Changing prevalence and treatment outcomes of patients with p16 human papillomavirus related oropharyngeal squamous cell carcinoma in New Zealand.

There has, to our knowledge, been no previous report of changes in the prevalence and outcomes of treatment of HPV-positive (+) oropharyngeal squamous cell carcinoma (SCC) in New Zealand. We identified all affected patients in the greater Wellington region between 1 January 1994 and 30 November 2014 from the New Zealand Cancer Registry. Their personal details, characteristics of their tumours, treatment, complications, and outcomes were collected retrospectively from their casenotes and the New Zealand Death Registry, followed by p16 immunohistochemical staining. Of the 161 patients included, 131 (81%) were men. p16 immunohistochemical staining was done routinely in 13 patients during investigations, and retrospectively for 135 patients. The proportion of p16+ oropharyngeal SCC increased from 24% during 1994-1999, to 76% during 2009-2014 (p<0.001). Oropharyngeal SCC among Europeans was more likely to be p16+ than in non-Europeans (67% compared with 44%, p=0.036). Patients with p16+ disease were younger (mean (SD) 56 (10) compared with 66 (9) years, p<0.01) with fewer coexisting conditions (mean (SD) Charlson Comorbidity Index: 2.45 (0.82) compared with 2.92 (1.16), p=0.01), and less likely to have smoked (57/81(70%) compared with 38/42 (91%) p=0.035), or misused alcohol (12/81 (15%) compared with 14/42 (31%), p=0.042), or both. They were also more likely to have poorly differentiated tumours (30/52 (58%) compared with 9/34 (26%), p=0.019) with nodal metastases (74/85 (87%) compared with 17/30 (57%), p=0.001). Overall 5-year all-cause survival was more favourable for patients with p16+ disease (65/86 (76%) compared with 15/49 (31%), p=0.000). Interestingly, all-cause age at death was younger in p16+ patients (62 (11.1) compared with 71 (11.2) years, p=0.001). The prevalence of p16+ oropharyngeal SCC had tripled in this population between 1994 and 2014, and affected patients have distinct characteristics and outcomes of treatment.

Primitive erythropoiesis in infantile haemangioma.

UNLABELLED: BACKGROUND; Infantile haemangioma (IH) is a tumour of the microvasculature composed predominantly of proliferating endothelial cells. It expresses markers associated with endothelial, haematopoietic and mesenchymal lineages. We have previously shown that the cells forming the capillary endothelium of proliferating IH express cell surface markers and transcriptions factors consistent with it being a haemogenic endothelium. OBJECTIVES: We wished to determine whether the expression of transcription factors associated with the erythroid lineage was of physiological relevance and sufficient for IH tissue cultured in vitro to undergo erythropoiesis. METHODS: Immunohistochemical staining of paraffin-embedded sections of proliferating IHs was undertaken and expression of the embryonically associated haemoglobin ζ (HBZ) chain and the erythropoietin receptor (EPO-R) was determined. Relative expression of mRNA encoding these proteins was determined by quantitative reverse transcription-polymerase chain reaction using snap-frozen biopsy samples. Differentiation towards erythrocytes was investigated using freshly resected tissue cultured as explants in Matrigel. RESULTS: The endothelium of the microvessels, but not the pericyte layer, was strongly immunoreactive for the EPO-R and the embryonically associated HBZ chain. Abundant expression of transcripts encoding these proteins was also detected, corroborating the immunohistochemical staining. When tissue was grown in culture the cells emanating from IH explants were able to generate enucleated erythrocytes in vitro. The erythrocytes were immunoreactive for the erythrocyte-specific marker glycophorin A. CONCLUSIONS: The microvessels in IH are a functional haemogenic endothelium that expresses the embryonically associated HBZ chain and is able to form erythrocytes in vitro. IH thus represents a possible extramedullary site for tumour-associated primitive erythropoiesis.

Parotid metastasis--an independent prognostic factor for head and neck cutaneous squamous cell carcinoma.

