Effect of NG-nitro-L-arginine on the anticonvulsant action of four second-generation antiepileptic drugs in pentetrazole-induced clonic seizures in mice

The exact role of compounds modulating nitric oxide (NO) content in the brain during seizure phenomena is under intensive investigation. This study was aimed at determining the effect of NG-nitro-L-arginine (L-NA; a non-selective NO synthase inhibitor) on the anticonvulsant activity of four second-generation antiepileptic drugs (AEDs: gabapentin [GBP], oxcarbazepine [OXC], tiagabine [TGB] and vigabatrin [VGB]) in the mouse pentetrazole (PTZ)-induced seizure model. The acute adverse-effect liability of the studied AEDs in combinations with L-NA were evaluated in the chimney test (motor coordination). Results indicate that L-NA (40 mg/kg; ip) significantly reduced the anticonvulsant activity of OXC in the PTZ test, by increasing its ED50 from 20.9 to 29.8 mg/kg (p < 0.05). Similarly, L-NA at doses of 20 and 40 mg/kg considerably attenuated the antiseizure effects of VGB by raising its ED50 from 595 to 930 mg/kg (p < 0.05), and 1022 mg/kg (p < 0.01), respectively. L-NA at lower doses of 10 and 20 mg/kg did not affect significantly the anticonvulsant effects of VGB and OXC in PTZ-induced seizures. Likewise, the co-administration of L-NA(40 mg/kg; ip) with GBP and TGB was associated with no significant changes in their anticonvulsant activities in PTZ-induced seizures in mice. Moreover, none of the examined combinations of L-NA (40 mg/kg; ip) and second-generation AEDs (at their ED50 values) affected motor coordination in the chimney test. Based on this preclinical study, one can conclude that L-NA reduced the anticonvulsant activities of VGB and OXC in the mouse PTZ-induced seizure model. Only, GBP and TGB were resistant to the action of L-NA in this model.     

Plasma gabapentin concentrations in children with epilepsy: influence of age,relationship with dosage,and preliminary observations on correlation with clinical response

The influence of age and administered daily dosage on the plasma concentrations of gabapentin (GBP) at steady state was evaluated in a group of 41 children and young adults (aged 3-30 years) receiving long-term adjunctive treatment with GBP for the management of refractory partial-onset seizures. For each patient, peak and trough concentrations were determined by a specific high-performance liquid chromatography (HPLC) method in samples obtained before the morning dose and 2.5 hours later, respectively. To assess within-subject relationship between plasma concentration and dosage, 30 patients were evaluated at more than one dosage level. Within the assessed dose range, plasma GBP concentrations were linearly related to dose. Apparent oral clearance values (mean +/- SD) in children aged 6 years or less (4.8 +/- 0.9 mL/kg/min) were comparable with those observed in children aged 7 to 15 years (4.6 + 1.5 mL/kg/min) and moderately higher than those found in young adults (3.9 + 0.9 mL/kg/min), even though differences among groups failed to reach statistical significance. There was, however, a significant difference in CL/F between children aged 10 years or less and older children (5.1 +/- 1.1 vs. 3.8 +/- 1.2 mL/kg/min, P < 0.005). Of the 41 patients who entered the study, 22 discontinued treatment, mostly due to insufficient efficacy. No significant difference in plasma GBP concentration was detected between patients showing a greater than 50% reduction in seizure frequency (4.1 +/- 1.9 microg/mL, n = 11, mean +/- SD) and those having no significant clinical improvement (4.4 +/- 1.7 microg/mL, n = 30). These results indicate that in children given dosages up to 50 mg/kg/d (mean, 25 mg/kg/d), GBP pharmacokinetic analyses show no important deviation from linearity. The data also suggest that, on average, children may need moderately higher dosages to reach plasma GBP concentrations comparable with those found in adults. There seems to be a large variation in the plasma concentrations of the drug associated with a favorable therapeutic response.     

