Guy Aymard

Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus.

Background: Poor adherence to treatment is difficult to diagnose accurately. Hydroxychloroquine (HCQ) has a long elimination half-life and its concentration in whole blood can be measured easily. Objective: To evaluate the utility of a very low blood HCQ concentration as a marker of poor compliance in patients with systemic lupus erythematosus (SLE). Methods: HCQ concentrations were determined on a blinded basis in 203 unselected patients with SLE. At the end of the study, the patients were informed of the results and retrospectively interviewed about their adherence to treatment. Results: 14 (7%) patients said that they had stopped taking HCQ (n = 8) or had taken it no more than once or twice a week (n = 6). Their mean (SD) HCQ concentration was 26 (46) ng/ml. range (0–129 ng/ml) By contrast, the other patients had a mean HCQ concentration of 1079 ng/ml range (205–2629 ng/ml). The principal barriers to adherence were related to HCQ treatment characteristics. Adherence subsequently improved in 10 of the 12 patients whose blood HCQ concentrations were remeasured. Conclusions: Very low whole-blood HCQ concentrations are an objective marker of prolonged poor compliance in patients with SLE. Regular drug assays might help doctors in detect non-compliance and serve as a basis for counselling and supporting these patients.

Potentiation of Vitamin K Antagonists by High-Dose Intravenous Methylprednisolone