BACKGROUND: Metastatic parotid cutaneous squamous cell carcinoma (SCC) is the most common parotid gland malignancy in New Zealand and Australia. The current AJCC TNM staging system does not account for the extent of nodal metastasis. A staging system that separates parotid (P stage) from neck disease (N stage) has been proposed recently. AIM: To review the outcome of patients with metastatic head and neck cutaneous SCC treated at our multidisciplinary Head and Neck Service using the proposed staging system. METHOD: Consecutive patients were culled from our Head and Neck/Skull Base Database, 1990-2004. These patients were restaged according to the proposed staging system: P stage: P0 = no disease in the parotid (i.e., neck disease only); P1 = metastatic node < or = 3 cm; P2=metastatic node > 3 cm and < or =6 cm, or multiple nodes; and P3 = metastatic node > 6 cm, or disease involving the facial nerve or skull base. N stage: N0=no disease in the neck (i.e., parotid disease only); N1 = single ipsilateral metastatic node < or = 3 cm; and N2 = multiple metastatic nodes, or any node > 3 cm, or contralateral neck involvement. Loco-regional recurrence and disease-specific survival were calculated using the Kaplan-Meier method and comparison of graphs made with the log-rank test. Multivariate analysis using the Cox regression model was carried out to assess the impact of various parameters. RESULTS: Sixty-seven patients with metastatic head and neck cutaneous SCC were identified. Thirty-seven patients had parotid metastasis (of whom 13 also had neck disease) while 21 had neck metastasis alone. Nine patients had dermal or soft tissue metastasis. These nine patients were excluded from this series, and data analysis was carried out on the remaining 58 (46 men, 12 women, mean age 71 years) patients. Sixty-seven percent of the patients underwent post-operative adjuvant radiotherapy. The five-year disease-specific survival rate was 54%. Among 56 patients followed up to disease recurrence or for a minimum period of 18 months, the loco-regional recurrence rate was 52%. The presence of parotid disease was an independent prognostic factor on survival (p < 0.01), and P3 fared significantly worse than P1 and P2. Those patients who had both parotid and neck disease fared worse than those who had parotid or neck disease alone (p = 0.01). N2 had a significantly poorer outcome compared with N1 (p < 0.01). Immunosuppression (p = 0.01) and a positive surgical margin (p < 0.01) were significant adverse prognostic factors for survival. Adjuvant radiotherapy, extracapsular spread, and perineural and vascular invasion did not influence survival. Our study demonstrates that the extent of parotid disease is an independent prognostic factor for metastatic head and neck cutaneous SCC.

Malignant peripheral nerve sheath tumour of the cervical vagus nerve in a neurofibromatosis type 1 patient.

One serious complication of neurofibromatosis type 1 (NF1) is the development of malignant peripheral nerve sheath tumours (MPNSTs). These malignancies often develop within pre-existing plexiform neurofibromas and their development is now thought to be associated with both tumour suppressor gene mutations and dysregulated growth factor signalling. Recent work demonstrates that the lifetime risk of malignant transformation is significantly greater than previously thought. Ionising radiation, a long-standing disease, particularly the presence of a large number of plexiform neurofibromas from an early age, are suggested risk factors. We present an NF1 patient who developed an MPNST of the cervical vagus nerve which was successfully treated with surgery. Close monitoring of patients with NF and a high level of suspicion towards rapidly enlarging and painful swellings is merited as these features may signify malignant transformation. Whether a positive history of MPNST in other affected family members predisposes the individual to a higher risk of malignant transformation is unclear.

A meta-analysis comparing eradication, healing and relapse rates in patients with Helicobacter pylori-associated gastric or duodenal ulcer.

AIM: To compare the effectiveness of Helicobacter pylori eradication in curing peptic ulcer disease in trials involving both gastric ulcer and duodenal ulcer. METHODS: Twenty-four relevant randomized controlled trials and randomized comparative trials met the predefined selection criteria. Only proton pump inhibitor-based eradication trials were considered for the evaluation of eradication efficacy and ulcer healing. For the determination of relapse rates, all trials independent of the eradication therapy regimen were considered. RESULTS: Data from 2102 patients were analysed comparing gastric ulcer with duodenal ulcer. No statistical differences between gastric ulcer and duodenal ulcer patients were found with regard to eradication rates (summarized odds ratio, 1.23; 95% confidence interval, 0.98-1.55) or ulcer relapse rates, whether in successfully H. pylori eradicated patients (summarized odds ratio, 0.69; 95% confidence interval, 0.26-1.84) or unsuccessfully H. pylori eradicated patients (summarized odds ratio, 1.48; 95% confidence interval, 0.85-2.56). Owing to heterogeneity, healing rates were not comparable. CONCLUSIONS: The eradication of H. pylori infection cures both gastric and duodenal ulcer, and the cure rates are similar. This suggests that H. pylori is the key factor in peptic ulcer disease independent of the ulcer site.

