Therapeutic drug monitoring of caffeine in preterm infants: Could saliva be an alternative to serum?

OBJECTIVE: Evaluate whether saliva could be a useful alternative to serum for routine therapeutic drug monitoring of caffeine in preterm infants using the enzyme multiplied immunoassay technique (EMIT) assay. METHODS: We conducted a prospective study including preterm infants (less than 34 weeks' amenorrhea) admitted to the intensive care and neonatal medicine department. All infants received 5, 10, 15, 20 and 25mg/kg/day of citrate caffeine intravenously from the first to the fifth day of birth, respectively. For each patient, two concomitant blood and saliva samples corresponding to the trough concentrations were collected 24hours after each caffeine dose. The caffeine concentrations were determined using the EMIT®2000 caffeine assay. RESULTS: Thirteen preterm infants were included. The saliva and the serum caffeine concentration increased proportionally to the administered dose. Saliva and serum kinetics were comparable and the saliva caffeine concentrations were correlated to the serum ones (r2=0.76). CONCLUSION: Saliva caffeine monitoring by EMIT is a valid, useful and safe alternative to serum in preterm infants.

Circadian variation of isoniazid pharmacokinetics in mice.

INTRODUCTION: This study is designed to investigate whether the pharmacokinetics of the antituberculous agent isoniazid (INH) varied according to the circadian dosing-time. METHODS: A total of 168 male mice aged 10 weeks and synchronized for 3 weeks to 12h light and 12h dark were used. A single INH (100mg/kg) dose was administered by intraperitonal (i.p.) route at either of the four different circadian stages (1, 7, 13 and 19h after light onset, HALO). At each circadian stage, blood samples were withdrawn at 0, 0.1, 0.2, 0.4, 1, 1.3, 2, 2.5, 4, 5, 6.3, 8, 24 and 48h following drug injection. The pharmacokinetics parameters (AUC0-∞, Ke, Cmax, T 1/2, ClT and Vd) were calculated for each circadian-time. RESULTS: There were relevant differences in Cmax between the four circadian groups (p<0.005), maximum and minimum Cmax were obtained when INH was injected at 1 HALO (490mgL-1) and at 7 HALO (270mgL-1) respectively. AUC0-∞ also varied significantly according to the circadian-time of injection (2093mgL-1h-1 at 1 HALO vs 759mgL-1h-1 at 7 HALO) (p<0.05). The highest and lowest mean values of plasma clearance (Cl) were observed at 7 HALO (0.22Lh-1kg-1) and 1 HALO (0.13Lh-1kg-1) respectively (p<0.05). The Cosinor analysis showed a circadian rhythm in different pharmacokinetic parameters. Cmax and AUC0-∞ have a significant circadian rhythm with an acrophase located at 2.64 HALO±0.21h (the beginning of the rest span) (p<0.001), whereas ClT and Vd showed a significant circadian rhythm with an acrophase located respectively at 7.4 HALO and at 8.66 HALO (the second half of the rest span) (p<0.001). CONCLUSION: Plasma INH chronopharmacokinetics might be involved in the mechanism of circadian variation of toxicity since the time of optimal tolerance to INH corresponds to that of the lowest Cmax and AUC0-∞ and the highest ClT occured when this drug injected in the second half of light-rest phase (7 HALO).

Circadian variation in murine hepatotoxicity to the antituberculosis agent «Isoniazide¼.

The circadian time is an important process affecting both pharmacokinetics and pharmacodynamics of drugs. Consequently, the desired and/or undesired effects vary according to the time of drug administration in the 24 h scale. This study investigates whether the toxicity in liver as well as oxidative stress varies according to the circadian dosing-time of isoniazid (INH) in mice. A potentially toxic INH dose (120 mg/kg) was injected by i.p. route to different groups of animals at three different circadian times: 1, 9, and 17 Zeitgeber time (ZT). INH administration at 1 ZT resulted in a maximum hepatotoxicity assessed by the significant increase in both serum transaminase (ALAT: alanine aminotransferase) and (ASAT: aspartate aminotransferase) and antioxidant enzyme activities (catalase: CAT and superoxide dismutase: SOD). The highest malondialdehyde (MDA) level indicating an induction of lipid peroxidation resulting in oxidative damage was also observed at 1 ZT. Liver histopathology from INH groups at 9 ZT and at 1 ZT showed moderate to severe cytoplasma vacuolation, hepatocyte hypertrophy, ballooning, and necrosis. The circadian variation in INH toxicity may help realize a chronotherapy protocol in humans based on the selection of the best time associated to optimal tolerance or least side effects.

