Showing papers in "British Journal of Clinical Pharmacology in 1996"
TL;DR: In this article, the effect of alpha 2-adrenoceptor antagonism with yohimbine on tramadol analgesia was investigated in a randomized, double-blind crossover, placebo (P) controlled design.
Abstract: 1. In humans, the central analgesic effect of tramadol 100 mg orally is only partially reversed by the opioid antagonist naloxone (0.8 mg intravenously). As suggested by in vitro and animal data tramadol analgesia may thus result from an action on opioid as well as monoaminergic pathways. We therefore investigated the effect of alpha 2-adrenoceptor antagonism with yohimbine on tramadol analgesia. 2. Healthy volunteers (n = 10) received tramadol (100 mg orally), followed (+3 h) by yohimbine (0.1 mg kg-1 intravenously), and yohimbine + naloxone (0.8 mg intravenously) and their respective placebo according to a randomized, double-blind crossover, placebo (P) controlled design. Analgesia was assessed over 8 h by subjective pain threshold (pain intensity numerical scale--PINS) and objective pain threshold (RIII nociceptive reflex--RIII) monitoring. 3. Tramadol induced a significant increase in both pain thresholds. Peak analgesic effect was observed at 3.7 h (RIII + 39.6 +/- 3.9% and PINS 50.1 +/- s.e.mean 5%) and the analgesia lasted about 6 h. 4. Yohimbine significantly reversed the analgesic effects of tramadol for 2.8 h with a maximum decrease of 97 +/- 4% (RIII) and 67 +/- 12% (PINS), whereas the addition of naloxone abolished tramadol effects throughout the study period with a decrease of 90 +/- 6% (RIII) and 79 +/- 9% (PINS), P < 0.05). 5. Yohimbine alone did not significantly reduce pain thresholds. 6. alpha 2-Adrenoceptor antagonism reverses tramadol effects, thus pointing to the significant role of monoaminergic modulation and the synergy with opioid agonism in tramadol antinociception after a single oral dose.
245 citations
TL;DR: In vitro findings predict phenotypic differences in the kinetics of venlafaxine in vivo, although the clinical importance of this is unclear as O-demethylvenlafxine is pharmacologically similar to the parent drug.
Abstract: 1 Several selective 5-HT reuptake inhibitors (SSRIs) are inhibitors of the genetically polymorphic drug metabolizing enzyme, CYP2D6. We studied the interaction of venlafaxine, a new SSRI, with CYP2D6 in human liver microsomes.
2 Venlafaxine was a less potent inhibitor of this enzyme activity in vitro than other SSRIs tested. The average apparent Ki values determined using CYP2D6-dependent dextromethorphan O-demethylation were: 33, 52 and 22 μM for rac-venlafaxine, R(+)-venlafaxine and S(-)-venlafaxine, respectively, vs 0.065 to 1.8 μM for paroxetine, fluoxetine, norfluoxetine, fluvoxamine and sertraline.
3 Microsomes from human livers (n= 3) and from yeast transformed with an expression plasmid containing human CYP2D6 cDNA catalyzed the O-demethylation of venlafaxine, which is the major metabolic pathway in vivo. Intrinsic metabolic clearance values (Vmax/Km) indicated that S(-)-venlafaxine was cleared preferentially via this pathway.
4 In microsomes from CYP2D6-deficient livers (n= 2), Vmax/Kmax of O-demethylation of venlafaxine was one to two orders of magnitude lower and was similar to the rate of N-demethylation.
5 Studies with chemical probes which preferentially inhibit P450 isoforms suggested that CYP3A3/4 is involved in venlafaxine N-demethylation.
6 These in vitro findings predict phenotypic differences in the kinetics of venlafaxine in vivo, although the clinical importance of this is unclear as O-demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.
225 citations
TL;DR: The extent of under-reporting of serious suspected adverse drug reactions to the Committee on Safety of Medicines from an acute hospital medical unit is confirmed and quantified.
Abstract: 1. We have retrospectively analysed data collected by a local adverse drug reactions reporting scheme in an acute hospital medical setting and have determined the numbers and types of reactions that would have merited notification as yellow card reports according to the guidelines of the Committee on Safety of Medicines. 2. The data related to 20,695 consecutive acute general medical admissions on seven general medical wards (140 beds) and were collected over 3 years, from April 1990 to March 1993. 3. Over 3 years there were 1420 reports of suspected adverse drug reactions, a rate of 68.7 per 1000 admissions. 4. If the guidelines for reporting issued by the Committee on Safety of Medicines had been strictly followed, 477 yellow cards would have been sent (23.1 per 1000 admissions). In 357 of these reports (74.8%), the reaction had caused admission to hospital. Only 31 of the 477 potential cards (6.5%) involved black triangle drugs and 10 of these were for minor reactions. 5. Only 30 of the 477 potential yellow cards (6.3%) were known to have been sent. The majority of those reactions not reported were for drug-related admissions, most of which were for well-known reactions to established drugs. 6. We have confirmed and quantified the extent of under-reporting of serious suspected adverse drug reactions to the Committee on Safety of Medicines from our hospital medical unit.
186 citations
TL;DR: There is evidence that lamotrigine, zonisamide, felbamate and, possibly, topiramate may also be effective in generalized epilepsies, and further studies are required to characterize their activity spectrum as well as their potential value in monotherapy.
