Lercanidipine, enalapril and their combination in the treatment of elderly hypertensive patients: placebo-controlled, randomized, crossover study with four ABPM.

This double-blind, placebo-controlled, four-way balanced design crossover study included hypertensive patients aged 60-85 years with mean office-measured sitting systolic blood pressure (SBP) 160-179 mm Hg and daytime SBP > or =135 mm Hg. After a 2-week run-in period, during which previous medications were discontinued, each patient received the following four treatments in randomized order for 4 weeks each: lercanidipine 10 mg (L), enalapril 20 mg (E), lercanidipine 10 mg plus enalapril 20 mg (L/E) and placebo (P). At the end of each treatment period, office trough blood pressure (BP) was measured and a 24-h Ambulatory Blood Pressure Monitoring (ABPM) was performed. Seventy-five patients (mean age 66 years, office BP 168/92 mm Hg, daytime SBP 151 mm Hg) were randomized and 62 completed the study with four valid post-baseline ABPMs. The administration of P, L, E and L/E was associated with a mean 24-h SBP of 144, 137, 133 and 127 mm Hg, respectively. All active treatments significantly reduced the mean 24-h SBP in comparison with placebo, but L/E was significantly more effective than L and E alone. Similarly, office SBP was significantly more reduced with L/E (-16.9 mm Hg) than with L (-5.0 mm Hg) or E (-5.9 mm Hg). A BP <140/90 mm Hg was recorded in 18% of patients with L, 19% with E and 45% with L/E. Two patients on P and two on L/E were withdrawn from the study due to adverse events. In conclusion, combination therapy with L/E has additive antihypertensive effects on both ambulatory and office BP in elderly patients and is well tolerated.

Comparison of 27-gauge (0.41-mm) Whitacre and Quincke spinal needles with respect to post-dural puncture headache and non-dural puncture headache.

BACKGROUND: The incidence of headache after spinal anaesthesia has varied greatly between studies. We compared the incidence of postoperative headache in general and postdural puncture headache (PDPH) when using 27-gauge (G) (outer diameter 0.41 mm) Quincke and Whitacre spinal needles in ambulatory surgery performed under spinal anaesthesia. METHODS: In a prospective, randomized study, 676 ASA physical status I-II day-case outpatients were given a spinal anaesthetic through either a 27-G (0.41 mm) Quincke or a 27-G (0.41 mm) Whitacre spinal needle. The incidence of any type of postoperative headache was assessed and the type of headache defined using a standardized questionnaire including PDPH criteria. The severity of the headache was defined using a 100-mm visual analogue scale. RESULTS: For the final analysis, 529 patients were available (259 patients in the Quincke group and 270 patients in the Whitacre group). The overall incidence of postoperative headache was 20.0%, but the incidence of true PDPH was very low (1.51%). The incidence of PDPH in the Quincke group was 2.70%, while in the Whitacre group it was only 0.37% (P < 0.05). The overall incidence of non-dural puncture headache was 18.5% and did not differ between the study groups. CONCLUSIONS: True PDPH seldom occurs when a 27-G (0.41 mm) spinal needle is used, although postoperatively a non-specific headache is common. Using the 27-G (0.41 mm) Whitacre spinal needle further reduced the incidence of PDPH. Thus, we recommend routine use of the 27-G (0.41 mm) Whitacre spinal needle when performing spinal anaesthesia.

Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid.

