[Medicaments and oral healthcare. Medicaments potentially inducing angioedema and/or urticaria]. / Serie: Medicamenten en mondzorg. Medicamenten die angio-oedeem en/of urticaria kunnen induceren.

Angioedema stems from increased vasodilation and vascular permeability, resulting in extravasation of fluid. Hereditary and acquired types of angioedema can be distinguished, with 3 and 4 subtypes, respectively. Groups of medicaments potentially inducing angioedema are, among others: ACE inhibitors, angiotensin II receptor blockers, dipeptidyl peptidase-4 inhibitors, thrombocyte aggregation inhibitors and immunosuppressive agents. Urticaria is characterised by red, slightly raised swellings, usually associated with a strong itching sensation and can be subdivided in an acute and a chronic type. Mast cells in the uppermost layer of the skin or the mucous membranes release a lot of histamine, increasing the dilation and permeability of blood capillaries, resulting in extravasation of fluid. Medicaments potentially inducing urticaria are, among others, the following groups: analgesics, anaesthetics, antibiotics, antidepressants, antihistamines, antihypertensives, antifungals, corticosteroids, H2 blockers, cancer medicaments, muscle relaxants, thrombocyte aggregation inhibitors and vaccines. Medical history and being alert when administering and prescribing anaesthetics, analgesics and antibiotics are very important in the prevention or treatment of angioedema and/or urticaria.

[Facial angioedema following pharmacotherapy with an ACE inhibitor]. / Angio-oedeem in het aangezicht na medicatie met een ACE-remmer.

A 56-year-old women suddenly had a swelling on her right cheek and on the right side of her upper lip, for which she decided to first visit her family physician and subsequently her family dentist. During the past two years, she was treated for an ovarian carcinoma by an oncologist. Recently, she was using the antihypertensive ACE inhibitor enalapril, prescribed by her family physician. Consultation between her family dentist, family physician and oncologist led to the diagnosis angioedema as an adverse effect of enalapril. The family physician replaced enalapril by the angiotensin II receptor blocker losartan. Subsequently, the swelling disappeared within two days. This angioedema type occurs most frequently in the head and neck area. Oropharyngeal, tongue and laryngeal oedema are very dangerous because they may cause airway obstruction. Today, a live-threatening or fatal condition is mostly prevented as a result of better vigilance of dentists and physicians. Nevertheless, such a condition will still occur occasionally.

[Medicaments and oral healthcare. Hyperpigmentation of oral soft tissues due to afamelanotide]. / Serie: Medicamenten en mondzorg. Hyperpigmentatie van de orale slijmvliezen door afamelanotide.

The medicament afamelanotide is an analogue of endogenous ?-melanocyte-stimulating hormone. It promotes cutaneous pigmentation, providing protection from sunlight. In dermatology, afamelanotide seems to establish therapeutic results for polymorphic light eruption, solar urticaria, erythropoietic protoporphyria, Hailey-Hailey disease, vitiligo and acne vulgaris. Afamelanotide is available for non-medical use to realise quick and easy skin tanning. Adverse effects of afamelanotide mentioned in the scientific literature are development and aggravation of melanocytic naevi, degeneration of melanocytic naevi to melanomas, melanonychia, systemic toxicity, rhabdomyolysis, posterior reversible encephalopathy syndrome, priapism and hyperpigmentation of oral soft tissues. Furthermore, numerous adverse effects of afamelanotide have been reported to the Netherlands pharmacovigilance centre LAREB as well as numerous adverse effects due to overdosage of afamelanotide to the National Poisons Information Centre. Dentists should be alert to hyperpigmentation of oral soft tissues due to afamelanotide.

[Series: Medicaments and oral healthcare. Medicaments and addictive substances, potentially inducing or ameliorating bruxism]. / Serie: Medicamenten en mondzorg. Medicamenten en verslavende middelen die potentieel bruxisme induceren of dempen.