A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders

There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine (LTG) and gabapentin (GBP) monotherapy versus placebo (PLC). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a standardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose (LTG 500 mg or GBP 4,800 mg). The primary outcome measure was the Clinical Global Impressions Scale (CGI) for Bipolar Illness as supplemented by other standard rating instruments. The mean doses at week 6 were 274 +/- 128 mg for LTG and 3,987 +/- 856 mg for GBP. Response rates (CGI ratings of much or very much improved) were the following: LTG, 52% (16/31); GBP, 26% (8/31); and PLC, 23% (7/31) (Cochran's Q = 6.952, df = 2, N = 31, p = 0.031). Post hoc Q differences (df = 1, N = 31) were the following: LTG versus GBP (Qdiff = 5.33, p = 0.011); LTG versus PLC (Qdiff = 4.76, p = 0.022); and GBP versus PLC (Qdiff = 0.08, p = 0.70). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study.     

Effect of vigabatrin and gabapentin on phynytoin pharmacokinetics in the dog.

The study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A group of five beagle dogs were given a daily dose of PT (12 mg/kg, i.v.) for a period of 1 week. On day 8, plasma samples were serially collected over 24 hr. after administration of the PT dose. PT administration was continued with oral supplementary dose of VGB (60 mg/kg) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mg/kg, i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n = 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parental PT. VGB, however markedly changed the drug's kinetics as evidenced by a 31% (P = 0.015) reduction in total body clearance (CL) and increase of over 45% in half-life (t1/2), (P = 0.013) and area under the plasma PT concentration-time curve (AUC), (P = 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in marked reduction in systemic clearance of the latter in the dog.     

Effect of vigabatrin and gabapentin on phenytoin pharmacokinetics in the dog

This study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A daily dose of PT (12 mgkg(-1)i.v.) was given to a group of five beagle dogs for a period of 1 week. On day eight, plasma samples were serially collected over 24 h, after administration of the PT dose. PT administration was continued, along with supplementary oral VGB (60 mgkg(-1)) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mgkg(-1), i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n= 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parenteral PT. However VGB markedly changed the drug's kinetics, as evidenced by a 31% (P= 0.015) reduction in total body clearance (CL) and an increase of over 45% in half-life (t(1/2)), (P= 0.013) and area under the plasma PT concentration-time curve (AUC), (P= 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in a marked reduction in systemic clearance of the latter in the dog.     

Pharmacokinetic profile of alniditan nasal spray during and outside migraine attacks

AIMS: To compare the pharmacokinetic profile of intranasal alniditan during and outside migraine attacks, and to investigate the relationship between initial rise of alniditan plasma concentration, and headache improvement. METHODS: Twenty-seven migraine patients (age: 18-65 years) were randomized to receive alniditan 2 mg or 4 mg, and investigated both during and outside a migraine attack. Maximal plasma concentrations (Cmax), time to Cmax (tmax), and the area under the curve over 2 h (AUC(0,2 h)), were calculated from the individual plasma concentration-time profile, obtained from 10 blood samples in each patient, during each of the two administrations. RESULTS: Alniditan was rapidly absorbed into the systemic circulation (tmax=11 min). All investigated pharmacokinetic parameters (Cmax, tmax, AUC(0,2 h)) were similar during and outside migraine attacks, both in the 2 mg (n = 13) and the 4 mg group (n = 14). In the 4 mg group, during attacks, mean plasma alniditan concentration at 5 min after administration (Ct=5) in responders (21+/-16 ng ml(-1); n=10) was significantly higher than the Ct=5 in nonresponders (3+/-3 ng ml(-1); P=0.01; n=4). However, the Cmax and AUC(0,2 h) in responders (33+/-18 ng ml(-1) and 12+/-6 ng ml(-1) h) were also significantly higher than the Cmax and AUC(0,2 h) in nonresponders (13+/-9 ng ml(-1); P=0.048 and 5+/-3 ng ml(-1) h; P=0.03). CONCLUSIONS: Absorption of alniditan nasal spray was not affected by migraine attacks, although 95% confidence intervals were wide. Early rise of plasma concentrations and the amount of drug in the circulation were related to headache improvement in the higher dose group.     

