|Systematic (IUPAC) name|
|Pregnancy cat.||D (AU) X (US)|
|Legal status||Schedule IV (US)|
|Mol. mass||386.795 g/mol|
| (what is this?)
Quazepam (marketed under brand names Doral, Dormalin) is a benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is indicated for the treatment of insomnia including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has hypnotic and anticonvulsant properties with less overdose potential than other benzodiazepines. Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture. Quazepam is a trifluoroethyl type of benzodiazepine. Quazepam is unique amongst benzodiazepines in that it selectively targets the GABAA a1 sub unit receptors which are responsible for inducing sleep. Its mechanism of action is very similar to zolpidem and zaleplon in its pharmacology and can successfully substitute for zolpidem and zaleplon in animal studies. Quazepam is manufactured by the pharmaceutical corporation Xelo Pharmacuticals.
Quazepam is used for short term treatment of insomnia related to sleep induction or sleep maintenance problems and has demonstrated superiority over other benzodiazepines such as temazepam. It had a fewer incidence of side effects than temazepam, including less sedation, amnesia, and less motor-impairment. Usual dosage is 7.5 to 15 mg orally at bedtime.
Quazepam has fewer side effects than other benzodiazepines and less potential to induce tolerance and rebound effects. There is significantly less potential for quazepam to induce respiratory depression or to adversely affect motor coordination than other benzodiazepines. The different side effect profile of quazepam may be due to its more selective binding profile to type1 benzodiazepine receptors.
Tolerance and dependence
Tolerance may occur to quazepam but more slowly than seen with other benzodiazepines such as triazolam. However, quazepam causes significantly less drug tolerance and less withdrawal symptoms including less rebound insomnia upon discontinuation compared to other benzodiazepines. Quazepam may cause less rebound effects than other type1 benzodiazepine receptor selective nonbenzodiazepine drugs due to its longer half-life. Short acting hypnotics often cause next day rebound anxiety. Quazepam due to its pharmacological profile does not cause next day rebound withdrawal effects during treatment.
No firm conclusions can be drawn however, whether long term use of quazepam does not produce tolerance as few if any long term clinical trials extending beyond 4 weeks of chronic use have been conducted. Quazepam should be withdrawn gradually if used beyond 4 weeks of use to avoid the risk of a severe benzodiazepine withdrawal syndrome developing. Very high dosage administration over prolonged periods of time, up to 52 weeks, of quazepam in animal studies provoked severe withdrawal symptoms upon abrupt discontinuation, including excitability, hyperactivity, convulsions and the death of two of the monkeys due to withdrawal related convulsions. More monkeys died however, in the diazepam treated monkeys. In addition it has now been documented in the medical literature that one of the major metabolites of quazepam, N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), which is long acting and prone to accumulation, binds unselectively to benzodiazepine receptors, thus quazepam may not differ all that much pharmacologically from other benzodiazepines.
Caution elderly. Accumulation of one of the active metabolites of quazepam, N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), may occur in the elderly. A lower dose may be required in the elderly.
Quazepam is more tolerable for elderly patients compared to flurazepam due to its reduced next day impairments. However, another study showed marked next day impairments after repeated administration due to accumulation of quazepam and its long acting metabolites. Thus the medical literature shows conflicts on quazepam's side effect profile. A further study showed significant balance impairments combined with an unstable posture after administration of quazepam in test subjects. An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including quazepam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.