Bruxism is described as a repetitive jaw-muscle activity characterised by clenching or grinding of the teeth and/or by bracing or thrusting of the mandible. This article provides an inventory of medications registered in the Netherlands and of addictive substances reported to potentially induce or aggravate bruxism as an adverse effect, and of medications registered in the Netherlands reported to potentially ameliorate existing bruxism. Groups of medications known as having the potential adverse effect of bruxism are amphetamines, anticonvulsants and selective serotonin reuptake inhibitors. Separate medicaments found in the scientific literature, having this potential are aripiprazole, atomoxetine, duloxetine, flecainide, ketotifen and methadone. Addictive substances with bruxism as potential adverse effect are alcohol, heroin, methamphetamine, methylenedioxymethamphetamine, nicotine and piperazines. Medications with the potential to ameliorate existing bruxism are botulinum toxin A, bromocriptine, buspirone, clonazepam, clonidine, gabapentin and levodopa.

[Medicaments and oral healthcare. Proliferation of the gingiva]. / Serie: Medicamenten en mondzorg. Proliferatie van de gingiva.

Adverse effects of medications and self care products on the gingiva can be divided into inflammation, intrinsic discolouration, irritation, trauma, cytotoxicity, lichenoid reaction, and proliferation. This article deals with the last-mentioned type of adverse effects; the other 6 have been discussed in a previous article. Proliferation of the gingiva as an adverse effect of medications has been reported for anticonvulsants, calcineurin inhibitors, calcium channel blockers and isotretinoin. With regard to the anticonvulsants that have been registered in the Netherlands, proliferation of the gingiva is predominantly induced by phenytoin, but also by carbamazepine, ethosuximide, phenobarbital, gabapentin, levetiracetam, primidone and valproic acid. All calcineurin inhibitors registered in the Netherlands may induce the adverse effect. This is also the case for nearly all calcium channel blockers, but particularly for dihydropyridines. Presumably, proliferation of the gingiva may be prevented or reduced in a number of ways. The most important one is good oral hygiene. Furthermore, proteins and cells that play an important role [in the process of gingival proliferation] have been discovered and there are medications that have the potential to eliminate these proteins and cells.

[Medicaments and oral healthcare. Adverse effects of medicines and self care products on the gingiva]. / Serie: Medicamenten en mondzorg. Bijwerkingen van medicamenten en zelfzorgmiddelen op de gingiva.

Medications and self care products may have adverse effects on the gingiva. These adverse effects can be divided into inflammation, intrinsic discolouration, irritation, trauma, cytotoxicity, lichenoid reaction, and proliferation. This article deals with the first 6 types of adverse effects mentioned: a subsequent article will deal with the last type mentioned. Since contraceptives were introduced, there have been indications that they cause or promote gingivitis, but with the current contraceptives this adverse effect is rarely seen. Intrinsic discolouration of the gingiva has been reported when using Staloral®, minocycline, contraceptives and hydroxychloroquine. Irritation and trauma of the gingiva are seen when self care products containing carbamide peroxide or hydrogen peroxide are used for external tooth whitening, or which have analgesic potential, such as acetylsalicylic acid and hydrogen peroxide or oral rinses containing alcohol. Several cytostatics may induce apoptosis of keratinocytes in the gingiva. Oral rinses with antibacterial ingredients have cytotoxic potential. Lichenoid reactions have been reported due to the use of several (groups of) medications.

[Medicaments and oral healthcare 5. Adverse effects of -medications and over-the-counter drugs on teeth]. / Serie: Medicamenten en mondzorg 5. Bijwerkingen van medicamenten en zelfzorg­middelen op gebitselementen.