Abstract: 1. After a hiatus of over 20 years, several new antiepileptic drugs (vigabatrin, lamotrigine, gabapentin, oxcarbazepine, topiramate, felbamate, zonisamide and tiagabine) have reached or approached the registration phase. 2. Compared with older agents, many new drugs exhibit simpler pharmacokinetics. This is especially true for vigabatrin and gabapentin, which are renally eliminated and have a low interaction potential. 3. Unlike most of the older agents, vigabatrin, lamotrigine, gabapentin and tiagabine are devoid of significant enzyme inducing or inhibiting properties. Topiramate, oxcarbazepine and felbamate may induce the metabolism of steroid oral contraceptives. In addition, felbamate also acts as a metabolic inhibitor. 4. To date, the efficacy of new drugs has been evaluated extensively only under add-on conditions in patients with partial seizures (with or without secondary generalization) refractory to conventional treatment. However, there is evidence that lamotrigine, zonisamide, felbamate and, possibly, topiramate may also be effective in generalized epilepsies. 5. In placebo-controlled studies, typically between 15 and 40% of patients with difficult-to-treat partial epilepsy have shown an improvement (defined as a 50% or greater decrease in seizure frequency) after addition of a new drug. Only a small minority of these patients achieved complete seizure control. 6. Compared with older agents, some of the new drugs may have a better tolerability profile. Felbamate, however, has been associated with a high risk of aplastic anaemia and hepatotoxicity. 7. At present, the main use of the new agents is in patients refractory to first-line drugs such as carbamazepine or valproate, and further studies are required to characterize their activity spectrum as well as their potential value in monotherapy. In most patients, new drugs cannot be recommended for first-line use until evidence is obtained that potential advantages in tolerability or ease of use outweigh the drawback of their high cost.
174 citations
119 citations
TL;DR: In this age of modern era, the use of internet must be maximized to get the on-line analysing survival data from clinical trials and observational studies book, as the world window, as many people suggest.
Abstract: In this age of modern era, the use of internet must be maximized. Yeah, internet will help us very much not only for important thing but also for daily activities. Many people now, from any level can use internet. The sources of internet connection can also be enjoyed in many places. As one of the benefits is to get the on-line analysing survival data from clinical trials and observational studies book, as the world window, as many people suggest.
108 citations
TL;DR: The active (-)R enantiomers of salbutamol undergoes significantly faster metabolism in man than the inactive (+)S enantiomer resulting in considerably lower bioavailability of the active enantiome following oral administration.
Abstract: 1 Salbutamol is a beta 2-adrenoceptor stimulant used clinically as a racemate where the activity resides predominantly in the (-)R enantiomer with little or no activity attributed to the (+)S enantiomer. Salbutamol undergoes extensive pre-systemic metabolism and active renal excretion. 2 The pharmacokinetics of the enantiomers of salbutamol have been investigated after intravenous (1.6 mg) and oral (4 mg) dosing with racemic drug to seven normal male volunteers. Plasma and urine samples were analysed by chiral h.p.l.c. after solid phase extraction. 3 The ratio of (-)R/(+)S salbutamol in plasma and urine following intravenous administration ranged from near unity soon after dosing to about 0.66 after 8 h. The ratio remained at about 0.3 in both plasma and urine over the 8 h following an oral dose. 4 The following pharmacokinetic parameters for (+)S and (-)R salbutamol were found to be significantly different (P < 0.05) after intravenous administration (clearance 0.39 +/- 0.12 vs 0.62 +/- 0.18 1 h-1 kg-1, terminal phase half-life 2.85 +/- 0.83 vs 2.00 +/- 0.49 h, amount excreted unchanged in urine 55 +/- 11 vs 46 +/- 8%) and following oral administration (amount excreted unchanged in urine 32 +/- 11 vs 8 +/- 4% and bioavailability 0.71 +/- 0.09 vs 0.30 +/- 0.07). 5 The active (-)R enantiomer of salbutamol undergoes significantly faster metabolism in man than the inactive (+)S enantiomer resulting in considerably lower bioavailability of the active enantiomer following oral administration.
107 citations
TL;DR: Olanzapine, clozapine and ketoconazole were all found to non-competitively inhibit 1'-hydroxy midazolam formation, form selective for CYP3A, yielding Ki values of 491, 99 and 0.11 microM, respectively.
Abstract: 1. The ability of olanzapine to inhibit the metabolism of marker catalytic activities for the cytochromes P450 CYP3A, CYP2D6, CYP2C9, and CYP2C19 was examined. This inhibitory capability was compared with that obtained with clozapine and known inhibitory compounds for the same cytochromes P450. 2. Olanzapine, clozapine, and ketoconazole were all found to non-competitively inhibit 1'-hydroxy midazolam formation, form selective for CYP3A, yielding Ki values of 491, 99 and 0.11 microM, respectively. The 1'-hydroxylation of bufuralol, form selective for CYP2D6, was competitively inhibited by olanzapine (Ki = 89 microM), clozapine (Ki = 19 microM), and quinidine (Ki = 0.03 microM). Tolbutamide metabolism to 4-hydroxy tolbutamide, form selective for CYP2C9, was competitively inhibited by clozapine and phenytoin (Ki of 31 microM and 17 microM, respectively). Olanzapine non-competitively inhibited tolbutamide metabolism with a Ki of 715 microM. The marker catalytic activity for CYP2C19 mediated metabolism, 4'-hydroxy S-mephenytoin formation, was competitively inhibited by clozapine (Ki = 69 microM) and omeprazole (Ki = 4.1 microM). Non-competitive inhibition of CYP2C19 mediated metabolism was seen with olanzapine with a Ki of 920 microM. 3. The calculated percent inhibition by olanzapine of substrates metabolized by CYP3A, CYP2D6, CYP2C9, and CYP2C19 was modeled assuming a total plasma concentration in the therapeutic range (0.2 microM). Total olanzapine vs unbound olanzapine was used to model the worst case (most conservative) situation. In all cases, the calculated percent inhibition of these cytochromes P450 by olanzapine was < 0.3%, suggesting that there would be little in vivo inhibition of the metabolism of substrates of these enzymes when co-administered with olanzapine.
