[Medication for ADHD and the risk of cardiovascular mortality]. / Medicatie voor aandachtstekort-hyperactiviteitstoornis (ADHD) en het risico op cardiovasculaire sterfte.

Recently, the FDA recommended a black-box warning describing the increased risk of cardiovascular events associated with the use of stimulant drugs (amphetamines; in the Netherlands: dexamphetamine, methylphenidate) in the treatment of attention deficit hyperactivity disorder (ADHD). The recommendation was based largely on the increased use of these drugs in children and adults in the USA, voluntary reporting of adverse events, and the pharmacological analogy with other sympathomimetic amines, such as ephedrine, pseudoephedrine and phenylpropanolamine, for which similarwarnings have been given previously. The Adverse Event Reporting System documented 25 cases of sudden death based on WHO criteria with the use of amphetamines and methylphenidate; most of the cases were children aged less than 18 years. Sudden death in children is most often caused by fatal arrhythmias due to congenital heart diseases, such as long QT syndrome and hypertrophic cardiomyopathy. An increase in heart rate can potentially provoke life-threatening arrhythmias when the QT interval does not compensate for the increase. In adults, increased blood pressure and heart rate are well-documented risk factors for cardiovascular events. The use of methylphenidate is increasing in the Netherlands, indicating that greater caution is warranted when prescribing these drugs.

No effect of the infiltration of local anaesthetic for total hip arthroplasty using an anterior approach: a randomised placebo controlled trial.

Only limited data are available regarding the infiltration of local anaesthetic for total hip arthroplasty (THA), and no studies were performed for THA using the anterior approach. In this prospective, randomised placebo-controlled study we investigated the effect of both standard and reverse infiltration of local anaesthetic in combination with the anterior approach for THA. The primary endpoint was the mean numeric rating score for pain four hours post-operatively. In addition, we recorded the length of hospital stay, the operating time, the destination of the patient at discharge, the use of pain medication, the occurrence of side effects and pain scores at various times post-operatively. Between November 2012 and January 2014, 75 patients were included in the study. They were randomised into three groups: standard infiltration of local anaesthetic, reversed infiltration of local anaesthetic, and placebo. There was no difference in mean numeric rating score for pain four hours post-operatively (p = 0.87). There were significantly more side effects at one and eight hours post-operatively in the placebo group (p = 0.02; p = 0.03), but this did not influence the mobilisation of the patients. There were no differences in all other outcomes between the groups. We found no clinically relevant effect when the infiltration of local anaesthetic with ropivacaine and epinephrine was used in a multimodal pain protocol for THA using the anterior approach.

Effect of probenecid on the formation and elimination of acyl glucuronides: studies with zomepirac.

When 100 mg oral zomepirac was taken with 500 mg b.i.d. oral probenecid by six healthy subjects, the disposition of zomepirac was markedly altered. Probenecid decreased total plasma clearance of zomepirac by 64%, which resulted in an increase in bioavailability from 0.55 without probenecid to 0.84 when given concurrently. The apparent metabolic clearance of zomepirac to form zomepirac acyl glucuronide was reduced 71% and zomepirac renal clearance, a minor elimination route, was reduced by 79%. When assayed by a method that prevents degradation of the labile acyl glucuronide, zomepirac glucuronide concentrations in plasma were comparable to those of zomepirac. Probenecid decreased the renal clearance of zomepirac glucuronide by 72%, which, together with the increased zomepirac levels, resulted in a 2.8-fold increase in the AUC of the conjugate. Urinary excretion of zomepirac glucuronide was reduced from 72% to 58% of the dose, but the excretion of free zomepirac was unchanged at 5% of the dose. The ratio of the total clearance/bioavailability of zomepirac in control subjects was 682 +/- 246 ml/min, which is double the value reported in previous studies of zomepirac disposition. We believe that this difference is due to degradation of the unstable zomepirac acyl glucuronide in the previous analytic methodologies used. Qualitatively, the effects of probenecid on zomepirac disposition are similar to those previously reported for other drugs of this class that are metabolized to acyl glucuronides. However, zomepirac appears unusual in that significant levels of its acyl glucuronide metabolite are found in vivo.

