hours (elderly or patients with renal impairment) Cytochrome P-450 (CYP450) isoenzyme t1/2 decreases over time due to autoinduction 25-65 hours (initial) 12-1 7 hours (adult multiple dosing) 8-14 hours (children multiple dosing) 2 hours (parent) 9 hours (metabolite) 5-20 hours (adult) 25 hours increases to 59 hours with concomitant valproic acid therapy... 

Plasma half-life. a-Adrenergic receptors with short plasma half-lives (e.g., prazosin) require multiple doses during the day. This is challenging for most patients, and, thus, prazosin is not recommended for BPH.11... 

Assess serum creatinine and aminoglycoside serum concentrations if the patient is being treated with an aminoglycoside. Adjust aminoglycoside dose based on serum concentrations target peak concentration with multiple doses per day = 6 mcg/mL (12.54 pmol/L). 

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