Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease.

Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N=511), and results were also stratified by apolipoprotein E (APOE) genotype (n=323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE epsilon4 allele status and ADAS-Cog (P=0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE epsilon4-negative patients on 8 mg RSG (P=0.024; not corrected for multiplicity). APOE epsilon4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P=0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE epsilon4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE epsilon4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

The tolerability of lamotrigine in elderly patients with epilepsy.

OBJECTIVE: To determine the tolerability of lamotrigine in elderly patients with epilepsy. DESIGN: Pooled data from 13 lamotrigine clinical trials. SETTING: Multicentre clinical trials conducted in primary care and neurology practices. PARTICIPANTS: 208 elderly patients (aged > or = 65 years) were identified: 146 lamotrigine-treated patients, 53 carbamazepine-treated patients and 9 phenytoin-treated patients. INTERVENTIONS: Extent of exposure, incidence of drug-related adverse events, serious adverse events and study withdrawals were examined. RESULTS: The median duration of exposure for lamotrigine monotherapy and add-on therapy was 24.1 and 47.4 weeks, respectively. The median daily dosage of lamotrigine was 100 mg for monotherapy (range 75 to 500 mg) and 300 mg for add-on therapy (range 25 to 700 mg). Overall, the incidence of drug-related adverse events was lower for lamotrigine than comparator drugs: 49% (72/146) for lamotrigine compared with 72% (38/53) for carbamazepine (p = 0.006), and 89% (8/9) for phenytoin (p = 0.035) although patient numbers in each treatment group were not comparable. Patients receiving lamotrigine reported incidences of somnolence (p = 0.012), rash (p = 0.034), and headache (nonsignificant) that were one-half the incidence reported with carbamazepine monotherapy. Rash was the most common reason for study withdrawal: 4% (6/146) lamotrigine, 17% (9/53) carbamazepine and 0% phenytoin. Seven (5%, 7/146) lamotrigine-treated patients, 4 (8%, 4/53) carbamazepine-treated patients and 1 (11%, 1/9) phenytoin-treated patient experienced drug-related serious adverse events. CONCLUSION: Lamotrigine, used in the currently prescribed adult dosage regimen, was well tolerated in elderly patients with epilepsy.

The tolerability of lamotrigine in children.

Lamotrigine is a novel anticonvulsant, which has proven to be effective both as add-on and monotherapy. 13 studies have demonstrated efficacy in 1096 children with a variety of seizure types. Tolerability information in these studies was collected in a standard fashion, where investigators reported all adverse events regardless of the perceived relationship to the test therapies. Generally, lamotrigine treatment in these clinical trials was generally given at higher initial doses and faster dose escalations than are currently recommended. Most adverse events associated with lamotrigine were mild to moderate in severity and did not result in discontinuation of treatment. Results from placebo-controlled, add-on trials showed that 85% of lamotrigine recipients experienced an adverse event compared with 83% of placebo recipients. Lamotrigine was associated with an increased risk of adverse events in the nervous system (dizziness, tremor, ataxia, and diplopia), gastrointestinal tract (nausea), and urinary tract (infection). The incidence of most adverse events was lower among lamotrigine recipients in monotherapy trials than in add-on trials, suggesting that concurrent anticonvulsant treatment or drug interactions can be confounding risk factors above that of lamotrigine treatment alone. Skin rash associated with hospitalisation and the discontinuation of study drug was reported more frequently by lamotrigine recipients than by placebo recipients and more frequently by children than by adults. The simultaneous use of valproic acid (sodium valproate) was associated with an increased incidence of rash. Lamotrigine, an effective broad spectrum anticonvulsant, is well tolerated in children. The qualitative features of adverse events that occur with lamotrigine treatment are similar for children and adults. The incidence of rash may be reduced with proper initial dosing and dose escalation.

A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group.

OBJECTIVE: To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures. BACKGROUND: Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children. METHODS: We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period. RESULTS: Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy. CONCLUSIONS: Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.

Population pharmacokinetics of lamotrigine adjunctive therapy in adults with epilepsy.

Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18-64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme-inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in non-whites and increased by 13% in patients receiving more than one concomitant enzyme-inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme-inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme-inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.