Citrate anticoagulation and dialysate with reduced buffer content in chronic hemodialysis.

Anticoagulation with trisodium citrate (510 mmol/l) at a rate of 126 ml/h in combination with a calcium-free, 35 mmol/l acetate dialysate and i. v. supplementation of calcium chloride (350 mmol/l) at a rate of 22.5 ml/h has been performed in renal failure patients at risk of bleeding or actively bleeding. Short-term use-i. e. on the average four dialyses in 15 patients-showed no adverse effects or clotting phenomena. However, long-term use-i. e. at least four weeks and on average sixteen dialyses in six chronic hemodialysis patients-caused paresthesias and muscular cramps possibly due to the combination of insufficient calcium supplementation and metabolic alkalosis. To prevent metabolic alkalosis, the acetate content of the dialysate and the infusion rate of citrate were reduced to 29.5 mmol/l and 100 ml/h, respectively. To prevent clotting at this infusion rate, a calcium and magnesium-free dialysate was used and i. v. supplementation of calcium chloride (350 mmol/l) and magnesium chloride (250 mmol/l) was performed at rates of 30 ml/h and 15 ml/h, respectively. Six chronic renal failure patients were dialyzed with this regimen for an average of four months. There were no side effects or metabolic alkalosis noted. When an equimolar amount of bicarbonate replaced the acetate in the calcium and magnesium-free dialysate, side effects and metabolic alkalosis were seen within three dialyses. When the bicarbonate concentration in the dialysate was reduced to 25 mmol/l neither side effects nor metabolic alkalosis was observed. Thus citrate anticoagulation in patients on chronic hemodialysis can only be performed when the buffer content of the dialysate is reduced.

[Early change from intravenous to oral antibiotics: 'switch therapy']. / Vroege omzetting van intraveneuze naar orale antibiotica: 'switchtherapie'.

There has been growing interest in recent years in early switch therapy: antibiotics are administered intravenously during the early phase of the infection, and then continued orally. A large number of recent prospective and randomized studies justify the application of an early switch. There is consensus in the literature about the circumstances in which an early switch is justified: (a) the patient must show clinical improvement; (b) the oral therapy should result in sufficiently high levels at the infection site; (c) the patient must be capable of taking oral medication, there must be no signs of malabsorption and interactions with food or with other drugs should be taken into account; (d) if these rules are observed, switch to oral therapy as a rule is justified after 2 to 3 days' intravenous administration. An early switch is more comfortable to the patient, eases the load on the nursing staff and considerably reduces expenses.

[Good results of treatment of reflex sympathetic dystrophy with a 50% dimethylsulfoxide cream]. / Goede resultaten van behandeling van acute reflectoir-sympathische dystrofie met een 50%-dimethylsulfoxide-crème.

In this open prospective study dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, was tested in a 50% concentration in a fatty cream base (cremor vaselini cetomacrogolis FNA) in a total of 37 patients suffering from reflex sympathetic dystrophy. Patients were selected according to an RSD screening protocol. They also received physiotherapy. Eligible patients presented with acute signs of RSD and needed to have a sensation of heat in the extremity, as well as at least two of the following symptoms: (distal) pain, redness, swelling, loss of function, hyperhidrosis or increased hair growth and/or nail growth. Endpoints were the clinical improvement of the patient together with the patient's assessment of the pain according to a Visual Analog Scale (VAS: 0-10; 0 = no pain, 10 = unbearable pain). Successful treatment was accomplished when the VAS was halved and clinical signs had improved. The results showed a significant improvement in VAS score from 5.3 (SD 2.9) to 0.9 (SD 1.3; p < 0.01) in a mean treatment time of 3.4 months (SD 1.9). Systemic side effects consisted of a sulfurous smell of the exhaled breath of 12 patients. Concerning local side effects a mild dry, scaling effect on the skin was seen.

