Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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3. Midazolam 3.2.2 Conscious sedation The guidelines for conscious sedation of the Society for the Advancement of Anesthesia in Dentistry (SAAD) defines conscious sedation as: “Technique in which the use of a drug or drugs produces a state of depression of the central nervous system enabling treatment to be carried out, but during which verbal contact with the patient is maintained throughout the period of sedation. The level of sedation must be such that the patient remains conscious, retains protective reflexes, and is able to respond to verbal commands”. MRI (magnetic resonance imaging) examinations are common diagnostic procedures. But many patients refuse this helpful diagnostic proceeding because of claustrophobia or unspecific anxiety. Anxiety in patients undergoing MRI examinations is a multifaceted phenomenon involving fear of enclosed places (claustrophobia), pain, the unknown situation, as well as apprehension about what the test might reveal [Katz et al., 1994]. For clear diagnostic MRI images the cooperation of the patient is essential (breathing on command during investigations of the upper abdomen). Therefore, anxiolysis without sedating the patient is desired. Conscious sedation is one of the most important approaches to help claustrophobic and anxious patients to cope with MRI examinations [Tschirch, et al. 2006]. Before and during diverse diagnostic or therapeutic procedures with or without local anesthesia, conscious sedation facilitates completing unpleasant procedures and increases patient’s comfort. In a review de Visser et al. evaluated published testing methods to assess effects of anxiolytic benzodiazepines in healthy volunteers. Even numerous psychopharmacology tests have been described to assess anxiolytic effects in human, no validated testing method exists. Furthermore, tests to assess anxiolysis are usually not specific enough to distinguish anxiolytic effects from sedating effects [de Visser et al., 2003]. Because standardized assessments for anxiolytic effects are leaking, no correlation of midazolam blood concentrations and anxiolytic effect has been established. For the evaluation of the benefit of an anxiolytic therapy in the clinical practice, phase III studies with anxious patients have to be performed. 3.3 Undesirable effects The characteristic undesirable effects of benzodiazepines are reported also for midazolam. Sedation, amnesia, impaired attention, and impaired muscular function may adversely affect the ability to drive or use machines. Paradoxal reaction such as agitation, involuntary movements, hyperactivity, hostility, rage reactions, aggressiveness, paradoxal excitement, and assault, have been reported. This reaction occurs mainly with high doses and/or when the injection is given rapidly. The highest risk for paradox reaction has been reported for children and elderly patients [Weinbroum et al., 2001], as well as patients with actual or amnestic psychiatirc diseases and patients with alcohol addiction [Mancuso et al., 2004]. Furthermore paradoxal reaction is often related to high midazolam doses [Litchfield 1981]. Katja Suter-Zimmermann Page 26 of 188 University of Basel, 2008
3. Midazolam Administration of high midazolam doses, overdoses or in situations with impaired pharmacokinetics, the most vital symptoms to be monitored are areflexia, hypotension, cardiorespiratory depression, and apnea. Higher risk for cardiorespiratory depression, apnea, and areflexia is reported for co-administration of other central nervous acting drugs and inhibitors of CYP 3A4. 3.4 Midazolam delivery In Switzerland, midazolam (Dormicum ® 1 mg/ml and 5 mg/ml) is approved for intravenous or intramuscular injection or oral administration as tablets (Dormicum ® 7.5 mg and 15 mg). Rectal administration of Dormicum ® (1 mg/ml and 5 mg/ml) is also compendial, but not widely used. Because of pain and distress, injections for drug administration are not popular and patients (adults and children) usually prefer alternative drug administration. Oral midazolam delivery, the most popular drug administration route, is associated with considerable first-pass effect (bioavailability only 30-50% [Documed 2006]). Furthermore, oral midazolam administration is disposed to a delayed onset of action, additionally impaired by ingestion. Due to the fluctuant bioavailability, the pharmacological effect is hard to predict and the dose to be applied difficult to define. The pharmacokinetic disadvantages of rectally applied midazolam are analog to the oral administration a slow onset of action and a low peak plasma concentration [Malinovsky et al., 1993]. Table 3-2 summarizes the characteristics of the different modes of midazolam delivery. Commonly, intravenous or intramuscular injection of midazolam is performed if rapid onset of action is desired [Burstein et al., 1997, Uygur-Bayramicli, 2002]. As a convenient and reliable alternative to intravenous and intramuscular administration, nasal midazolam delivery has received considerable attention not only for pediatric patients (see Table 3-4). Intranasal drug delivery is painless, results in rapid drug absorption and circumvents hepatic first pass metabolism. Additionally, the convenient administration results in high acceptance by the patients. A number of studies report the beneficial effects of nasal delivered midazolam in patients, both children and adults (see Table 3-4). Katja Suter-Zimmermann Page 27 of 188 University of Basel, 2008
Page 1: TRANSMUCOSAL NASAL DRUG DELIVERY Sy
Page 5 and 6: Acknowledgments At the Hospital Pha
Page 7: Index EXPERIMENTAL SECTION 5 Projec
Page 11 and 12: Summary Summary Transmucosal nasal
Page 13: Summary Project III: In this random
Page 17: THEORETICAL SECTION
Page 20 and 21: 1. Nasal drug delivery 1.2 Transmuc
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7. Project III: Transmucosal nasal
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8 Overall discussion pharmacokineti
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8 Overall discussion considered as
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Appendix
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10 Appendix 10.2 Project I 10.2.1 R
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10 Appendix 10.2.4 Specification: M
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10 Appendix 10.2.6 Specification: C
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10 Appendix Katja Suter-Zimmermann
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10 Appendix 10.2.9 Specification: C
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10 Appendix 10.3.2 Case report form
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10 Appendix Frequency 10.3.5 Intens
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10 Appendix 10.3.7 Serumconcentrati
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10 Appendix Identification midazola
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10 Appendix 10.3.8 Midazolam serum
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10 Appendix 10.3.10 Nasal delivery
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10 Appendix 10.4.3 Flowchart: multi
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11 References 11 References Abrams,
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11 References Erjefalt, J.S., I. Er
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11 References Irie, T. and K. Uekam
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11 References Malinovsky, J.M., C.
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11 References Scheepers, M., B. Sch
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12 Curriculum vitae 12 Curriculum v
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