Cutaneous adverse reactions to clindamycin: results of skin tests and oral exposure.

BACKGROUND: Clindamycin is an antibiotic used in anaerobic and severe complicated infections. It is often selected for patients with a history of allergy to other antibiotics. OBJECTIVES: To study the occurrence of clindamycin hypersensitivity and to determine whether skin tests are useful in cases of suspected clindamycin allergy. METHODS: Six patients with an exanthematous rash and a history strongly suggestive of clindamycin hypersensitivity were studied with skin tests and oral exposure. Cases of suspected adverse drug reactions to clindamycin reported to the National Register of Adverse Effects of Drugs (NRAED) in Finland during 1973-2000 were analysed. RESULTS: In the skin tests true-positive patch test reactions were seen in four of six patients, while 22 healthy control patients were negative. One false-positive and one false-negative patch test reaction were seen. During 1973-2000, 29 suspected cases of skin and/or mucosal membranes affected by clindamycin were reported to the NRAED. CONCLUSIONS: Clindamycin hypersensitivity is not common. Delayed-type allergic reactions occur and patch tests are useful in those cases. Oral exposure is the method of choice if possible, as false-negative and false-positive reactions may occur.

Benzodiazepines in the treatment of epilepsy in people with intellectual disability.

All the benzodiazepines (BZDs) in clinical use have the capacity to promote the binding of the major inhibitory neurotransmitter, gamma-amino-butyric acid (GABA), to sub-types of GABA receptors which exist as multi-subunit ligand-gated chloride channels. Thus, the BZDs facilitate the actions of GABA in the brain. The BZDs in use as antiepileptic drugs are diazepam, clonazepam, clobazam, nitrazepam, and lately, also lorazepam and midazolam as emergency therapy. The BZDs have a wide-spectrum of proven clinical efficacy in the prevention of different kind of seizures. Clonazepam and clobazam, as well as nitrazepam in some cases, can be useful as an adjunct treatment in refractory epilepsies. However, the clinical use of BZDs for the prophylactic treatment of epilepsy is associated with two major problems which have limited the long-term use of these drugs: the potential for side-effects, especially sedative effects, and the high risk of development of tolerance. Despite the limitations of BZDs in the prophylactic treatment of epilepsies, these drugs play a prominent role in clinical practice in the emergency management of acute seizures and status epilepticus. Diazepam, clonazepam and lorazepam are all considered first-line agents in the emergency management of acute seizures and status epilepticus. Furthermore, the value of midazolam as an emergency therapy in epilepsy has been increasingly recognized in recent years.

Personality profiles and state aggressiveness in Finnish alcoholic, violent offenders, fire setters, and healthy volunteers.

BACKGROUND: Based on clinical observations in a series of studies on Finnish alcoholic, violent offenders, we asserted that the impulsive offenders represented an extreme group of type 2 alcoholics. We also observed that these subjects were vulnerable to hypoglycemia after the administration of oral glucose load. Furthermore, we believe that while being hypoglycemic, the impulsive offenders are particularly irritable and aggressive. In the present study, we addressed these issues by studying psychological trait and state variables in a new group of violent offenders and fire setters, and age- and sex-matched healthy volunteers. METHODS: Fifty-eight alcoholic, violent offenders and impulsive fire setters and 21 healthy volunteers were administered the Karolinska scales of personality and the Rosenzweig picture frustration test after an oral aspartame and glucose challenge. RESULTS: The psychological test results and the criminal histories of the offenders, together with biochemical measurements, suggest that a low 5-hydroxyindoleacetic acid concentration in cerebrospinal fluid in the alcoholic offenders is associated with irritability and impaired impulse control, and a high free testosterone concentration in cerebrospinal fluid is associated with increased aggressiveness, monotony avoidance, sensation seeking, suspiciousness, and reduced socialization. CONCLUSION: Finnish alcoholic, impulsive offenders have personality profiles characteristic of Scandinavian early-onset male alcoholics with antisocial traits, who have been also referred to as type 2 alcoholics.

CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers.

