Sara Messina

Topiramate pharmacokinetics in children and adults with epilepsy: A case-matched comparison based on therapeutic drug monitoring data

ObjectiveTo compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting.Study designRetrospective, case-matched pharmacokinetic evaluation.PatientsSeventy children (aged 1–17 years) with epilepsy and 70 adult controls (aged 18–65 years) with epilepsy, matched for sex and comedication.MethodsTopiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney’s U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed.ResultsIn the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 ± 21.0 vs 28.4 ± 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 ± 35.1 vs 46.1 ± 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis.ConclusionTopiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.

Serum Carbamazepine Concentrations in Elderly Patients : A Case-matched Pharmacokinetic Evaluation Based on Therapeutic Drug Monitoring Data

Summary:  Purpose: To assess the influence of aging on the steady‐state pharmacokinetics of carbamazepine (CBZ) in a large population of patients evaluated in a therapeutic drug monitoring (TDM) setting.

Shock Waves in the Treatment of Post-Traumatic Myositis Ossificans

Myositis ossificans (MO) is a fairly common evolution in sports activity and can be due to direct trauma or to repeated micro-injuries. The traditional therapeutic approach relies on a variety of treatments, such as physical therapy but evidence of their proven clinical efficacy is lacking. The latest therapeutic option is surgical removal but this is a demolitive procedure and is frequently associated with a significant loss of functional integrity. There are few articles in literature about the treatment of post-traumatic MO, and none on extracorporeal shock wave therapy (ESWT). We illustrate a case series of 24 sportsmen treated with three sessions of electro-hydraulic shockwave therapy and an associated rehabilitation program. Only a partial reduction of the ossification was observed in the X-ray images but all the patients showed signs of functional improvement immediately after therapy. Two months after the therapy, a normal range of motion and no signs of weakness were observed. Three months after treatment, 87.5% of patients resumed regular sports activities.

Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data

The influence of aging on the pharmacokinetics of phenytoin at steady-state was evaluated retrospectically by comparing apparent oral clearance values (CL/F) in 75 patients aged 65-90 years (mean, 71.7 +/- 5.3 years) receiving phenytoin alone (n = 58) or in combination with phenobarbital (n = 17) and in an equal number of control patients aged 20-50 years (mean, 36.7 +/- 8.5 years) matched for gender, body weight, and comedication. All data were derived from the database of the therapeutic drug monitoring service (TDMS) of an academic neurological hospital. On average, elderly patients were found to exhibit slightly higher CL/F values compared with controls (14.6 +/- 4.7 ml h(-1) kg(-1) versus 13.1 +/- 4.2 ml h(-1) kg(-1), P < 0.05), the difference being probably related to the dose-dependent nature of phenytoin metabolism and the fact that elderly patients received lower dosages (4.4 +/- 1.1 mg kg(-1)day(-1) versus 5.3 +/- 1.1 mg kg(-1) day(-1), P < 0.001) and had lower serum phenytoin concentrations (14.1 +/- 5.7 microg ml(-1) versus 18.6 +/- 6.8 microg ml(-1), P < 0.0001). Gender and phenobarbital comedication were not found to exert any statistically significant influence on phenytoin CL/F. By contrast, in the elderly group, CL/F values were negatively correlated with age. On average, CL/F values decreased by about one-third between 65 and 85 years of age, but interindividual variability was considerable and age explained only 7.8% of the variation in CL/F in the elderly group. Overall, these findings indicate that aging is associated with a progressive decline in phenytoin clearance, presumably as a result of decreased drug metabolizing capacity. Because assessment was based on total serum phenytoin concentrations and the unbound fraction of phenytoin is known to decrease in old age, the influence of aging as quantified in this study may underestimate the magnitude of changes in the clearance of unbound, pharmacologically active drug. Based on these data, it is prudent to utilize initially smaller phenytoin dosages in old patients, and to make subsequent dose adjustments based on clinical response and serum drug level measurements. Interpretation of the latter, however, should take into account the possibility of an increase in the fraction of unbound drug.

Single-dose pharmacokinetics of lamotrigine in children: influence of age and antiepileptic comedication.

To evaluate the influence of pediatric age and antiepileptic comedication on the single-dose pharmacokinetics of lamotrigine, 19 patients with epilepsy (10 comedicated with enzyme inducers and 9 comedicated with valproic acid) aged 8 months to 30 years received a single oral dose of lamotrigine (0.6 to 2.2 mg/kg) after an overnight fast. Blood samples were collected for at least 36 hours and plasma lamotrigine concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were calculated by noncompartmental analysis. Lamotrigine half-life (T1/2) and oral clearance (Cl/F) values were significantly lower and significantly higher, respectively, in patients comedicated with enzyme inducers than in those receiving valproic acid (T1/2 = 8.1 vs. 41.7 hours respectively, P < 0.001; Cl/F = 0.11 vs. 0.04 L/h per kg respectively, P < 0.005, geometric means), whereas Cmax and Tmax values were comparable in the two groups. The differences in pharmacokinetic parameters persisted when comparisons were made within subgroups stratified according to age. Within groups of patients homogeneous for type of comedication, Cmax and AUC values tended to be lower in children aged less than 12 years than in older patients. There was no significant relationship between half-life values and age. The authors conclude that both age and type of comedication influence lamotrigine pharmacokinetics. The reduction in lamotrigine concentrations caused by enzyme inducers and the elevation caused by valproic acid can be explained by stimulation and inhibition, respectively, of lamotrigine glucuronidation. On the other hand, the lower plasma lamotrigine levels in children than in adolescents and older patients may not be explainable solely by differences in metabolic rate.

