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Oc028—A New Pharmaceutical Form Of Paracetamol: Efficacy Of Transmucous Buccal Paracetamol In Acute Pain Patients
Oral Communications Abstracts Oc026—Impact Of Circulating Levels Of Interleukin-17 And Cardiovascular Outcomes In Patients With Acute Myocardial Infarction T. Simon1*; S. Taleb2; N. Danchin3; L. Laurans4; B. Rousseau5; S. Simon Cattan6; J.-M. Montely7; O. Dubourg8; A. Tedgui4; S. Kotti9; and Z. Mallat10 1 Clinical Pharmacology, APHP, St Antoine Hospital, UPMCParis06, Paris; 2inserm; 3Cardiology, HEGP, APHP, Université Paris Descartes, Paris; 4Inserm, U970; 5Clinical Pharmacology, URC-EST, APHP, Hopital St Antoine, UPMC-Paris 06 University, Paris; 6Cardiology, Montfermeil Hospital, Montfermeil; 7 Cardiology, Aulnay Hospital, Aulnay; 8Cardiology, APHP, Ambroise Paré, Boulogne Billancourt; 9Clinical Pharmacology, URC-EST, APHP, Hopital St Antoine, Paris, France; and 10 Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom Introduction and Background: IL-17 pathway is being clinically targeted in immune-mediated diseases, most of which are associated with a significant cardiovascular risk. We investigated the relationship between serum levels of IL-17 and the risk of cardiovascular events in patients with acute myocardial infarction. Patients (or Materials) and Methods: We used data from patients enrolled in the prospective, multicenter French registry of acute ST elevation or non–ST-elevation myocardial Infarction (Fast-MI, NCT00673036). Of the 374 centers in France that treated patients with acute MI, 223 (60%) participated in the registry. Among these, 100 centers recruited 1029 patients who contributed to a serum bank. Their baseline characteristics were comparable to the overall population of the registry. Written informed consent was provided by each patient. More than 99% of patients were Caucasian. Two-year follow-up was > 98% complete. Results: Serum levels of IL-17 were associated with the risk of allcause death and recurrent MI at 2 years, with levels of IL-17 below the median indicative of a worse outcome. The impact of IL-17 remained significant after adjustment for known cardiovascular risk factors, CRP, and treatments including statins: hazard ratio (HR) = 1.40 (1.03–1.91); P = 0.03.IL-17 inhibited mononuclear cell adhesion to endothelium and reduced endothelial VCAM-1 expression. Patients with low (below the median) IL-17 levels and high (above the median) soluble VCAM-1 (sVCAM-1) levels were at particularly increased risk of death and MI: adjusted HR = 2.22 (1.32–3.75) compared with the high IL-17/low sVCAM-1 group (P = 0.002). Conclusion: Low serum levels of IL-17 are associated with a higher risk of major cardiovascular events in Caucasian patients with acute MI. Our results raise possible concern about the use of inhibitors of IL-17 pathway in clinical settings associated with a high cardiovascular risk. Disclosure of Interest: T. Simon Other: Fast-MI is a registry if the French Society of Cardiology, supported by unrestricted grants from Pfizer and Servier and a research grant from the French Caisse Nationale d’Assurance Maladie. S. Taleb: None declared. N. Danchin: None declared. L. Laurans: None declared. B. Rousseau: None declared. S. Simon Cattan: None declared. J.-M. Montely: None declared. O. Dubourg: None declared. A. Tedgui: None declared. S. Kotti: None declared. Z. Mallat: None declared.