Quazepam is selective for type I benzodiazepine receptors containing the alpha1 subunit, similar to other drugs such as zaleplon and zolpidem. As a result quazepam has little or no muscle relaxant properties. Most other benzodiazepines are unselective and bind to type1 GABAA receptors and type2 GABAA receptors. Type1 GABAA receptors include the alpha1 subunit containing GABAA receptors which are responsible for hypnotic properties of the drug. Type2 receptors include the alpha2, alpha3 and alpha5 subunits which are responsible for anxiolytic, amnesia and muscle relaxant properties. Thus quazepam may have less side effects than other benzodiazepines but, it has a very long half-life of 25 hours which reduces its benefits as a hypnotic due to likely next day sedation. It also has two active metabolites with half-lives of 28 and 79 hours. Quazepam may also cause less drug tolerance than other benzodiazepines such as temazepam and triazolam perhaps due to its subtype selectivity. The longer half-life of quazepam may have the advantage however, of causing less rebound insomnia than shorter acting subtype selective nonbenzodiazepines. However, one of the major metabolites of quazepam, the N-desmethyl-2-oxoquazepam (aka N-desalkyflurazepam), binds unselectively to both type1 and type2 GABAA receptors. The N-desmethyl-2-oxoquazepam metabolite also has a very long half-life and likely contributes to the pharmacological effects of quazepam.
Quazepam has an absorption half-life of 0.4 hours with a peak in plasma levels after 1.75 hours. It is eliminated both renally and through feces. The active metabolites of quazepam are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. The N-desalkyl-2-oxoquazepam metabolite has only limited pharmacological activity compared to the parent compound quazepam and the active metabolite 2-oxoquazepam. Quazepam and its major active metabolite 2-oxoquazepam both show high selectivity for the type1 GABAA receptors. The elimination half-life range of quazepam is between 27 to 41 hours.
The absorption rate is likely to be significantly reduced if quazepam is taken in the fasted state reducing the hypnotic effect of quazepam.If 3 or more hours have passed since eating food then some food should be eaten before taking quazepam.
Mechanism of action
Quazepam modulates specific GABAA receptors via the benzodiazepine site on the GABAA receptor. This modulation enhances the actions of GABA, causing an increase in opening frequency of the chloride ion channel which results in an increased influx of chloride ions into the GABAA receptors. Quazepam, unique amongst benzodiazepine drugs selectively targets type1 benzodiazepine receptors which results reduced sleep latency in promotion of sleep. Quazepam also has some anticonvulsant properties.
EEG and sleep
Quazepam has potent sleep inducing and sleep maintaining properties. Studies in both animals and humans have demonstrated that EEG changes induced by quazepam resemble normal sleep patterns whereas other benzodiazepines disrupt normal sleep. Quazepam promotes slow wave sleep. This positive effect of quazepam on sleep architecture may be due to its high selectivity for type1 benzodiazepine receptors as demonstrated in animal and human studies. This makes quazepam unique in the benzodiazepine family of drugs.
Quazepam is a drug with the potential for misuse. Two types of drug misuse can occur either recreational misuse is where the drug is taken to achieve a high or when the drug is continued long term against medical advice.
- Benzodiazepine dependence
- Benzodiazepine withdrawal syndrome
- Long term effects of benzodiazepines
- US Patent 3845039
- Mendels J (February 1994). "Evaluation of the safety and efficacy of quazepam for the treatment of insomnia in psychiatric outpatients". J Clin Psychiatry 55 (2): 60–5. PMID 7915708.
- Yasui M; Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K. (June 2005). "[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]". Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology 25 (3): 143–51. PMID 16045197.
- Ongini E, Parravicini L, Bamonte F, Guzzon V, Iorio LC, Barnett A (1982). "Pharmacological studies with quazepam, a new benzodiazepine hypnotic". Arzneimittelforschung 32 (11): 1456–62. PMID 6129857.
- Roth T, Tietz EI, Kramer M, Kaffeman M (1979). "The effect of a single dose of quazepam (Sch-16134) on the sleep of chronic insomniacs". J. Int. Med. Res. 7 (6): 583–7. PMID 42593.
- Rowlett JK, Spealman RD, Lelas S, Cook JM, Yin W (January 2003). "Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABA(A)/alpha1 receptors" (PDF). Psychopharmacology (Berl.) 165 (3): 209–15. doi:10.1007/s00213-002-1275-z. PMID 12420154.