An active-control trial of lamotrigine monotherapy for partial seizures.

OBJECTIVE: We report the results of a double-blind, double-dummy, active-control study designed to evaluate the efficacy and safety of lamotrigine (LTG) administered as monotherapy to adult outpatients with partial seizures. BACKGROUND: The effectiveness of LTG as add-on therapy for partial seizures in adults has previously been established. METHODS: After an 8-week baseline during which patients continued their baseline antiepileptic drug (carbamazepine or phenytoin monotherapy), 156 patients were randomly assigned to receive increasing doses of LTG (target 250 mg b.i.d.) or valproic acid (VPA; target low dose of 500 mg b.i.d.) during the first 4 weeks of an 8-week transition period. Carbamazepine or phenytoin was withdrawn over the next 4 weeks; then patients entered a 12-week monotherapy period. Study drug treatment was discontinued in patients who met predetermined escape criteria for seizure worsening. RESULTS: More patients receiving LTG were successfully maintained on monotherapy compared with patients receiving VPA (56% versus 20%; p < 0.001). The time to meet the escape criteria was also significantly longer in LTG-treated patients (median = 168 days) than in VPA-treated patients (median = 57 days; p = 0.001). The incidence of adverse events during the monotherapy period was lower than during the transition period. Four LTG patients and five VPA patients reported serious adverse events. Two of those patients experienced a rash that led to withdrawal soon after adding LTG to carbamazepine. CONCLUSIONS: We conclude that LTG is effective and well tolerated when administered as monotherapy in adult patients with partial seizures.

Lamotrigine high-dose tolerability and safety in patients with epilepsy: a double-blind, placebo-controlled, eleven-week study.

PURPOSE: This study was undertaken to evaluate the dose tolerability and safety of a chronic ascending twice-daily (b.i.d.) dosage regimen of < or = 700 mg/day lamotrigine (LTG) and to include determination of the LTG pharmacokinetic profile at doses > or = 500 mg/day in patients receiving concomitant enzyme-inducing antiepileptic drugs (AEDs). METHODS: Twelve adult male epileptic patients treated with enzyme-inducing AEDs received < or = 700 mg/day (b.i.d.) oral LTG (n = 8) or placebo (controls, n = 4). For 3 weeks, as outpatients they had their LTG dosage increased from 100 to 400 mg/day. Then, in a clinical research study unit, patients received regimens of 500, 600, and 700 mg/day for 1 week each. Controls received matching placebo in the same sequence. At study end, dosages were tapered in 2 weeks. Follow-up evaluations were made 7 days later. RESULTS: Five LTG patients tolerated 700 mg/day for 1 week. LTG was reduced to 600 mg/day in a patient with mild diplopia and to 500 mg/day in a patient with mild oscillopsia and diplopia. One patient discontinued 300 mg/day therapy with a moderately intense diffuse papular skin rash, attributed to LTG. Headache, drowsiness, faintness, and diplopia, the common adverse events (AEs), were mild to moderate in intensity and occurred in 50-75% of patients in both groups (except for diplopia, occurring only with LTG). Concomitant AED plasma concentrations were not markedly changed by LTG. LTG pharmacokinetics were linear over the range of 500-700 mg/day. CONCLUSIONS: LTG doses < or = 700 mg/day can be tolerated in patients receiving concomitant enzyme-inducing AEDs.

Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial.

The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mg/day. Seizure frequency with LTG decreased by > or = 50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2:1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEDs. Adverse experiences were generally minor and most frequently were CNS-related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice-daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.

Primary spontaneous pneumothorax. Therapeutic considerations.

Primary pneumothorax represents the single most frequent cause of admission of young adults to a hospital's thoracic service. However, the best management of these patients with rupture of subpleural blebs in the apical region remains controversial. In a retrospective analysis of 108 consecutive patients with spontaneous primary pneumothorax treated at a university hospital over a 5-year period, we were able to examine the risks and benefits of various treatment approaches. Interestingly, although male patients outnumbered female patients approximately 2:1, female patients were statistically more likely to undergo operative intervention.

Mivacurium-induced neuromuscular blockade following single bolus doses and with continuous infusion during either balanced or enflurane anesthesia.