OBJECTIVE: The aim of this study was to examine the effect of carbamazepine on the pharmacokinetics of orally administered simvastatin in healthy volunteers. METHODS: In a randomised, two-phase crossover study and a wash out of 2 weeks, 12 healthy volunteers took carbamazepine for 14 days (600 mg daily except 200 mg daily for the first 2 days) or no drug. On day 15, each subject ingested 80 mg simvastatin. Serum concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 24 h. RESULTS: Carbamazepine decreased the mean total area under the serum concentration-time curve of simvastatin and simvastatin acid by 75% ( P<0.001) and 82% ( P<0.001), respectively. The mean peak concentrations of both simvastatin and simvastatin acid were reduced by 68% ( P<0.01), and half-life of simvastatin acid was shortened from 5.9+/-0.3 h to 3.7+/-0.5 h ( P<0.01) by carbamazepine. CONCLUSION: Carbamazepine greatly reduces the serum concentrations of simvastatin and simvastatin acid, probably by inducing their metabolism. Concomitant administration of carbamazepine and simvastatin should be avoided or the dose of simvastatin should be considerably increased.

Serious overdoses involving buprenorphine in Helsinki.

BACKGROUND: Buprenorphine is used as maintenance therapy for opioid-dependent patients. In comparison with other opioids it is thought to be safer because it is less likely to cause serious respiratory depression. However, concomitant use of psychotropics, especially benzodiazepines, and intravenous injection of dissolved buprenorphine tablets increase the risk of a serious overdose. METHODS: As part of a larger retrospective study of opioid overdoses in Helsinki, the emergency medical services (EMS) records from January 1995 to April 2002 were reviewed for overdoses involving buprenorphine. Hospital records were reviewed when available. RESULTS: We report 11 overdoses in which buprenorphine was involved. The classic symptoms and signs of an opioid overdose (respiratory depression, miosis and central nervous system depression) were present in most of the cases. At least eight of the patients had an overdose that was potentially fatal. One of the patients had a heroin overdose and was reportedly 'treated' by his friends with intravenously administered buprenorphine. CONCLUSION: The high-dosage formulation of buprenorphine used for opioid-dependent patients might have caused several dangerous and potentially fatal overdoses in Helsinki. However, it does cause considerably less serious overdoses than heroin. Drug abusers might be intravenously administering buprenorphine themselves to treat heroin overdoses.

Preoperative diclofenac is a useful adjunct to spinal anesthesia for day-case varicose vein repair.

PURPOSE: To examine if preoperative diclofenac 50 mg or diazepam 10 mg po are useful adjuncts to spinal anesthesia for day-case varicose vein repair. METHODS: Two hundred ASA physical status I-II outpatients, age 18-60 yr, were randomized to receive either diclofenac 50 mg po or diazepam 10 mg po one hour before operation in a double-blind fashion (100 patients in both groups). If the patient was distressed or feared the spinal puncture and requested sedation, a bolus dose of alfentanil 0.5 mg was given i.v. as a rescue medication. On request, patients received diclofenac 50 mg po and, when needed, oxycodone 0.1 mg x kg(-1) im for postoperative pain relief. They were discharged with a supply of diclofenac 50 mg tablets and were asked to record postoperative pain using a visual analogue scale (VAS) and quantity of tablets taken. RESULTS: The VAS scores (+/- SD) eight hours after surgery, the next morning, and in the morning and at the end of the first and second postoperative days were 23 +/- 21, 12 +/- 17, 11 +/- 15, 8 +/- 15 and 8 +/- 15 in the diclofenac group, and 24 +/- 23, 12 +/- 20, 10 +/- 17, 8 +/- 16 and 7 +/- 14 in the diazepam group, respectively (NS). In the diclofenac and diazepam groups, 31% and 67% of the patients required postoperative diclofenac during the first eight postoperative hours (P <0.05). Diazepam premedication did not alter the number of patients who required alfentanil before spinal puncture. CONCLUSION: Diclofenac premedication reduced the analgesic requirements during the first eight hours after varicose vein repair.

Intra-articular ropivacaine injection does not alleviate pain after day-case knee arthroscopy performed under spinal anaesthesia.