Predictors of clinical outcome in schizophrenic patients responding to clozapine

Many of the patients who respond better to clozapine (CLZ) than to typical antipsychotics still have residual psychopathology, but CLZ drug resistance data are lacking. The aim of this study was to evaluate the possible predictive factors of a clinical response to CLZ in a group of 20 schizophrenic patients (DSM-IV: 13 males and 7 females with a mean age of 35.5 years +/- 7.1 SD) resistant to typical antipsychotics but CLZ responders as assessed by the Brief Psychiatric Rating Scale (BPRS) (>20% improvement). After a 1-week washout period, CLZ was started at a dose of 25 mg/d, which was increased by the third week up to a maximum of 600 mg/d (mean 365.00 +/- 129.88 mg/d SD) and remained unchanged until the end of the study (week 8).The patients showed a significant improvement in the mean scores of the rating scales for positive (SAPS) and negative symptoms of schizophrenia (Scale for the Assessment of Negative Symptoms, SANS) (P < 0.003, P < 0.02). All of the patients included in the study were BPRS responders; 65% were also SAPS and 75% SANS responders (>20% improvement). The improvement in the SANS score was significantly greater among the female patients (P < 0.05). The SAPS and SANS responders had a significantly higher mean metabolic ratio [MR = (NCLZ/CLZ)] than the nonresponders (P < 0.01), and the percentage of improvement significantly correlated with the increase in MR. This finding suggests that the individual pharmacogenetics indicated by metabolic capacity may be related to clinical response. All of the patients showed a reduction in white blood cell counts, but this was significantly less in the SANS responders than the SANS nonresponders (P = 0.047). The SAPS responders had significantly lower neutrophil counts than the nonresponders (P = 0.03). Our results seem to suggest the importance of pharmacodynamic, constitutional, and genetic data over strict pharmacokinetics in determining the clinical response to CLZ.     

Vigabatrin-induced decrease in serum phenytoin concentration does not involve a change in phenytoin bioavailability

The possibility that vigabatrin (VGB) decreases serum phenytoin (PHT) concentration by lowering the oral bioavailability of PHT was investigated in 21 patients with epilepsy. Each patient was switched from oral to intravenous PHT for 5 days before and after combined treatment with VGB. After VGB (2-3.5 g day(-1) for at least 5 weeks), serum PHT concentrations decreased slightly from 87 +/- 25 to 76 +/- 31 micromol l(-1) (means +/- s.d., P < 0.05), but in a subgroup of seven patients the decrease was more prominent (from 72 +/- 22 to 49 +/- 17 micromol l(-1), P < 0.005). At baseline (before VGB), serum PHT remained unaffected (85 +/- 30 micromol l(-1)) after switching PHT dosage to the intravenous route, indicating that the oral availability of the drug was virtually complete. During VGB treatment, serum PHT was also unchanged (74 +/- 34 micromol l(-1)) after switching from oral to intravenous therapy, and this was also true for the subgroup of patients showing a prominent interaction (48 +/- 18 micromol l(-1)). The urinary recoveries of PHT and its metabolites pHPPH and mHPPH remained constant throughout the study. It is concluded that the oral availability of PHT is unaffected by VGB and that the VBG-induced decrease in serum PHT is mediated by alternative mechanisms.     

A comparative study of vigabatrin vs. carbamazepine in monotherapy of newly diagnosed partial seizures in children

Carbamazepine (CBZ) is a drug of choice for the treatment of simple or complex partial seizures and secondary generalized seizures in adults and children. Vigabatrin (VGB) is a relatively new second line antiepileptic drug and was first registered for use in Poland more than ten years ago. Few reports have been published on the comparison of efficacy of VGB in children with epilepsy. The objective of this study is to evaluate the safety, efficacy and EEG effects of initial VGB monotherapy compared with initial CBZ monotherapy in children with newly diagnosed epilepsy. We present results of a prospective, outpatient and open study carried out in the University Hospital Center in Bia?ystok. Twenty-six children with partial epilepsy treated with VGB and 28 patients treated with CBZ were studied. The evaluation of the efficacy of the two drugs did not reveal any significant differences. Very good (reduction > 75%) seizure control was achieved in 22 out of 26 patients (84.6%) in the VGB group. One patient had a 50-75% decrease of seizures (good effect), similarly one child had a 25-50% reduction of seizures (mild effect). In two patients, we observed increased seizures (myoclonic jerks). Very good seizure control was achieved in 17 out of 28 patients (60.7%) in the CBZ group. Good seizure control was achieved in 5 out of 28 patients (17.8%) and mild control was seen in two children. No improvement was observed in 4 (14%) of the patients. The EEG background activity was improved in VGB-treated patients. No effect on the EEG background activity was observed in CBZ-treated children. VGB seems to be a safe and effective antiepileptic drug as primary monotherapy for epilepsy in children with similar proportion of side effects as CBZ.     