101 citations
TL;DR: It is demonstrated that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA, suggesting that it would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.
Abstract: 1 The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg-1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.-ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same samples by a sensitive bioassay (BA).
2 Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l-1 and for DHA of 1009 (639 to 1379) nmol l-1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half-life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.-ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo.
3 Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC(0,6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether.
4 These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.
89 citations
TL;DR: Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.
Abstract: 1. Cyclophosphamide pharmacokinetics were measured in 38 children with cancer. 2. A high degree of inter-patient variation was seen in all pharmacokinetic parameters. Cyclophosphamide half-life varied between 1.1 and 16.8 h, clearance varied between 1.2 and 10.61 h-1 m-2 and volume of distribution varied between 0.26 and 1.48 1 kg-1. 3. The half-life of cyclophosphamide was prolonged at high dose levels (P = 0.008). 4. Children who had received prior treatment with dexamethasone showed a mean increase in clearance of 2.51 h-1 m-2 (P = 0.001) presumably as a result of CYP450 enzyme induction. 5. Treatment with allopurinol or chlorpromazine was associated with a significant increase in cyclophosphamide half-life (P < 0.001 in both cases). 6. Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.
79 citations
TL;DR: It is concluded that amlodipine and diltiazem are fairly similar in lowering blood pressure from an efficacy point of view, however, during short periods of noncompliance blood pressure control will persist markedly better with the agent with a long vs the one with a short elimination half-life.
Abstract: 1. Calcium antagonists with long vs short elimination half-life may show marked differences in their antihypertensive effect during short interruptions of therapy by missed doses. 2. In the present study we evaluated the blood pressure lowering effect of amlodipine vs diltiazem both on active maintenance treatment and after active treatment was interrupted for 2 days by placebo using a double-blind randomized design. After a single blind placebo run-in period, hypertensive patients were randomized to amlodipine 5 mg once daily or diltiazem 90 mg twice daily. After 4-6 weeks, doses were increased to 10 mg once daily or 180 mg twice daily, if necessary for control of diastolic blood pressure. During week 9 or 10 on active treatment blisterpacks contained 2 days of placebo. Twenty-four hour blood pressure monitoring was performed at the end of run-in period and during week 9 and 10 on active vs interrupted therapy. 3. Active therapy by amlodipine (n = 20) lowered day systolic blood pressure by 17 +/- 2 mmHg and diastolic blood pressure by 12 +/- 2 mmHg and did not change heart rate. In second day of interrupted therapy most of these responses were still present. Diltiazem (n = 14) lowered day systolic blood pressure by 13 +/- 2 mmHg, diastolic blood pressure by 11 +/- 2 mmHg and heart rate by 10 +/- 2 beats min-1. Most of these responses had disappeared during the second day of interrupted therapy. 4. We conclude that amlodipine and diltiazem are fairly similar in lowering blood pressure from an efficacy point of view. However, during short periods of noncompliance blood pressure control will persist markedly better with the agent with a long vs the one with a short elimination half-life.
TL;DR: Since sumatriptan is usually administered as a single dose at infrequent intervals, the low level of excretion in breast milk suggests that continued breast feeding following its use will not pose a significant risk to the suckling infant.
Abstract: 1. The excretion of a 6 mg subcutaneous dose of sumatriptan in breast milk was studied in five lactating volunteer subjects with a mean age of 27.6 years and a mean body weight of 75 kg. Drug concentrations in milk and plasma over the ensuing 8 h were measured by high-performance liquid chromatography. 2. The mean milk:plasma ratio estimated from the areas under the milk and plasma concentration-time curves (AUC) was 4.9 (95% CI 4.1-5.7), indicating a significant transfer of sumatriptan into the milk compartment. 3. The mean total recovery of drug in milk was estimated to be only 14.4 micrograms (95% CI 6.1-22.7 micrograms), or 0.24% of the 6 mg administered dose. On a weight-adjusted basis this corresponded to a mean infant exposure of 3.5% of the maternal dose (95% CI 0.3-6.7%). 4. If oral bioavailability in the infant is similar to that in adults (14%), the weight-adjusted infant dose is reduced to 0.49%. Furthermore, allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in a very premature neonate to 0.7% in a 30 week old infant. 5. Since sumatriptan is usually administered as a single dose at infrequent intervals, the low level of excretion in breast milk suggests that continued breast feeding following its use will not pose a significant risk to the suckling infant. Even this minor exposure could be largely avoided by expressing and discarding all milk for 8 h after the dose.
TL;DR: Even a small 50 mg daily dose of fluconazole can interact with triazolam and the extent of the interaction increases with increasing flu Conazole dose, which should be reduced, accordingly.
Abstract: 1. Azole antimycotics interact with the short acting hypnotic triazolam. The effect of fluconazole dose on the extent of fluconazole-triazolam interaction was investigated in a double-blind, randomized cross-over study of four phases. 2. Eight healthy volunteers received either 50 mg, 100 mg or 200 mg (400 mg on day 1) of fluconazole or placebo orally once a day for 4 days. On day 4, they took a 0.25 mg oral dose of triazolam, after which plasma samples were collected and pharmacodynamic effects measured for 18 h. 3. The mean area under the triazolam concentration-time curve (AUC) was increased 1.6-, 2.1- and 4.4-fold (P < 0.001) by fluconazole 50 mg, 100 mg and 200 mg, respectively. The increase in the elimination half-life of triazolam (t1/2,z) varied from 1.3-fold (fluconazole 50 mg, P < 0.05) to 2.3-fold (fluconazole 200 mg, P < 0.001). The peak concentration of triazolam was also increased significantly during all fluconazole phases; more than twofold by fluconazole 200 mg (P < 0.001). 4. The pharmacodynamic effects of triazolam were increased significantly (P < 0.05) by fluconazole 100 mg and 200 mg. 5. Even a small 50 mg daily dose of fluconazole can interact with triazolam and the extent of the interaction increases with increasing fluconazole dose. When triazolam is used concomitantly with fluconazole 50-200 mg, the dose of triazolam should be reduced, accordingly. Simultaneous use of triazolam with higher fluconazole doses should be avoided.