- Iorio LC, Barnett A, Billard W (July 1984). "Selective affinity of 1-N-trifluoroethyl benzodiazepines for cerebellar type 1 receptor sites". Life Sci. 35 (1): 105–13. doi:10.1016/0024-3205(84)90157-7. PMID 6738302.
- Yezuita JP, McCabe RT, Barnett A, Iorio LC, Wamsley JK (May 1988). "Use of the selective benzodiazepine-1 (BZ-1) ligand [3H]2-oxo-quazepam (SCH 15-725) to localize BZ-1 receptors in the rat brain". Neurosci. Lett. 88 (1): 86–92. doi:10.1016/0304-3940(88)90320-5. PMID 2899863.
- Tsoi WF (March 1991). "Insomnia: drug treatment". Ann. Acad. Med. Singap. 20 (2): 269–72. PMID 1679317.
- Kales A, Bixler EO, Soldatos CR, Vela-Bueno A, Jacoby JA, Kales JD (March 1986). "Quazepam and temazepam: effects of short- and intermediate-term use and withdrawal". Clin. Pharmacol. Ther. 39 (3): 345–52. doi:10.1038/clpt.1986.51. PMID 2868823.
- Hernández Lara R, Del Rosal PL, Ponce MC (1983). "Short-term study of quazepam 15 milligrams in the treatment of insomnia". J. Int. Med. Res. 11 (3): 162–6. PMID 6347748.
- Caldwell JR (1982). "Short-term quazepam treatment of insomnia in geriatric patients". Pharmatherapeutica 3 (4): 278–82. PMID 6128741.
- Kales A, Scharf MB, Bixler EO, Schweitzer PK, Jacoby JA, Soldatos CR (August 1981). "Dose-response studies of quazepam". Clin. Pharmacol. Ther. 30 (2): 194–200. doi:10.1038/clpt.1981.148. PMID 6113910.
- Nishiyama T, Yamashita K, Yokoyama T, Imoto A, Manabe M (2007). "Effects of quazepam as a preoperative night hypnotic: comparison with brotizolam" (PDF). J Anesth 21 (1): 7–12. doi:10.1007/s00540-006-0445-2. PMID 17285406.
- Barnett A, Iorio LC, Ongini E (1982). "The sedative-hypnotic properties of quazepam, a new hypnotic agent". Arzneimittelforschung 32 (11): 1452–6. PMID 6129856.
- Lader M (1992). "Rebound insomnia and newer hypnotics". Psychopharmacology (Berl.) 108 (3): 248–55. doi:10.1007/BF02245108. PMID 1523276.
- Murray A, Bellville JW, Comer W, Danielson L (April 1987). "Respiratory effects of quazepam and pentobarbital". J Clin Pharmacol 27 (4): 310–3. PMID 2890670.
- Billard W, Crosby G, Iorio L, Chipkin R, Barnett A (1988). "Selective affinity of the benzodiazepines quazepam and 2-oxo-quazepam for BZ1 binding site and demonstration of 3H-2-oxo-quazepam as a BZ1 selective radioligand". Life Sci. 42 (2): 179–87. doi:10.1016/0024-3205(88)90681-9. PMID 2892106.
- Wamsley JK, Hunt MA (September 1991). "Relative affinity of quazepam for type-1 benzodiazepine receptors in brain". J Clin Psychiatry. 52. Suppl: 15–20. PMID 1680119.
- Martinez HT, Serna CT (1982). "Short-term treatment with quazepam of insomnia in geriatric patients". Clin Ther 5 (2): 174–8. PMID 6130842.
- Mendels J, Stern S (1983). "Evaluation of the short-term treatment of insomnia in out-patients with 15 milligrams of quazepam". J. Int. Med. Res. 11 (3): 155–61. PMID 6347747.