Oc027—Dual Reuptake Inhibitor Milnacipran And Spinal Pain Pathways In Fibromyalgia Patients: A Randomized Double-Blind Placebo-Controlled Trial A. Matthey1*; C. Cedraschi1; V. Piguet1; M. Besson1; J. Chabert1; Y. Daali1; D. Courvoisier1; A. Montagne2; P. Dayer1; and J.A. Desmeules1
2013
1
Division of Clinical Pharmacology & Toxicology, HUG, Geneva, Switzerland; and 2CRD, Pierre Fabre Médicament, Boulogne Billancourt, France Introduction: Investigations based on quantitative sensory testing have consistently evidenced allodynia in FMS patients involving both spinal and supraspinal pain regulatory systems. Functional imaging studies have demonstrated enhanced neural activities in pain related brain areas as well as impairment of pain inhibition in the descending nociceptive regulatory system. Higher state of excitability of spinal nociceptive neurons as evidenced by lowered nociceptive flexion reflex R-III (NFR) threshold was reported for FMS patients. The NFR procedure has been shown to be a valuable tool to evaluate pharmacologically active therapeutic agents at the spinal level. Serotoninnoradrenaline reuptake inhibitors have been shown to reduce pain in fibromyalgia syndrome patients possibly through descending monoaminergic pain pathways modulation. This randomized double- blind, placebo-controlled trial assessed the pharmacodynamic activity of the dual-reuptake inhibitor milnacipran (MLN) at the spinal level by means of the objective spinal NFR. Patients (or Materials) and Methods: Seven-week exposure (100, 150, 200 mg/d) in female fibromyalgia patients. Evaluation consisted of extensive quantitative sensory testing, including determination of the nociceptive flexion reflex threshold (NFR), self-reported standard questionnaires investigating pain: visual analog scales; fibromyalgia impact, health-related quality of life, depression, and anxiety questionnaires as well as and Patient’s Global Impression of Change (PGIC). Analysis of covariance adjusted for baseline value was used for all end points. Results: Seventy-seven (39 placebo, 38 milnacipran all doses) of 80 randomized patients were available for analysis. The absence of influence of MLN (any dose) on the NFR surprisingly contrasted with the dose-dependent analgesic effect observed in MLN-treated patients with an adjusted change difference of –18.4 mm (–30.9; –5.8) in pain reduction between placebo and the maximum dosage (200 mg) MLN groups (P = 0.02). Unchanged depression and anxiety scores confirmed the predominant selectivity of the analgesic effect of MLN on nociceptive pain pathway. Self-reported questionnaires consistently reflected the positive effects of MLN on quality of life and psychological well-being. Odds ratio 5.1 for PGIC responders (ie, much/ very much improved) was significantly in favor of MLN (P = 0.04). Conclusion: Milnacipran has a predominantly supraspinal analgesic effect as evidenced by the significant clinical benefits and the absence of changes in the nociceptive spinal reflex threshold. Higher dose was associated with higher pain reduction. Reported analgesia was independent of patients’ emotional status. Disclosure of Interest: A. Matthey: Grant/research support from sponsor. C. Cedraschi: Grant/research support from sponsor. V. Piguet: Grant/research support from sponsor. M. Besson: Grant/ research support from: sponsor. J. Chabert: Grant/research support from sponsor. Y. Daali: Grant/research support from sponsor. D. Courvoisier: Grant/research support from sponsor. A. Montagne: Employee of sponsor. P. Dayer: Grant/research support from sponsor. J. Desmeules: Grant/research support from sponsor.
Oc028—A New Pharmaceutical Form Of Paracetamol: Efficacy Of Transmucous Buccal Paracetamol In Acute Pain Patients G. Pickering1,2*; F. Moustafa3; N. Macian1; and C. Dubray1 Clinical Pharmacology Center; 2Inserm CIC501 and Faculty of Medicine, Clermont-ferrand; and 3CHU Clermont-Fd, Accident and Emergency Department, Clermont-Ferrand, France
1
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Clinical Therapeutics Introduction: Oral or intravenous (IV) paracetamol (APAP) is used for mild to moderate pain but has a latency to be effective. When fast relief is required and oral/IV routes are not available because of the patient’s condition, the transmucosal buccal route may be an alternative. A new transmucosal buccal (b) pharmaceutical form of APAP that had been previously assessed in healthy volunteers is studied in patients admitted to hospital for acute pain. Patients (or Materials) and Methods: A randomized doubleblind noninferiority clinical trial (NCT01586143) included 38 patients admitted to the Accident and Emergency Department of Clermont-Fd University Hospital, France, for trauma of the upper or lower limb, and with pain intensity between 4 and 6 on a 0 to 10 numerical scale (NS). Patients were injected at t0 over a 15-minute period with placebo (0.9% saline) or APAP (1 g) and concomitantly, 125 mg of APAP dissolved in 1 mL of an hydroalcoholic solution (HAS) or placebo (HAS only) was applied in the left mucogingival sulcus. Patients were asked not to swallow for 1:30 minutes. NS evaluations were done at t10, t30, t120, and t180 minutes after administration. Primary end point was the pain intensity difference (PID) between t30 min and t0. PID of both arms were compared by Student t test with a P < 0.05 significance. Secondary end points were PID at other times. Results: Results (mean [SD]) show no significant PID difference between bAPAP and ivAPAP, respectively: t10min (–0.9 [1.3] vs –1.3 [1.8]), t30min (–2.0 [1.8] vs –2.4 [1.5]), t120min (–2.9 [1.9] vs –3.3 [1.5]), t180 (–2.1 [2.2] vs –3.4 [1.8]; all P > 0.05). Conclusion: Transmucosal buccal APAP has a similar analgesic effect than ivAPAP in patients admitted to hospital for acute trauma pain of mild to moderate intensity. The mechanism of action of this pharmaceutical form must now be studied further. This attractive alternative to other routes would be useful in situations where oral or IV routes are not available or in vulnerable populations (cancer pain, palliative care, geriatrics) for acute pain paroxysms. Disclosure of Interest: None declared.