Coadministration of gabapentin or MK-801 with lamotrigine slows tolerance to its anticonvulsant effects on kindled seizures

The development of tolerance to therapeutic effects of antiepileptic drugs can be a problem in the treatment of epilepsy, bipolar disorder, and pain syndromes. In the present study, acute treatment with the new antiepileptic drug lamotrigine (LTG, 15 mg/kg) markedly suppressed seizure stage and seizure duration in amygdala-kindled rats; but this antiseizure effect was rapidly lost following 4-8 days of repeated treatment. When gabapentin (GBP, 20 mg/kg) was coadministered with LTG, the ability of LTG to suppress seizure stage, seizure duration, and after-discharge (AD) duration was markedly extended. In addition, GBP coadministration with LTG decreased the number of animals that developed LTG-related running fits (Stage 6 seizures) and lengthened the number of days required to develop running fits or complete tolerance. Neither acute nor repeated treatment with MK-801 (0.3 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, had effects on kindled seizures. However, cotreatment with MK-801 markedly extended the anticonvulsant effects of LTG on the three seizure indices and reduced running fits. These data indicate that cotreatment with either GBP or MK-801 slows tolerance development to the anticonvulsant effects of LTG on kindled seizures. Therapeutic implications of the present study remain to be explored.     

Association between patient age and gabapentin serum concentration-to-dose ratio: a preliminary multivariate analysis

OBJECTIVES: To evaluate the association between patient age and gabapentin (GBP) concentration-to-dose ratio by a multivariate analysis. METHODS: The association between patient age and the trough steady-state serum concentration of gabapentin (GBP) normalized to 1 mg/kg body weight or concentration-to-dose ratio (CDR) was retrospectively assessed by analysis of covariance. Potential confounding factors considered were GBP dosage, the number of GBP doses per day, and the presence of concomitant antiepileptic drugs (AEDs). Concentrations that had been measured in predose "trough" samples collected from 66 patients, aged 5-84 years, with partial seizures or neuropathic pain chronically receiving GBP BID (n = 21) or TID (n = 45), alone (n = 15) or in combination with other AEDs (n = 51) were used in this retrospective analysis. RESULTS: Average GBP CDR was 0.23 +/- 0.18 (mean +/- SD). The GBP CDR increased with age (r2 = 0.46, P < 0.001), and the correlation was improved when only samples from patients taking GBP BID were separately considered (r2 = 0.68, P < 0.001). The ratio was lower in the 10 children younger than 11 years of age (0.07 +/- 0.05) than in 8 adolescents aged 12 to 18 years (0.14 +/- 0.04), lower than in 35 adults aged 19 to 65 years (0.22 +/- 0.13), and lower than in 13 patients older than 65 years of age (0.45 +/- 0.20) by 1-way analysis of variance (F = 19.4, P < 0.001). Analysis of covariance showed a significant influence on GBP CDR of patient age (P < 0.001) and the number of GBP daily doses (P < 0.01), but GBP daily dosage or concomitant AEDs had no significant influence on the ratio. CONCLUSIONS: In this retrospective study of a small, select group of patients, (1) the GBP CDR increased significantly with age when potential confounding factors such as GBP dosage, number of GBP doses per day, and concomitant AEDs were considered by analysis of covariance, and (2) patients older than 65 years, even without any known renal disease, may have double GBP CDR than younger adults and, therefore, may need half of the GBP dose per body weight to achieve a similar concentration.     

