`
`Notes
`
`Biol. Pharm. Bull. 22(4) 425—427 (1999)
`
`425
`
`Intranasal Administration of Diazepam Aiming at the Treatment of Acute
`Seizures: Clinical Trials in Healthy Volunteers
`
`Sveinbjorn GIZURARSON,*‘" Fridrik K. GUDBRANDSSON,b Helgi JONSSON,” and Erik BECHGAARDd
`
`Department of Pharmacy, University 0f1ce/and,“ PO. Box 7171, 127 Reykjavik, Iceland, Department ofENI Reykjavik
`Hospital,” 108 Reykjavik, Iceland, Department ofMedicine. University ofIceland,” Vatnsmyrarveg, 101 Reykjavik, Iceland,
`and Department of Pharmaceutics, The Royal Danish School of Pharmacy,'1 Universitetsparken 2, 2100 Copenhagen 0,
`Denmark. Received August 17, 1998; accepted December 23, 1998
`
`Intranasal administration of diazepam may be a practical alternative to the conventional acute medication
`of seizures, such as status epilepticus. Nine healthy students participated in an open crossover study on in-
`tranasal versus intravenous administration of diazepam (2 mg). Blood samples were collected, pharmacodynamic
`tests were performed, and the volunteers filled out questionnaire. Peak concentration was achieved after 18:11
`min and the bioavailability was 50.4:23.3%. A pharmacodynamic efl‘ect was observed after about 5 min, but the
`dose, even for i.v. administration, was too low to generate a strong measurable etfect. The results indicate that in—
`tranasally administered diazepam may be an eflective alternative to i.v. administration in relief of seizures, e.g. in
`an acute situation when a physician or nurse is not available on location.
`intranasal administration; diazepam; volunteers; bioavailability
`Key words
`
`Treatment of epileptic seizures should be controlled with-
`out causing adverse reactions and in such a way that it pro-
`motes a good quality of life. The preferred drugs for the
`treatment of epileptic seizures are diazepam or clonazepam
`intravenously (i.v.), followed by phenytoin or phenobarbi-
`tal.” These drugs are effective for hospitalized or institu-
`tionalized patients. They are, however, not applicable to pa-
`tients living at home with their families, because i.v. adminis-
`tration of these drugs to a patient in seizure requires skilled
`personnel and an acute care facility, since the treatment may
`be associated with hypotension, cardiac dysrhythmias or cen-
`tral nerv0us system depression.
`Rectal administration of diazepam as a clysma is an alter-
`native in pediatric therapy. Parents and other caregivers may
`easily be trained to give these drugs rectally. Such therapy,
`however,
`is not that convenient in adults, though clinical tri-
`als show that this treatment results in less psychological, so-
`ciological and financial stress for the family,
`including re-
`duced hospitalizations, and it improves the quality of 1ife.3‘5)
`In a study by Kriel et til.” it was shown that rectal adminis-
`tration of diazepam was effective in controlling seizures in
`85% of the patients and improved quality of life in 58% of
`the patients.
`The intranasal administration of drugs may be an altema-
`tive to the rectal delivery. Drugs are absorbed rapidly from
`the nasal cavity, due to the highly vascularized nasal tissue
`and the relatively leaky epithelium. This rapid absorption is a
`benefit for acute medication. The absorption should also be
`fast, since drugs that are not absorbed within 10~—30 min are
`cleared down to the nasopharynx and swallowed, due to the
`mucociliary clearance mechanisms)
`A non-toxic intranasal delivery system for water—insoluble
`substances, such as benzodiazepines, has been developed”)
`When a clinically relevant dose of diazepam and clonacham
`was administered to rabbits, both peak concentration and
`the pharmacodynamic response were achieved within 5 and
`3 1/2 min, respectively.” The aim of the present study is to
`compare the pharmacokinetic and pharmacodynamic para-
`meters after intranasal and intravenous administration of di-
`
`azepam to humans.
`
`* To whom correspondence should be addressed.
