Bengt Götrick

Studies of muscarinic receptor subtypes in salivary gland function in anaesthetized rats.

The in vivo study aimed to examine whether muscarinic receptor subtypes other than muscarinic M3 receptors exert exocrine functional roles in the rat salivary glands. The effects of pirenzepine, methoctramine and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) were examined on secretion from the major salivary glands evoked by acetylcholine (0.001-10 micromol kg(-1) i.v.) in pentobarbitone-anaesthetized rats. Observations were occasionally made on glandular blood flow. 4-DAMP (0.1-100 nmol kg(-1) i.v.) markedly and equipotently inhibited the acetylcholine-evoked fluid responses in all glands. Pirenzepine (0.1 micromol kg(-1) i.v.-10 mmol kg(-1) i.v.) showed significantly lower inhibitory potency than 4-DAMP, most conspicuously in the parotid, while methoctramine (0.1 micromol kg(-1) i.v.-10 mmol kg(-1) i.v.) exerted an even lesser inhibitory effect. Also against acetylcholine-evoked blood flow increases, 4-DAMP showed a conspicuous potency. At 1 and 10 micromol kg(-1) i.v. of pirenzepine, the antagonist reduced the protein concentration in the submandibular saliva, but not in the parotid saliva. While 4-DAMP (1 and 10 nmol kg(-1) i.v.) significantly inhibited acetylcholine-evoked protein secretory responses in the submandibular glands, methoctramine (below 10 micromol kg(-1) i.v.) affected the responses in neither gland. The reduction of the protein concentration in submandibular saliva caused by 4-DAMP and pirenzepine was inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME; 30 mg kg(-1) i.p.), while L-NAME had no or only minute effects on the parotid protein secretion. Thus, in addition to muscarinic M3 receptors, other muscarinic receptors contribute to in vivo functional responses in rat submandibular and sublingual glands. While these other receptors are muscarinic M1 receptors in the sublingual gland, they may be a different subtype, possibly muscarinic M5 receptors, in the submandibular gland. However, muscarinic M1 receptors may induce indirect effects via nitric oxide in the submandibular gland.

Oral Pilocarpine for Treatment of Opioid-induced Oral Dryness in Healthy Adults

Pilocarpine induces a profuse flow of saliva when administered orally, but effects on drug-induced oral dryness have not been examined. The aim of this trial was to investigate if pilocarpine increases production of saliva in individuals suffering from dry mouth due to treatment with opioids. Sixty-five individuals were enrolled in a randomized, double-blind, placebo-controlled trial. The subjects received tramadol (50 mg t.d.s.) to induce oral dryness, and were thereafter assigned to one of three groups. Secretion rate of saliva was measured before and after tramadol, and after the oral administration of pilocarpine (5 mg), placebo, or no treatment. Baseline characteristics did not differ among the groups (mean ± SEM: 0.37 ± 0.06 mL/min), and tramadol lowered the secretion at the same level in all groups (0.15 ± 0.02 mL/min). Pilocarpine increased the flow above that observed with placebo (0.66 ± 0.19 vs. 0.15 ± 0.02 mL/min). Thus, pilocarpine re-establishes the flow of saliva in the state of tramadol-induced oral dryness.

Tramadol-induced oral dryness and pilocarpine treatment: Effects on total protein and IgA

Pilocarpine induces a profuse flow of saliva, and it may re-establish saliva production in cases of drug-induced oral dryness. The aim of the study (a sub-study to the previous trial investigating the pilocarpine fluid effects in individuals suffering from drug-induced dry mouth) was to search for saliva quality changes induced by the treatments. Sixty-five individuals were enrolled in a randomized, double-blind, placebo-controlled trial. The subjects received tramadol to induce oral dryness. Secretion rate was measured before and after tramadol, and then after pilocarpine, placebo, or no treatment. All saliva was analyzed for its protein and IgA content in the pilocarpine (n=15) and placebo groups (n=12). At baseline, the flow of saliva was 0.47±0.05ml/min, the protein output 0.17±0.2mg/min and the IgA output 0.022±0.002mg/min. After tramadol treatment (50mg 3×/day over two days), the flow was reduced by 64%, protein output by 52% and the IgA output by 38%. While placebo treatment did not affect any of the variables, the flow was 120%, the protein output 193% and the IgA output 83% of the baseline characteristics after pilocarpine treatment (5mg). Thus, the pilocarpine-induced increase in the flow rate in the state of tramadol-induced oral dryness results in saliva with a well preserved protein concentration but with a decrease in IgA concentration. However, compared to baseline, there was neither a decrease in output nor in concentration of IgA.