Therapeutic drug monitoring of levetiracetam by high-performance liquid chromatography with photodiode array ultraviolet detection: preliminary observations on correlation between plasma concentration and clinical response in patients with refractory epilepsy

Levetiracetam is a new antiepileptic drug prescribed for the treatment of patients with refractory partial seizures with or without secondary generalization as well as for the treatment of juvenile myoclonic epilepsy. A rapid and specific method by high-performance liquid chromatography diode array detection was developed to measure the concentration of levetiracetam in human plasma. The trough plasma concentrations measured in 69 epileptic patients treated with 500 to 3000 mg/d of levetiracetam ranged from 1.1 to 33.5 microg/mL. The mean (range) levetiracetam plasma concentrations in responders and nonresponders were 12.9 microg/mL (4.6-21 microg/mL) and 9.5 microg/mL (1.1-20.9 microg/mL), respectively. A wide variability in concentration-response relationships was observed in patients. Using a receiver operating characteristic curve, the threshold levetiracetam concentration for a therapeutic response was 11 microg/mL. The sensitivity and specificity for this threshold levetiracetam concentration were 73% and 71%, respectively. According to chi analysis, this finding was not significant probably because of the small number of patients and because of their refractory seizure type. Nevertheless, the levetiracetam plasma concentration could be used to help clinicians detect severe intoxication or to verify compliance by repeating the measurement in patients.     

The effect of serum potassium on theophylline-induced seizures

Generalized seizures may be associated with therapeutic or intentional theophylline overdose. Toxic levels of theophylline are also associated with a fall in potassium which could potentiate theophylline-induced seizures. To evaluate the role of serum potassium concentration in theophylline-induced seizures we investigated the seizure threshold in normokalemic and hyperkalemic rats during theophylline infusion to toxic levels. Hyperkalemic rats were prepared with intraperitoneal amiloride and potassium chloride and had a mean +/- SEM initial potassium of 5.29 +/- 0.15 mEq/L. Control animals received either amiloride or potassium and had initial serum potassium concentrations of 4.00 +/- 0.08 and 3.93 +/- 0.16 mEq/L, respectively. Potassium levels after 30 minutes of theophylline infusion were 4.11 +/- 0.18 mEq/L in the hyperkalemic rats and 3.47 +/- 0.06 and 3.51 +/- 0.12 mEq/L in the control animals. There were no significant differences in the serum theophylline concentrations at time of seizure, nor was there a correlation between serum potassium concentration and theophylline concentration at time of seizure. Since the preservation of normokalemia does not influence the onset of seizures in theophylline toxicity, this suggests that the potassium level has little effect on seizure activity in this model.     

Milnacipran plasma levels and antidepressant response in Japanese major depressive patients

The relationship between antidepressant effects and plasma levels of milnacipran was studied in 49 cases of major depression without psychotic features during 6 weeks of milnacipran treatment. The daily dose of milnacipran was 50 mg/day for the first week, and up to 100 mg/day thereafter. Depressive symptoms were evaluated by the Montgomery and Asberg depression rating scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of this study. Thirty-four patients (69.4%) were responders (defined as a 50% or greater decrease in the baseline MADRS score). Significant differences of MADRS scores were seen from 1 week after the beginning of this study (p=0.004, unpaired t-test) between responders and nonresponders. The mean plasma milnacipran level of responders, 82.0 +/- 29.4 ng/ml, was similar to that of non-responders, 78.6+/-23.1 ng/ml; there was no significant difference between responders and nonresponders. Neither a significant linear nor a curvilinear relationship was obtained between the final MADRS score and the plasma levels of milnacipran. Although there was no significant relationship between the plasma levels of milnacipran and the antidepressant response, milnacipran should be considered an efficacious agent in the treatment of major depressive patients.     