Simultaneous determination of zomepirac and its major metabolite zomepirac glucuronide in human plasma and urine.

A method is described for the simultaneous determination of zomepirac and its primary metabolite, zomepirac glucuronide, in plasma and urine. Reversed-phase liquid chromatography is used with an ion-pairing mobile phase of methanol-tetrabutylammonium hydrogen sulfate. Detection is by UV at 313 nm. Biological samples are cooled immediately, then adjusted to pH 3 to avoid zomepirac glucuronide degradation. Samples (0.5 ml) are then deproteinated with acetonitrile or acetone, the supernatant concentrated and dissolved in acetonitrile-acetate buffer, with up to one half of the sample injected onto the LC system. Recovery is greater than 70% and reproducible. The measurable concentration range is linear from 0.05 to 200 micrograms/ml. Total elution time of the assay is less than 10 min. Selectivity of zomepirac and zomepirac glucuronide is optimized. Sample preparation prior to analysis so as to prevent zomepirac glucuronide degradation is emphasized.

Pharmacokinetics of simultaneously administered hexobarbital and heptabarbital in rats: an alternative approach to metabolic correlation studies.

The pharmacokinetics of hexobarbital and heptabarbital were studied after simultaneous oral administration to rats in order to correlate their rates of metabolism. Hexobarbital and heptabarbital were chosen for this purpose as model substrates because of their structural, pharmacokinetic as well as metabolic similarity. Blood concentrations were measured for 2 hr after administration by a capillary gas chromatographic method. In control rats (n = 8) elimination half-lives and intrinsic clearance values ranged between 13 to 28 min and 96 to 435 ml/min X kg for hexobarbital and between 8 to 21 min and 84 to 371 ml/min X kg for heptabarbital, respectively. A short-term pretreatment of rats (n = 7) with phenobarbital resulted in small but significant increases in the rates of metabolism of both barbiturates, whereas treatment of rats with 3-methylcholanthrene (n = 5) resulted in a reversed effect. Correlation of the elimination half-lives of the two drugs in all experiments was only weak (r = 0.70). The intrinsic clearance values reflecting enzyme activity in vivo, however, were found to correlate very strongly (r = 0.97). The results of this study suggest that an experimental approach, in which intraindividual differences are eliminated, appropriate kinetic parameters are studied and similarity of metabolic profiles are taken into consideration are preferable to the previously applied longitudinally designed correlation studies.

Fumaric acid therapy in psoriasis: a double-blind comparison between fumaric acid compound therapy and monotherapy with dimethylfumaric acid ester.

In a 4-month double-blind study the effects of dimethylfumaric acid esters (DMFAE-EC) and DMFAE plus salts of monoethylfumaric acid esters (fumaric acid combination, FAC-EC) in enteric-coated tablets were compared in 22 respectively 23 patients with psoriasis. In both groups about 50% showed a considerable improvement, i.e. the initial score was more than halved. The therapeutic effects showed no significant differences in both groups with respect to the total psoriasis score or the different parameters. In the FAC-EC group the effects were obtained more rapidly. Most frequently observed side effects in both groups were flushings, stomachache and diarrhea. Due to these complaints 3 respectively 8 patients discontinued therapy. Eosinophilia, leukopenia and lymphopenia were the most frequently observed differences in lab tests. It was concluded that FAC-EC had no significantly better effect than monotherapy with DMFAE-EC. Moreover, enteric coating of the tablets did not prevent stomach complaints. Until more information has been obtained about the pharmacokinetics, the toxicity and optimal composition of the drug, the fumaric acid therapy in psoriasis should be seen as experimental.

Simultaneous determination of midazolam and its three hydroxy metabolites in human plasma by electron-capture gas chromatography without derivatization.