BACKGROUND AND AIMS: To evaluate the effect of intra-articular ropivacaine injection on postoperative knee pain after day case arthroscopy. MATERIAL AND METHODS: We studied one hundred outpatients in a prospective, randomized, double-blind fashion to examine the postoperative analgesic effect of intra-articular ropivacaine or saline injected into the knee joint after day-case knee arthroscopy performed under spinal anaesthesia. Patients were interviewed postoperatively with a standardized questionnaire. The postoperative pain was measured using a 100-mm visual analogue scale (VAS). RESULTS: There were no statistically significant differences in the VAS scores of knee pain eight hours or more after the operation between the intra-articular ropivacaine and saline groups, and there was no significant difference in the need for postoperative pain killer. CONCLUSIONS: This study failed to demonstrate a decrease in postoperative VAS scores at eight hours and later postoperatively when 20 ml of ropivacaine 0.5% were injected intra-articularly after day-case knee arthroscopy performed under spinal anaesthesia. Furthermore, there was no significant difference in the need for postoperative pain medication between the study groups.

Diclofenac premedication but not intra-articular ropivacaine alleviates pain following day-case knee arthroscopy.

PURPOSE: To compare the postoperative analgesic effects of 50 mg diclofenac p.o. before surgery and intra-articular ropivacaine injected after diagnostic day-case knee arthroscopy performed under spinal anesthesia. METHODS: In a randomized, double-blind investigation, 200 ASA physical status 1-2 outpatients, age 18-60 yr, received either 50 mg diclofenac p.o. or placebo one hour before operation (100 patients per group), and intraarticular injections of either 20 ml of ropivacaine 0.5% or 20 ml of saline 0.9% (50 patients in each premedication groups). Patients received 50 mg diclofenac p.o. prn and, if needed, 0.1 mg x kg(-1) oxycodone im for postoperative pain relief. Patients were discharged home with a supply of 50 mg diclofenac tablets and were given a sheet of paper with knee pain VAS scales and a questionnaire of analgesics taken. Patients rated their VAS scores eight hours after surgery and in the moming and at the end of the first and the second postoperative days, respectively. RESULTS: The only statistically significant difference was found when the diclofenac groups were combined and compared with the combined placebo premedication groups. The VAS scores of knee pain at eight hours after the operation were 19+/-22 in the two diclofenac premedication groups and 32+/-28 in the two placebo groups (P = 0.001). CONCLUSIONS: Diclofenac premedication p.o. reduced the VAS scores at eight hours postoperatively while intra-articular ropivacaine did not.

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem.

OBJECTIVE: Zolpidem is a short-acting imidazopyridine hypnotic which is biotransformed in humans mainly by CYP3A4. Itraconazole strongly interacts with many substrates of CYP3A4 such as midazolam and triazolam. In this study, the effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem was investigated to uncover a possible clinically significant interaction. METHODS: In a randomized cross-over study with two phases, ten healthy volunteers took either 200 mg itraconazole or placebo once daily for 4 days. A single oral dose of 10 mg zolpidem was given on day 4. Plasma drug concentrations were measured up to 17 h and effects of zolpidem up to 9 h after the ingestion of zolpidem. RESULTS: Itraconazole had no marked effects on the pharmacokinetics of zolpidem; the total area under the plasma zolpidem concentration-time curve (AUC0-infinity) was 34% larger during the itraconazole phase (759 ng x h x ml(-1)) than during the placebo phase (567 ng x h x ml(-1)). Exophoria of the eyes by the Maddox wing test was significantly increased by itraconazole, but the results of the digit symbol substitution test, critical flicker fusion test, postural sway tests and the visual analogue scale tests for subjective drowsiness and overall drug effect did not differ between the phases. CONCLUSION: The pharmacokinetics and pharmacodynamics of zolpidem were not remarkably affected by itraconazole in healthy volunteers. Therefore, unlike triazolam, for example, zolpidem can be used in normal or nearly normal doses together with itraconazole and probably also with other CYP3A4 inhibitors.

Rifampin reduces plasma concentrations and effects of zolpidem.