Oc029—Interaction Between Mycophenolate Mophetil And Tacrolimus In Kidney Graft Recipients J. Strojil1*; K. Urbánek1; P. Anzenbacher1; J. Orság2; and K. Krejčí2 1 Department of Pharmacology; and 2Department of Internal Medicine III–Nephrology, Rheumatology and Endocrinology, Palacký University, Olomouc, Czech Republic Introduction: The calcineurin inhibitor (CI) tacrolimus remains the mainstay of kidney transplant maintenance immunosuppression. In most patients, it is combined with mycophenolate mofetil (MPA) and corticosteroids. As part of an investigation of effect of drug–drug interactions in the setting of routine care, we investigated the effect of mycophenolate mofetil dose on the kinetics of tacrolimus. Patients (or Materials) and Methods: We performed a retrospective analysis of TDM measurements in the past 5 years at a single transplant center in the University Hospital in Olomouc, Czech Republic. More than 4000 measurements of trough concentrations (C0) of CIs and MPA were included in the analysis made in 111 male and 70 female kidney transplant recipients (181 in total). Patients were aged 13 to 72 years (average, 45.7). Average time from transplant was 5.6 years (0.4 to 18). Drug measurements were obtained from the hospital information system, and information on prescription was ascertained from prescription database and patient clinical records (including dosing instructions and specific temporary instructions concerning co-prescription of interacting medication). CI levels were expressed as normalized dose (ND) required to reach a unit concentration and a linear
e12
regression model was constructed to quantify effects of various interacting factors (eg, age, sex, prednisone dose, MPA dose, body weight). Tacrolimus ND = a0-a1 × MPA + a2 × Tx-a3 × ATB-a4 × INTER + a5 × DOSE-a6 × AGE Where MPA is the dose of mycophenolate mofetil in mg/kg body weight, Tx is time from transplantation in years, ATB is 1 if the patient is treated with an antimicrobial, INTER is 1 is the patient is treated with an interacting antimicrobial, DOSE is the dose of tacrolimus in μ g/kg of body weight, and AGE is patient’s age in years. Results: The constructed model yielded the following statistically significant parameters: The coefficient for MPA dose means that for each 100 mg of MPA there was on average a 0.99 l/kg reduction in the dose of tacrolimus to reach a unit concentration (14%). Other significant factors included time from transplantation, interacting antimicrobials, and age (all, P < 0.001).
a0 (Intercept) a1 (MPA) a2 (Tx) a3 (ATB) a4 (INTER) a5 (DOSE) a6 (AGE)
Estimate
Std. Error
Significance
7.090e-03 –9.978e-04 2.128e-04 –5.921e-04 –2.557e-03 1.522e-04 –2.533e-05
1.965e-04 1.326e-04 1.890e-05 2.644e-04 5.149e-04 3.059e-06 6.984e-06
P < 0.001 P < 0.001 P < 0.001 P < 0.01 P < 0.001 P < 0.001 P < 0.001
Conclusion: Our data from routine clinical practice indicate the presence of a mycophenolate-mofetil and tacrolimus interaction. Some literature reports confirm this interaction, but data are still conflicting, and more studies are needed to confirm its clinical significance. Funding Source: Supported by grant CZ.1.07/2.3.00/20.0040. Disclosure of Interest: None declared.
