Immunogenicity of subcutaneous TNF inhibitors and its clinical significance in real-life setting in patients with spondyloarthritis.

KEY MESSAGES: Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1-2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

Lack of effect of terfenadine on the pharmacokinetics of the CYP3A4 substrate buspirone.

The effects of terfenadine, a non-sedating antihistamine on the pharmacokinetics and pharmacodynamics of buspirone, a CYP3A4 substrate, were investigated in a randomised, placebo-controlled, two-phase cross-over study. Ten healthy volunteers took either 120 mg terfenadine or matched placebo orally once daily for 3 days. On day 3, 10 mg buspirone was taken orally. Plasma concentrations of buspirone were measured up to 18 hr and its pharmacodynamic effects up to 8 hr. Terfenadine slightly but not significantly increased plasma concentrations of buspirone. No psychomotor deterioration was observed during the terfenadine phase. In conclusion, terfenadine did not significantly affect the pharmacokinetics of buspirone, a CYP3A4 substrate shown to be very susceptible to interactions with CYP3A4 inhibitors. Thus, terfenadine is expected to have little effect on the pharmacokinetics of CYP3A4 substrates in general.

Interactions of buspirone with itraconazole and rifampicin: effects on the pharmacokinetics of the active 1-(2-pyrimidinyl)-piperazine metabolite of buspirone.

The effects of inhibition and induction of the metabolism of buspirone on the plasma concentrations of 1-(2-pyrimidinyl)-piperazine (a piperazine metabolite), the principal active metabolite of buspirone, were investigated. Two separate randomized, placebo-controlled cross-over studies with two phases were carried out in healthy volunteers. In Study I, six subjects took itraconazole 200 mg daily or matched placebo orally for 4 days. On day 4, 10 mg buspirone was administered orally. In study II, six subjects took rifampicin 600 mg daily or matched placebo orally for 5 days. On day 6, 30 mg buspirone was administered orally. Buspirone and piperazine metabolite concentrations in plasma were determined by gas chromatography. Itraconazole decreased the mean AUC of the piperazine metabolite by 50% (P<0.05) and the Cmax by 57% (P<0.05) compared with placebo, whereas the mean AUC and Cmax of unchanged buspirone were increased 14.5-fold (P<0.05) and 10.5-fold (P<0.05), respectively, by itraconazole. Rifampicin had no significant effect on the AUC of the piperazine metabolite, but it increased the mean Cmax of the piperazine metabolite by 35% (P=0.08). The mean AUC and Cmax of parent buspirone were reduced by 91% (P<0.05) and 85% (P<0.05), respectively, by rifampicin. The mean ratio of the AUC of the piperazine metabolite to that of buspirone was decreased 34-fold (P<0.05) by itraconazole and increased 7.6-fold (P<0.05) by rifampicin. In conclusion, itraconazole and rifampicin caused only relatively minor changes in the plasma concentrations of the active piperazine metabolite of buspirone, although they had drastic effects on the concentrations of parent buspirone.

Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone.

BACKGROUND: Buspirone has an extensive first-pass metabolism, which makes it potentially susceptible to drug interactions. The aim of this study was to investigate possible interactions of buspirone with verapamil and diltiazem. METHODS: In a randomized, placebo-controlled, three-phase crossover study, nine healthy volunteers received either 80 mg verapamil, 60 mg diltiazem, or placebo orally three times a day. On day 2, after the fifth dose, 10 mg buspirone was given orally. Plasma concentrations of buspirone, verapamil, and diltiazem were determined up to 18 hours, and the effects of buspirone were measured up to 8 hours. RESULTS: Verapamil and diltiazem increased the area under the buspirone plasma concentration-time curve [AUC (0-infinity)] 3.4-fold (p < 0.001) and 5.5-fold (p < 0.001), respectively. The peak plasma concentration of buspirone was increased 3.4-fold (p < 0.001) and 4.1-fold (p < 0.001) by verapamil and diltiazem, respectively. The effect of diltiazem on the AUC(0-infinity) of buspirone was significantly (p < 0.05) greater than that of verapamil. The elimination half-life of buspirone was not changed by verapamil and diltiazem. Of the six pharmacodynamic variables, only the subjective overall drug effect of buspirone was significantly increased with verapamil (p < 0.05) and diltiazem (p < 0.05). Side effects of buspirone occurred more often (p < 0.05) with diltiazem than with placebo. CONCLUSIONS: Both verapamil and diltiazem considerably increase plasma buspirone concentrations, probably by inhibiting its CYP3A4-mediated first-pass metabolism. Thus enhanced effects and side effects of buspirone are possible when it is used with verapamil, diltiazem, or other inhibitors of CYP3A4.