BACKGROUND: Zolpidem is a short-acting imidazopyridine hypnotic drug that is metabolized mainly by CYP3A4. Rifampin (INN, rifampicin) is a potent inducer of many cytochrome P450 enzymes, and it greatly reduces the plasma concentrations and effects of, for example, midazolam, triazolam, and zopiclone. In this study, the effects of rifampin on the pharmacokinetics and pharmacodynamics of zolpidem were studied. METHODS: In a randomized crossover study with two phases and a washout of 4 weeks, eight young healthy female volunteers took either 600 mg rifampin or placebo once a day for 5 days. On day 6, 20 mg zolpidem was administered orally. Plasma concentrations and effects of zolpidem were measured up to 10 hours. RESULTS: The total area under the plasma zolpidem concentration-time curve after administration of rifampin was 27% of that after administration of placebo (336 +/- 67 versus 1202 +/- 157 ng.hr/ml [mean value +/- SEM; p < 0.01]). Rifampin decreased the peak plasma concentration of zolpidem by 58%, that is, from 293 +/- 61 to 117 +/- 25 ng/ml (p < 0.01) and the elimination half-life from 2.5 +/- 0.2 to 1.6 +/- 0.1 hours (p < 0.01). A significant (p < 0.05) reduction in the effects of zolpidem was seen in all six pharmacodynamic tests after rifampin pretreatment. CONCLUSIONS: The effects of zolpidem are considerably reduced by rifampin because of enhanced metabolism of zolpidem. It is likely that zolpidem also shows a reduced hypnotic effect when used concomitantly with other potent inducers of CYP3A4, such as phenytoin and carbamazepine.

Pharmacokinetic-pharmacodynamic modelling of zopiclone effects on human central nervous system.

The present data shows the pharmacokinetics and concentration-effect relationship of a single 7.5 mg oral dose of zopiclone in ten healthy volunteers. Plasma concentrations and effects of zopiclone on central nervous system as quantified by changes in saccadic peak velocity and digit symbol substitution test were measured for 17 hr after ingestion of zopiclone. Pharmacokinetics was described with a linear one-compartment open model. Maximum effects preceded peak plasma zopiclone concentrations causing a clockwise hysteresis, i.e. proteresis, in concentration versus effect loops. Therefore, pharmacodynamics was described both with a tolerance model and a model with distributional pseudo-tolerance where the concentration in the blood sampling site is assumed to equilibrate slower with arterial blood than the site of action of zopiclone. Both models related the changes in pharmacodynamics linearly to changes in zopiclone concentrations. The median (range) values for clearance, volume of distribution and elimination half-life were 21 (15-53) L/hr, 132 (58-161) L and 3.4 (1.7-5.7) hr, respectively. Both pharmacodynamic models were able to describe the relationship between zopiclone concentrations and changes in psychomotor performance equally well. However, because the pharmacodynamics of zopiclone were studied in a non-steady-state situation, the mechanism for proteresis, i.e. true tolerance versus distributional pseudotolerance cannot be identified.

Interaction between erythromycin and the benzodiazepines diazepam and flunitrazepam.

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of diazepam and flunitrazepam was investigated in two randomized, double-blind, cross-over studies. Healthy volunteers ingested erythromycin for one week 500 mg t.i.d. On the 4th day they ingested a single 5 mg dose of diazepam (6 subject, Study 1) or 1 mg dose of flunitrazepam (5 subjects, Study 2), respectively. Plasma drug concentrations and psychomotor effects were measured during 42 hr after the ingestion of diazepam or flunitrazepam. In Study 1 erythromycin increased the area under the diazepam plasma concentration-time curve [AUC (0-42 hr)] by 15% (P < 0.05) and the concentration of diazepam in plasma at 42 hr by 63% (P < 0.05). The median peak concentration (Cmax) and the half-life (t1/2) of diazepam were increased but they did not change significantly (P = 0.17 and 0.12, respectively). Plasma N-desmethyldiazepam concentrations were slightly reduced during erythromycin treatment up to 8 hr (P < 0.05). In Study 2 the AUC (0-42 hr) of flunitrazepam was increased by 25% (P < 0.05) during the erythromycin treatment. The t1/2 of flunitrazepam increased significantly (P < 0.05), but the Cmax remained unchanged. The psychomotor effects of diazepam or flunitrazepam were not changed significantly by erythromycin. These pharmacokinetic interactions can be explained by the reduced metabolic elimination of diazepam and flunitrazepam. The interactions of erythromycin with diazepam and flunitrazepam seem to be slight and of limited clinical significance only.

