Optimization of Diltiazem hydrochloride osmotic formulation using QBD approach

Abstract Diltiazem hydrochloride (DLH) is a calcium channel blocker useful for the treatment of angina pectoris, arrhythmia, and hypertension. DLH having a short half-life needs frequent administration for successful treatment but this poses a problem of poor patient compliance. These requirements are served by elementary osmotic pump tablets (EOP) based controlled-release (CR) systems. Quality by design (QbD) approach assists in screening various factors with subsequent assessment of critical parameters that can have a major impact on the scalability of EOP. Tablets were formulated using wet granulation method followed by osmotic coating. Factorial design based QbD strategy aided in defining the risk assessment of influential variables such as hydrophilic polymers and osmotic coat component on the in-vitro release kinetics of the designed EOP tablets. These formulated EOP systems followed zero-order kinetics, a characteristic feature of EOPs. EOP tablets were formulated applying a systematic QbD statistical approach. The formulated DLH EOP systems with improved concentration-independent behavior helped to address the challenges of IR formulation. Application of QbD strategy in ascertaining the scalability of DLH EOP formulation would help pharmaceutical industries in the translation of EOP based drug delivery systems from R&D to market.

ß-Citronellol, an alcoholic monoterpene with inhibitory properties on the contractility of rat trachea

β-Citronellol is an alcoholic monoterpene found in essential oils such Cymbopogon citratus (a plant with antihypertensive properties). β-Citronellol can act against pathogenic microorganisms that affect airways and, in virtue of the popular use of β-citronellol-enriched essential oils in aromatherapy, we assessed its pharmacologic effects on the contractility of rat trachea. Contractions of isolated tracheal rings were recorded isometrically through a force transducer connected to a data-acquisition device. β-Citronellol relaxed sustained contractions induced by acetylcholine or high extracellular potassium, but half-maximal inhibitory concentrations (IC50) for K+-elicited stimuli were smaller than those for cholinergic contractions. It also inhibited contractions induced by electrical field stimulation or sodium orthovanadate with pharmacologic potency equivalent to that seen against acetylcholine-induced contractions. When contractions were evoked by selective recruitment of Ca2+ from the extracellular medium, β-citronellol preferentially inhibited contractions that involved voltage-operated (but not receptor-operated) pathways. β-Citronellol (but not verapamil) inhibited contractions induced by restoration of external Ca2+ levels after depleting internal Ca2+ stores with the concomitant presence of thapsigargin and recurrent challenge with acetylcholine. Treatment of tracheal rings with L-NAME, indomethacin or tetraethylammonium did not change the relaxing effects of β-citronellol. Inhibition of transient receptor potential vanilloid subtype 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1) receptors with selective antagonists caused no change in the effects of β-citronellol. In conclusion, β-citronellol exerted inhibitory effects on rat tracheal rings, with predominant effects on contractions that recruit Ca2+ inflow towards the cytosol by voltage-gated pathways, whereas it appears less active against contractions elicited by receptor-operated Ca2+ channels.

Practice of Indian Physicians Towards Use of Calcium Channel Blockers in the Management of Hypertension : A Paper Based Questionnaire Survey.