Intrinsic tooth discoloration may occur as an adverse effect of fluoride and tetracyclines. Extrinsic tooth discoloration may occur as superficial staining or as discoloration of the superficial pellicle and/or biofilm due to chlorhexidine, liquid iron salts, essential oils, some antibiotics and stannous fluoride. Inhibition of orthodontic tooth movement has been reported due to the use of prostaglandin synthetase inhibitors. If medications or over-the-counter drugs induce hyposalivation or contain much sucrose, caries may develop. Erosion may occur if the acidity of medications or over-the-counter drugs is excessive. Attrition is a well-known adverse effect of serotonin reuptake inhibitors, antiparkinson agents, and antipsychotics. Congenital dysplasia is observed following childhood treatment with cytostatic drugs. External cervical root resorption is an adverse effect of internal teeth-whitening products. Prenatal exposure to antiepileptic drugs and childhood treatment with cytostatic drugs may cause dental agenesis. Antiseptic drugs applied for external teeth-whitening and toothpastes with additional ingredients to prevent extrinsic discoloration and creation of calculus, may cause tooth hypersensitivity.

Causality methods in cosmetovigilance: comparison of Colipa and PLM versus global introspection.

The European Cosmetics Regulation requires a post-marketing system for detection of undesirable effects on human health of cosmetic products. Colipa, the European Cosmetic, toiletry and perfumery association, provided guidelines for causality assessment of these effects. In addition another causality method originally designed for causality rating in Post Launch Monitoring (PLM) of novel foods has been employed to assess causality of cosmetic products. In this study these two causality schemes for consumer cosmetic products were validated against clinical assessment, using the method of global introspection (GI) in 100 reported cases. Causality assessments were performed by three experienced assessors in pharmacovigilance. In the event of discordance between the assessors, an adapted Delphi method was used. The overall Spearman correlation coefficient was 0.74 for comparison of Colipa versus GI, whereas this was 0.50 for PLM versus GI. According to current guidelines, the sensitivity was 0.95 for both the Colipa and PLM method, specificity was 0.84 for Colipa and 0.40 for PLM. From these results it can be concluded the performance of the Colipa causality method yielded better correlation to GI than PLM causality method. The factor identified from comparison of these two schemes as having greatest impact was the course of the reaction.

[Recurrent attacks of angioedema ascribed to the use of estrogen preparations and a pregnancy (hereditary angioedema type 3)]. / Recidiverende aanvallen van angio-oedeem toegeschreven aan het gebruik van oestrogeenpreparaten en aan zwangerschap (hereditair angio-oedeem type 3).

A woman experienced recurrent attacks of angioedema from the age of 17 to 21 years and these appeared to be associated with the use of oestrogens. After stopping the medication her complaints disappeared, but they returned during her first pregnancy. Angioedema is a serious condition, which can lead to acute abdominal symptoms, oedema of the upper respiratory tract and death by asphyxiation. The most well-known cause is hereditary angioedema, an autosomal dominant disorder that is characterized by deficiency of C1 esterase inhibitor (C1-INH). Recently, a new type of hereditary angioedema (type 3) has been reported that occurs exclusively in women and is characterised by oestrogen dependency (both endogenous and exogenous), normal C1-INH concentrations and severe attacks of angioedema, which are clinically indistinguishable from the classic form.

Prediction of metal bioavailability in Dutch field soils for the oligochaete Enchytraeus crypticus.

Current risk assessment procedures ignore that variation in soil properties results in substantial differences for uptake and effects in organisms in different soils. In this contribution is presented the results of a study on the soil-related factors that modulate metal uptake and elimination by the oligochaete worm Enchytraeus crypticus. Uptake of Cd, Cu, Pb, and Zn was quantified in 20 Dutch field soils as a function of time. Uptake rate constants and equilibrium concentrations were estimated using compartment modeling. Internal metal concentrations varied less than the corresponding external levels. Zn and especially Cu provided the most extreme examples of this general behavior, which suggests regulation by the organism. Body residues by Cd increased linearly over time in 11 of the 20 soils studied, whereas in the remaining 9 soils equilibration of internal Cd levels was observed. CaCl2 extraction could be used to discriminate the 9 soils in which there is Pb accumulation from the 11 soils in which bioavailable Pb levels were too low to allow for uptake. Multivariate expressions that describe uptake rate constants and bioaccumulation factors as a function of soil characteristics were derived. pH and cation exchange capacity were the most important parameters. The formulae were very similar to those describing partitioning of metals over the solid and liquid phase of the soils, which suggests pore water-mediated uptake. A semi-mechanistic approach yielded further evidence of pore water-related uptake, modulated by competition between H+ and metal ions at the active sites of the membranes.