Concentrations and effects of buspirone are considerably reduced by rifampicin.

AIMS: The effects of rifampicin on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated. METHODS: In a randomized, placebo-controlled cross-over study with two phases, 10 young healthy volunteers took either 600 mg rifampicin or matched placebo once daily for 5 days. On day 6, 30 mg buspirone was administered orally. Plasma buspirone concentrations and effects of buspirone were measured up to 10 h. RESULTS: The total area under the plasma buspirone concentration-time curve after rifampicin was 10.4% (95% CI, 6.3-14.5%) of that after placebo (1.64+/-0.35 ng ml(-1) h vs 22.0+/-15.1 ng ml(-1) h (mean+/-s.d.); P< 0.01). Rifampicin decreased the peak plasma concentration of buspirone from 6.6+/-3.7 ng ml(-1) to 0.84+/-0.23 ng ml(-1) (P< 0.01) and the half-life from 2.8+/-0.7 h to 1.3+/-0.5 h (P< 0.01). A significant (P<0.05) reduction in the effects of buspirone was observed in three of the six psychomotor tests employed (postural sway test with eyes closed, subjective drowsiness and overall drug effect) after rifampicin pretreatment. CONCLUSIONS: The strong interaction between rifampicin and buspirone is probably mostly due to enhanced CYP3A4-mediated first-pass metabolism of buspirone. Buspirone will most likely show a greatly reduced anxiolytic effect when used together with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.

The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone.

OBJECTIVE: The effects of fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor antidepressant, on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated. METHODS: In a randomized, placebo-controlled, two-phase cross-over study, ten healthy volunteers took either 100 mg fluvoxamine or matched placebo orally once daily for 5 days. On day 6, 10 mg buspirone was taken orally. Plasma concentrations of buspirone and its active metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), were measured up to 18 h and the pharmacodynamic effects of buspirone up to 8 h. RESULTS: The total area under the plasma buspirone concentration-time curve was increased 2.4-fold (P < 0.05) and the peak plasma buspirone concentration 2.0-fold (P < 0.05) by fluvoxamine, compared with placebo. The half-life of buspirone was not affected. The ratio of the total area under the plasma concentration-time curve of 1-PP to that of buspirone was decreased from 7.4 [6.3 (SD)] to 4.4 (3.6) by fluvoxamine (P < 0.05). The results of the six pharmacodynamic tests remained unchanged. CONCLUSION: Fluvoxamine moderately increased plasma buspirone concentrations and decreased the production of the active 1-PP metabolite of buspirone. The mechanism of this interaction is probably inhibition of the CYP3A4-mediated first-pass metabolism of buspirone by fluvoxamine. However, this pharmacokinetic interaction was not associated with impairment of psychomotor performance and it is probably of limited clinical significance.

Grapefruit juice substantially increases plasma concentrations of buspirone.