Malignant mixed Müllerian tumour of the cervix treated with concurrent chemoradiation.

Malignant mixed Müllerian tumours of the cervix are very uncommon. Of the 26 cases reported in the literature only 8 consist of homologous sarcoma with squamous cell carcinoma. Historically, treatment has been with radiation or surgery or a combination of both. We describe a locally advanced case treated with concurrent chemoradiation.

[Paracetamol-induced tubulointerstitial nephritis in a chronic alcoholic patient]. / Paracetamol indukálta akut tubulointerstitialis nephritis krónikus alkoholfogyasztó betegben.

Hepatic and renal toxicity of paracetamol overdosage is well known like the fact that ethanol enhances the toxicity of the drug. Scanty data report on reversible hepatic and renal failure appearing after therapeutic dose of paracetamol in alcohol-abusers. Renal damage might also occur without gross hepatocellular damage in alcoholics. We report the case of a young alcoholic male whose first renal biopsy disclosed mesangiocapillary glomerulonephritis. One month later he took 1.5 g paracetamol to control the fever caused by upper respiratory tract infection. Soon he got hospitalised due to fever, toxicoderma, elevated liver and renal function test. While liver enzymes returned to normal, macroscopic haematuria, nephrotic range proteinuria oliguria, uraemia developed. A repeated renal biopsy revealed severe interstitial inflammation, tubular atrophy, progression of the vascular changes seen in the first biopsy. Haemodialysis was started and he got steroids (1 mg/kg body-weight) besides aggressive antihypertensive medication. He showed considerable recovery of renal function in some weeks. The case points to the possibility that paracetamol--even in therapeutic dosage--might result in hepatic and renal damage in alcoholics. The sudden deterioration in renal function was due to the acute tubulointerstitial nephritis superimposed on mesangiocapillary glomerulonephritis, provoked by paracetamol. Early diagnosis, immediate withdrawal of the toxic drug, steroid treatment might have kidney and life saving effect.

Vasculitis-induced colonic strictures: report of two cases.

PURPOSE: The clinical presentations of gastrointestinal involvement from systemic vasculitis are diverse. Colonic involvement from systemic vasculitis is unusual. We report the first case of a symptomatic colonic stricture associated with rheumatoid vasculitis and another associated with systemic lupus erythematosus. METHODS: The clinical, radiologic, and histologic features of two cases of symptomatic colonic strictures secondary to colonic involvement with vasculitis are described. The literature covering gastrointestinal involvement from vasculitis in these conditions is reviewed. RESULTS: Surgical resection of the colonic strictures was required in both patients and had a satisfactory outcome. CONCLUSIONS: These cases provide further evidence of the protean clinical presentations of intestinal involvement in systemic vasculitis. Although immunosuppression has been shown to be of value in the treatment of vasculitis affecting the gastrointestinal tract, surgical resection is required for established strictures.

Guidelines for the treatment of acidaemia with THAM.