Onset of action of eformoterol by dry powder inhaler: objective and subjective measures.

This double-blind, randomised, placebo-controlled crossover trial in 18 adults with asthma evaluated the onset of efficacy of doses of 12 and 24 micrograms eformoterol delivered as a dry powder, and compared patients' subjective assessments of efficacy with objective measures. Bronchodilatory efficacy was measured in terms of specific conductance (sGaw) and forced expiratory volume in one minute (FEV1). With both doses of eformoterol, a bronchodilatory effect was observed one minute after inhalation. The difference in bronchodilator effect (sGaw and FEV1) between both eformoterol doses and placebo was statistically significant (p < 0.01) from one minute onwards. No significant difference in onset of action or peak effect was seen between the two doses of eformoterol. Patients' subjective reports were closely related to the observed onset of efficacy and indicated no difference between the two eformoterol doses.

Formoterol suspension aerosol. Comparison with formoterol solution aerosol for 12 weeks in asthmatic patients.

UNLABELLED: Formoterol solution aerosol has proved to be a fast and long-acting beta 2-sympathicomimetic drug in many clinical trials. The physical stability, however, was such that storage needed to be at 4 degrees C to 8 degrees C before first use; afterwards, the aerosol could be used for another three months at room temperature. To improve the stability, new ways have been investigated to formulate ann aerosol with improved shelf life and thus more convenient storage conditions, which was reached with a formoterol suspension aerosol. Equivalent single doses between the two formulations revealed no differences in onset or duration of action. In a double-blind, randomized parallel group multicenter study, organized in the Netherlands, 186 patients with stable asthma and reversible airway obstruction were treated either with one puff of 12 micrograms twice daily of formoterol metered dose inhaler (MDI) supension (SP) or a same dose of solution (SL) aerosol for 12 weeks to study the efficacy and tolerability of both presentations after a longer period of use. The following criteria of effectiveness were used: the FEV1 values on the mornings of the control days at 0, +4, +8, and + 12 weeks, the peak flow values (PEF) in the mornings and in the evenings before, and 1/2 to 1 h after treatment, the number of asthma attacks at night and during the day, the number of extra puffs at night and during day, and the subjective impression of patients and investigator. RESULT: No statistically significant differences between the two formoterol preparations were found. There was no indication of tachyphylaxis. CONCLUSION: The results are consistent with the hypothesis that the biologic effects of formoterol when delivered from MDI containing the two different formulations of the drug are equivalent.

Formoterol as dry powder inhalation. A dose finding study in comparison with formoterol metered dose inhaler and placebo.

We compared the bronchodilator effects and systemic tolerability of 12, 24 and 48 micrograms formoterol DP capsules with 12 micrograms formoterol MDI and placebo in 30 patients with reversible obstructive airway disease. Pulmonary function tests were done and pulse rate and blood pressure were recorded. We observed significant differences between all active substances vs placebo regarding peak effect, duration of effect and AUC value. No significant difference was observed between either 12 or 24 micrograms formoterol DP and 12 micrograms from MDI in all mentioned parameters. With 48 micrograms DP, increased peak effect, AUC and duration of effect were noted. Heart rate Holter monitoring showed a slightly more pronounced effect with 48 micrograms. We conclude that 12 to 24 micrograms formoterol DP capsules are equivalent to 12 micrograms of formoterol MDI regarding efficacy and tolerability, while 48 micrograms formoterol DP capsules cause more profound effects in bronchodilation and on the heart rate.