Mivacurium chloride (BW B1090U) was administered to 72 patients during their elective surgery. The eight groups (nine subjects per cell) in the 2 x 2 x 2 study design differed in three factors: the size of the mivacurium bolus dose administered, whether or not this dose was followed by an infusion of mivacurium, and in the technique used for the maintenance of anesthesia. Four groups received a single bolus dose of mivacurium, 0.15 mg/kg, and the remaining four groups received mivacurium, 0.25 mg/kg, administered iv in 15 s. Precisely 2 min later, tracheal intubation was attempted. Conditions were judged to be good or excellent on most occasions, but intubation was not possible for two of the patients in the low-dose and one in the high-dose groups. Four groups, two at each bolus dose, received no additional mivacurium: there was a dose-dependent decrease in the rate of spontaneous recovery following the bolus dose. The other subdivision of groups was the use of either barbiturate-nitrous oxide-narcotic (balanced) anesthesia, or enflurane-nitrous oxide anesthesia; the anesthetic technique did not affect the pattern of spontaneous recovery from either bolus dose. Four groups, again two at each bolus dose, subsequently received an infusion of mivacurium, adjusted to depress the twitch response by approximately 95%. Infusion rates averaged 6.0 micrograms.kg-1.min-1 in the groups receiving balanced anesthesia and 4.2 micrograms.kg-1.min-1 for those receiving enflurane anesthesia. Recovery following administration by infusion was slower than that observed following a bolus dose of mivacurium, 0.15 mg/kg but did not differ between the anesthetic groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Nicotine and some related compounds: effects on schedule-controlled behaviour and discriminative properties in rats.

Behavioural effects of d- and l-nicotine, d- and l-nornicotine and l-cotinine were studied in two paradigms. In experiment 1, rats responded under a multiple fixed-interval (FI) 5 min, fixed-ratio (FR) 20 schedule of food presentation. Aside from differences in potency and time course, l-nicotine and the stereoisomers of nornicotine produced qualitatively similar effects on rates of responding. With increasing doses of drugs, FI response rates first increased and then decreased, while FR response rates only decreased. In contrast, d-nicotine did not significantly increase FI response rates at lower doses, and only decreased FI and FR response rates at higher doses. At doses up to 100 mg/kg, cotinine produced only dose-dependent increases in FI response rates and had no effect on FR response rates. Rate-increasing effects of cotinine were not blocked by mecamylamine. In experiment 2, rats were trained to discriminate between l-nicotine (0.1 mg/kg SC) and saline (0.1 ml/kg SC) in a two-bar, operant conditioning procedure under a tandem variable-interval (VI) 1 min, FR 10 schedule of food presentation. Full generalization was obtained to d-nicotine and to l- and d-nornicotine. Generalization to cotinine occurred only with large doses that contained significant amounts of nicotine present as an impurity. There was no generalization to non-nicotinic drugs (morphine and clenbuterol), even at doses that reduced response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition kinetics of nicotine and cotinine enantiomers in rabbits and beagle dogs.

The disposition kinetics of nicotine and cotinine enantiomers was determined in rabbits. The clearance of (R)-nicotine was similar to that of (S)-nicotine, but clearance of (R)-cotinine was twice that of (S)-cotinine. Fractional conversions of both enantiomers of nicotine to cotinine were approximately 50%. These results suggest that in rabbits the biotransformation pathways of cotinine, but not nicotine, are influenced by stereochemistry. The disposition kinetics of nicotine enantiomers in beagle dogs was also studied. In dogs, the clearance of (R)-nicotine was slightly greater than the clearance of (S)-nicotine. Methods for the synthesis of (R)-nicotine and (R)-cotinine of high enantiomeric purity and a gas chromatographic method for determination of nicotine enantiomeric purity are described.

Effects of the stereoisomers of nicotine and nornicotine on schedule-controlled responding and physiological parameters of dogs.