Oc030—Gemfibrozil Impairs Imatinib Absorption And Inhibits The Cyp2c8Mediated Formation Of Its Main Metabolite In Healthy Volunteers A.M. Filppula1*; A. Tornio1,2; M. Niemi1,2; P.J. Neuvonen1,2; and J.T. Backman1,2 1 Department of Clinical Pharmacology, University of Helsinki; and 2 HUSLAB, Helsinki University Central Hospital, Helsinki, Finland Introduction: According to the product information of imatinib, imatinib is mainly metabolized by CYP3A4. Because our recent in vitro findings indicate that CYP2C8 participates in imatinib N-demethylation2 and there are no clinical data concerning the role of CYP2C8 in its metabolism, we studied the effects of the strong CYP2C8 inhibitor gemfibrozil on the single-dose pharmacokinetics of imatinib in healthy volunteers. Patients (or Materials) and Methods: In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3. The plasma concentrations of imatinib and its main metabolite N-desmethylimatinib (N-DMI) were determined using a liquid chromatography–tandem mass spectrometry system. The pharmacokinetics of imatinib and N-DMI were calculated by noncompartmental analysis. Logarithmic transformation was used for pharmacokinetic variables, and statistical comparisons between the phases were made with the paired t test. Because imatinib may time dependently inhibit its own CYP3A4-mediated elimination,3 the obtained clinical data was then applied to a physiologically based pharmacokinetic (PBPK) model to predict the contribution of CYP2C8 to imatinib metabolism during multiple-dose administration.
Volume 35 Number 8S
Oc027—Dual Reuptake Inhibitor Milnacipran And Spinal Pain Pathways In Fibromyalgia Patients: A Randomized Double-Blind Placebo-Controlled Trial A. Matthey1*; C. Cedraschi1; V. Piguet1; M. Besson1; J. Chabert1; Y. Daali1; D. Courvoisier1; A. Montagne2; P. Dayer1; and J.A. Desmeules1
2013
1
Division of Clinical Pharmacology & Toxicology, HUG, Geneva, Switzerland; and 2CRD, Pierre Fabre Médicament, Boulogne Billancourt, France Introduction: Investigations based on quantitative sensory testing have consistently evidenced allodynia in FMS patients involving both spinal and supraspinal pain regulatory systems. Functional imaging studies have demonstrated enhanced neural activities in pain related brain areas as well as impairment of pain inhibition in the descending nociceptive regulatory system. Higher state of excitability of spinal nociceptive neurons as evidenced by lowered nociceptive flexion reflex R-III (NFR) threshold was reported for FMS patients. The NFR procedure has been shown to be a valuable tool to evaluate pharmacologically active therapeutic agents at the spinal level. Serotoninnoradrenaline reuptake inhibitors have been shown to reduce pain in fibromyalgia syndrome patients possibly through descending monoaminergic pain pathways modulation. This randomized double- blind, placebo-controlled trial assessed the pharmacodynamic activity of the dual-reuptake inhibitor milnacipran (MLN) at the spinal level by means of the objective spinal NFR. Patients (or Materials) and Methods: Seven-week exposure (100, 150, 200 mg/d) in female fibromyalgia patients. Evaluation consisted of extensive quantitative sensory testing, including determination of the nociceptive flexion reflex threshold (NFR), self-reported standard questionnaires investigating pain: visual analog scales; fibromyalgia impact, health-related quality of life, depression, and anxiety questionnaires as well as and Patient’s Global Impression of Change (PGIC). Analysis of covariance adjusted for baseline value was used for all end points. Results: Seventy-seven (39 placebo, 38 milnacipran all doses) of 80 randomized patients were available for analysis. The absence of influence of MLN (any dose) on the NFR surprisingly contrasted with the dose-dependent analgesic effect observed in MLN-treated patients with an adjusted change difference of –18.4 mm (–30.9; –5.8) in pain reduction between placebo and the maximum dosage (200 mg) MLN groups (P = 0.02). Unchanged depression and anxiety scores confirmed the predominant selectivity of the analgesic effect of MLN on nociceptive pain pathway. Self-reported questionnaires consistently reflected the positive effects of MLN on quality of life and psychological well-being. Odds ratio 5.1 for PGIC responders (ie, much/ very much improved) was significantly in favor of MLN (P = 0.04). Conclusion: Milnacipran has a predominantly supraspinal analgesic effect as evidenced by the significant clinical benefits and the absence of changes in the nociceptive spinal reflex threshold. Higher dose was associated with higher pain reduction. Reported analgesia was independent of patients’ emotional status. Disclosure of Interest: A. Matthey: Grant/research support from sponsor. C. Cedraschi: Grant/research support from sponsor. V. Piguet: Grant/research support from sponsor. M. Besson: Grant/ research support from: sponsor. J. Chabert: Grant/research support from sponsor. Y. Daali: Grant/research support from sponsor. D. Courvoisier: Grant/research support from sponsor. A. Montagne: Employee of sponsor. P. Dayer: Grant/research support from sponsor. J. Desmeules: Grant/research support from sponsor.