TL;DR: 311C90 showed no clinically significant effects on blood pressure, heart rate, ECG or laboratory variables at any dose and demonstrated a tolerability and pharmacokinetic profile compatible with an acute oral migraine treatment.
Abstract: 1 311C90 is a novel and selective agonist at 5-HT1D receptors, with central and peripheral actions, currently in development for the acute oral treatment of migraine.
2 The pharmacokinetic and tolerability profiles of single oral doses from 1–50 mg 311C90 were investigated in 12 healthy male volunteers in a double-blind, placebo-controlled, dose-escalating study.
3 311C90 was well tolerated with most adverse experiences of mild and transient nature.
4 Absorption was rapid with dose-independent kinetics. Median tmax was 2–4 h although 50–85% of eventual Cmax was attained within 1 h. The t1/2 was 2.5-3 h with a high apparent plasma clearance (CL/F > 2000 ml min-1) and apparent volume of distribution (VZ/F) of 400–5001.
5 Three metabolites were detected in plasma and urine, one of which, the N-desmethyl metabolite, has 5-HT1D agonist activity.
6 311C90 showed no clinically significant effects on blood pressure, heart rate, ECG or laboratory variables at any dose and demonstrated a tolerability and pharmacokinetic profile compatible with an acute oral migraine treatment.
TL;DR: It is emphasized that the smooth muscle of the bronchi most likely are exposed to considerably higher concentrations of the potentially toxic (+)-enantiomer than of theBronchodilating (-)-enaliomer during therapy with (+/-)-salbutamol.
Abstract: 1 The metabolism of (+)-, (-)- and (±)-salbutamol by sulphoconjugation was determined in vitro using human lung cytosol and bronchial epithelial BEAS-2B cell homogenate.
2 For the lungs the intrinsic clearance (Vmax/Km) value for the pharmacologically active (-)-salbutamol (0.49 ± 0.32 ml min--1 g-1 protein) exceeded that of (+)-salbutamol (0.046 ± 0.028 ml min-1 g-1 protein) by 11-fold. This was mainly due to a difference in Km value, which was 16 times higher for (+)-salbutamol (1300 ± 170 μM) than for (-)-salbutamol (83 ± 12 μM).
3 The stereoselectivity of sulphoconjugation of salbutamol was very similar in the BEAS-2B cells, although the absolute activity was considerably lower.
4 The enzyme catalyzing this reaction both in the lungs and in the BEAS-2B cells was the monoamine (M) form phenolsulphotransferase.
5 These observations emphasize that the smooth muscle of the bronchi most likely are exposed to considerably higher concentrations of the potentially toxic (+)-enantiomer than of the bronchodilating (-)-enantiomer during therapy with (±)-salbutamol.
TL;DR: It is concluded that reboxetine at doses of 4 mg and below is free from disruptive effects on cognitive function and psychomotor performance, and that it does not act synergistically with alcohol, in contrast to amitriptyline.
Abstract: Reboxetine is a novel antidepressant that has been shown to be effective in the treatment of major depressive disorders. The present experiment was designed to assess whether it affects the cognitive and psychomotor skills necessary for optimum function in everyday life. Ten healthy male volunteers received reboxetine 0.5 mg, 1 mg or 4 mg, amitriptyline 25 mg, or matched placebo with and without alcohol (0.6 mg kg−1) in a double-blind 10-way crossover study. A psychometric test battery was administered at baseline and at 1, 2.25, 3.5, 6 and 9 h post-dose. The results showed that reboxetine had little or no effect on performance at any dose, compared with placebo. Amitriptyline, however, with and without alcohol, lowered critical flicker fusion threshold compared with placebo and/or reboxetine at all test points (e.g. at 3.5 h: 28.51 vs 30.33 Hz; P<0.05); increased reaction time (e.g. 619 vs 540 ms; P<0.05); increased tracking error (e.g. 16.34 vs 8.54 RMS units; P<0.05); and slowed short-term memory scanning (e.g. 742 vs 590 ms; P<0.05). It is concluded that reboxetine at doses of 4 mg and below is free from disruptive effects on cognitive function and psychomotor performance, and that it does not act synergistically with alcohol, in contrast to amitriptyline.
TL;DR: Fifteen drugs which inhibit the in vitro metabolism of tacrolimus were identified: bromocriptine, corticosterone, dexamethasone, ergotamine, erythromycin, ethinyloestradiol, josamycin, ketoconazole, miconazoles, midazolam, nifedipine, omeprazole, tamoxifen and troleandomycin.
Abstract: 1. Tacrolimus, an immunosuppressive macrolide, is metabolized by enzymes of the cytochrome P450 3A subfamily. In this study, 34 drugs were tested for their interactions with tacrolimus metabolism by human liver microsomes. 2. Fifteen drugs which inhibit the in vitro metabolism of tacrolimus were identified: bromocriptine, corticosterone, dexamethasone, ergotamine, erythromycin, ethinyloestradiol, josamycin, ketoconazole, miconazole, midazolam, nifedipine, omeprazole, tamoxifen, troleandomycin and verapamil.