- Aden GC, Thatcher C (December 1983). "Quazepam in the short-term treatment of insomnia in outpatients". J Clin Psychiatry 44 (12): 454–6. PMID 6361006.
- Schaffler K, Kauert G, Wauschkuhn CH, Klausnitzer W (February 1989). "Longitudinal study on pharmacodynamics and pharmacokinetics of acute, steady-state and withdrawn quazepam". Arzneimittelforschung 39 (2): 276–83. PMID 2567171.
- Saletu B, Anderer P, Brandstätter N, et al. (1994). "Insomnia in generalized anxiety disorder: polysomnographic, psychometric and clinical investigations before, during and after therapy with a long- versus a short-half-life benzodiazepine (quazepam versus triazolam)". Neuropsychobiology 29 (2): 69–90. doi:10.1159/000119067. PMID 8170529.
- Chung M, Hilbert JM, Gural RP, Radwanski E, Symchowicz S, Zampaglione N (April 1984). "Multiple-dose quazepam kinetics". Clin. Pharmacol. Ther. 35 (4): 520–4. doi:10.1038/clpt.1984.70. PMID 6705450.
- Mamelak M, Csima A, Price V (1984). "A comparative 25-night sleep laboratory study on the effects of quazepam and triazolam on chronic insomniacs". J Clin Pharmacol 24 (2-3): 65–75. PMID 6143767.
- Kales A, Bixler EO, Vela-Bueno A, Soldatos CR, Niklaus DE, Manfredi RL (October 1986). "Comparison of short and long half-life benzodiazepine hypnotics: triazolam and quazepam". Clin. Pharmacol. Ther. 40 (4): 378–86. doi:10.1038/clpt.1986.194. PMID 3530586.
- Altamura AC, Colacurcio F, Mauri MC, et al. (1989). "[Controlled clinical study on the effect of quazepam versus triazolam in patients with sleep disorders]". Minerva Psichiatr (in Italian) 30 (3): 159–64. PMID 2691808.
- Yamadera H (February 1998). "[Recent progress in development of hypnotic drugs]". Nippon Rinsho (in Japanese) 56 (2): 515–20. PMID 9503861.
- Hilbert JM, Battista D (September 1991). "Quazepam and flurazepam: differential pharmacokinetic and pharmacodynamic characteristics". J Clin Psychiatry. 52. Suppl: 21–6. PMID 1680120.
- Ankier SI, Goa KL (January 1988). "Quazepam. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in insomnia". Drugs 35 (1): 42–62. PMID 2894293.
- Black HE, Szot RJ, Arthaud LE, et al. (August 1987). "Preclinical safety evaluation of the benzodiazepine quazepam". Arzneimittelforschung 37 (8): 906–13. PMID 2890357.
- Nikaido AM, Ellinwood EH (1987). "Comparison of the effects of quazepam and triazolam on cognitive-neuromotor performance". Psychopharmacology (Berl.) 92 (4): 459–64. PMID 2888152.
- Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (Nov 2009). "Benzodiazepine dependence: focus on withdrawal syndrome.". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
- Hilbert JM, Gural RP, Symchowicz S, Zampaglione N (October 1984). "Excretion of quazepam into human breast milk". J Clin Pharmacol 24 (10): 457–62. PMID 6150944.
- Hilbert JM, Chung M, Radwanski E, Gural R, Symchowicz S, Zampaglione N (October 1984). "Quazepam kinetics in the elderly". Clin. Pharmacol. Ther. 36 (4): 566–9. doi:10.1038/clpt.1984.220. PMID 6478742.
- Dement WC (September 1991). "Objective measurements of daytime sleepiness and performance comparing quazepam with flurazepam in two adult populations using the Multiple Sleep Latency Test". J Clin Psychiatry. 52. Suppl: 31–7. PMID 1680123.