`
`MATERIALS AND METHODS
`
`Diazepam was kindly provided by Lyfjaverslun Islands
`(Reykjavik, Iceland), polyethylene glycol 200 by Union Car-
`bide (Charleston, U.S.A.) and glycofurolum 75 by Hofman—la
`Roche (Basle, Switzerland). The intranasal diazepam formu-
`lation (20 mg/ml) consisted of a mixture 5% glycofurol
`in
`polyethylene glycol 200. The subjects received 100,111 into
`one nostril. For comparison, a commercial
`intravenous di-
`azepam formulation was used (Stesolid®, Dumex-Alpharma
`A/S, Copenhagen, Denmark).
`The protocol was an open crossover trial, approved by the
`local ethics committee and the National Health Authorities
`of Iceland and the State Committee on Pharmaceuticals.
`
`Nine healthy volunteers, between 20—30 years old (weigh-
`ing 58»—80 kg), were chosen among 20 caucasian students
`who applied for participation, on the basis of normal
`liver
`and kidney function and no sign of a cold within the last two
`weeks prior to the first experimental day. They could not use
`any drugs that may interact with diazepam nor sedatives such
`as tranquilizers or alcohol, 3 d prior and during the experi-
`ment. Blood samples were withdrawn at time 0, 2, 5, 10, 30,
`105, 300 min after administration. The serum diazepam con—
`centration was measured by means of a fluorescence polar-
`ization immunoassay (FPIA) from Abbott A/S (Copenhagen,
`Denmark). Prior to and 30min after application, the nasal
`mucous membranes in both nostrils were inspected by an
`evaluator, and the volunteers were asked to note all adverse
`reactions at l, 10 and 30min afier the administration. After
`0, 5, 30 and 90 min, the subjects were tested for some phar-
`macological tests (short time memory, catching, vigilance,
`concentration and tension) and recorded by the investigators.
`Short time memory was measured by reading 10 single num-
`bers with a fixed speed followed by allowing the participants
`to repeat the numbers. The number of right numbers was
`recorded. Catching was measured by asking the participants
`to catch a pencil dropping 1.5 m from above. Vigilance, con»
`centration and tension were based on a questionnaire.
`Standard methods were used to calculate the pharmacoki-
`netic parameters. lntraindividual comparison was carried out
`
`© 1999 Pharmaceutical Society of Japan
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`426
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`for all subjects. The area—under-the-curve (AUC) was calcu-
`lated using the trapezoidal method, the time to [mm was read
`from the plasma concentration profiles Fmtal was calculated
`as the percent of AUCnm, over AUCLV'. Standard statistical
`techniques were used throughout the study. For the evalua-
`tion of significance, one way ANOVA was used.
`
`RESULTS AND DISCUSSION
`
`Intranasal administration of diazepam resulted in a rapid
`absorption of the drug. Peak concentration was achieved
`after about 18:11 min (5 out of 9 had tum: 10min), provid-
`ing 32.9:21.6% of the concentration, compared to the serum
`concentration obtained 10min after an intravenous injection
`(Fig. 1, Table 1). The rate of absorption (kabs) was found to
`be 0.43 :0. 19 min‘ ’. The most important time (clinically) for
`a successful treatment of seizure are the first 10min. When
`this study was compared with other studies in the literature,
`32.9i2l.6% concentration is achieved after 10min, com-
`pared with 12—27% in other studies after IOmin’O—m and
`46.5:19.1°/o after 30 min. The dose was kept at minimum
`(only 2 mg), since this study was the first clinical trial for this
`formulation. Sampling of plasma was only carried out over a
`5 h period because the treatment of seizures is an acute treat-
`ment. Apparent half-life for diazepam was about 16h since
`its terminal half-life ranges over 24h. A six-fold increase in
`the dose should be possible using these vehicles, although
`the solubility of benzodiazepines is very low. The results in-
`dicate that clinically relevant amounts of diazepam can be
`absorbed within 10min after the administration. This form
`
`for administration has the advantage that problems such as
`respiratory depression, etc. associated with intravenous injec-
`tion are eliminated, providing a safer delivery system.