Hypertension is a prevalent condition. Improving blood pressure control would depend on understanding concerns and limitations of physicians. Objective: Understanding practice of calcium channel blockers use among physicians. Material and methods: A cross-sectional, observational paper based questionnaire survey among 218 Indian physicians. Results: According to 55.83% of physicians (n=218), prevalence of hypertension ranges between 21-40%. Sixty percent physicians get referred cases mostly from the general physicians (69.48%). More than 20% patients have concomitant illness according to 33.81% physicians, most common being diabetes (33.44%).According to 96.30% physicians, due to asymptomatic nature, hypertension remains undiagnosed, untreated and uncontrolled. Stress (32.35%), obesity (23.13%), physical inactivity (22.78%) and smoking (20.52%) are responsible for sympathetic over activity. Calcium channel blockers (CCBs) (37.19%), beta blockers (30.43%), angiotensin receptor blocker (ARB) (12.14%) and angiotensin converting enzyme (ACE) inhibitors (4.02%) are used as first choice in patients with sympathetic over activity. Ischemic event, stroke, heart failure and renal failure occur due to ignoring sympathetic over activity according to 30.91%, 25.39%, 20.97% and 22.30% physicians respectively. According to 51.63% of physicians, patient compliance to antihypertensive therapy is > 70%. Lack of awareness (40.5%) and dosage frequency (24%) are two most common reasons for noncompliance. According to 89.72% of physicians, the current CCBs primarily inhibit L-type calcium channels but cause sympathetic over activity. A total of 48.34% physicians, >10% patients complain of pedal edema with amlodipine. In physicians opinion, blockage of L and N type of calcium channels (56.47%), unique mode of action (11.76%), arteriolar and venous dilation (9.41%) and inhibition of reninangiotensin- aldosterone (RAS) system (7.06%) are responsible for less pedal edema with cilnidipine. A total of 98.7% and 99.54% physicians rated efficacy and safety of cilnidipine as “good-very good” compared to other CCB respectively. Conclusion: In hypertension, sympathetic over activity may cause many complications. As per the physicians opinion survey, cilnidipine because of its unique mechanism of action offers multiple benefits in hypertensive patients and can be preferred over amlodipine.

Evaluación de efectividad y seguridad de las combinaciones de los antagonistas de los receptores de angiotensina con calcio antagonistas y/o diuréticos en pacientes con hipertensión arterial / Evaluation of the effectiveness and safety of combinations of angiotensin receptor antagonists with calcium antagonists and / or diuretics in patients with hypertension

Introducción: La HTA es una enfermedad crónica caracterizada por un aumento sostenido en los niveles de la TA normal. La cronicidad de la HTA afecta otras estructuras anatómicas siendo un factor de riesgo para el desarrollo de varias enfermedades. Sin embargo, a pesar de contar con varias opciones terapéuticas, determinar su efectividad comparativa y escoger la terapia antihipertensiva es difícil, ya que la selección de ésta puede estar influenciado por muchas variables y por la amplia gama de terapia que está disponible. Objetivo: Evaluar la efectividad y seguridad de la combinación de los ARA II con CA o diuréticos, comparados entre sí para el tratamiento de pacientes con HTA. Metodología: se realizó una evaluación crítica a través de una búsqueda sistemática en bases de datos electrónicas, diseñadas con vocabulario controlado y no controlado, además, de indagar con expertos sobre la disponibilidad de estudios publicados y no publicados, en inglés y español, la tamización de los resultados fue llevada a cabo por 2 revisores expertos. Los hallazgos de efectividad y seguridad fueron extraídos de los estudios con mejor calidad metodológica, buscando obtener información para todas las comparaciones y desenlaces de interés. Resultados: La combinación telmisartán/diurético, mostró una mayor reducción de la TA que la combinación de otros ARA II con diurético (-2.91 mmHg, IC 95% -3.66, -2.15). La triple terapia es más efectiva que la terapia dual (OR 1.86, IC 95% 1.69, 2.04) para alcanzar TA controladas. Conclusiones: En términos de reducción de la TA tanto sistólica como diastólica la evidencia hallada no encuentra diferencias significativas entre la combinacion de losartán/calcio antagonistas, y valsartán/calcio antagonistas a diferentes dosis pero si una diferencia entre la combinación telmisartán/diurético comparado contra olmesartán, ó valsartán ó losartán combinado con diurético. Asi mismo, la terapia de triple combinación es más efectiva que la terapia dual. Seguridad: No se hallaron comparaciones de seguridad entre terapia dual. Sin embargo, la combinación de los tres tipos de fármacos no se asoció con un exceso de riesgo frente a la terapia dual.(AU)