Oc028—A New Pharmaceutical Form Of Paracetamol: Efficacy Of Transmucous Buccal Paracetamol In Acute Pain Patients G. Pickering1,2*; F. Moustafa3; N. Macian1; and C. Dubray1 Clinical Pharmacology Center; 2Inserm CIC501 and Faculty of Medicine, Clermont-ferrand; and 3CHU Clermont-Fd, Accident and Emergency Department, Clermont-Ferrand, France
1
e11
Clinical Therapeutics Introduction: Oral or intravenous (IV) paracetamol (APAP) is used for mild to moderate pain but has a latency to be effective. When fast relief is required and oral/IV routes are not available because of the patient’s condition, the transmucosal buccal route may be an alternative. A new transmucosal buccal (b) pharmaceutical form of APAP that had been previously assessed in healthy volunteers is studied in patients admitted to hospital for acute pain. Patients (or Materials) and Methods: A randomized doubleblind noninferiority clinical trial (NCT01586143) included 38 patients admitted to the Accident and Emergency Department of Clermont-Fd University Hospital, France, for trauma of the upper or lower limb, and with pain intensity between 4 and 6 on a 0 to 10 numerical scale (NS). Patients were injected at t0 over a 15-minute period with placebo (0.9% saline) or APAP (1 g) and concomitantly, 125 mg of APAP dissolved in 1 mL of an hydroalcoholic solution (HAS) or placebo (HAS only) was applied in the left mucogingival sulcus. Patients were asked not to swallow for 1:30 minutes. NS evaluations were done at t10, t30, t120, and t180 minutes after administration. Primary end point was the pain intensity difference (PID) between t30 min and t0. PID of both arms were compared by Student t test with a P < 0.05 significance. Secondary end points were PID at other times. Results: Results (mean [SD]) show no significant PID difference between bAPAP and ivAPAP, respectively: t10min (–0.9 [1.3] vs –1.3 [1.8]), t30min (–2.0 [1.8] vs –2.4 [1.5]), t120min (–2.9 [1.9] vs –3.3 [1.5]), t180 (–2.1 [2.2] vs –3.4 [1.8]; all P > 0.05). Conclusion: Transmucosal buccal APAP has a similar analgesic effect than ivAPAP in patients admitted to hospital for acute trauma pain of mild to moderate intensity. The mechanism of action of this pharmaceutical form must now be studied further. This attractive alternative to other routes would be useful in situations where oral or IV routes are not available or in vulnerable populations (cancer pain, palliative care, geriatrics) for acute pain paroxysms. Disclosure of Interest: None declared.