Pulse high-dose intravenous methylprednisolone is widely used for the treatment of flares in inflammatory and autoimmune diseases (1). Most of these diseases carry a risk for venous and arterial occlusion (2-4). In addition, patients may have individual indications for oral anticoagulation that are independent of inflammatory disease, such as atrial fibrillation and mechanical prosthetic heart valves. Therefore, oral anticoagulants and methylprednisolone are often administered concomitantly in clinical practice. In early studies, oral anticoagulants had both enhanced (5) and diminished effects (6, 7) when given concurrently with oral corticosteroids. Corticosteroids are not thought to potentiate oral anticoagulants (8). In a patient receiving oral anticoagulation, we observed a sharp increase in the international normalized ratio (INR) after concomitant administration of methylprednisolone. This observation, and the lack of relevant published data, prompted us to conduct a prospective study of the potential interaction of methylprednisolone with oral anticoagulants. Methods Patients We studied 10 consecutive patients who were referred to the internal medicine department of Piti-Salptrire Hospital in Paris, France. The 4 women and 6 men (mean age, 51 years [range, 20 to 79 years]) were taking oral anticoagulants and received methylprednisolone for giant-cell arteritis (n=2), autoimmune thrombocytopenic purpura (n=2), vasculitis (n=3), multiple myeloma (n=1), lupus flare (n=1), or mediastinal fibrosis (n=1). Methylprednisolone was given in the form of 1 g or 500 mg of hemisuccinate methylprednisolone (Solu-Medrol, Pharmacia & Upjohn, Saint-Quentin en Yvelines, France) reconstituted in 5% dextrose in water (total volume, 250 mL) and was infused intravenously over 1 hour. All 10 patients were taking vitamin K antagonists (fluindione [n=8] and acenocoumarol [n=2]) for atrial fibrillation (n=3), the antiphospholipid syndrome (n=3), thromboembolic events (n=2), distal limb ischemia (n=1), or the superior vena cava syndrome (n=1). Daily doses were 4 mg of acenocoumarol (n=2) and 5 mg (n=1), 10 mg (n=2), 20 mg (n=3), 25 mg (n=1), or 40 mg (n=1) of fluindione; these doses had not been increased in the 10 days before administration of the first methylprednisolone pulse. Except for the first patient, informed consent was obtained in each case before study enrollment. The control group consisted of five consecutive patients (mean age, 50 years [range, 21 to 80 years]) who were receiving methylprednisolone for giant-cell arteritis (n=2), lupus flare (n=1), idiopathic retroperitoneal fibrosis (n=1), or Crohn disease (n=1). Controls did not receive oral anticoagulants before or during methylprednisolone administration. All of the cases were reported to the Paris-Piti-Salptrire regional pharmacovigilance center. Concomitant Medications Concomitant medications were screened for drugs known to potentiate oral anticoagulants (8, 9). Two patients were receiving concomitant amiodarone therapy, but the doses had not been modified during the 6 months before the study began and were not modified during the study. Three patients were receiving acetaminophen, but the weekly dose was less than 4550 mg (the minimum dose that has been found to increase the INR) during the week before methylprednisolone administration and throughout the study (10). Clotting Tests The prothrombin time, interpreted as the INR, was measured by using the Simplastin Excel S reagent with an international sensitivity index of 1.31 (Organon Teknika Corp., Durham, North Carolina). Factors II, VII, IX, and X were routinely measured by using an STA IX analyzer (Diagnostica Stago, Asnires-sur-Seine, France), as described elsewhere (11). Levels of protein C and free protein S were assayed by using an amidolytic method (Berichrom Protein C, Dade Behring, Liederbach, Germany) and a procoagulant method (Protein S Reagent, Dade Behring), respectively, on a Behring Coagulation Timer (Dade Behring). Total (free and protein-bound) fluindione levels were assayed by using high-performance liquid chromatography, as described elsewhere (12). Results International Normalized Ratio after Administration of High-Dose Intravenous Methylprednisolone For all patients, the target INR was 2.0 to 4.0. The INR was checked during the 12 hours before methylprednisolone infusion. At baseline, the mean INR was 2.75 (range, 2.02 to 3.81). In all patients, the INR increased to a mean of 8.04 (range, 5.32 to 20.0) after methylprednisolone administration (Figure 1). The maximum increase in the INR occurred after a mean of 92.7 hours (range, 29 to 156 hours). Because the INR reached life-threatening levels in five patients (patients 1, 2, 4, 6, and 8), we administered vitamin K, which decreased the INR in 4 to 12 hours (Figure 1). In four other patients (patients 3, 5, 7, and 9), oral anticoagulation was discontinued and the INR returned to baseline in 36 to 48 hours (Figure 1). Figure 1. Potentiation of vitamin K antagonists by intravenous high-dose methylprednisolone in patients 1 through 10. INR Levels of protein C; free protein S; and vitamin K-dependent factors II, VII, IX, and X decreased as the INR increased. However, levels of factor V remained normal in every case (data not shown). International Normalized Ratio after Methylprednisolone Alone To determine whether INR elevation was caused by the action of methylprednisolone on clotting factors, we assessed the prothrombin time in five consecutive controls who received methylprednisolone (1 g/d for 3 days) without concomitant oral anticoagulation. The prothrombin time was checked every day and remained stable for 7 days after the first dose of methylprednisolone was administered (Figure 2). Figure 2. Lack of effect of intravenous high-dose methylprednisolone alone on prothrombin time in five controls. Elevation of the International Normalized Ratio after Concomitant Administration of Methylprednisolone and Oral Anticoagulation To rule out in vitro interference between methylprednisolone and INR reagents, we collected plasma from nine patients who were being treated with fluindione and added methylprednisolone at concentrations of 0 mg/L, 5 mg/L, and 20 mg/L (based on the peak concentration of methylprednisolone in vivo in patients treated with methylprednisolone [13]). The resulting INRs were not influenced by the baseline INR or by the dose of methylprednisolone added (data not shown). Total plasma fluindione concentrations were serially assayed in three patients (patients 6, 8, and 10). Fluindione concentrations and the INR always increased after methylprednisolone administration (Figure 1). Discussion To determine whether methylprednisolone potentiated oral anticoagulation, we studied variations of the INR in 10 consecutive patients who were taking oral anticoagulants and received methylprednisolone concomitantly. The INR increased sharply, exceeding 6.0 in almost all patients. In contrast, methylprednisolone alone did not interfere with clotting factors (prothrombin time). These results suggest that INR elevation was due to potentiation of oral anticoagulation by methylprednisolone. Although no bleeding complications occurred in this small series, the INR elevation was severe enough to warrant vitamin K supplementation or withdrawal of the vitamin K antagonist, and we were therefore unable to observe the maximum potential increase in the INR. Our data are in keeping with those of Kaufman (14), who described two patients with multiple sclerosis who were receiving warfarin: one for a prosthetic valve and one for pulmonary embolism. In these patients, the INR reached 10.0 and 12.0, respectively, after methylprednisolone administration. Of note, two patients in our study received acenocoumarol, a coumarin congener that chemically differs from warfarin only by its nitro group at the para position in the phenyl ring. Although our study included a small number of patients, it is unlikely that the INR increased because of spontaneous fluctuations in each patients response to oral anticoagulants. The INR reached 6 in almost all of our consecutive patients; however, in a recent study of 29 000 INRs observed during a 6-month period (15), only 85 exceeded 6.0. Furthermore, our patients did not have any of the conditions reported to increase the INR, such as alcoholism, liver disease, frequent modification of oral anticoagulant dose, and recent withdrawal or initiation of medications known to interact with oral anticoagulants. In a study of 55 625 INRs in which 131 patients had INRs that exceeded 8.0, one of two hemorrhage-related deaths involved a patient taking warfarin who was receiving high-dose steroids for vasculitis (16) . Although the precise mechanism of the interaction between methylprednisolone and oral anticoagulants is unclear, several lines of evidence strongly suggest that it is due to inhibition of oral anticoagulant catabolism by high-dose methylprednisolone. First, the increase in the INR observed after methylprednisolone administration occurred through a vitamin K-dependent pathway. The INR increased regardless of the anticoagulant used (acenocoumarol, warfarin, or fluindione, a noncoumarin indanedione anticoagulant that is common in Europe). In addition, this increase was rapidly reversed by administration of vitamin K (14). Second, because oral anticoagulants are almost completely absorbed from the gastrointestinal tract (9), it is unlikely that elevated fluindione concentrations were due to increased absorption. Third, because we measured total fluindione, it is unlikely that the elevated concentrations resulted from a change in the ratio between free and protein-bound fluindione. Fourth, methylprednisolone inhibits the cytochrome P450 enzyme system (17), which is involved in the metabolism of oral anticoagulants (18). It is therefore possible that high-dose methylprednisolone potentiates vitamin K antagonists by inhibiting thei

