Diana Balenović

Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157

We demonstrate the full counteracting ability of stable gastric pentadecapeptide BPC 157 against KCl-overdose (intraperitoneal (i), intragastric (ii), in vitro (iii)), NO-system related. (i) We demonstrated potential (/kg) of: BPC 157 (10ng, 10μg ip, complete counteraction), l-arginine (100mg ip, attenuation) vs. L-NAME (5mg ip, deadly aggravation), given alone and/or combined, before or after intraperitoneal KCl-solution application (9mEq/kg). Therapy was confronted with promptly unrelenting hyperkalemia (>12mmol/L), arrhythmias (and muscular weakness, hypertension, low pressure in lower esophageal and pyloric sphincter) with an ultimate and a regularly inevitable lethal outcome within 30min. Previously, we established BPC 157-NO-system interaction; now, a huge life-saving potential. Given 30min before KCl, all BPC 157 regimens regained sinus rhythm, had less prolongation of QRS, and had no asystolic pause. BPC 157 therapy, given 10min after KCl-application, starts the rescue within 5-10min, completely restoring normal sinus rhythm at 1h. Likewise, other hyperkalemia-disturbances (muscular weakness, hypertension, low sphincteric pressure) were also counteracted. Accordingly with NO-system relation, deadly aggravation by L-NAME: l-arginine brings the values to the control levels while BPC 157 always completely nullified lesions, markedly below those of controls. Combined with l-arginine, BPC 157 exhibited no additive effect. (ii) Intragastric KCl-solution application (27mEq/kg) - (hyperkalemia 7mmol/L): severe stomach mucosal lesions, sphincter failure and peaked T waves were fully counteracted by intragastric BPC 157 (10ng, 10μg) application, given 30min before or 10min after KCl. (iii). In HEK293 cells, hyperkalemic conditions (18.6mM potassium concentrations), BPC 157 directly affects potassium conductance, counteracting the effect on membrane potential and depolarizations caused by hyperkalemic conditions.

Mortal Furosemide-Hypokalemia-Disturbances in Rats NO-System Related Shorten Survival by L-NAME. Therapy Benefit with BPC 157 Peptide More Than With L-Arginine

Background: We focused on NO-system-relations (worsening/amelioration) of furosemide (100 mg/kg intraperitoneally)-diuresis-hypokalemia mortal course in rats and beneficial effect of BPC 157 therapy. Methods: Electrocardiographically 90-150 min post-furosemide application duration of PR, RR, QRS, QT intervals, P, R, S, T waves and its amplitude as well were analysed along with appearance of AV block, ventricular premature beats, ventricular tachycardia. Clinically, skeletal muscle myoclonal activity and lethality at 150 min were also analysed. Results: All NO-system-related agents (alone and/or combined, before/after furosemide) not changed hypokalemia and all averted to some extent furosemide-forced diuresis. NOS-blocker, L-NAME (5 mg/kg intraperitoneally) accelerated mortality, aggravated cardiac and extra-cardiac manifestations, thereby, NO-systemrelated. Prevented hypokalemia-mortality was with NO-precursor L-arginine (100 mg/kg intraperitoneally) and stable gastric pentadecapeptide BPC 157 (10 ug, 10 ng/kg intraperitoneally/intragastrically). Specifically, BPC 157 showed most complete benefit. i. BPC 157 given 15 min before furosemide. All BPC 157 regimens maintained sinus rhythm, had no ventricular premature beats, ventricular tachycardia, AV block, no prolongation of intervals and waves without reduction of amplitude. ii. BPC 157 given 90 min after furosemide (with hypokalemia, 3rd grade AV block and/ or ventricular tachycardia being present). Within 5-10 minutes, BPC 157 regimens normalized P, R, S, T waves, PR, RR, QRS, QT interval duration, R, S, T wave amplitude, total AV block and terminated ventricular tachycardia. Likewise, BPC 157 eliminated skeletal muscle myoclonus. Conclusion: L-NAME/L-arginine was mutual counteraction while BPC 157 completely eliminated L-NAME (arrhythmias, myoclonus, mortality), without an additive benefit when combined with L-arginine. Thus, we showed potentially effective therapeutic interventions for acute hypokalemia.

Stable gastric pentadecapeptide BPC 157 and bupivacaine

Bupivacaine toxicity following accidental overdose still lacks therapeutic solution. However, there are major arguments for testing BPC 157 against bupivacaine toxicity in vivo in rats, in particular, and then finally, in vitro. These are: the lack of any known BPC 157 toxicity, a lifesaving effect via the mitigation of arrhythmias in rats underwent hyperkalemia or digitalis toxicity, the elimination of hyperkalemia and arrhythmias in rats underwent succinylcholine toxicity and finally, the reduction of potassium-induced depolarization in vitro (in HEK293 cells) in severe hyperkalemia. Most importantly, BPC 157 successfully prevents and counteracts bupivacaine cardiotoxicity; BPC 157 is effective even against the worst outcomes such as a severely prolonged QRS complex. Here, rats injected with bupivacaine (100mg/kg IP) exhibited bradycardia, AV-block, ventricular ectopies, ventricular tachycardia, T-wave elevation and asystole. All of the fatalities had developed T-wave elevation, high-degree AV-block, respiratory arrest and asystole. These were largely counteracted by BPC 157 administration (50µg/kg, 10µg/kg, 10ng/kg, or 10pg/kg IP) given 30min before or 1min after the bupivacaine injection. When BPC 157 was given 6min after bupivacaine administration, and after the development of prolonged QRS intervals (20ms), the fatal outcome was markedly postponed. Additionally, the effect of bupivacaine on cell membrane depolarization was explored by measuring membrane voltages (Vm) in HEK293 cells. Bupivacaine (1mM) alone caused depolarization of the cells, while in combination with BPC 157 (1µm), the bupivacaine-induced depolarization was inhibited. Together, these findings suggest that the stable gastric pentadecapeptide BPC 157 should be a potential antidote for bupivacaine cardiotoxicity.