Oc029—Interaction Between Mycophenolate Mophetil And Tacrolimus In Kidney Graft Recipients J. Strojil1*; K. Urbánek1; P. Anzenbacher1; J. Orság2; and K. Krejčí2 1 Department of Pharmacology; and 2Department of Internal Medicine III–Nephrology, Rheumatology and Endocrinology, Palacký University, Olomouc, Czech Republic Introduction: The calcineurin inhibitor (CI) tacrolimus remains the mainstay of kidney transplant maintenance immunosuppression. In most patients, it is combined with mycophenolate mofetil (MPA) and corticosteroids. As part of an investigation of effect of drug–drug interactions in the setting of routine care, we investigated the effect of mycophenolate mofetil dose on the kinetics of tacrolimus. Patients (or Materials) and Methods: We performed a retrospective analysis of TDM measurements in the past 5 years at a single transplant center in the University Hospital in Olomouc, Czech Republic. More than 4000 measurements of trough concentrations (C0) of CIs and MPA were included in the analysis made in 111 male and 70 female kidney transplant recipients (181 in total). Patients were aged 13 to 72 years (average, 45.7). Average time from transplant was 5.6 years (0.4 to 18). Drug measurements were obtained from the hospital information system, and information on prescription was ascertained from prescription database and patient clinical records (including dosing instructions and specific temporary instructions concerning co-prescription of interacting medication). CI levels were expressed as normalized dose (ND) required to reach a unit concentration and a linear
e12
regression model was constructed to quantify effects of various interacting factors (eg, age, sex, prednisone dose, MPA dose, body weight). Tacrolimus ND = a0-a1 × MPA + a2 × Tx-a3 × ATB-a4 × INTER + a5 × DOSE-a6 × AGE Where MPA is the dose of mycophenolate mofetil in mg/kg body weight, Tx is time from transplantation in years, ATB is 1 if the patient is treated with an antimicrobial, INTER is 1 is the patient is treated with an interacting antimicrobial, DOSE is the dose of tacrolimus in μ g/kg of body weight, and AGE is patient’s age in years. Results: The constructed model yielded the following statistically significant parameters: The coefficient for MPA dose means that for each 100 mg of MPA there was on average a 0.99 l/kg reduction in the dose of tacrolimus to reach a unit concentration (14%). Other significant factors included time from transplantation, interacting antimicrobials, and age (all, P < 0.001).
a0 (Intercept) a1 (MPA) a2 (Tx) a3 (ATB) a4 (INTER) a5 (DOSE) a6 (AGE)
Estimate
Std. Error
Significance
7.090e-03 –9.978e-04 2.128e-04 –5.921e-04 –2.557e-03 1.522e-04 –2.533e-05
1.965e-04 1.326e-04 1.890e-05 2.644e-04 5.149e-04 3.059e-06 6.984e-06
P < 0.001 P < 0.001 P < 0.001 P < 0.01 P < 0.001 P < 0.001 P < 0.001
Conclusion: Our data from routine clinical practice indicate the presence of a mycophenolate-mofetil and tacrolimus interaction. Some literature reports confirm this interaction, but data are still conflicting, and more studies are needed to confirm its clinical significance. Funding Source: Supported by grant CZ.1.07/2.3.00/20.0040. Disclosure of Interest: None declared.
Oc030—Gemfibrozil Impairs Imatinib Absorption And Inhibits The Cyp2c8Mediated Formation Of Its Main Metabolite In Healthy Volunteers A.M. Filppula1*; A. Tornio1,2; M. Niemi1,2; P.J. Neuvonen1,2; and J.T. Backman1,2 1 Department of Clinical Pharmacology, University of Helsinki; and 2 HUSLAB, Helsinki University Central Hospital, Helsinki, Finland Introduction: According to the product information of imatinib, imatinib is mainly metabolized by CYP3A4. Because our recent in vitro findings indicate that CYP2C8 participates in imatinib N-demethylation2 and there are no clinical data concerning the role of CYP2C8 in its metabolism, we studied the effects of the strong CYP2C8 inhibitor gemfibrozil on the single-dose pharmacokinetics of imatinib in healthy volunteers. Patients (or Materials) and Methods: In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3. The plasma concentrations of imatinib and its main metabolite N-desmethylimatinib (N-DMI) were determined using a liquid chromatography–tandem mass spectrometry system. The pharmacokinetics of imatinib and N-DMI were calculated by noncompartmental analysis. Logarithmic transformation was used for pharmacokinetic variables, and statistical comparisons between the phases were made with the paired t test. Because imatinib may time dependently inhibit its own CYP3A4-mediated elimination,3 the obtained clinical data was then applied to a physiologically based pharmacokinetic (PBPK) model to predict the contribution of CYP2C8 to imatinib metabolism during multiple-dose administration.
Volume 35 Number 8S