Pharmacokinetics of abacavir in HIV-1-infected patients with impaired renal function.

Background: Abacavir is a potent, novel 2′-deoxyguanosine analogue reverse transcriptase inhibitor (NRTI) which effectively suppresses HIV-1 replication. To date, there is no pharmacokinetic study in patients with renal impairment. Methods: Five HIV-1-infected patients with various degrees of renal dysfunction (creatinine clearance 60, 40, 25, 20 and 1 haemodialyzed patient) were evaluated after being treated for at least 2 months with multi-antiretroviral therapy including abacavir. After an overnight fast, the subjects received their abacavir dosage (600 or 300 mg). Blood samples were withdrawn and plasma concentrations determined. A nonparametric pharmacokinetic analysis was then performed. The dialysability of abacavir was also evaluated. Results: Time of maximum plasma concentration (Tmax) was constant among the subjects with a mean value of 0.7 ± 0.27 h (range 0.33–1). Maximum plasma concentration (Cmax) ranged from 2.76 to 4.15 mg/l (mean 3.44 ± 0.59). The elimination half-life ranged from 1.31 to 2.67 h (mean 2.08 ± 0.51). Normalized Cmax/dose ranged from 0.007 to 0.014 mg/l and normalized AUC(0-inf)/dose ranged from 0.014 to 0.035 mg·h/l. In haemodialysis the dialysance was 60–80 ml/min with a fractional drug removal of 24% during a 4-hour haemodialysis session with a high permeability membrane. Discussion: In our patients, absorption, elimination and distribution phases were not altered by renal insufficiency. Furthermore, our pharmacokinetic data are similar to those obtained in patients with normal renal function. Therefore, dosage adjustment is not necessary in patients with renal insufficiency. In haemodialyzed patients, treatment can be administered independently to the dialysis session because of the negligible elimination of abacavir in the dialysate.

Relationship between blood hydroxychloroquine and desethylchloroquine concentrations and cigarette smoking in treated patients with connective tissue diseases.

Cigarette smoking has been suspected to increase the risk and the activity of systemic lupus erythematosus (SLE)1 2 and cutaneous lupus.3 4 Some data indicate that cigarette smoking might interfere with the effectiveness of hydroxychloroquine and chloroquine in cutaneous lupus.3 4 As these antimalarial agents are partly metabolised via the cytochrome P450 enzyme system and as the constituents of cigarette smoke are known potent inducers of cytochrome P450, it has been hypothesised that the resistance of cutaneous lupus might be explained by a modification of the metabolism of these …

Atenolol administration via a nasogastric tube after abdominal surgery: an unreliable route.