Electron-capture gas chromatography was carried out to determine midazolam and its three hydroxy metabolites (1-hydroxymethylmidazolam, 4-hydroxymidazolam and 1-hydroxymethyl-4-hydroxymidazolam) in human plasma. The assay involves extraction from plasma, buffered to pH 9.3, into cyclohexane-dichloromethane (6:4) and analysis by gas chromatography. The use of an HP-17 cross-linked, capillary column makes derivatization unnecessary. The sensitivity of the method was 2-3 ng/ml for midazolam, 1-hydroxymethylmidazolam and 4-hydroxymidazolam, and 20 ng/ml for 1-hydroxymethyl-4-hydroxymidazolam. The extraction recovery of midazolam, 1-hydroxymethylmidazolam, 4-hydroxymidazolam and 1-hydroxymethyl-4-hydroxymidazolam was 99.3 +/- 2.4, 67.0 +/- 4.6, 92.7 +/- 4.7 and 28.7 +/- 6.3%, respectively. This gas chromatographic assay was used to assess the concentration-time profiles of midazolam and its metabolites in human plasma after rectal and intravenous administration of midazolam.

Systemic therapy with fumaric acid derivates: new possibilities in the treatment of psoriasis.

For the past two decades fumaric acid (FA) therapy has become an increasingly popular treatment in Western Europe for psoriasis. FA therapy originally was developed by Schweckendiek and subsequently standardized by Schäfer. Schäfer's fumaric acid compound therapy (FACT) consists of the oral intake of dimethylfumaric acid ester (DMFAE) and several salts of monoethylfumaric acid ester (MEFAE) in combination with topical fumaric acid therapy (1% to 3% MEFAE in an ointment or FA in bathing oils) and a diet. Schäfer claimed excellent results in a large number of patients. Preliminary studies by German dermatologists, however, revealed contradictory therapeutic results and serious side effects, and FA treatment was soon abandoned by dermatologists. To assess the value of FA therapy we conducted an open pilot study of 36 patients in which FACT therapy appeared to be rather effective. Thereafter, several controlled studies with MEFAE sodium in two different dosages versus placebo, and DMFAE versus placebo, were done. The results indicated that MEFAE sodium in dosages up to 240 mg daily was ineffective, whereas daily dosages of 720 mg resulted in a significant decrease in scaling and itching but did not affect extension of the eruption. DMFAE, 240 mg daily, produced a significant amelioration and prevented extension. Side effects of FA treatment were nausea, diarrhea, general malaise, and severe stomachache. Mild disturbances of liver and kidney function during treatment were observed with the 720 mg dosage of MEFAE and with the 240 mg dosage of DMFAE. Moreover, a relative lymphopenia with a selective decrease of suppressor T lymphocytes occurred in about 50% of the patients treated with DMFAE.(ABSTRACT TRUNCATED AT 250 WORDS)

Early switch from intravenous to oral antibiotics: guidelines and implementation in a large teaching hospital.

In recent years 'switch therapy' has been advocated: short intravenous antibiotic therapy, for 2-3 days, followed by oral treatment for the remainder of the course. Little is known about the number of patients that could benefit from early switch therapy and the consequences of introducing this strategy in everyday practice. We prospectively registered all antibiotic courses on wards for Internal Medicine, Surgery, and Pulmonology during a 2 month period, before (n = 362, inventorial phase) and after (n = 281, implementation phase) the introduction of guidelines for switching therapy. Approximately 40% of all patients who started on iv antibiotics were candidates for an early iv-oral switch. During the inventorial phase, 54% (52/97) of eligible patients were switched to oral treatment, after a median of 6 days (range 2-28 days). After implementation of the guidelines, this percentage rose to 83% (66/80) (difference 29%, 95% CI 16-42%; P < 0.001). Therapy was also switched earlier, after a median of 4 days (range 2 to 16 days). In the 6 weeks after completion of the oral course, recurrence of infections, or readmissions due to reinfections did not occur. Compared with the inventorial phase, 43% of iv administrations could be avoided, that is >6000 per year. This means a potential annual reduction of dfl.60,000 (c. US$30,000) of administration costs. The potential savings in purchase costs of the antibiotics were dfl.54,000 (US$27,000) annually. In conclusion, a substantial number of patients starting on iv antibiotics were candidates for an early iv-oral switch. The guidelines were well accepted by the physicians and substantial savings in costs and nursing time were achieved.