`Several
`studies have been conducted where benzodi—
`
`azepines have been administered intranasally to animals and
`
`1000 —
`
`100
`
`10
`
`
`
`Concentration(ng/ml,
`
`Vol. 22, No. 4
`
`humans. The most common is midazolam, administered in
`the form of undiluted parenteral solution for inducing seda~
`tion in children.l4_'9’ These studies show solely pharmaco-
`dynamic data but not clinical pharmacokinetic information.
`Few pharmacokinetic studies have been performed where
`plasma concentration profiles are presented. Time to maxi-
`mal plasma concentration was between 12—15 min in those
`studies (except for one, where tmax was 83 min),‘0’ and the
`concentration around 15 min was about 12—27%, relative to
`an iv. dose. Studies on rectal administration of diazepam
`show that 12 min onset time is sufficient for improving qual-
`ity of life and effective in controlling seizures in the majority
`of patients, suffering from multiple seizures.”
`Even after i.v. administration, the pharmacological effects
`were small, due to the low dose used. However, some effects
`were measured. Table 2 shows a summary of the pharmaco-
`dynamic responses after the administration. Intravenously
`administered diazepam was effective in decreasing the ability
`to concentrate and decreased vigilance, but the effect was not
`strong due to the low dose administered.
`Intranasally administered diazepam, however, was effec-
`tive in decreasing tension and the ability to memorize (short-
`time memory). The onset of effect on short-time memory
`was rapid and significantly different after nasal application as
`compared to the intravenous group, indicating that some of
`the diazepam may have been transported directly from the
`nasal cavity to the brain through the olfactory area”)
`No signs of irritation were seen on the nasal mucosa, ex-
`cept for one volunteer who had a minor redness 30 min after
`the administration. The majority of subjects felt some irri-
`tation immediately after the administration. Thirty minutes
`later, however, all subjects had no or only minor sense of irri-
`tation. Eight out of nine participants would prefer nasally to
`intravenously administered diazepam for the treatment of
`acute seizures in themselves or in their child. It may be con-
`cluded that intranasal delivery of diazepam may be an alter-
`native to i.v. and rectal treatment of acute seizures.
`
`Table 1. Kinetic Parameters of Diazepam in Humans after Single Admin-
`istration (2 mg) Intranasally and lntravenously
`
`
`
`
`
` Parameter Intravenous lntranasal
`
`2
`2
`Dose (mg)
`0.43:0.19
`—
`kabs (min'l)
`018910.077
`0064:0017
`ke (h’ ')
`17.8: 15.5
`14.4: 7.0
`[”2 (h) (apparent)
`18: |
`l
`—
`[max (min)
`39:17
`—
`Cmax (ng/ml)
`l,095:412
`2,9721980
`AUC0_mmm (ng-min/ml)
`
`Fm, (%)
`— 50.4:233
`
`Time (mi n)
`
`Plasma Concentration—Time Profile (:SD.) for Diazepam afier
`1.
`Fig.
`lntranasal (O) and Intravenous (I) Administration of 2mg Diazepam to
`Healthy Human Volunteers
`
`Table 2. The Onset of Individual Pharmacodynamic Tests, after Single lntranasal or Intravenous Administration of Diazepam (2 mg) to Healthy Volun-
`teers.
`
`Test
`intravenous
`lntranasal
`Significance
`Comments
`onset (mm)
`onset (min)
`(p)
`
`
`No
`5
`S
`Decreased ability to concentrate
`Stronger effect after i.v.
`0.1
`5—30
`5
`Decreased vigilance
`Stronger effect afier i.n.
`0.17
`30
`30
`Decreased tension
`Stronger effect after in.
`0.05
`5
`5—30
`Decreased ability to memorise
`
`
`
`No effect No eifectDecreased ability to catch No
`
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`Acknowledgements This study was kindly supported by
`Peptech Europe A/S (Hillerod, Denmark). The FPIA was
`partly sponsored by Abbott A/S (Vedbak, Denmark). The au-
`thors thank Dorthe Seir Petersen and Henriette Bierregaard
`Sorensen for skillful technical assistance and the students for
`
`participating in this study.
`
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