Effects of amphetamine on salivary secretion

Amphetamine induces xerogenic effects, but its mechanism of action and xerogenic potency are unknown. In the current in vivo study on the rat parotid gland, the effects of amphetamine on reflex-evoked and acetylcholine-evoked salivation were examined in the absence and presence of adrenergic and dopaminergic antagonists. Under anaesthesia, amphetamine increased the secretion of salivary fluid and the amount of protein therein in response to acetylcholine. Phentolamine abolished the increase in salivary flow and had no effect on the salivary protein concentration, whereas propranolol only reduced the salivary protein concentration. Reflex activation of the secretion evoked a well-maintained level of secretion that was reduced by amphetamine [50% inhibitory dose (ID(50)) 1.9 +/- 0.1 mg kg(-1) intravenously); the salivary protein concentration was increased in the presence of amphetamine. Phentolamine and haloperidol reduced the amphetamine-inhibitory effect on the reflex-evoked fluid response, whereas propranolol had no effect on the fluid response. The xerogenic effect of amphetamine is mainly exerted by central mechanisms involving alpha-adrenoceptors, while, indirectly, amphetamine causes secretion of protein by inducing the release of noradrenaline from glandular nerve terminals.

In vivo studies of effects of antidepressants on parotid salivary secretion in the rat

Tricyclic antidepressants (TCA) are well-known xerogenic drugs, while antidepressants such as selective serotonin reuptake inhibitors (SSRI) are considered less xerogenic. The antimuscarinic effect of the TCAs has been considered to be the principal mechanism causing a dry mouth. Although the muscarinic receptor is commonly targeted by xerogenic pharmaceuticals, the salivation reflex arc may be affected at other levels as well. We currently wondered whether or not antidepressants exert an inhibition of the salivary reflex not only at the glandular level but at a central level as well. In this study, the effects of a TCA (clomipramine), a SSRI (citalopram) and a serotonin-noradrenaline reuptake inhibitor (SNRI; venlafaxine) were examined on reflex- (0.5M citric acid applied on the tongue) and methacholine-evoked salivary secretion. While all three compounds inhibited citric acid-evoked secretion (-40 to -60% at 5mg/kg i.v. of the antidepressants), only clomipramine inhibited methacholine-evoked secretion (-30% at 5mg/kg i.v.). On the contrary, both citalopram and venlafaxine increased the methacholine-evoked secretion (+44 to 49%). This was particularly obvious for the salivary protein output (>200%). In the presence of α- and β-adrenoceptor antagonists, the citalopram- and venlafaxine-induced increases were reduced. Thus, antidepressants irrespective of type may exert xerogenic effects by inhibiting the salivary reflex in the central nervous system. However, while TCAs may also hamper the secretory response by antimuscarinic effects, the SSRI and the SNRI groups of pharmaceuticals seem to lack this additional xerogenic mechanism indicating a better therapeutic profile and better opportunities for pharmacological treatment of drug-induced xerostomia.

Prevalence, initiating factor and treatment outcome of medication-related osteonecrosis of the jaw - a four year prospective study

OBJECTIVES Medication-related osteonecrosis of the jaw (MRONJ) has a wide range of prevalence, and a standard therapy has not yet been established. The aim of this study was to analyze the prevalence and initiating factors of MRONJ and the outcomes of surgical therapy. STUDY DESIGN In a prospective cohort study, all patients diagnosed with MRONJ in the Region of Skåne, in Sweden, were included. Predictor variables (comorbidity, site, stage, gender) and initiating factors (tooth extraction, periodontitis) were recorded. Surgical treatment was sequestrectomy or block resection, and the outcome variable was healing after 2 months. To estimate the prevalence, data on the use of bisphosphonate and denosumab were used. RESULTS Fifty-five patients with MRONJ were identified. The prevalence of MRONJ was 0.043% among patients treated with oral bisphosphonates, 1.03% among those on intravenous bisphosphonates and 3.64% in those on high-dose denosumab. Periodontal disease preceded development of MRONJ in 41 patients. Fifty patients were treated surgically and followed up for at least 2 months. Remission or healing occurred in 80% of patients treated with sequestrectomy and in 92.5% of patients treated with block resection. CONCLUSIONS The prevalence of MRONJ in Sweden is low. Periodontitis is the most common initiating factor. The outcome of treatment of MRONJ is healing in most patients treated surgically.