Mibefradil reduces blood glucose concentration in db/db mice

OBJECTIVE: Numerous recent studies suggest that abnormal intracellular calcium concentration ([Ca2+]i) is a common defect in diabetic animal models and patients. Abnormal calcium handling is an important mechanism in the defective pancreatic β-cell function in type 2 diabetes. T-type Ca2+ channel antagonists lower blood glucose in type 2 diabetes, but the mechanism remains unknown. METHODS: We examined the effect of the Ca2+ channel antagonist mibefradil on blood glucose in male db/db mice and phenotypically normal heterozygous mice by intraperitoneal injection. RESULTS: Mibefradil (15 mg/kg, i.p., b.i.d.) caused a profound reduction of fasting blood glucose from 430.92±20.46 mg/dl to 285.20±5.74 mg/dl in three days. The hypoglycemic effect of mibefradil was reproduced by NNC 55-0396, a compound structurally similar to mibefradil but more selective for T-type Ca2+ channels, but not by the specific L-type Ca2+ channel blocker nicardipine. Mibefradil did not show such hypoglycemic effects in heterozygous animals. In addition, triglycerides, basal insulin and food intake were significantly decreased by mibefradil treatment in the db/db mice but not in the controls. Western blot analysis, immunohistochemistry and immunofluorescence staining showed a significantly increased expression of T-type Ca2+ channel α-subunits Cav3.1 and Cav3.2 in liver and brain tissues from db/db mice compared to those from heterozygous animals. CONCLUSIONS: Collectively, these results suggest that T-type Ca2+ channels are potential therapeutic targets for antidiabetic drugs. .

Manejo preoperatorio de medicamentos en pacientes hipertensos / Preoperative pharmacological management of hypertensive patients

The proportion of older hypertensive patients that require a surgical procedure has increased in the last years. These patients require a through preoperative assessment, considering the medications in use, laboratory and images. An adequate pharmacological management of patients with hypertension in the perioperative period will prevent cardiovascular complications. Therefore the health care team must assure that patients with hypertension will be operated in optimal conditions.

La hipertensión arterial es una enfermedad con alta prevalencia en la población chilena, llegando a casi el 75 por ciento en el grupo de mayores de 65 años. En el ámbito quirúrgico, el número de pacientes de edad mayor y que padecen hipertensión arterial ha aumentado significativamente, lo que nos obliga a realizar una adecuada y detallada evaluación preoperatoria del paciente hipertenso con el fin de conocer su condición al momento de la cirugía, los medicamentos antihipertensivos que utiliza y solicitar los exámenes de laboratorio y/o de imágenes necesarios. Una adecuada asesoría al paciente respecto al manejo de su medicación antihipertensiva preoperatoria pretende disminuir las complicaciones en todo el período perioperatorio, tanto por su suspensión como por su mantención. De esta forma se busca establecer las medidas que permitan al paciente enfrentar el procedimiento quirúrgico en las mejores condiciones posibles.

Estado atual do tratamento farmacológico das arritmias cardíacas / Current status of the pharmacological treatment of cardiac arrhythmias

O tratamento das arritmias cardíacas é prerrogativa do clínico. Quando são diagnosticadas, é o médico assistente quem opta pela forma de tratar o que, na grande maioria dos casos , se baseia na prescrição de fármacos. Os medicamentos são úteis para a reversão de uma crise aguda e também para a prevenção de recorrências, mas não curam o paciente. A necessidade de tratar ou não uma arritmia depende de vários fatores, como a forma de apresentação clínica baseada na qualidade dos sintomas e a presença ou não de uma cardiopatia. Arritmias que causam colapso hemodinâmico estão associadas a elevado risco de complicações, como traumas físico e até parada cardiorespiratória, como acontece com a taquicardia ventricular. O tratamento, muitas vezes não somente com fármacos, deve ser agressivo visando à proteção do paciente. A presença de uma cardiopatia com disfunção ventricular pode tornar uma arritmia potencialmente maligna e o seu tratamento com fármacos envolve-se de alto risco, não somente pela eficácia apenas moderada dos medicamentos disponíveis, como também pelo risco de agravamento da arritmia, efeito conhecido como pró-arritmia. Não se deve transformar o tratamento mais grave do que a próxima arritmia. Com o avanço no conhecimento dos mecanismos de origem e manutenção das arritmias, houve certa redução da importância e da dependência do antiarrítmico no esquema terapêutico, já que outras classes de fármacos mostraram perfil favorável no tratamento, tal como acontece com os betabloqueadores, inibidores da enzima de conversão da angiotensina, espironolactona, estatinas, etc. Neste artigo, serão discutidos aspectos atuais do tratamento farmacológico das arritmias cardíacas.