Circadian variation of Valproic acid pharmacokinetics in mice.

Valproic acid (VPA) is currently one of the most commonly used antiepileptic drugs. This study aims to investigate whether VPA pharmacokinetics varied according to circadian dosing-time. A single dose of VPA (350 mgkg(-1)) was administered by intraperitonally (i.p.) route to a total of 132 mice synchronized for 3 weeks to 12h light (rest span) and 12 h dark (activity span). Four different circadian times (1, 7, 13 and 19 HALO) of drug injection were used (33 mice/circadian time). At each circadian time, blood samples were withdrawn at (0 h) and at 0.083, 0.166, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2 and 3h after VPA injection. Plasma VPA concentrations were determined by an EMIT method. There were no significant differences in T(max) of VPA whatever the circadian-time of injections (T(max)=0.166 h). However, there were relevant differences in C(max) between the four circadian groups (p<0.005), it varied between 386 ± 30.86 mg L(-1) in mice treated at 7 HALO and 824 ± 39.85 mg L(-1) in mice treated at 19 HALO. The AUC(0-∞) was significantly two times higher when VPA was administered at 19 HALO as compared to the injection at 7 HALO. Drug dosing at 7 HALO resulted in highest Cl(T) value: 0.405 ± 0.006 L h(-1)kg(-1), whereas Cl(T) was significantly slower when VPA was administered at 19 HALO (0.157 ± 0.009 L h(-1)kg(-1)) (p<0.0001). The AUC(0-∞) was significantly 2-fold higher when VPA was administered at 19 HALO (2216.65 ± 138.91 mg h(-1)L(-1)) as compared to the injection at 7 HALO (864.09 ± 16.82 mg h(-1)L(-1)) (p<0.0001). Cosinor analysis showed circadian rhythm in different pharmacokinetic parameters. C(max) and AUC(0-∞) have a significant circadian rhythm with an acrophase located at 20.16 HALO ± 0.16 h (the middle of the active span) (p<0.001), whereas Cl(T) and Vd showed a significant circadian rhythm with an acrophase located respectively at 7.86 HALO ± 0.57 h and 6.13 HALO ± 0.07 h (the middle of the rest span) (p<0.001). The large circadian variation of VPA pharmacokinetic processes might be involved in the mechanisms of circadian rhythm in murine toxicity since the optimal tolerance corresponded to the time which induces lowest C(max) and AUC values.

Carbamazepine-induced DRESS and HHV6 primary infection: the importance of skin tests.

SUMMARY: A 34-year-old male with a 20-year history of epilepsy was treated with valproic acid and phenobarbital. As he had frequent convulsive fits, carbamazepine (CBZ) was added. Thirty-four days later, the patient developed hyperthermia, (39.5 degrees C), cervical lymphadenopathy and generalized cutaneous exfoliated maculae and papulae. Biochemical investigation was characterized by a white cell count of 16.1 x 103/microl (17% eosinophils) and increased levels of aspartate aminotransferase and alanine aminotransferase (50 and 116 IU/L, respectively). HHV6 serological tests performed on day 21, detected anti HHV6 IgM, suggesting a HHV6 primary infection. Hence, CBZ was discontinued. One month later, the skin eruption, fever, lymph node swelling, liver dysfunction, and eosinophilia were progressively relieved. Six weeks after complete recovery, prick and patch skin tests were performed. They were strongly positive at 48-h reading. This report suggests the usefulness of skin tests in diagnosing CBZ-induced-DRESS, as well as s possible association between DRESS and HHV6 primary infection.