Interaction between erythromycin and nitrazepam in healthy volunteers.

Interaction between erythromycin, a strong inhibitor of CYP3A4, and nitrazepam, a long-acting benzodiazepine, was investigated in a double-blind and randomized cross-over study of two phases. Ten healthy volunteers received erythromycin (500 mg x 3) orally or placebo for 6 days. On the fourth day they were given a challenge dose of 5 mg nitrazepam. Plasma samples were collected and psychomotor effects were measured during 42 hr after intake of nitrazepam. There was a statistically significant pharmacokinetic interaction between erythromycin and nitrazepam. Erythromycin increased the area under the nitrazepam concentration-time curve by 25% (P < 0.05) and the peak concentration by 30% (P < 0.05). The concentration peak time of nitrazepam was shortened by over 50% (P < 0.05). The elimination half-lives did not change. Accordingly, as far as the metabolism of nitrazepam is concerned, erythromycin does not cause any major changes in the metabolism of nitrazepam. In psychomotor performance only minor differences were seen. It is concluded that the interaction between erythromycin and nitrazepam is of little clinical significance.

Lack of interaction of erythromycin with temazepam.

Erythromycin is a strong inhibitor of cytochrome P450 [CYP3A4] and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between erythromycin and a short-acting benzodiazepine, temazepam, was investigated in a double-blind, randomized crossover study. Ten healthy volunteers received 500 mg erythromycin or placebo orally three times a day for 6 days followed by a challenge dose of 20 mg temazepam. Plasma samples were collected for the determination of temazepam, oxazepam, and erythromycin, and psychomotor effects were measured during the 24 h after intake of temazepam. Erythromycin did not change the pharmacokinetics or pharmacodynamics of temazepam to a statistically significant degree. The metabolic fate of temazepam and its almost complete bioavailability explain the lack of interaction. Temazepam, unlike midazolam or triazolam, can thus be prescribed in the usual doses for patients receiving erythromycin.

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone.

1. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of oral zopiclone, a non-benzodiazepine hypnotic, was investigated in a double-blind, cross-over study. 2. Ten healthy volunteers were given placebo or 500 mg erythromycin orally three times a day for 6 days followed by an oral dose of 7.5 mg zopiclone. 3. Erythromycin increased plasma zopiclone concentration by 4-fold at 0.5 h (P < 0.05) and by 2-fold at 1 h (P < 0.05). There were increases of 3- and 2-fold in the AUC(0,1 h) and AUC(0,2 h) values (P < 0.05). The total AUC of zopiclone increased by 80% (P < 0.05) but the peak concentration by only 40% (P < 0.05). The peak time of zopiclone concentration was reduced from 2 to 1 h (P < 0.001). 4. Significant pharmacodynamic differences between the treatments were observed from 0.5 h to 2 h with respect to saccadic latency and digit symbol substitution tests. 5. The interaction between erythromycin and zopiclone resulted mainly in accelerated absorption which may lead to a faster hypnotic effect in patients.

A potentially hazardous interaction between erythromycin and midazolam.

Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pretreatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration-time curve after oral intake more than four times (p < 0.001) and reduced clearance of intravenously administered midazolam by 54% (p < 0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p < 0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.