TL;DR: The pharmacokinetics of four single-dose treatments of the metformin administered orally (as the HCl salt) were compared in 24 healthy subjects and found that bioavailability is 24% lower, and the peak concentration delayed about 37 min when an 850 mg tablet is administered with food.
Abstract: The pharmacokinetics of four single-dose treatments of the metformin administered orally (as the HCl salt) were compared in 24 healthy subjects: 500 mg and 850 mg tablets and 850 mg solution fasting and 850 mg tablet with food Solution and tablet formulations are bioequivalent Bioavailability of a 500 mg tablet is 14% greater than that of an 850 mg tablet Compared with the fasting state, bioavailability is 24% lower, and the peak concentration delayed about 37 min when an 850 mg tablet is administered with food
TL;DR: Overall, the denominator-based description of the safety profile in actual practice shows terbinafine to be well-tolerated against a wide background of age and coexisting illness.
Abstract: 1 The safety profile of terbinafine, the first orally active allylamine, was monitored in the UK in a post-marketing setting. The study recruited 10 361 patients, a number which is approximately 5% of the population who received oral terbinafine in the UK during the period of the study.
2 Follow-up data were available on 9879 patients. During the course of the study 14.5% patients reported medical events. 49% were thought to be possibly or probably related to terbinafine treatment. Seventy-four of the events (<1%) were classified as 'serious’and of these only five were assessed as possibly or probably related to treatment.
3 Taste disturbance occurred in 0.6% of the patients and emerged as the only new adverse reaction probably attributable to terbinafine: this was significantly commoner in females and reversible on stopping treatment, with a median time to recovery of 42 days.
4 The study approach successfully combined hospital based dermatology outpatient and general practice centres. Source data verification was conducted on 13% of the cohort selected randomly.
5 Overall, the denominator-based description of the safety profile in actual practice shows terbinafine to be well-tolerated against a wide background of age and coexisting illness.
TL;DR: Nebulization is a rapid but inefficient method of administering morphine that may provide more rapid pain relief compared with oral morphine but clinical studies are needed to confirm this.
Abstract: The inhalation of nebulized morphine has been advocated to treat dyspnoea and pain in patients with cancer. We have compared plasma morphine concentrations in healthy volunteers after nebulized (50 mg in 4 ml saline), oral (10 mg solution) and intravenous (5 mg) morphine sulphate. Bioavailability was estimated by dividing the morphine concentration AUC/dose by that obtained after intravenous morphine. Peak plasma morphine concentrations were achieved more rapidly after nebulized than oral morphine, occurring within 10 min in all subjects. The systemic bioavailabilities of morphine (mean +/- s.d.) were 5 +/- 3% and 24 +/- 13% for the nebulized and oral routes respectively. Nebulization is a rapid but inefficient method of administering morphine. It may provide more rapid pain relief compared with oral morphine but clinical studies are needed to confirm this.
TL;DR: Mefloquine prophylaxis does not appear to produce low-grade but debilitating neurological symptoms or to alter the results of sensitive tests of cerebral function, however, there may be situations in which mefloquine might contribute to hypoglycaemia and cardiac dysrhythmias.
Abstract: 1To assess neurological, cardiovascular, metabolic and other side-effects of mefloquine given in conventional prophylactic dose to healthy volunteers, a double-blind, randomized, placebo-controlled trial was conducted. In addition, the identity of the active drug was concealed until the end of the trial.
2A total of 106 healthy adults were recruited, of whom 95 (mean age 24 years; 45% males) completed the full study protocol.
3Subjects had a baseline assessment, received placebo as first dose, were randomized to mefloquine 250 mg or placebo weekly for 4 weeks starting a week later, and were reassessed after the 2nd and 4th active/placebo doses. Subjects kept a daily symptom diary from 2 weeks before until 2 weeks after the dosing period.
4Plasma mefloquine assay suggested compliance in all 46 subjects allocated active treatment (week 5 mean±s.d.; 2.35±0.94 μmol l−1). Mefloquine did not alter calcium homoeostasis but produced a mean 0.5 mmol l−1 fall in serum glucose over the study period (P<0.001) and relative hyperinsulinaemia. Symbol digit modalities, and digit forwards and backwards test scores, were similar in active and placebo groups across the three assessments, as were lying/standing blood pressure and high-tone hearing loss. Electrocardiographic QTc interval prolongation and diarrhoea were mild but transient side-effects of mefloquine (P<0.01). Neurological symptoms were comparable in the two groups throughout the study. There was no evidence of drug toxicity in 11 subjects who withdrew.
5Mefloquine prophylaxis does not appear to produce low-grade but debilitating neurological symptoms or to alter the results of sensitive tests of cerebral function. However, there may be situations in which mefloquine might contribute to hypoglycaemia and cardiac dysrhythmias.
TL;DR: The present study confirms the previous observation that riz atriptan is less effective than sumatriptan in causing contraction of human isolated coronary artery and shows that the lower maximum contractile response to rizatripta is not merely the consequence of variability in response to 5-HT1D-receptor agonists between patients or between segments from the same artery.