Fluocinonide in an adhesive base for treatment of oral lichen planus. A double-blind, placebo-controlled clinical study.

Patients with symptomatic oral lichen planus frequently require therapy to reduce signs and symptoms. For this purpose, corticosteroids are often applied topically. In a randomized, double-blind, placebo-controlled study, the efficacy of the topical application of 0.025% fluocinonide was evaluated. Forty consecutive patients with oral lichen planus diagnosed on the basis of histopathologic and immunofluorescence findings participated in this study. All patients were followed for 3 to 17 months. No adverse effects were noted during follow-up period. In the group of 20 patients that received the drug, 4 patients (20%) showed a complete remission, and 12 patients (60%) had a good or partial response to topical treatment. In the placebo-group, these figures were 0 and 6 (30%), respectively. The majority of the placebo-group (70%) did not respond at all with regard to signs (Xt2 = 10.4; p = 0.0013) and symptoms (Xt2 = 6.97, p = 0.008). The results from this study suggest that topical application of fluocinonide in an adhesive base is a safe and effective drug to reduce signs and symptoms in oral lichen planus.

Cyclosporin A in an adhesive base for treatment of recalcitrant oral lichen planus. An open trial.

Patients with symptomatic oral lichen planus often require therapy to reduce signs and symptoms of the condition. For this purpose, corticosteroids are frequently used. In this study the effect of another immunosuppressive drug, cyclosporin A was evaluated; it was applied as a topical drug four times daily and contained 0.025% cyclosporin A. The study group was composed of nine symptomatic patients in whom the diagnosis of oral lichen planus was confirmed by histopathologic examination including immunofluorescence. All patients had unsuccessfully undergone previous treatment with topical or systemic corticosteroids. The minimum follow-up period in the present study was at least 4 months. Four patients showed partial response to treatment with respect to signs and symptoms. None of the patients had a complete remission. Five patients showed no response or even complained of an increase of signs and symptoms. No adverse side effects of the drug were recorded during follow-up. Although the number of patients has been small, the results of this study indicate that topical application of cyclosporin A (0.025%) in the treatment of recalcitrant oral lichen planus does not offer a distinct advantage over the use of topical corticosteroids.

Treatment of acute reflex sympathetic dystrophy with DMSO 50% in a fatty cream.

Acute Reflex Sympathetic Dystrophy (acute RSD) was defined using a reproducible classification. Elevated temperature of the affected extremity ("calor"), measured by the dorsal side of the observer's hand and mentioned by the patient, pain ("dolor") measured by the Visual Analogue Scale (VAS), redness ("rubor"), edema ("tumor") and limited active range of motion ("functio laesa"), all contributed to the classification system. Patients scoring 4 to 5 positive symptoms were considered to have acute RSD. A prospective, randomized and double blind study was performed in 32 patients, all suffering from acute RSD. In all of these patients the primary injury was the result of a previous accident. One patient was taken out of the study because of his surgery. The study involved treatment with a fatty cream with 50% dimethyl sulfoxide (DMSO, group A), or without DMSO (placebo, group B), both for 2 months. All patients received physiotherapy applied within pain limits. Application of the creams resulted in both groups in an improvement of RSD-scores and VAS-scores after 2 months. However, the improvement of the RSD score in patients of group A (DMSO-group) was significantly (P < 0.01) better compared to group B. The results suggest a certain activity of DMSO 50% cream in patients suffering from RSD and is, therefore, recommendable.