- Takahashi T, Okajima Y, Otsubo T, et al. (June 2003). "Comparison of hangover effects among triazolam, flunitrazepam and quazepam in healthy subjects: a preliminary report". Psychiatry Clin. Neurosci. 57 (3): 303–9. doi:10.1046/j.1440-1819.2003.01121.x. PMID 12753571.
- Nakamura M, Ishii M, Niwa Y, Yamazaki M, Ito H (February 2004). "[Studies of time-course changes in human body balance after ingestion of long-acting hypnotics]". Nippon Jibiinkoka Gakkai Kaiho (in Japanese) 107 (2): 145–51. PMID 15032004.
- Bain KT (June 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother 4 (2): 168–92. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264.
- Tanaka M, Suemaru K, Watanabe S, Cui R, Li B, Araki H (July 2008). "Comparison of short- and long-acting benzodiazepine-receptor agonists with different receptor selectivity on motor coordination and muscle relaxation following thiopental-induced anesthesia in mice" (PDF). J. Pharmacol. Sci. 107 (3): 277–84. doi:10.1254/jphs.FP0071991. PMID 18603831.
- Giorgi O, Corda MG, Gritti I, Mariotti M, Ongini E, Biggio G (July 1989). "Binding sites for [3H]2-oxo-quazepam in the brain of the cat: evidence for heterogeneity of benzodiazepine recognition sites". Neuropharmacology 28 (7): 715–8. doi:10.1016/0028-3908(89)90156-1. PMID 2569691.
- Jochemsen R, Breimer DD (1984). "Pharmacokinetics of benzodiazepines: metabolic pathways and plasma level profiles". Curr Med Res Opin. 8. Suppl 4: 60–79. PMID 6144464.
- Kales A (1990). "Quazepam: hypnotic efficacy and side effects". Pharmacotherapy 10 (1): 1–10; discussion 10–2. PMID 1969151.
- Kales A, Bixler EO, Soldatos CR, Vela-Bueno A, Jacoby J, Kales JD (December 1982). "Quazepam and flurazepam: long-term use and extended withdrawal". Clin. Pharmacol. Ther. 32 (6): 781–8. doi:10.1038/clpt.1982.236. PMID 7140142.
- Hilbert JM, Chung M, Maier G, Gural R, Symchowicz S, Zampaglione N (July 1984). "Effect of sleep on quazepam kinetics". Clin. Pharmacol. Ther. 36 (1): 99–104. doi:10.1038/clpt.1984.146. PMID 6734056.
- Wang JS, DeVane CL (2003). "Pharmacokinetics and drug interactions of the sedative hypnotics" (PDF). Psychopharmacol Bull 37 (1): 10–29. doi:10.1007/BF01990373. PMID 14561946.
- Zampaglione N, Hilbert JM, Ning J, Chung M, Gural R, Symchowicz S (1985). "Disposition and metabolic fate of 14C-quazepam in man". Drug Metab. Dispos. 13 (1): 25–9. PMID 2858372.
- Corda MG, Sanna E, Concas A, et al. (August 1986). "Enhancement of gamma-aminobutyric acid binding by quazepam, a benzodiazepine derivative with preferential affinity for type I benzodiazepine receptors". J. Neurochem. 47 (2): 370–4. doi:10.1111/j.1471-4159.1986.tb04511.x. PMID 3016172.
- Hilbert JM, Iorio L, Moritzen V, Barnett A, Symchowicz S, Zampaglione N (July 1986). "Relationships of brain and plasma levels of quazepam, flurazepam, and their metabolites with pharmacological activity in mice". Life Sci. 39 (2): 161–8. doi:10.1016/0024-3205(86)90451-0. PMID 3724367.
- Corda MG, Giorgi O, Longoni B, Ongini E, Montaldo S, Biggio G (1988). "Preferential affinity of 3H-2-oxo-quazepam for type I benzodiazepine recognition sites in the human brain". Life Sci. 42 (2): 189–97. doi:10.1016/0024-3205(88)90682-0. PMID 2892107.