BACKGROUND: Buspirone has a low oral bioavailability because of extensive first-pass metabolism. The effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of orally administered buspirone is not known. METHODS: In a randomized, 2-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water 3 times a day for 2 days. On day 3, each subject ingested 10 mg buspirone with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 hour and 1 1/2 hours after buspirone administration. Timed blood samples were collected up to 12 hours after ingestion, and the effects of buspirone were measured with 6 psychomotor tests up to 8 hours after ingestion. RESULTS: Grapefruit juice increased the mean peak plasma concentration of buspirone 4.3-fold (range, 2-fold to 15.6-fold; P < .01) and the mean area under the plasma buspirone concentration-time curve 9.2-fold (range, 3-fold to 20.4-fold; P < .01). The time of the peak concentration (tmax) of buspirone increased from 0.75 to 3 hours (P < .01), and the elimination half-life (t1/2) was slightly increased (P < .01) by grapefruit juice. A significant increase in the pharmacodynamic effects of buspirone by grapefruit juice was seen only in subjective overall drug effect (P < .01). CONCLUSIONS: Grapefruit juice considerably increased plasma buspirone concentrations. The probable mechanism of this interaction is delayed gastric emptying and inhibition of the cytochrome P450 3A4-mediated first-pass metabolism of buspirone caused by grapefruit juice. Concomitant use of buspirone and at least large amounts of grapefruit juice should be avoided.

Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole.

BACKGROUND: The oral bioavailability of buspirone is very low as a result of extensive first-pass metabolism. Erythromycin and itraconazole are potent inhibitors of CYP3A4, and they increase plasma concentrations and effects of certain drugs, for example, oral midazolam and triazolam. The possible interactions of buspirone with erythromycin and itraconazole have not been studied before. METHODS: The pharmacokinetics and pharmacodynamics of buspirone were investigated in a randomized, double-blind, double-dummy crossover study with three phases. Eight young healthy volunteers took either 1.5 gm/day erythromycin, 200 mg/day itraconazole, or placebo orally for 4 days. On day 4, 10 mg buspirone was administered orally. Timed blood samples were collected up to 18 hours, and the effects of buspirone were measured with four psychomotor tests up to 8 hours. RESULTS: Erythromycin and itraconazole increased the mean area under the plasma concentration-time curve from time zero to infinity [AUC(0-infinity] of buspirone about sixfold (p < 0.05) and 19-fold (p < 0.01), respectively, compared with placebo. The mean peak plasma concentration (Cmax) of buspirone was increased about fivefold (p < 0.01) and 13-fold (p < 0.01) by erythromycin and itraconazole, respectively. These interactions were evident in each subject, although a striking interindividual variability in the extent of both interactions was observed. The elimination half-life of buspirone did not seem to be prolonged by either erythromycin or itraconazole. The effect of itraconazole on the Cmax and AUC(0-infinity) of buspirone was significantly (p < 0.01) greater than that of erythromycin. The greatly elevated plasma buspirone concentrations resulted in increased (p < 0.05) pharmacodynamic effects (as measured by the Digit Symbol Substitution test and the Critical Flicker Fusion test) and in side effects of buspirone. CONCLUSIONS: Both erythromycin and itraconazole greatly increased plasma buspirone concentrations, obviously by inhibiting its CYP3A4-mediated first-pass metabolism. These pharmacokinetic interactions were accompanied by impairment of psychomotor performance and side effects of buspirone. The dose of buspirone should be greatly reduced during concomitant treatment with erythromycin, itraconazole, or other potent inhibitors of CYP3A4.

Concentrations and effects of zopiclone are greatly reduced by rifampicin.

AIMS: The effects of rifampicin on the pharmacokinetics and pharmacodynamics of zopiclone, a non-benzodiazepine hypnotic, were studied. METHODS: In a randomized, placebo-controlled cross-over study with two phases, eight young healthy volunteers took either 600 mg rifampicin or placebo once daily for 5 days. On the 6th day, 10 mg zopiclone was administered orally. Plasma zopiclone concentrations and effects of zopiclone were measured for 10 h. RESULTS: The total area under the plasma zopiclone concentration-time curve after rifampicin was 18.0% (95% CI 13.5-22.5%) of that after placebo (86.1 +/- 34.5 ng ml(-1) h vs 473 +/- 114 ng ml(-1) h (mean +/- s.d.); P<0.001). Rifampicin decreased the peak plasma concentration of zopiclone from 76.9 +/- 27.2 ng ml(-1) to 22.5 +/- 6.0 ng ml(-1) (P<0.001) and the half-life from 3.8 +/- 0.6 h to 2.3 +/- 0.9 h (P<0.005). A significant (P<0.02) reduction in the effects of zopiclone was seen in three of the five psychomotor tests used (digit symbol substitution test, critical flicker fusion test and Maddox wing test) after rifampicin pretreatment. CONCLUSIONS: The strong interaction of rifampicin with zopiclone is due to enhanced metabolism of zopiclone. Zopiclone may show a reduced hypnotic effect when used concomitantly with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.