THAM (trometamol; tris-hydroxymethyl aminomethane) is a biologically inert amino alcohol of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. At 37 degrees C, the pK (the pH at which the weak conjugate acid or base in the solution is 50% ionised) of THAM is 7.8, making it a more effective buffer than bicarbonate in the physiological range of blood pH. THAM is a proton acceptor with a stoichiometric equivalence of titrating 1 proton per molecule. In vivo, THAM supplements the buffering capacity of the blood bicarbonate system, accepting a proton, generating bicarbonate and decreasing the partial pressure of carbon dioxide in arterial blood (paCO2). It rapidly distributes through the extracellular space and slowly penetrates the intracellular space, except for erythrocytes and hepatocytes, and it is excreted by the kidney in its protonated form at a rate that slightly exceeds creatinine clearance. Unlike bicarbonate, which requires an open system for carbon dioxide elimination in order to exert its buffering effect, THAM is effective in a closed or semiclosed system, and maintains its buffering power in the presence of hypothermia. THAM rapidly restores pH and acid-base regulation in acidaemia caused by carbon dioxide retention or metabolic acid accumulation, which have the potential to impair organ function. Tissue irritation and venous thrombosis at the site of administration occurs with THAM base (pH 10.4) administered through a peripheral or umbilical vein: THAM acetate 0.3 mol/L (pH 8.6) is well tolerated, does not cause tissue or venous irritation and is the only formulation available in the US. In large doses, THAM may induce respiratory depression and hypoglycaemia, which will require ventilatory assistance and glucose administration. The initial loading dose of THAM acetate 0.3 mol/L in the treatment of acidaemia may be estimated as follows: THAM (ml of 0.3 mol/L solution) = lean body-weight (kg) x base deficit (mmol/L). The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient). When disturbances result in severe hypercapnic or metabolic acidaemia, which overwhelms the capacity of normal pH homeostatic mechanisms (pH < or = 7.20), the use of THAM within a 'therapeutic window' is an effective therapy. It may restore the pH of the internal milieu, thus permitting the homeostatic mechanisms of acid-base regulation to assume their normal function. In the treatment of respiratory failure, THAM has been used in conjunction with hypothermia and controlled hypercapnia. Other indications are diabetic or renal acidosis, salicylate or barbiturate intoxication, and increased intracranial pressure associated with cerebral trauma. THAM is also used in cardioplegic solutions, during liver transplantation and for chemolysis of renal calculi. THAM administration must follow established guidelines, along with concurrent monitoring of acid-base status (blood gas analysis), ventilation, and plasma electrolytes and glucose.

Influence of phorbol esters on contractile force, action potential and calcium current of isolated guinea-pig heart tissues.

Phorbol-12, 13-dibutyrate (PDB) reduced concentration-dependently the contractile force of guinea-pig papillary muscles (EC50 1.07 mumol/l) while phorbol-12-myristate-13-acetate (PMA) was ineffective. The protein kinase C inhibitors staurosporine (0.1 mumol/l) and polymyxin B (70 mumol/l) did not antagonize the negative inotropic effect of PDB. Neither PMA nor PDB, in concentrations up to 30 mumol/l, caused significant changes of the maximum depolarization velocity, the action potential duration or the functional refractory period in intact papillary muscles. In isolated ventricular cardiomyocytes the inward calcium current was halved by either 1 mumol/l PDB or 10 mumol/1 PMA. PKC inhibitors attenuated, but could not completely abolish this effect of the phorboles. It is concluded that the negative inotropic effect of PDB is caused by a reduction of the slow inward calcium current and that this inhibition is, for the greater part, not mediated by an activation of protein kinase C.

Activators of sodium, calcium and potassium channels modulate the cardiac effects of quinidine in vitro.

Quinidine (25.5 mumol/l) reduced the beating frequency of isolated right guinea-pig atria, caused a negative inotropic effect in papillary muscles and slightly raised the contractile force of left atria. The functional refractory period of both tissues was prolonged. A 20% increase of the extracellular sodium concentration did not reverse the effects of quinidine. The Na-channel activator BDF 9148 (1 mumol/l) and the Ca-channel agonist Bay-K-8644 (0.5 mumol/l) further increased the contractile force and caused an additional prolongation of the functional refractory period in quinidine-pretreated atria. Only Bay-K-8644 was able to reverse the negative inotropic effect of quinidine in papillary muscles. The influence of Bay-K-8644 on the contractile force in quinidine-pretreated muscles was not attenuated by lemacalim (3 mumol/l), an activator of ATP-dependent potassium channels, but the duration of the functional refractory period was significantly reduced. These results suggest that a combination of a calcium channel activator and a potassium channel opener might be able to improve the treatment of quinidine intoxications.

Angiotensin II increases norepinephrine release from atria by acting on angiotensin subtype 1 receptors.

Norepinephrine stores in electrically driven guinea pig isolated atria were loaded with [3H]norepinephrine, and norepinephrine release was deduced from the radioactivity efflux. Electrical field stimulation of sympathetic nerve endings was applied during the refractory period of atrial contractions. The stimulation-induced release of norepinephrine was increased by angiotensin II (Ang II) (10(-8) to 10(-6) mol/L) in a concentration-dependent manner. The maximum observed effect was a 55% augmentation. The effects of 10(-7) and 10(-6) mol/L Ang II were abolished by 10(-6) and 10(-5) mol/L of the subtype 1 Ang II receptor antagonist losartan, respectively. Losartan by itself (10(-6) mol/L) caused a 14% reduction of norepinephrine release. The subtype 2 Ang II receptor ligand PD 123319 (1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate) in a concentration of 10(-4) mol/L had no detectable influence on transmitter release and did not antagonize the effect of Ang II. Angiotensin I (10(-6) and 10(-5) mol/L) increased norepinephrine release maximally by 23%. This effect was antagonized by 10(-5) mol/L losartan and did not appear in the presence of 10(-6) mol/L of the converting enzyme inhibitor ramiprilat. These results suggest that Ang II increases norepinephrine release by an activation of subtype 1 receptors, whereas angiotensin I is converted to Ang II to become effective.