The effect of maximal doses of formoterol and salbutamol from a metered dose inhaler on pulse rates, ECG, and serum potassium concentrations.

In a randomized, double-blind, crossover cumulative study, the individual maximal bronchodilator dosages for formoterol (F) and salbutamol (S) were assessed for their respective influence on ECG, pulse rate, and serum potassium levels in 13 patients with stable and reversible asthma. The following dosages were administered with an interval of 1 h: 12-24-48-(48)-(48) micrograms for F and 100-200-400-400-(400)-(400) micrograms for S. The study day was discontinued if pulse rate was above 140 beats min-1, a flattening of T wave on the ECG was recorded, or a maximal bronchodilation in FEV1 was observed (above 110 percent of the predicted value or an increase in FEV1 in the last two measurements below 5 percent). The maximal individual dose of F administered was 84 micrograms in six patients, 132 micrograms in three patients, 180 micrograms in three patients, and 228 micrograms in one patient. For S, the maximal individual dose was 400 micrograms in three patients, 2,200 micrograms in eight patients, 3,000 micrograms in one patient, and 3,800 micrograms in one patient. The mean maximal increase in FEV1 was 36.0 percent after F and 35.1 percent after S. Pulse rate increased from 73 to S3 beats.min-1 after F and from 75 to 84 beats.min-1 after S (both statistically significant). No pulse rate above 140 beats.min-1 was observed. In the high-therapeutic range (up to 36 micrograms of F and 6,090 micrograms of S), no changes in potassium level were observed. In still higher dosages, mean potassium level decreased from 4.16 to 3.78 mmol.L-1 after F and from 4.02 to 3.88 mmol.L-1 after S (not clinically relevant). The lowest individual potassium level recorded was 3.1 mmol.L-1. No clinically important changes in ECG were observed. In conclusion, very high doses of F and S administered from a metered dose inhaler proved to be safe for patients.

Formoterol in the treatment of nocturnal asthma.

Formoterol fumarate is a new beta 2-adrenergic agonist with a long lasting effect. The bronchospasmolytic effect of 12 micrograms of formoterol was compared with that of 200 micrograms of albuterol (salbutamol) in a single-center, double-blind, randomized within-patient study. The drugs were given as aerosols by MDI to 16 patients with nocturnal asthma in a stable phase. The inhalations were given at 10 PM and the FEV1 values as parameter were measured before and at 1, 2, 6, 8, 10, and 12 hours afterwards. The FEV1 6 hours after administration of formoterol was significantly higher than that after albuterol (ANCOVA: p = 0.008), and this was still the case 12 hours after the test dose at 10 AM the following morning (ANCOVA: p = 0.009). At 4 AM, the FEV1 fell below the basic starting value after albuterol, whereas it remained at least 10 percent above the formoterol inhalation. Five patients required rescue therapy after albuterol and two after formoterol. We conclude that formoterol in a dose of 12 micrograms via MDI confers good protection against nocturnal asthma; this was only insufficient for some patients with severe asthma, and further studies with higher dosages in these patients are clearly indicated.

Bronchodilator effect of inhaled formoterol vs salbutamol over 12 hours.

The bronchodilator effects were compared in 16 stable asthma patients for 12 hours after either 12 micrograms formoterol or 200 micrograms salbutamol from a metered-dose aerosol in a randomized, double-blind, crossover study. The FEV1 measured before 1, 2, 4, 6, 8, 10 and 12 hours after administration was used as the parameter. From 2 hours onwards after dosage, the bronchodilator effect of formoterol was statistically significantly greater than that of salbutamol. The effect of formoterol lasted longer, and even after 12 hours, the FEV1 was still 20 percent above the baseline value. This is clinically significant and offers new possibilities for treatment of the so-called "morning dip." Both agents were well tolerated.