Abstract: 1. Rizatriptan (MK-462, (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine)) and its structurally related analogue L-741,519 (N-methyl-4-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]piperidine) are novel 5-HT1D-receptor agonists. Rizatriptan has shown efficacy as an anti-migraine agent in clinical trials. Since angiographic studies in patients have shown that sumatriptan (an established 5-HT1D-receptor agonist) can cause coronary artery vasoconstriction, we compared the effects of rizatriptan and L-741,519 with those of 5-HT and sumatriptan on endothelium-denuded segments of human coronary artery in vitro. 2. Coronary arteries were obtained from explanted hearts from patients undergoing cardiac transplantation (n = 16 viable arteries from 13 males, 3 females, aged 38-68 years) and arterial segments (5-6 mm in length) were mounted in organ baths for isometric tension recording. Each segment was first exposed to 45mM KCl and then to 5-HT (1 nM-100 microM). Concentration-effect curves to rizatriptan and sumatriptan (Study 1, n = 6 or 7 arteries) or sumatriptan and L-741,519 (Study 2, n = 8 arteries) were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. 3. One artery showed severe atheroma and was not included in the analysis. ANOVA showed that 5-HT responsiveness varied significantly between arteries from different patients; but not between arterial segments from the same patient. Desensitization was seen consistently across all agonists but did not significantly affect inter-agonist comparisons. 4. There was graded effectiveness in the ability of the agonists to cause contraction with the rank order of Emax values being 5-HT >> sumatriptan > L-741,519 > rizatriptan. In terms of EC50 values, L-741,519 was significantly more potent than sumatriptan. 5. The present study (using a 'cross-over' experimental protocol) confirms our previous observation that rizatriptan is less effective than sumatriptan in causing contraction of human isolated coronary artery. Furthermore, it shows that the lower maximum contractile response to rizatriptan, compared with that of sumatriptan, is not merely the consequence of variability in response to 5-HT1D-receptor agonists between patients or between segments from the same artery.
TL;DR: Patients who report not having been informed of adverse effects of NSAIDs are less likely to reduce intake in response to epigastric pain than patients who report having received such information.
Abstract: We set out to determine the extent to which two groups of patients reported having been informed about the adverse effects of NSAIDs. These consisted of 50 patients who had suffered an acute gastrointestinal bleed while taking a NSAID, and 100 age, sex and drug matched controls who had not. Eight (16%) of the index patients, and 41 (41%) of the control patients remembered having been informed of potential adverse effects, an odds ratio of 3.65 (95% CI 1.55-8.58, P < 0.002). Two (4%) of the index patients recalled having been advised what to do should adverse symptoms develop, whereas 21 (21%) of the control patients did so, an odds ratio of 6.38 (95% CI 1.4-28.4, P < 0.01). Eighteen (36%) of patients who bled had experienced gastrointestinal pain prior to the bleed, but of these only two (11%) admitted reduced compliance with NSAID therapy. In contrast, 10 (67%) of the 15 control patients who had suffered epigastric discomfort admitted reduced compliance, an odds ratio of 16.0 (95% CI 2.6-98.8, P < 0.001). Our results suggest that patients who report not having been informed of adverse effects of NSAIDs are less likely to reduce intake in response to epigastric pain than patients who report having received such information. If the patients who bled had reduced their intake of NSAIDs to the same extent as apparently better informed control patients in response to epigastric pain, it is possible that some episodes of acute gastrointestinal bleeding would have been avoided.
TL;DR: This study has shown the usefulness of this newer technique to detect differences in efficacy between low doses of analgesics under ambulant conditions, with very limited loss of data.
Abstract: 1. The objective of this study was to investigate the efficacy of home-medicated non-steroidal anti-inflammatory (NSAID) analgesics, using an electronic patient diary. Single doses of ketoprofen 25 mg and ketoprofen 50 mg were compared with ibuprofen 200 mg and placebo in the treatment of a single occasion of episodic tension-type headache, using a double-blind, randomized, parallel group design. 2. A total of 166 patients with headache compatible with episodic tension-type headache and no refractory headaches or contraindications to NSAIDs were contacted by advertisements and selected by questionnaires. Patients performed the study at home, using an electronic diary for headache assessment, with a form to allow comments and corrections. Visual analogue scales (VAS 10 cm) of headache severity, five-item headache relief rating (HRR) scales, and time of intake of 'escape' analgesics were scored regularly, for 4 h following intake of trial medication. 3. VAS-scores (n = 1407) and HRRs (n = 452) were returned by 159 patients. Of these scores, 1.5% were inadvertently omitted from the electronic diary or modified on the comment forms. 4. Headache (VAS and HRR) improved more with all three NSAIDs than with placebo, although the effect of ibuprofen was significant for HRR only. After 2 and 4 h respectively, the reduction in VAS-ratios was 17 and 19% with placebo, 18 and 53% with ibuprofen 200 mg, 41 and 61% with ketoprofen 25 mg, and 47 and 59% with ketoprofen 50 mg. After 4 h, headache improved strongly (highest HRR) in 18% of patients on placebo, 39% on ibuprofen 200 mg, 62% on ketoprofen 25 mg, and 55% on ketoprofen 50 mg. Headache disappeared completely (VAS-score = 0) in one patient (3%) with placebo (after 180 min), 10% with ibuprofen 200 mg (average 211 min), 18% with ketoprofen 25 mg (159 min), and 28% with ketoprofen 50 mg (146 min). 5. The effects of ketoprofen 50 mg were more pronounced than those of ibuprofen 200 mg, which seemed to start later. Ketoprofen 25 mg and 50 mg were very similar, suggesting a maximal effect of the lower dose. Mild to moderate adverse events were reported by 9% of the patients, half of which occurred with ketoprofen 50 mg. Treatment of headache with ketoprofen can start with 25 mg, and possibly less. 6. Although a direct comparative study would be necessary to determine the relative benefits of the novel electronic patient diaries over traditional paper-and-pencil methods, this study has shown the usefulness of this newer technique to detect differences in efficacy between low doses of analgesics under ambulant conditions, with very limited loss of data. Electronic patient diaries appear to be an important new attribute for the efficacy assessment of self-medicated drugs.