The influence of old age and enzyme inducing comedication on the pharmacokinetics of valproic acid at steady-state: A case-matched evaluation based on therapeutic drug monitoring data

PURPOSE To evaluate the influence of aging on the pharmacokinetics of valproic acid (VPA) at steady-state and on the susceptibility of VPA metabolism to enzyme induction by antiepileptic comedication. METHODS The database of the therapeutic drug monitoring service of a large neurological hospital was searched to identify patients aged > or = 65 years stabilized on VPA therapy. Apparent VPA oral clearance (CL/F) calculated for each elderly patient was compared with that determined in an equal number of VPA-treated controls aged 20-50 years and matched for gender, body weight and antiepileptic drug (AED) comedication. RESULTS A total of 71 elderly patients aged 70.0+/-4.4 years, including 20 receiving enzyme inducing AEDs, was included in the main evaluation. In the absence of enzyme inducing comedication, VPA CL/F in the elderly was similar to that found in non-elderly controls (9.7+/-4.6 versus 10.2+/-4.6mlh(-1)kg(-1)). Elderly patients on enzyme inducing comedication, on the other hand, had lower CL/F values than enzyme induced younger controls (11.7+/-5.4 versus 16.0+/-6.3mlh(-1)kg(-1), p<0.05). Since VPA CL/F is known to increase with increasing dosage, a lower VPA dosage in elderly patients comedicated with enzyme inducers compared with controls may have contributed to differences in CL/F between the two groups. CONCLUSIONS In the absence of enzyme inducing comedication, VPA clearance in the elderly was comparable to that observed in controls. VPA clearance in elderly patients receiving enzyme inducing AEDs was lower than in controls, the difference being probably due to an influence of age as well as to the fact that mean VPA dosage was lower in these patients than in controls. Since our measurements of clearance were based on total serum VPA concentrations and VPA binding to plasma proteins is known to be reduced in old age, it is likely that the clearance of unbound, pharmacologically active, VPA was decreased to an important extent in the elderly, presumably as a result of a decline in drug metabolizing capacity.

Phenobarbital Pharmacokinetics in Old Age: A Case-matched Evaluation Based on Therapeutic Drug Monitoring Data

Summary:  Purpose: To assess the influence of aging on the pharmacokinetics of phenobarbital (PB) at steady state in patients receiving long‐term therapy.

Effectiveness evaluation of an integrated automatic termomechanic massage system (SMATH ® system) in non-specific sub-acute and chronic low back pain - a randomized double-blinded controlled trial, comparing SMATH therapy versus sham therapy: study protocol for a randomized controlled trial

BackgroundLow back pain (LBP) is a major health problem in modern society, with 70-85% of the population experiencing LBP at some time in their lives. Each year, 5-10% of the workforce misses work due to LBP, most for less than 7 days. Almost 10% of all patients are at risk of developing chronic pain and disability. Little clinical evidence is available for the majority of treatments used in LBP therapy. However, moderate evidence exists for interdisciplinary rehabilitation, exercise, acupuncture, spinal manipulation, and cognitive behavioral therapy for subacute and chronic LBP. The SMATH® system (system for automatic thermomechanic massage in health) is a new medical device (MD) that combines basic principles of mechanical massage, thermotherapy, acupressure, infrared therapy, and moxibustion. SMATH® is suitable for automatic multidisciplinary treatment on patients with non-specific sub-acute and chronic LBP.Methods/designThis paper describes the protocol for a double-blinded, sham-controlled, randomized, single-center short term clinical trial in patients with non-specific sub-acute and chronic LBP aged 18 to 70 years. The primary outcome will be the effectiveness of SMATH® versus sham therapy (medical device without active principles) determined by evaluating self perceived physical function with Roland Morris Disability Questionnaire (RMDQ) scores after 4 weeks of treatment (end of treatment). Major secondary outcome will be effectiveness of SMATH® determined by evaluating self perceived physical function comparing RMDQ scores between end of treatment and baseline. The trial part of the study will take 7 months while observational follow-up will take 11 months. The sample size will be 72 participants (36 for each arm). The project has been approved by the Ethical Committee of Cremona Hospital, Italy on 29 November 2010.DiscussionCompared to other medical specialties, physical and rehabilitation medicine (PRM) has not yet received the deserved recognition from clinicians and researchers in the scientific community, especially for medical devices. The best way to change this disadvantage is through well-conducted clinical research in sham-controlled randomized trials. Sham treatment groups are essential for improving the level of evidence-based practice in PRM. The present trial will counter the general lack of evidence concerning medical devices used in LBP therapy.Trial RegistrationISRCTN: ISRCTN08714168

The Use of a High-Tech Knee Pad for Reduction of the Postoperative Effusion after Total Knee Arthroplasty

Purpose  After total knee arthroplasty (TKA), pain and swelling, especially in older and less cooperative patients, can limit the retrieval of a good range of motion and muscle tone and consequently the achievement of an optimal function outcome. A high-tech knee pad made of metal fibers emitting infrared energy was used in a group of patients undergoing TKA to assess its efficacy in the postoperative period with respect to a group with a placebo. Methods  Twelve patients used knee pads after surgery for 3 weeks and were evaluated using visual analog scale (VAS), Knee Society Rating Score, Cincinnati Knee Rating Score, and painkillers at specific timings. Results  At 3 weeks, all scores improved in a significant manner in the treated group compared with the placebo group. At 2 months after surgery, VAS was better in the study group than the control group, whereas other parameters were similar. However, the use of rescue drugs was less in the study group than in the placebo group. Conclusion  A high-tech knee pad may contribute to a faster recovery within the first week after a knee replacement, limiting the use of painkillers and allowing a quick functional recovery by the control of pain and postoperative effusion. Level of Evidence  Level II, randomized prospective study with small sample size.