The behavioral and physiological effects of five tobacco alkaloids were assessed in two different test paradigms. One group of beagle dogs (N = 5) responded under a multiple fixed-interval (FI) 300 sec, fixed-ratio (FR) 30 response schedule of food presentation. With both l-nicotine (0.1-3.0 mumol/kg i.m.) and l-nornicotine (0.1-10.0 mumol/kg i.m.), FI response rates, when averaged across the entire session, were increased at low doses and decreased at high doses; FR response rates were only decreased. d-Nicotine (0.1-30.0 mumol/kg i.m.), and d- and dl-nornicotine (0.1-10.0 mumol/kg i.m.) produced a transient increase in FI response rates at low doses. The effects of the same five compounds on pupillary diameter, rectal temperature and heart rate were measured in a second group of beagle dogs (N = 6). Both pupillary diameter and rectal temperature were decreased initially by l-nicotine (0.6 mumol/kg i.v.), d-nicotine (6.0 mumol/kg i.v.) and d-, l- and dl-nornicotine (3.0 mumol/kg i.v.); base-line levels were recovered within 60 min. Aside from differences in potency, the time courses of action were similar for all five compounds. Increases in heart rate also were produced by all five compounds, but there were marked differences in the duration of action. l-Nicotine and d- and dl-nornicotine produced appreciable, sustained increases in heart rate, whereas d-nicotine and l-nornicotine produced moderate, brief increases. The combined results of the present experiments indicate the stereoisomers of nicotine and nornicotine are behaviorally and physiologically active, and may contribute in varying amounts to the pharmacologic actions of tobacco.

Pharmacologic and reinforcing properties of phencyclidine and the enantiomers of N-allylnormetazocine in the dog.

Experiments were conducted to evaluate the degree of phencyclidine (PCP)-like activity associated with the dextro and levo enantiomers of the sigma agonist N-allylnormetazocine (NANM). In chronic spinal dogs, d- and l-NANM generally produced similar physiologic and gross animal behavior effects which included miosis, tachycardia, hyperthermia, increased secretory activity (lacrimation, rhinorrhea and salivation), nystagmus and stereotyped head movements. For these effects, d- and l-NANM were generally equal in potency and both were about 1/10th as potent as PCP. However, the NANM enantiomers could be differentiated on the basis of their effects on nociceptive reflexes. Comparisons of dose-response curves and efficacies demonstrated that d-NANM was more similar to PCP in its effectiveness in depressing the flexor and skin twitch reflexes than was l-NANM. In addition, naltrexone selectively antagonized or reduced only the effects of l-NANM on reflex activity. In intact dogs, d-NANM and PCP, but not l-NANM maintained self-administration behavior under FR15 or FI900 (FR10:S) schedules of reinforcement. This represented the most stereospecific action of the NANM enantiomers. Additionally, l-NANM failed to maintain self-administration behavior, even following pretreatment with naltrexone, thus suggesting that the opiate activity of l-NANM was not responsible for its lack of reinforcing efficacy. Taken together, the data demonstrate that both d- and l-NANM have PCP-like properties, but d-NANM is pharmacologically more equivalent than l-NANM to PCP and l-NANM has additional activity which is not PCP-like.

Effects of L-cocaine on local cerebral glucose utilization in the rat.

The 2-deoxy-D-[l-14C]glucose method was used to map the in vivo metabolic response (local cerebral glucose utilization. LCGU) to L-cocaine in the rat brain. Injections of L-cocaine HCl (30 mg/kg, i.p.) selectively enhanced LCGU in 5 out of 56 brain regions that were examined (caudate-putamen, globus pallidus, substantia nigra pars reticulata, subthalamic nucleus, cerebellar vermis), but 10 or 30 mg/kg L-cocaine reduced LCGU in the habenula. In general, the acute effects of L-cocaine on LCGU resembled previously reported effects of D-amphetamine and apomorphine.

Intravenous self-administration of fencamfamine and cocaine by beagle dogs under fixed-ratio and progressive-ratio schedules of reinforcement.

Catheterized beagle dogs were given access to response-contingent intravenous injections of fencamfamine (FEN) or cocaine (COC) injections under a fixed-ratio (FR) schedule of reinforcement. Both drugs maintained self-administration behavior considerably above saline levels; there was an inverted U-shaped relationship between the number of injections per daily session and the dose per injection. Presession treatment with the dopaminergic antagonist pimozide (PIM) appreciably altered both the FEN and COC dose-effect curves, suggesting a dopaminergic component in the reinforcing properties of these substances. When tested under a progressive-ratio (PR) schedule, both FEN and COC maintained nearly identical FR-values which were considerably above those seen for saline. It appears from these data that FEN may have a cocaine-like abuse potential.