Resistant Hypertension and Chronotherapy

Resistant hypertension is defined as blood pressure that remains above 140/90 mmHg in spite of the continuous use of three antihypertensive agents in optimal dose, including diuretic, and lifestyle changes. According to data from United States of America and Europe, the prevalence ranges from 10 up to 30% in patients with hypertension. Numerous biological and lifestyle factors can contribute to the development of resistant hypertension: medications, volume overload, obesity, diabetes mellitus, older age, renal parenchymal and renovascular disease, primary aldosteronism, obstructive sleep apnea, pheochormocytoma, Cushing’s syndrome, thyroid diseases, aortic coarctation. For diagnosing patient’s history is important, assessing compliance, regular blood pressure measurement, physical examination, biochemical evaluation and noninvasive imaging. The evaluation including 24h ambulatory monitoring of blood pressure (ABPM) in the identification of “non-dipper” hypertension. Non-dipper has particular importance and the prevalence of abnormally high sleep blood pressure is very often in chronic kidney patients. Therapeutic restoration of normal physiologic blood pressure reduction during night-time sleep (circadial variation) is the most significant independent predictor of decreased risk and the basis for the chronotherapy. The resistant hypertension treatment is achieved with nonpharmacological and pharmacological approach, treating secondary hypertension causes and invasive procedures.

Sa1949 Intragastric Kcl-Overdose Induces Severe Stomach Mucosal Lesions, Sphincters Failure and Peaked T Waves, Fully Counteracted by Intragastric BPC 157 Application, Given Before or After Kcl Intragastric Challenge

Background. Experimental evidence obtained in rats (J Pharmacol Sci. 2006 Nov;102(3):26977, Dig Dis Sci. 1996 Jul;41(7):1518-26) suggests a novel causative and mutually detrimental relation between esophagitis-sphincter failure and acute pancreatitis (Gastroenterology, 2009). Aim. To show that the acute pancreatitis patients have lower pressure in esophageal sphincters compared with healthy subjects. Methods/Results. In 10 patients with acute pancreatitis (6 women and 4 men, mean age 54.5 ± 8.2 years), esophageal manometry was performed immediately after admission to the department. In 8 patients the cause of pancreatitis was biliary in 2 etilic genesis. The majority of patients (7 cases) had mild pancreatitis and the recovery proceeded without any major complications. All patients underwent esophageal manometry according to standard protocol, and the results were compared with values of control healthy subjects (our GI motility lab) (Table 1). The following parameters investigated esophageal motility: the length, pressure, and the ability to relax the upper and lower esophageal sphincter, values of contraction amplitude in the upper, lower and middle esophagus and peristaltic wave velocity along the body of the esophagus. The results of this preliminary study show that patients with acute pancreatitis had significantly lower mean pressure at rest in both the lower and in upper esophageal sphincter compared to a control group of healthy subjects. There were no statistically significant differences in other parameters studied esophageal motor function between compared groups. Table 1

708 FREQUENCY OF HYPERTENSION IN PATIENTS WITH CHRONIC INFLAMMATORY DISEASE S IS UNDERESTIMATED

Objective: Patients with autoimmune diseases (AID) have an increased prevalence of several key classic risk factors such as hypertension (H). Other specific factors such as chronic inflammation and immune activation resulting in oxidative stress. What about the prevalence of H in patients with AID expecially in patients with systemic lupus (SLE)? Design and Method: In this work we evaluated frequency of H among 80 (M:F = 9:71, age 47 ± 5 years) SLE patients. H was defined as blood pressure (BP) ≥140/90mmHg for the general population and ≥130/80mmHg for patients with diabetes or kidney disease. Patients were evaluated for current use of antihypertensive drugs. Estimated glomerular filtration rate (eGFR) was evaluated by Modification of Diet in Renal Disease (MDRD) formula. Results: Detection of H was 65%, eGFR was 61.2 ± 18.5 ml/min/1.73m2, BP 149 ± 14/72 ± 11 mmHg. Of those (52 patients, 65%) only 42% received antihypertensive therapy, but only 20% were optimally controlled. We devided patinets in two groups. Strategies in first group include renin-angiotensin-aldosterone blockade with angiotensin-converting enzyme inhibitor (ACEI) (lisinopril 20 mg/day or perindoril 4 mg/day), second group was without ACEI (CCB, diuretics, beta blockers). After 6 months BP decreased by 10 ± 6/5 ± 3 mmHg in group with ACEI, and 7 ± 5/3 ± 2 mmHg in group without ACEI. In firs group renal function was stabile, in second group (without ACEI) small worsening in eGFR was found. Conclusions: There is a burden of unrecognized H in SLE patients. The use of ACEI as therapies in this high risk population can be usefull in slowing progression of accelerated atherosclerosis.