TL;DR: In Australia DTCs were involved in policy, education and management initiatives to promote best practice in therapeutics and reported an ability to implement 75% of decisions with teaching hospitals perceived to perform better than other hospital types.
Abstract: 1 This study describes stakeholders' opinions on Drug and Therapeutics Committees (DTCs) and measures the composition, activities and perceived effectiveness of DTCs in Australia 2 Focus groups explored the opinions of clinicians, consumers and administrators on the goals, objectives and strategies of DTCs 3 A national survey was sent to 306 hospitals to collect data on the composition, committee processes, goals, objectives, educational activities, policies and decision making of DTCs 4 Stakeholders believed the DTC should optimise therapeutic health outcomes for patients and economic outcomes for the hospital Important objectives were availability of safe, efficacious and cost-effective medicines, affordability of medicines and quality use of medicines 5 The national survey of DTCs found that over 92% of respondents had a DTC in their hospital Composition was generally representational and most commonly included members from the disciplines of internal medicine, pharmacy and nursing More than half the DTCs had executive authority although only 21% had an appeals mechanism 6 The most commonly cited issues for DTCs in 1994-95 were quality drug use, drug policies and spending on high cost drugs 7 While access to clinical pharmacologists and specialist drug utilisation evaluation (DUE) pharmacists was poor, 71% of DTCs had access to DUE data of some sort Guidelines (61%), prescribing restrictions (60%) and pharmacist monitoring (63%) were the most commonly used strategies to implement DTC policies and decisions Audit-feedback activities (61%) and drug bulletins (56%) were the most commonly used interventions 8 Available information for formulary decision making varied with small rural hospitals having access to significantly less information The most commonly used information was availability of a therapeutic alternative (87%), efficacy (83%), cost (80%) and estimated usage (78%) 9 On average DTCs reported an ability to implement 75% of decisions (range 0-95%) with teaching hospitals perceived to perform better than other hospital types 10 This study reveals a high level of expectation for DTC activities and achievements In Australia DTCs were involved in policy, education and management initiatives to promote best practice in therapeutics Few committees appeared to have adequate resources to extend services to their wider community
TL;DR: The use of medicines in children is an area of increasing after this syndrome was noted, pharmacokinetic studiesinterest and it is important to realise that drug metabolism in the children who died following penicillin and the children differs from that of adults.
Abstract: The use of medicines in children is an area of increasing after this syndrome was noted, pharmacokinetic studiesinterest [1]. Many medicines are being used outside the showed that newborn infants had impaired metabolismterms of their product licence [2] thereby increasing of chloramphenicol and that a reduction of the dosagethe risk of drug toxicity. Clinicians need to ensure not from 100 mgkg−1daily to 50 mg kg−1daily preventedonly that toxicity is kept to a minimum but also that the development of this syndrome [12].children arenot denied theuse ofappropriate medicines.This can only be achieved by the scientific study of drugtoxicity in children and is ideally carried out byprospective studies of drug surveillance. This involvesspecifically monitoring for drug toxicity, either in Toxicity in youngchildrenrelation to particular drugs [3,4] or selected patientgroups [5,6].Drug use in children may be accompanied Althoughtheseinitialstudies described clinicalproblemsby problems not seen in adults, or cause adverse drug in newborn infants, and the preterm infant in particular,reactions that are more frequent than in adults. An problems with other drugs have highlighted theexampleofthisismetoclopramide whichcausesdystonia enhanced toxicity of some medicines in children.in teenagers and Parkinsonism in the elderly [7]. Hepatotoxicity in association with the anticonvulsantsodium valproate was initially reported in 1979 [13].Subsequently more than 100 patients died, the majorityof whom were children. A retrospective review [14] of37 patients who died in the USA, showed that thoseAntibiotictoxicity inneonates patients at greatest risk fell into one of three categories:(i) age under 3 years; (ii) receiving other anticonvuls-Infectionshavealwaysbeena majorprobleminneonates ants as well as valproate; (iii) developmental delay.with significant mortality and morbidity. The introduc- Subsequent changes in prescribing habits resulted in ation of antibiotic therapy resulted in major clinical dramatic reduction in the number of deaths due toadvances [8]. However, antibiotic therapy also pro- sodium valproate [15]. The mechanism of valproateduced particular clinical problems. Silverman et al. hepatotoxicity is not fully understood but is thought toreported considerably higher mortality in neonates relate to abnormal metabolism [16]. Other anticonvul-receiving a combination of penicillin and sulphisoxazole sants result in enzyme induction and, therefore, enhancethan those receiving oxytetracycline [9]. There was a certain metabolic pathways resulting in the formationsignificantly higher incidence of kernicterus, both clini- of toxic intermediate metabolites. These pathways maycally(opisthotonos,spasticity,seizures, oculogyricmove- be more prominent in children under the age of 3 yearsments) and pathologically (yellow staining of the brain) and it is important to realise that drug metabolism inin the children who died following penicillin and the children differs from that of adults.sulphonamide. Subsequently, others have shown that The other drug causing hepatotoxicity specifically insulphonamides are highly protein bound and displace children was aspirin. The use of salicylates in childrenbilirubin from albumin [10]. As the preterm infant is with a mild viral infection resulted in a greater risk ofusually jaundiced, the sulphonamide displaced bilirubin developing Reye’s syndrome—a life threatening illnessfrom albumin and this is thought to increase the associated with drowsiness, coma, hypoglycaemia, seiz-incidence of kernicterus. ures and liver failure. Epidemiological work confirmedNewborninfants receivingchloramphenicoldeveloped the association between salicylate ingestion and theabdominaldistension,vomiting, cyanosis,cardiovascular development of Reye’s syndrome [17], although thecollapse, irregular respiration and subsequent death possible association had been postulated 15 years[11]. This was termed the grey baby syndrome. Shortly previously [18]. Starko et al. [17] studied children
TL;DR: The lung bioavailability of CFC-free was greater than that of C FC or DPI formulations of salbutamol, and there were no significant differences between CFC and D PI formulations.