Field stimulation-induced noradrenaline release from guinea-pig atria is modulated by prejunctional alpha 2-adrenoceptors and protein kinase C.

Guinea-pig left atria were loaded with 10 microCi 7-[3H]noradrenaline, and noradrenaline release from sympathetic nerve endings was then elicited by refractory period field stimulation. When one pulse of 0.2 ms duration was applied during each refractory period, the resulting transmitter release was halved by 3 x 10(-7) mol/l of the alpha 2-adrenoceptor agonist clonidine and increased about 2.5-fold by either 3 x 10(-7) mol/l of the alpha 2-adrenoceptor antagonist idazoxan, 5 x 10(-3) mol/l of the potassium channel blocker tetraethylammonium chloride (TEA) or 3 x 10(-7) mol/l phorbol-12-myristate-13-acetate (PMA), an activator of protein kinase C (PKC). Phorbol-12-myristate-13-acetate-4-O-methylether, a compound which does not stimulate PKC, was ineffective. The stimulatory effect of PMA was antagonized by 7 x 10(-5) mol/l of the PKC inhibitor polymyxin B. No significant transmitter release was observed when either PMA or TEA was applied together with 10(-7) mol/l of the sodium channel blocker tetrodotoxin. Combinations of either idazoxan and TEA or PMA and TEA caused greater increases of the noradrenaline release than any individual drug given alone. Thus, different mechanisms of action seem to mediate the increase of noradrenaline release by action potential prolongation on the hand and activation of PKC or inhibition of alpha 2-adrenoceptors on the other hand. In contrast, the effects of idazoxan and PMA were not additive, which suggests a common mechanism of action. In atria pretreated for 10 min with 10(-4) mol/l N-ethylmaleimide, an alkylating agent which inactivates Gi-proteins neither idazoxan nor PMA caused a significant increase of the stimulation-induced transmitter release, while TEA was still effective. When a train of four pulses, lasting 0.05 ms each, was applied during each refractory period, the resulting transmitter release was not modified by idazoxan or PMA, but was significantly increased by TEA. From these results, a scheme is proposed which links the regulation of noradrenaline release by prejunctional alpha 2-adrenoceptors and protein kinase C via an influence on a common inhibitory Gi-protein.

Cardiotoxic effects of nitrofurantoin and tertiary butylhydroperoxide in vitro: are oxygen radicals involved?

Langendorff rat hearts were perfused for 15, 30 or 75 min. with the oxygen radical generators nitrofurantoin (0.25 or 0.5 mmol/l) or tertiary butylhydroperoxide (0.25 mmol/l). Both agents reduced the force of contraction and increased the release of glutathione, oxidized glutathione, lactate dehydrogenase and creatine phosphokinase into the perfusion fluid. The tissue concentration of glutathione was reduced. While there were no signs of an increased production of conjugated dienes, the tissue concentration of malondialdehyde was greater than in control experiments. The variability of the latter effect was large, however, and in most cases the increase was not statistically significant. Addition of catalase (100 mU/ml) or catechin (0.5 mmol/l) to the perfusion medium abolished the nitrofurantoin induced release of oxidized glutathione but did not not prevent or attenuate enzyme leakage from the cells and the development of a negative inotropic effect. These results suggest that the cardiotoxic effects of nitrofurantoin and tertiary butylhydroperoxide cannot be explained by the appearance of oxygen radicals alone and that an increased lipid peroxidation is not the mechanism which is primarily responsible for cell death.

Beta-adrenoceptor blocking effects of two bopindolol metabolites in isolated guinea-pig atria.