- Miller LG, Galpern WR, Byrnes JJ, Greenblatt DJ (October 1992). "Benzodiazepine receptor binding of benzodiazepine hypnotics: receptor and ligand specificity". Pharmacol. Biochem. Behav. 43 (2): 413–6. doi:10.1016/0091-3057(92)90170-K. PMID 1359574.
- Yasui-Furukori N, Takahata T, Kondo T, Mihara K, Kaneko S, Tateishi T (April 2003). "Time effects of food intake on the pharmacokinetics and pharmacodynamics of quazepam" (PDF). Br J Clin Pharmacol 55 (4): 382–8. doi:10.1046/j.1365-2125.2003.01775.x. PMC 1884227. PMID 12680887.
- Kim Y, Morikawa M, Ohsawa H, et al. (October 2003). "Effects of foods on the pharmacokinetics and clinical efficacy of quazepam". Nihon Shinkei Seishin Yakurigaku Zasshi 23 (5): 205–10. PMID 14653226.
- Meldrum BS, Chapman AG (1986). "Benzodiazepine receptors and their relationship to the treatment of epilepsy". Epilepsia. 27. Suppl 1: S3–13. PMID 3017690.
- Corda MG, Giorgi O, Longoni BM, et al. (1988). "Characterization of 3H-2-oxo-quazepam binding in the human brain". Prog. Neuropsychopharmacol. Biol. Psychiatry 12 (5): 701–12. doi:10.1016/0278-5846(88)90015-2. PMID 2906158.
- Roth TG, Roehrs TA, Koshorek GL, Greenblatt DJ, Rosenthal LD (October 1997). "Hypnotic effects of low doses of quazepam in older insomniacs". J Clin Psychopharmacol 17 (5): 401–6. doi:10.1097/00004714-199710000-00009. PMID 9315991.
- Chapman AG, De Sarro GB, Premachandra M, Meldrum BS (September 1987). "Bidirectional effects of beta-carbolines in reflex epilepsy". Brain Res. Bull. 19 (3): 337–46. doi:10.1016/0361-9230(87)90102-X. PMID 3119161.
- Mauri MC, Gianetti S, Pugnetti L, Altamura AC (1993). "Quazepam versus triazolam in patients with sleep disorders: a double-blind study". Int J Clin Pharmacol Res 13 (3): 173–7. PMID 7901174.
- Wettstein JG (October 1988). "Effects of the novel benzodiazepine agonist quazepam on suppressed behavior of monkeys". Eur. J. Pharmacol. 155 (1-2): 19–25. doi:10.1016/0014-2999(88)90398-6. PMID 2907488.
- Mariotti M, Ongini E (August 1983). "Differential effects of benzodiazepines on EEG activity and hypnogenic mechanisms of the brain stem in cats". Arch Int Pharmacodyn Ther 264 (2): 203–19. PMID 6139096.
- Kawasaki H, Urabe M, Nuki C, Yamamoto R, Takasaki K, Ohno H (October 1987). "[Electroencephalographic study of Sch 161 (quazepam), a new benzodiazepine hypnotic, in rats and rabbits]". Nippon Yakurigaku Zasshi (in Japanese) 90 (4): 221–38. doi:10.1254/fpj.90.221. PMID 3428780.
- Sieghart W (July 1983). "Several new benzodiazepines selectively interact with a benzodiazepine receptor subtype". Neurosci. Lett. 38 (1): 73–8. doi:10.1016/0304-3940(83)90113-1. PMID 6136944.
- Wamsley JK, Golden JS, Yamamura HI, Barnett A (1985). "Quazepam, a sedative-hypnotic selective for the benzodiazepine type 1 receptor: autoradiographic localization in rat and human brain". Clin Neuropharmacol. 8. Suppl 1: S26–40. PMID 2874881.
- Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry. 66. Suppl 9: 31–41. PMID 16336040.