&bgr;-Adrenoceptor antagonists, especially atenolol, reduce perioperative cardiac morbidity. Because there are no data on the bioavailability of atenolol given by nasogastric tube in the postoperative period, we assessed the efficacy of this route of administration in 18 patients scheduled for abdominal surgery. We found a 36% reduction in the area under the atenolol concentration curve and a 46% reduction in the peak concentration of atenolol in the postoperative period compared with preoperative values. In addition, patients had more rapid mean heart rates on the second postoperative day compared with the day before surgery. We conclude that the administration of atenolol via nasogastric tube in the postoperative period does not result in adequate plasma concentrations.

Pharmacokinetics of Tramadol in a Hemodialysis Patient

Accessible online at: www.karger.com/journals/nef Dear Sir, Tramadol is a centrally acting analgesic agent which is extensively metabolized in the liver. However, 30% of a dose is excreted unchanged in urine [1] and renal impairment may alter the pharmacokinetics of tramadol. However, there are no data for patients with end-stage renal disease undergoing hemodialysis. We thus report a pharmacokinetic study of tramadol in a patient requiring chronic hemodialysis. The patient was a 70-year-old male (65 kg, 170 cm) with a long history of multiple myeloma. He suffered from renal failure with the following laboratory values within the last 6 months: serum creatinine 180 Imol/l, urea 25 mmol/l, and normal liver enzymes. He was treated with ibuprofen for acute pain secondary to pathologic thigh bone fracture and developed end-stage renal disease. On admission, the patient complained of pain and leg cramps. Analgesic treatment with tramadol was instituted (50 mg twice daily) with a good analgesic efficacy. Because of persistent anuric renal insufficiency, hemodialysis was started. The study of tramadol pharmacokinetics was performed 1 week after starting hemodialysis, after oral administration of a 50-mg dose in the pattern of a long-term twice-daily treatment. Blood samples were collected just before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 8 h after oral administration. The study was conducted on a hemodialysis-free day. Paired arterial and venous blood samples were also obtained simultaneously 2 h after starting a hemodialysis session, on a hemodialysis day. On that day, the patient was administered tramadol 1 h before the session was started. Hemodialysis was performed for 4 h using a F60 polysulfone dialyzer (surface area 1.6 m2) with a double-needle access to a double lumen catheter with a constant dialysate flow rate of 500 ml/min and blood flow rate between 250 and 300 ml/min. Pharmacokinetic parameters were compared to those of subjects with normal renal function [2], FHD, which represents the participation of hemodialysis clearance in total body clearance of the drug during the session was calculated using the formula: FHD = CLHD/(CLHD + CLER) [3], where CLHD is hemodialysis clearance and CLER is ‘extrarenal’ clearance, equal to interdialytic total body clearance of the drug. Neither clinical side effects, nor overdosage symptoms, such as obnibulation, respiratory system depression, nor constipation, were observed. Our results (table 1) showed that Tmax and T1/2 were the same in our patient and in healthy subjects. However, total body clearance was decreased in our patient as compared to healthy subjects. Since the apparent total body clearance of a drug CL/F is linked to its volume of distribution Vd/F with the relation CL/F = (0.693/T1/2) ! Vd/F, the decrease in CL/F in our patient was due to an Table 1. Pharmacokinetic parameters of tramadol in an hemodialysis patient

Relationships between plasma concentrations of morphine, morphine-3-glucuronide, morphine-6-glucuronide, and intravenous morphine titration outcomes in the postoperative period.

Although intravenous morphine titration (IMT) is widely used to control moderate to severe postoperative pain, the relationships between plasma concentrations of morphine and its metabolites, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G), and IMT outcomes in the postanesthesia care unit (PACU) have not been yet investigated. IMT was administrated as a bolus of 2 or 3 mg every 5 min. Titration was interrupted in case of pain relief (visual analog score ≤30), adverse events, sedation, or failure of morphine titration. Blood samples were collected at the end of morphine titration to determine plasma concentration of morphine and its two metabolites. Data from 214 patients were analyzed; 143 (67%) of the patients achieved complete pain relief, 39 (18%) experienced adverse events, and 32 (15%) failure of morphine titration. At the end of titration, there were no significant differences in morphine, M6G, M3G concentrations between sedated and nonsedated patients (32 vs. 42 ng/mL (P = 0.07), 38 vs. 45 ng/mL (P = 0.51), 300 vs. 342 ng/mL (P = 0.29), respectively), or patients with or without adverse events (40 vs. 41 ng/mL (P = 0.95), 37 vs. 46 ng/mL (P = 0.51), 287 vs. 340 ng/mL (P = 0.72), respectively). Our study demonstrated a lack of relationship between plasma concentrations or ratios of morphine, M3G, and M6G, with IMT outcomes in PACU. This result suggests that the kinetics of morphine and its metabolites have limited value for explaining clinical effects of morphine in this clinical setting.