BACKGROUND: There is an extensive literature describing a central serotonin deficit in alcoholic, impulsive, violent offenders and fire setters. In the present study, we investigated biochemical concomitants of impulsivity and aggressiveness, and the physiological consequences of reduced central serotonin turnover. METHODS: Forty-three impulsive and 15 nonimpulsive alcoholic offenders and 21 healthy volunteers were studied in the forensic psychiatry ward of a university psychiatric department. The subjects underwent lumbar punctures and oral glucose and aspartame challenges, and their diurnal activity rhythm was measured with physical activity monitors. Discriminant function analyses were used to investigate psychophysiological and biochemical concomitants of aggressive and impulsive behaviors. RESULTS: Alcoholic, impulsive offenders with antisocial personality disorder had low mean cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and corticotropin levels and high mean CSF testosterone concentrations. Compared with healthy volunteers, they showed increased physical activity during the daytime. Alcoholic, impulsive offenders with intermittent explosive disorder had a low mean CSF 5-HIAA concentration and blood glucose nadir after an oral glucose challenge, and desynchronized diurnal activity rhythm. Healthy volunteers had mean CSF 5-HIAA concentrations that were intermediate between those of alcoholic, impulsive and nonimpulsive offenders. Alcoholic, nonimpulsive offenders had a significantly higher mean CSF 5-HIAA concentration than all the other groups, including healthy volunteers. CONCLUSIONS: In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence.

Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism.

BACKGROUND: To examine whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme in the biosynthesis of serotonin, may be a factor influencing serotonin turnover and behaviors controlled by serotonin. METHODS: Using a polymerase chain reaction-based method, TPH genotype was determined in DNA samples from 56 impulsive and 14 nonimpulsive, alcoholic, violent offenders and 20 healthy volunteers. RESULTS: In the behaviorally extreme impulsive group, we observed a significant association between TPH genotype and cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) concentration. No association of TPH genotype with impulsive behavior was detected. The polymorphism was also associated with a history of suicide attempts in all violent offenders, independent of impulsivity status and cerebrospinal fluid 5-HIAA concentration. CONCLUSION: In some individuals, a genetic variant of the TPH gene may influence 5-HIAA concentration in the cerebrospinal fluid and predisposition to suicidal behavior.

D2 dopamine receptor genotype and cerebrospinal fluid homovanillic acid, 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenylglycol in alcoholics in Finland and the United States.

If a genetic association between the D2 dopamine receptor genotype and alcoholism is mediated by altered dopamine function, then a stronger association might be found in alcoholics who are deviant in indices of dopamine function and by comparing alcoholics to nonalcoholics matched for ethnic origin. Therefore, we evaluated the D2/TaqI polymorphism in 29 impulsive violent alcoholic Finns, 17 nonimpulsive violent alcoholic Finns and 36 Finnish controls free of mental disorders, alcoholism and substance abuse. In 37 of the alcoholics, we measured cerebrospinal fluid (CSF) homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol. There was no relationship between D2/Taq 1 genotype and concentrations of these monoamine metabolites in this group, which exhibits lower CSF HVA and 5-HIAA as compared to controls. There was also no genotypic difference between Finnish alcoholics and nonalcoholic controls. The lack of relationship between D2/Taq1 genotype and HVA concentration was replicated in 24 Caucasian alcoholics in the United States.

Prevention of alcohol withdrawal seizures with carbamazepine and valproic acid.

To evaluate the value of the nonsedative anticonvulsants carbamazepine and valproic acid a controlled study including drug monitoring was carried out. Intoxicated alcoholics (n = 138) were admitted for inpatient detoxication and randomly assigned to either carbamazepine (n = 43), sodium valproate (n = 46) or placebo (n = 49) in a double-blind fashion. Drug treatment lasted for four days and the daily doses of both drugs amounted to 1200 mg in the beginning of the study. Sodium valproate induced gastric distress, nausea and vomiting more frequently than placebo. About half of the subjects had to stop carbamazepine because of intolerable side-effects including vertigo, nausea, vomiting, diplopia and rash. Serum carbamazepine levels (18-89 mumol/l) were found to be high (greater than 40 mumol/l) in many but not all of these subjects. Seizures occurred in 3 subjects on placebo, 2 on carbamazepine and 1 on sodium valproate. Delirium tremens developed in 2 on sodium valproate and 1 on placebo. The study demonstrates that drug side-effects may seriously hamper the utility of carbamazepine and sodium valproate as routine treatment for the prevention of alcohol withdrawal symptoms.

The effect of metoclopramide and prochlorperazine on the absorption of effervescent paracetamol in migraine.

Antiemetics modify gastric emptying, a rate-limiting step in drug absorption. The absorption of effervescent paracetamol in water solution was studied in three groups of 10 female patients during acute migraine attacks. Paracetamol was preceded 30 min earlier by a rectal dose of metoclopramide, prochlorperazine maleate, or placebo. Each patient was retested with paracetamol when headache-free. Migraine attacks delayed slightly the absorption of paracetamol solution. Prior administration of rectal prochlorperazine had a minor delaying effect on paracetamol absorption. The peak concentration, the time to reach the peak, and the area under the time-concentration curve from 0 to 6 h of paracetamol were similar with the three treatments.