The treatment of cardiac arrhythmias is a prerogative of the clinician. When they are diagnosed is the physician who chooses the way of dealing with that, in most cases, is based on prescription of antiarrhythmic drugs. The drugs are useful for the reversal of an acute attack and also for the prevention of recurrences, but not to cure the patient. The need to treat an arrhythmia or not depends on several factors, such as clinical presentation based on the quality of symptoms and the presence or absence of heart disease. Hemodynamic collapse caused by arrhythmias are associated with increased risk of complications, including physical trauma and even cardiac arrest as what happens during verntricular tachycardia. Treatment often, not only with drugs, should be aggressive in order to protect the patient. Some types of arrhythmias in the presence of heart disease with left ventricular dysfunctioin can be become a potentially malignant arrhythmia and its treatment with drugs engages high risk, not only for the modest effectiveness of the medications available but also due to the risk of aggravation of arrhythmia, an effect know as proarrhythmia. One should not make the treatment worse than the arrhythmia itself. With the advances in knowledge of the mechanisms of origin and maintenance of arrhythmia, there was some reduction of the importance and reliance on antiarrhytmic agent in the therapeutic regimen, as other classes of drugs showed favorable profile during treatment, as what happens with beta-blockers, angiotensin converting enzyme inhibitors, spironolactone, statins, etc. This paper will discuss current aspects of pharmacological treatment of cardiac arrhythmias.

A Case of Severe Coronary Spasm Associated with 5-Fluorouracil Chemotherapy

Cardiotoxicity associated with 5-fluorouracil (FU) is an uncommon, but potentially lethal, condition. The case of an 83-year-old man with colon cancer who developed chest pain during 5-FU infusion is presented. The electrocardiogram (ECG) showed pronounced ST elevation in the lateral leads, and the chest pain was resolved after infusion of nitroglycerin. A coronary angiogram (CAG) revealed that the patient had significant atherosclerosis in the proximal left circumflex artery. Coronary artery spasm with fixed stenosis was considered, and a drug-eluting stent was implanted. After 8 hours, the patient complained of recurring chest pain, paralleled by ST elevation on the ECG. The chest pain subsided after administration of intravenous nitroglycerin followed by sublingual nifedipine. Repeated CAG showed patency of the previous stent. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, indicating that a calcium channel blocker may be effective in the prevention or treatment of 5-FU cardiotoxicity.

Farmacovigilancia activa en pacientes afiliados al sistema general de seguridad social en salud / Active pharmacosurveillance of patients affiliated to the Colombian general social security/health system

Objetivos Determinar los posibles resultados negativos asociados a la medicación mediante la metodología de búsqueda activa de posibles interacciones medicamentosas en bases de datos de pacientes afiliados al Sistema General de Seguridad Social en Salud. Métodos A partir de las bases de datos de dispensación de medicamentos de Audifarma S.A a unos 4 millones de usuarios del país, se hizo una revisión sistemática de estadísticas de una serie de medicamentos identificados por presentar interacciones de riesgo, dosis diferentes a las recomendadas o dispensación irregular. Los casos son socializados con las EPS responsables. Resultados Se encontró un caso de nefrotoxicidad por ácido zoledrónico; el 37,0 por ciento de los usuarios de clopidogrel recibían concomitantemente omeprazol, que reduce la efectividad del primero; el 29,9 por ciento de los pacientes que toman losartan están recibiendo dosis superiores a las recomendadas para su indicación; el 2,0 por ciento de los pacientes que toman metoprolol o verapamilo, los recibe simultáneamente, con riesgo de generar bradicardia sinusal, bloqueos auriculoventriculares o disfunción sistólica. Todos los casos fueron notificados a los responsables en la EPS que atienden estos pacientes. Discusión La farmacovigilancia activa permite optimizar recursos, prevenir eventos adversos que puedan potencialmente causar morbilidad importante o incluso letalidad o determinar problemas que podrían ser responsables del fracaso terapéutico. Este tipo de estrategia se anticipa a la aparición de posibles riesgos para el paciente por lo que se recomienda considerarla para reforzar los programas de vigilancia de uso de medicamentos en el país.