Pharmacokinetics of ritonavir and saquinavir in a haemodialysis patient.

Accessible online at: www.karger.com/journals/nef Dear Sir, Protease inhibitor therapy is one of the most important recent advances in the treatment of HIV infection [1]. Hepatic clearance is the major route of elimination of ritonavir and saquinavir (95%). Therefore, it has been suggested that no dosage adjustment is necessary in patients with renal insufficiency [2, 3]. However, no study is available on these drugs administered in patients with renal insufficiency. We report on the pharmacokinetics of these drugs in a HIV-1-infected patient undergoing haemodialysis. A 50-year-old man, haemodialyzed for 4 years for HIV-associated nephropathy, was treated with multitherapy including ritonavir 200 mg every 12 h and saquinavir 600 mg every 12 h for 1 year without side effects and with a decrease of his viral load from 22,400 copies/ml to undetectable levels (!200 copies/ml). Blood samples were collected just before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 h after oral drug administration. Our patient was studied between and during dialysis sessions. Paired arterial and venous blood samples were also taken simultaneously 2 h after the start of haemodialysis. Also

Beraprost sodium‐fluindione combination in healthy subjects: pharmacokinetic and pharmacodynamic aspects

Abstract— Beraprost sodium (BPS), an orally active PGI2 (prostaglandine I2) analogue possesses vasodilatating and platelet aggregation inhibiting properties. It is being developed in peripheral arterial occlusive disease. As in future clinical practice BPS might be co‐prescribed with oral anticoagulants, we investigated its interaction with fluindione, a vitamin K antagonist in healthy subjects in a randomised, double‐blind, placebo‐controlled, crossover study. Twelve healthy Caucasian male subjects randomly received BPS 40 μg t.i.d. or placebo for 3 days. There was a 7 day wash out between the two treatment periods. On day 3 of each treatment, the subjects ingested concomitantly a single oral dose of 20 mg of fluindione. The main assessment criterion was fluindiones pharmacokinetics. Secondarily, pharmacodynamic measurements of coagulation (prothrombin time, and International Normalised Ratio, INR) and platelet function (in vitro closure time assessed by PFA‐100×) were performed. Fluindione was assayed by HPLC with UV detection up to 96 h post‐drug. No statistical difference could be evidenced on any fluindione pharmacokinetic parameters between BPS and placebo phases: t1/2 (h): 35.9 (8.2) vs. 34.0 (4.2) [90% CI 105.8 (95.5–116.2)]; Tmax (h): 2.0 (0.5–6.0) vs. 4.0 (0.5–6.0) [90% CI 136.4 (70.7–208.9)]; Cmax (mg/L): 3.1 (0.6) vs. 2.9 (0.5) [90% CI 94.1 (85.8–103.2)]; AUC 0‐inf (mg/h/L): 117.0 (31.5) vs. 113.9 (33.8) [90% CI 97.6 (87.5–108.8)]. The studied doses of BPS did not affect platelet function, at least as assessed by the in vitro platelet function testing. Twenty milligrams of fluindione marginally modified the PT ratio and INR, however, no statistically significant difference was found between BPS and placebo phases. In conclusion, a 3 day regimen of BPS 40 μg t.i.d. by oral route does not seem to affect pharmacokinetic parameters of a fluindione 20 mg single dose.

Pharmacokinetic-pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjects.

Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK–PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 μg/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi‐compartmental model with zero‐order absorption and a bi‐compartmental model with first‐order absorption. PK–PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi‐compartmental model with zero‐order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0→∞ and Cmax (normalised to the dose 1 μg/kg), t1/2α and t1/2β. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL·min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53).