Can barbiturate anaesthesia cure infantile spasms?

Five patients with infantile spasms and hypsarrhythmia and one with Lennox-Gastaut syndrome were treated with brief thiopentone anaesthesia as the primary treatment of infantile spasms. Thiopentone (30 mg/kg) was given intravenously and burst suppression was reached in EEG in three patients by this dose. The results were disappointing. In three patients a transient beneficial effect on spasms and hypsarrhythmia was seen, but all patients relapsed. Three other patients had anaesthesia for surgery. The spasms ceased and hypsarrhythmia disappeared dramatically, and the effect was permanent. The possible mechanisms of the therapeutic effect are discussed. It seems advisable to give anaesthesia and surgery prior to steroid treatment in any case where the both are needed.

Tolfenamic acid in combination with caffeine: absorption during acute migraine.

Tolfenamic acid is an anti-inflammatory analgesic which is used in the treatment of migraine attacks. Because caffeine is used in certain analgesic combinations, its effects on the absorption of tolfenamic acid was studied in a crossover study in migraine patients. Caffeine did not significantly change the absorption of tolfenamic acid during migraine attacks. The extent of absorption following oral administration of tolfenamic acid is decreased during migraine attacks, irrespectively if the volunteers received caffeine or placebo in combination with the drug. The reasons are discussed. It seems obvious that the migraine itself is responsible for the lack of absorption that cannot be counteracted with caffeine. Pain relief within a five-hour testing period was not influenced by concomitant administration of caffeine. It is concluded that tolfenamic acid alone is sufficient in treating migraines.

Tolfenamic acid, metoclopramide, caffeine and their combinations in the treatment of migraine attacks.

Tolfenamic acid is a fenamate which inhibits prostaglandin (PG) biosynthesis and may act as a PG antagonist as well. Caffeine and metoclopramide are used in combination with analgesics and ergotamine in the treatment of migraine attacks, but controlled clinical studies on fixed combinations with analgesics are rare. The effects of orally given tolfenamic acid (200 mg), caffeine (100 mg), metoclopramide (10 mg), tolfenamic acid + caffeine (200 mg + 100 mg), tolfenamic acid + metoclopramide (200 mg + 10 mg) and placebo were studied in 49 migraine patients (3 men, 46 women) in a double-blind randomized cross-over study comprising 482 migraine attacks. The patients were allowed to take either one or two capsules of each preparation for an attack. Additional drugs were allowed after 3 h. Parameters characterizing the effects and side-effects of the drugs were registered. Tolfenamic acid and its combinations were found to be effective in the treatment of acute migraine, but caffeine and metoclopramide alone did not differ from placebo. Combination with metoclopramide was better than tolfenamic acid alone as judged by the smaller dose needed and the intensity of attack. Between tolfenamic acid alone and its caffeine combination there were no statistically significant differences.

Effect of migraine attacks on paracetamol absorption.

The absorption of effervescent paracetamol (1000 mg) was investigated in nine female patients during a migraine attack and in the same patients when headache free. Migraine attack decreased (P less than 0.05) the areas under the serum paracetamol concentration-time curves (AUC) of 0-2 h, 0-4 h and 0-6 h and the peak serum concentration. The severity of nausea correlated significantly with the decrease in the AUC values. Our results support findings of delayed gastric emptying in migraine attacks. Both a delay and an impairment of drug absorption may follow.

Effects of migraine attack and metoclopramide on the absorption of tolfenamic acid.

The effect of acute migraine attack and rectally given metoclopramide on the absorption of orally given tolfenamic acid (300 mg) was investigated in seven female patients in a crossover study consisting of four phases, two without migraine and two during migraine. Metoclopramide hydrochloride (20 mg) or placebo was given double-blind. Migraine attacks delayed the absorption of tolfenamic acid. Serum concentrations of tolfenamic acid 1.5 and 2 h after drug administration remained smaller, the peak serum concentration (tmax) occurred later and the area under the serum concentration-time curve between zero and 2 h (AUC0-2 h) remained decreased during migraine. Metoclopramide pretreatment in migraine attacks increased the serum concentration of tolfenamic acid at 1.5 h, but its peak concentration, time to peak concentration and the AUC0-5 h remained unchanged as compared with the values obtained with tolfenamic acid alone. Between the absorption of tolfenamic acid without migraine and after metoclopramide pretreatment during migraine no significant differences existed. When the patients were studied without migraine the serum concentrations of tolfenamic acid 45 min and 60 min after its administration were higher after metoclopramide than after placebo pretreatment. During migraine attacks the serum concentrations and the AUC0-5.5 h of metoclopramide were slightly lowered. The impairment of drug absorption by migraine was not related to the duration or severity of the attack. The observed changes in drug absorption during migraine attacks are obviously due to the delay in gastric emptying. Rectally administered metoclopramide accelerates the absorption of orally given tolfenamic acid.