Abstract: With the future advent of a world wide ban on chlorofluorocarbon containing aerosols, a study was designed to compare the in vivo lung bioavailability of salbutamol via chlorofluorocarbon-containing metered-dose inhaler (CFC), chlorofluorocarbon-free metered-dose inhaler (CFC-free), and dry powder inhaler (DPI). Twelve healthy male subjects were given 1200 micrograms salbutamol and measurements made of plasma and urinary salbutamol. CFC-free produced significantly higher plasma salbutamol levels (ng ml-1; mean and 95% CI for difference) than either CFC or DPI: Cmax, CFC-free 4.18 vs CFC 3.29 (95% CI 0.10-1.68), vs DPI 3.42 (95% CI -0.03-1.56). The ratio for the difference in Cmax between CFC and CFC-free formulations was 1.32 (95% CI 1.02-1.61). There were no significant differences between CFC and DPI formulations. Urinary salbutamol results did not reveal any significant differences between the three inhalers (micrograms 30 min-1): CFC-free 42.4, CFC 43.8, DPI 45.3. Thus, the lung bioavailability of CFC-free was greater than that of CFC or DPI formulations of salbutamol.
TL;DR: Results indicated fluvoxamine has a modest inhibitory effect on the activity of CYP2C19, but no effect on that of CyP2D6 in vivo.
Abstract: Studies were performed in eight healthy extensive metabolizers of mephenytoin and debrisoquine to determine the effect of fluvoxamine on the activities of S-mephenytoin 4'-hydroxylase (CYP2C19) and metoprolol alpha-hydroxylase (CYP2D6). Therapeutic dosing with fluvoxamine (100 mg day-1) for 2 weeks caused a significant increase in the 0-8 h urinary S/R ratio of mephenytoin from 0.16 to 0.55 (95% confidence interval for difference between means: 0.28-0.50; P 0.05) or the 0-8 h urinary recovery of alpha-hydroxymetoprolol (95% confidence interval for difference between means: -0.61-0.70 mg; P > 0.05). These results indicated fluvoxamine has a modest inhibitory effect on the activity of CYP2C19, but no effect on that of CYP2D6 in vivo.
TL;DR: Pantoprazole was well tolerated and did not cause clinically relevant changes in heart rate, blood pressure, ECG and routine clinical laboratory parameters, and diazepam metabolism to desmethyldiazepam was not affected.
Abstract: Pantoprazole, a substituted benzimidazole, is a potent and well tolerated inhibitor of the gastric H+,K+-ATPase with a low potential to inhibit cytochrome P450. In this randomized, placebo-controlled two-period crossover study, 12 healthy volunteers received placebo (reference) and 240 mg of pantoprazole (test) i.v. within 2 min once daily for 7 days each. On day 4 of either period, a 1 min bolus of diazepam (0.1 mg kg−1 body weight) was additionally injected. Pantoprazole was well tolerated and did not cause clinically relevant changes in heart rate, blood pressure, ECG and routine clinical laboratory parameters. There was no effect on diazepam clearance (0.021 l h−1 kg−1 for test and reference) and elimination half-life (36.8 h for test, 40.4 h for reference). Diazepam metabolism to desmethyldiazepam was not affected by pantoprazole. In conclusion, pantoprazole and diazepam may be administered concomitantly without dose adjustment even when high doses of pantoprazole are required.
TL;DR: It is suggested that the large inter-ethnic difference in nifedipine clearance are not generalizable to all CYP3A4 substrates.
Abstract: A threefold higher area under the plasma drug concentration-time curve (AUC) of nifedipine, a substrate of cytochrome P4503A (CYP3A), has been shown in Southern Asians when compared with Caucasians. To determine if these differences are specific to nifedipine or apply to other substrates of CYP3A, we examined the pharmacokinetics and pharmacodynamics of 0.375 mg triazolam, another substrate of CYP3A, in eight healthy Caucasians and eight healthy Southern Asians in a double-blind placebo-controlled study. When compared with Caucasians, Southern Asians achieved higher maximum plasma concentration (Cmax) (8.0 +/- 2.6 vs 4.8 +/- 1.9 ng ml-1; the 95% confidence interval (CI) of the mean difference was 0.76 to 5.7; P < 0.01) and had a shorter time to reach maximal concentration (tmax) (45 min (range 30-75) vs 90 min (range 60-145); the 95% CI of the mean difference was -69 to -20; P < 0.002). Triazolam AUC, clearance and partial metabolic clearance did not differ significantly between Southern Asians and Caucasians. Significant differences were found in postural sway after triazolam when compared with placebo in both Caucasians (double stance: eyes open (DSEO): 172.9 +/- 82.9 vs 1138.9 +/- 1182.4; the 95% CI of the mean difference was -1897.2 to -34.4; P < 0.04; and Southern Asians (DSEO: 216.2 +/- 80.9 vs 1086.0 +/- 827.1; the 95% CI of the mean difference was -1564.2 to -175.6; P = 0.02; double stance: eyes closed (DSEC): 207.5 +/- 89.8 vs 1156.9 +/- 932.1; the 95% CI of the mean difference was -1718.5 to -178.5; P = 0.02; with no significant difference between the two ethnic groups. These results suggest that the large inter-ethnic difference in nifedipine clearance are not generalizable to all CYP3A4 substrates.