A comparison of the efficacy of carbamazepine and the novel anti-epileptic drug levetiracetam in the tetanus toxin model of focal complex partial epilepsy

1. The tetanus toxin seizure model, which is associated with spontaneous and intermittent generalized and non-generalized seizures, is considered to reflect human complex partial epilepsy. The purpose of the present study was to investigate and compare the anticonvulsant effects of carbamazepine with that of levetiracetam, a new anti-epileptic drug in this model. 2. One microl of tetanus toxin solution (containing 12 mLD(50) microl(-1) of tetanus toxin) was placed stereotactically into the rat left hippocampus resulting in generalized and non-generalized seizures. 3. Carbamazepine (4 mg kg(-1) h(-1)) and levetiracetam (8 and 16 mg kg(-1) h(-1)) were administered during a 7 day period via an osmotic minipump which was placed in the peritoneal cavity. Carbamazepine (4 mg kg(-1) h(-1)) exhibited no significant anticonvulsant effect, compared to control, when the entire 7 day study period was evaluated but the reduction in generalized seizures was greater (35.5%) than that for non-generalized seizures (12.6%). However, during the first 2 days of carbamazepine administration a significant reduction in both generalized seizure frequency (90%) and duration (25%) was observed. Non-generalized seizures were unaffected. This time-dependent anticonvulsant effect exactly paralleled the central (CSF) and peripheral (serum) kinetics of carbamazepine in that steady-state concentrations declined over time, with the highest concentrations achieved during the first 2 days. Also there was a significant 27.3% reduction in duration of generalized seizures during the 7 day study period (P=0.0001). 4. Levetiracetam administration (8 and 16 mg kg(-1) h(-1)) was associated with a dose-dependent reduction in the frequency of both generalized (39 v 57%) and non-generalized (36 v 41%) seizures. However, seizure suppression was more substantial for generalized seizures. Also a significant dose-dependent reduction in overall generalized seizure duration was observed. 5. These data provide experimental evidence for the clinical efficacy of levetiracetam for the management of patients with complex partial seizures. Furthermore, levetiracetam probably does not act by preventing ictogenesis per se but acts to reduce seizure severity and seizure generalization.     

A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression

We examined the efficacy and tolerability of augmentation with an extended release formulation of methylphenidate (OROS MPH, Concerta) in patients with major depression who were nonresponders or partial responders to antidepressants. Sixty subjects with treatment-resistant depression (TRD) participated in a 4-week, randomized, double-blind, placebo-controlled study of augmentation with methylphenidate (18-54 mg/d). The preexisting antidepressant dose was unchanged. The primary efficacy measure was change in the 21-item Hamilton Depression Rating Scale from randomization to end of treatment. Data were analyzed with intent-to-treat with last observation carried forward approach. There were no statistically significant differences between the methylphenidate (n = 30) and placebo (n = 30) groups in reduction in 21-item Hamilton Depression Rating Scale scores (drug, -6.9; placebo, -4.7) from baseline to end of treatment (F1,47 = 1.24, P = 0.22), although responders were numerically higher in the extended-release methylphenidate group (40.0%) than in the placebo group (23.3%). On the secondary efficacy measures of changes in Clinical Global Impression-Improvement and Severity scores and Beck Depression Inventory-Second Edition, the drug failed to separate from placebo, although the proportion of responders in the drug group were numerically higher than placebo. There were no significant differences in weight, heart rate, and blood pressure changes between the 2 groups. The common adverse events were loss of appetite, nausea, headache, and anxiety. The mean dose of drug was 34.2 mg/d. The study did not demonstrate a statistically significant benefit for augmentation with methylphenidate in TRD. Combination of methylphenidate with antidepressants was well tolerated. Adequately powered, randomized, controlled trials are necessary to fully evaluate the efficacy of extended-release methylphenidate in TRD.     

Influence of ambroxol on lung tissue penetration of amoxicillin

Lung amoxicillin levels were assessed in tissue obtained from 16 patients who underwent lung resection due to different pulmonary diseases. In this double-blind placebo controlled study patients were allocated to two groups in randomized order; one group received amoxicillin 1000 mg t.i.d. (n = 8) and the other amoxicillin 1000 mg + ambroxol 60 mg t.i.d. (n = 8). A trend towards higher antibiotic lung tissue levels was observed in patients who received the antibiotic together with the mucolytic agent. The ratio pulmonary tissue/serum amoxicillin levels reached a significant difference being higher in the amoxicillin plus ambroxol group than in the other one (0.411 +/- 0.04 vs 0.672 +/- 0.07; p less than 0.01), even if the amoxicillin plasma levels were lower. A possible effect of ambroxol on lung tissue penetration of amoxicillin is suggested and discussed.     