Pharmacokinetics of antiepileptic drugs.

The rational use of antiepileptic drugs requires the consideration of their pharmacokinetics, which may be influenced by the physiological and pathological factors. Pharmacokinetic interactions between antiepileptic drugs may lead to considerable fluctuation in plasma drug concentration, and monotherapy is often preferable. The absorption of phenytoin depends on pharmaceutical formulation. Phenytoin is highly bound to plasma proteins, thus the changes in the unbound fraction are of clinical significance. The saturation kinetics of its metabolism and drug interactions have further consequences. Carbamazepine is well absorbed and largely metabolized. Due to the autoinduction its half-life shortens in chronic administration. Valproate is highly, but variably bound to plasma proteins. It is eliminated mainly by metabolism. Due to the long half-life of phenobarbital its plasma concentrations change slowly, and time to the steady-state may be up to 30 days, if no loading dose is given. Primidone is partly metabolized to phenobarbital, and at steady-state plasma concentration of phenobarbital often exceeds that of primidone. Diazepam, clonazepam and nitrazepam are largely bound to plasma proteins and extensively metabolized with the half-lives of 20 to 60 hours.

The effect of metoclopramide on the absorption of tolfenamic acid.

The effect of metoclopramide on the absorption of orally given tolfenamic acid (300 mg) was investigated using rectal metoclopramide hydrochloride (20 mg) pretreatment in a randomized crossover study in eight voluntary migraine patients when headache-free. Tolfenamic acid and metoclopramide serum concentrations were estimated by high-performance liquid chromatograhic (HPLC) methods using UV detection. Metoclopramide given 30 min prior to tolfenamic acid significantly increased serum tolfenamic acid levels at 45 and 60 min after ingestion, compared to the levels obtained with placebo pretreatment. The bioavailability of tolfenamic acid, measured as the area under the serum tolfenamic acid concentration-time curve (AUC0-5 h) and the peak concentration, was not influenced by metoclopramide. The peak concentration of tolfenamic acid was 4.1 +/- 0.9 micrograms/ml (mean +/- s.e.m.), the time peak 1.9 +/- 0.2 h, and the elimination half-life 2.3 +/- 0.5 h calculated from the values without metoclopramide. The peak concentration of metoclopramide was 69 +/- 6.3 ng/ml and the time to peak 118 +/- 29 min. The results suggest that rectal metoclopramide enhances the rate of absorption of tolfenamic acid without changing its bioavailability.

Cimetidine-phenytoin interaction: effect on serum phenytoin concentration and antipyrine test.

In a prospective study in nine patients the effects of phenytoin and of cimetidine (1000 mg/day) + phenytoin on the antipyrine test and serum phenytoin concentrations were studied. Serum phenytoin increased from the steady state level of 5.7 +1.3 mg/l to 9.1 +1.4 mg/l after three weeks on cimetidine (p less than 0.01), and fell to 5.8 +1.2 mg/l within two weeks after withdrawal of cimetidine. The protein binding of phenytoin was not changed by cimetidine. After use of phenytoin for 2-4 months, antipyrine clearance increased from 0.67 +0.06 ml/min/kg to 1.61 +0.22 ml/min/kg, and antipyrine half-live fell from 10.9 +1.3 h to 4.5 +0.6 h as compared to the values before phenytoin treatment (p less than 0.01). After three weeks combined use of cimetidine and phenytoin, antipyrine clearance was decreased to 1.01 +0.07 ml/min/kg and antipyrine half-life was prolonged to 6.1 +0.5 h, (p less than 0.01) compared to the values on phenytoin alone. The distribution volume of antipyrine was not affected by phenytoin nor by cimetidine + phenytoin. The half-life of cimetidine was 2.8 +0.3 h in the patients in the longterm phenytoin treatment. There was a significant positive correlation (p less than 0.001) between the increase in serum phenytoin concentration and the prolongation of antipyrine half-life caused by cimetidine. Thus, cimetidine increases serum phenytoin concentration, very probably by inhibiting its metabolism. Care should be taken in the concomitant use of cimetidine ad phenytoin, and the dose of phenytoin should be modified according to the clinical symptoms and serum phenytoin concentrations.