The beta-adrenoceptor blocking effects of the bopindolol (Wandonorm, CAS 62658-63-3) metabolites 18-502 (indole-2,4- methylaminopropoxy(N-tert.butyl)-tartrate) and 20-785 (indole-2,4-carboxyaminopropoxy(N-tert.butyl] were studied in electrically stimulated guinea-pig left atria and in spontaneously beating guinea-pig atria in vitro. Both compounds shifted the concentration-response curve of isoprenaline to the right, but did not reduce the maximum effect of this drug. For compound 20-785, pA2 values of 7.44 (left atrium, inotropic effect) and 7.58 (right atrium, chronotropic effect) were calculated. The metabolite 18-502 had a much greater beta-adrenoceptor blocking potency, as judged from its pA2 values of 9.53 and 9.48, resp., and in the concentration of 10(-8) mol/l it caused a significant flattening of the concentration-response curve of isoprenaline. From these results, compound 20-785 can be classified as a competitive beta-adrenoceptor antagonist, while for higher concentrations of the metabolite 18-502 additional noncompetitive mechanisms of action cannot be excluded.

Pre- and postjunctional effects of phorbol 12-myristate-13-acetate in the mouse vas deferens.

The protein kinase C stimulator phorbol 12-myristate-13-acetate (PMA) increased the release of noradrenaline from field-stimulated mouse vasa deferentia and antagonized the inhibitory effect of xylazine and FK 33-824. The mechanical response to field stimulation was not modified by PMA in unpretreated vasa, but the contractility was partly restored when the stimulation-response curve had been depressed by xylazine or FK 33-824. In contrast, PMA decreased the contractile response to exogenous noradrenaline and bethanechol. A similar but smaller reduction was obtained with 1,2-dioctanoyl-sn-glycerol. In vasa depolarized by KCl, PMA and verapamil reduced the amplitude of contractions elicited by CaCl2. Only the effect of verapamil could be reversed by the calcium ionophore A 23187, while the effect of PMA was greatly attenuated in muscles pretreated with ouabain. Phorbol 12-myristate-13-acetate-4-O-methylether was ineffective in all experiments. These results suggest that PMA increases noradrenaline release (prejunctional effect) and decreases vasal contractility (postjunctional effect) by activation of protein kinase C.

Inotropic and electrophysiological effects of BDF 9148, a congener of DPI 201-106, in guinea-pig atria and papillary muscles.

1. BDF 9148 is a newly synthesized congener of DPI 201-106 in which the piperazidinyl moiety has been replaced by an azetidine-3-oxy-moiety. The inotropic effect of both drugs was studied as well as their influence on the action potential, by use of standard microelectrode techniques. 2. BDF 9148 increased the contractile force of guinea-pig atria and papillary muscles. The EC50 was 1.32 X 10(-7) mol l-1 and 0.7 X 10(-6) mol l-1 respectively. DPI 201-106 was effective in a similar concentration-range, the EC50 being 2.6 X 10(-7) mol l-1 for atria and 2.8 X 10(-7) mol l-1 for papillary muscles. 3. Both drugs caused a concentration-dependent prolongation of the relaxation time of the isometric contraction curve. With 10(-6) mol l-1 BDF 9148, the mean increase was 39.1 +/- 4.4 ms in atria and 39.4 +/- 7.5 ms in papillary muscles while 10(-6) mol l-1 DPI 201-106 caused increases of 56.7 +/- 2.5 ms and 79.3 +/- 11.7 ms, respectively. The effect of BDF 9148 was not prevented by propranolol, but was reversed by 3 X 10(-6) mol l-1 tetrodotoxin. Pretreatment of atria with 3 X 10(-8) mol l-1 BDF shifted the concentration-response curve of ouabain to the left and reduced the EC50 of the glycoside from 3.21 X 10(-7) mol l-1 to 2 X 10(-7) mol l-1. 4. BDF 9148 and DPI 201-106 concentration-dependently increased the action potential duration of papillary muscles and their functional refractory period. The drugs did not modify the resting potential, the action potential amplitude or the maximum depolarization velocity.5. All effects of BDF 9148 persisted after washout. The lipophilic drug accumulated in the tissues and the tissue drug concentration was little reduced by washout of BDF 9148 from the organ bath.6. In contrast to DPI 201-106, which had a prominent negative chronotropic effect in right atria, BDF 9148 caused only a slight reduction of the beating frequency with the largest (3 x 10 5mol 11) concentration.7. The results are consistent with BDF 9148 being a sodium channel activator with much weaker influence on the beating frequency than the parent compound DPI 201-106.