Behavioral effects of CGS 8216 alone, and in combination with diazepam and pentobarbital in dogs.

Beagle dogs (N = 3) responded under a multiple fixed-interval (FI) 300 sec, fixed-ratio (FR) 30 schedule of food presentation. The pyrazoloquinoline derivative CGS 8216, given either intravenously (0.01-3.0 mg/kg) or orally (0.1-30.0 mg/kg) had little effect on either the rate or temporal pattern of responding during either component. Both diazepam (0.3 to 17.5 mg/kg, PO) and pentobarbital (0.1-17.5 mg/kg, PO) produced qualitatively similar effects on behavior. Rates of responding during the FI components first increased, then decreased with increasing doses; both drugs produced only dose-related decreases in the rate of responding during the FR components. CGS 8216 antagonized some of the behavioral effects of diazepam; FI and FR response rates returned to baseline, however the effects of diazepam on quarter-life values were not appreciably altered by CGS 8216. The effects of pentobarbital on schedule-controlled responding were not antagonized by CGS 8216. These results indicate CGS 8216 is a selective benzodiazepine antagonist that does not produce benzodiazepine-like behavioral effects.

Discriminative stimulus properties and schedule effects of fencamfamine in rats.

The behavioral properties of fencamfamine, a sympathomimetic central stimulant recently identified in alleged cocaine samples, were studied in two different paradigms. In Experiment I, rats were trained to discriminate between injections of saline (0.1 ml/kg, IP) and cocaine (3.0 mg/kg, IP) in a two-lever drug discrimination task on a fixed-ratio (FR) 10 schedule of water presentation. Fencamfamine (0.3-3.0 mg/kg, IP) produced cocaine-appropriate choice behavior and was slightly more potent than cocaine in producing this effect. In Experiment II, rats responded under a multiple fixed-interval (FI) 300 sec, FR 20 schedule of water presentation. Fencamfamine (0.1-10.0 mg/kg, IP) and cocaine (0.1-30.0 mg/kg, IP) produced qualitatively similar effects on responding under this schedule. With increasing doses of either drug, FI responses rates first increased, then decreased; FR response rates were only decreased. Fencamfamine was approximately three times more potent than cocaine in producing these effects. The results of these two experiments indicate that fencamfamine and cocaine have similar behavioral properties.

Effects of nicotine, cocaine and some of their metabolites on schedule-controlled responding by beagle dogs and squirrel monkeys.

The behavioral effects of nicotine were compared with those of its metabolites, nornicotine and cotinine, in beagle dogs and squirrel monkeys. Subjects responded under a multiple fixed-interval (FI) 300-sec, fixed-ratio (FR) 30 response schedule of food presentation. Nicotine (0.01-1.0 mg/kg i.m.) and nornicotine (0.03-3.0 mg/kg i.m.) produced qualitatively similar effects in both dogs and monkeys. Nicotine produced dose-related increases, then decreases in rates of responding during FI components; rates of responding during FR components were only decreased. Nornicotine produced only dose-dependent decreases in responding during both FI and FR components. In the dogs, cotinine (0.01-10.0 mg/kg i.m.) produced only dose-dependent decreases in rates of responding during both FI and FR components. In the squirrel monkeys, however, cotinine (0.1-3.0 mg/kg i.m.) increased responding during FI components; a high dose of 30.0 mg/kg decreased responding during both FI and FR components. The behavioral effects of cocaine (0.03-3.0 mg/kg i.m.) and its metabolite norcocaine (0.01-1.0 mg/kg i.m.) were compared in the dogs. FI rates of responding first increased and then decreased with increasing doses of each drug, whereas FR rates of responding only decreased in a dose-related manner. Norcocaine was slightly more potent than cocaine in producing these effects on schedule-controlled responding in dogs. These experiments indicate the metabolites of nicotine and cocaine are behaviorally active and may contribute to the pharmacological profile of the parent compounds.