Hearing loss after continuous or single-shot spinal anesthesia.

BACKGROUND AND OBJECTIVES: Hearing loss after spinal anesthesia is probably caused by cerebrospinal fluid (CSF) leakage. Spinal catheters may mechanically plug the hole in the dura and cause inflammatory swelling which should prevent cerebrospinal fluid leakage and hearing loss. An audiometric evaluation was therefore performed in patients who had spinal anesthesia by single-shot or catheter. METHODS: Twenty-one patients received single-shot spinal anesthesia and 19 patients continuous spinal anesthesia for orthopedic surgery of the lower limbs. Spinal catheters were removed 24 hours after the start of anesthesia. Audiometry was performed on the day before the operation and on the first, second, and third postoperative day and repeated on the fifth postoperative day, if necessary. RESULTS: The frequency of hearing impairment (threshold change > 10 dB) was 43% in the single-shot and 37% in the continuous spinal group. The deterioration lasted longer in the continuous spinal group (3 days vs. 1.4 days; P < .01). CONCLUSION: Although inflammatory swelling of the dura mater around the spinal catheter had been observed, use of such a catheter for 24 hours did not prevent hearing loss after its removal.

[Bacterial urovirulence factors and their association with functional and anatomical abnormalities and recurrence of urinary tract infections in children]. / Factores de urovirulencia bacteriana: asociación con recurrencias y anomalías anatómicas y funcionales en niños con infección del tracto urinario.

BACKGROUND: Urinary tract infections in children are associated with functional and anatomical abnormalities of the urinary tract, they tend to recur and can cause permanent kidney damage. AIM: To study in children with urinary tract infections, microbiological factors associated to recurrence, functional and anatomical abnormalities of the urinary tract. PATIENTS AND METHODS: A prospective sample of children was incorporated into a follow-up protocol after their first episode of bacteriologically-demonstrated urinary tract infection. In all patients an abdominal ultrasound examination and a mictional urethrocystography were done and the presence of fimbriae was studied in isolated strains of Escherichia coli. RESULTS: Two hundred fifteen cases bad an adequate adherence to the study protocol, 190 caused by E coli. Fimbriated E coli strains were isolated with greater frequency from children with pyelonephritis than from those with a low urinary tract infection (50 and 28% respectively). The absence of fimbriae in E coli strains was associated with a higher risk of recurrent infections (odds ratio = 3, confidence intervals = 2-9.2) and an abnormal urethrocystography (odds ratio = 3, confidence intervals = 1.1-10.2). CONCLUSIONS: These data are consistent with foreign reports and support the need to study adhesins in E coli strains isolated from children with urinary tract infections.

Auditory disturbance associated with interscalene brachial plexus block.

We performed an audiometric study in 20 patients who underwent surgery of the shoulder region under an interscalene brachial plexus block (IBPB). Bupivacaine 0.75% with adrenaline was given followed by a 24-hr continuous infusion of 0.25% bupivacaine. Three audiometric threshold measurements (0.25-18 kHz) were made: the first before IBPB, the second 2-6 h after surgery and the third on the first day after operation. In four patients hearing impairment on the side of the block was demonstrated after operation, in three measurements on the day of surgery and in one on the following day. The frequencies at which the impairment occurred varied between patients; in one only low frequencies (0.25-0.5 kHz) were involved. The maximum change in threshold was 35 dB at 6 kHz measured at the end of the continuous infusion of bupivacaine. This patient had hearing threshold changes (15-20 dB) at 6-10 kHz on the opposite side also. IBPB may cause transient auditory dysfunction in the ipsilateral ear, possibly via an effect on sympathetic innervation.