Dose-related pharmacokinetics after oral administration of a new formulation of erythromycin base.

1 Erythromycin concentrations in serum and urine were determined in 24 healthy male, fasting subjects after oral administration of 250, 500, or 1000 mg of erythromycin base (250 mg capsules containing enteric-coated pellets). The subjects also received a film-coated erythromycin stearate tablet (equivalent to 500 mg base). 2 The mean +/- s.d. maximal serum erythromycin concentrations were 1.9 +/- 0.8, 3.8 +/- 1.4, 6.5 +/- 2.9 and 2.9 +/- 1.7 mg/l for 250, 500, or 1000 mg base and 500 mg stearate, respectively. The serum peaks usually occurred after 2 h irrespective of dosage form given. 3 The mean +/- s.d. areas under the serum concentration v time curves (AUC0-infinity) were 4.5 +/- 1.7, 11.2 +/- 4.3, 27.2 +/- 10.6 and 7.5 +/- 3.4 mg l -1 . h after 250, 500, or 1000 mg base, and 500 mg stearate, respectively. 4 The urinary recoveries were 5.0, 6.7, 8.6% of the base doses given and 4.4% of the stearate dose given. 5 Dose-dependent excretion of erythromycin occurred. The increase in AUC was larger than multiples of the lowest base dose.     

Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects.

As a result of the low oral bioavailability of ganciclovir, a prodrug was developed to improve the bioavailability of ganciclovir. This study was designed to investigate the fasting, single-dose pharmacokinetics as well as the absolute and relative bioavailability of a valine ester prodrug of ganciclovir, valganciclovir, as compared to oral and intravenous ganciclovir in asymptomatic HIV+ and CMV+ subjects. In this open-label, randomized, three-period crossover study, 18 subjects received, in random order, single oral doses of valganciclovir 360 mg and ganciclovir 1000 mg and an intravenous infusion of ganciclovir 5 mg/kg over 1 hour. Valganciclovir was rapidly and extensively hydrolyzed to ganciclovir, resulting in significantly greater bioavailability compared to 1000 mg oral ganciclovir (60.9% vs. 5.6%, respectively). Higher peak serum concentrations were reached earlier following valganciclovir (ganciclovir [2.98 +/- 0.77 micrograms/mL at 1.0 +/- 0.3 h]) than following oral ganciclovir (0.47 +/- 0.17 microgram/mL and 2.2 +/- 1.0 h). Mean total ganciclovir AUCs following oral ganciclovir (1000 mg) and 360 mg valganciclovir (3.8 +/- 1.2 and 10.8 +/- 1.9 micrograms-h/mL) were less than that following a standard 5 mg/kg intravenous infusion of ganciclovir (25.1 +/- 3.8 micrograms-h/mL). In summary, valganciclovir is a prodrug with a favorable safety profile with enhanced bioavailability and significantly higher serum concentrations of ganciclovir than following oral administration of ganciclovir itself.     

Anticonvulsant action and long-term effects of gabapentin in the immature brain

The anticonvulsant action and the long-term effects on learning, memory and behavior of the new generation antiepileptic drug gabapentin (GBP) were investigated in immature animals. Kainic acid (KA) was administered to rats on postnatal day (P) 35. Animals were treated with GBP or saline from P36 to P75 and spontaneous seizure frequency was monitored. After tapering the drug, the rats were tested in the water maze and open field test. Brains were then analyzed for histological lesions. Animals treated with GBP following KA-induced status epilepticus had a reduced incidence of spontaneous recurrent seizures, a better pathology score, and less aggressiveness compared to saline-treated controls. Effectiveness of GBP on seizure threshold was tested using flurothyl inhalation in 10 separate age groups of animals ranging from the newborn period to adulthood. Furthermore, GBP plasma concentration peaks were determined in all age groups. At all ages, GBP pre-treated animals demonstrated a higher seizure threshold. Plasma GBP concentrations did not significantly change with age. These data suggest that acute administration of a single therapeutic dose of GBP increases the seizure threshold at all ages studied, while chronic treatment following the status reduces spontaneous seizure frequency and cell damage and has no long-term adverse consequences on cognitive processes during development.