Objectives Determining negative results associated with medication through an active search of possible drug interactions in databases for patients affiliated to the Colombian general social security/health system. Methods Statistics related to Audifarma S.A. dispensation drug databases for about 4 million Colombian users were systematically reviewed for identifying drugs having known interactions involving risk, doses different from recommended ones or irregular dispensation. The pertinent health-care providing services were made aware of the above. Results There was one case of nephrotoxicity being caused by zoledronic acid. 37 percent of clopidogrel users concomitantly received omeprazole which reduces the former's effectiveness. 29.9 percent of patients who were taking losartan were receiving doses higher than the recommended ones. 2.0 percent of patients who were taking metoprolol or verapamil were simultaneously receiving them, at the risk of generating first-degree heart block, bradycardia, or systolic dysfunction. All these cases were notified to the pertinent health-care services. Conclusions Active pharmacosurveillance leads to resources being optimised, adverse events which can potentially cause morbidity or lethality being prevented or even determining problems which could be responsible for therapeutic failure. This type of strategy anticipates the appearance of possible risks for patients, meaning that drug use monitoring programmes in Colombia should be reinforced.

Subarachnoid haemorrhage: possibly caused by the illegitimate use of sildenafil citrate.

Sildenafil (Viagra) has been developed as a drug to treat male impotence. It has also been used to reduce symptoms (e.g. improved exercise capacity) in patients with pulmonary arterial hypertension. A case of subarachnoid haemorrhage (SAH) following the illicit use of sildenafil is reported.

Comparison of intralesional verapamil with intralesional triamcinolone in the treatment of hypertrophic scars and keloids.

BACKGROUND: The calcium channel blocker, verapamil stimulates procollagenase synthesis in keloids and hypertrophic scars. AIM: To study the effect of verapamil in the treatment of hypertrophic scars and keloids and to evaluate the effect of verapamil on the rate of reduction of hypertrophic scars and keloids in comparison with triamcinolone. METHODS: The study was a randomized, single blind, parallel group study in which 54 patients were allocated to to receive either verapamil or triamcinolone. Drugs were administered intralesionally in both groups. Improvement of the scar was measured using modified Vancouver scale and by using a centimeter scale serially till the scar flattened. RESULTS: There was a reduction in vascularity, pliability, height and width of the scar with both the drugs after 3 weeks of treatment. These changes were present at one year of follow-up after stopping treatment. Scar pigmentation was not changed desirably by either drug. Length of the scars was also not altered significantly by either drug. The rate of reduction in vascularity, pliability, height and width of the scar with triamcinolone was faster than with verapamil. Adverse drug reactions were more with triamcinolone than with verapamil. CONCLUSION: Intralesional verapamil may be a suitable alternative to triamcinolone in the treatment of hypertrophic scars and keloids.

Management of acute coronary syndromes in secondary care settings in Kerala: impact of a quality improvement programme.

BACKGROUND: Evidence-based therapies that have been shown to improve outcomes in acute coronary syndromes (ACS) are often underused in clinically eligible patients. We evaluated the impact, efficacy and acceptability of a quality improvement programme to manage ACS. METHODS: A well-defined geographical area was identified and a situational analysis done. All physicians in the area, who were actively involved in the detection and management of ACS, were invited to participate in the quality improvement programme. The programme involved the use of a service delivery package which consisted of standard admission orders and patient-directed discharge instructions. Concurrently, health education in the community to promote self-detection, self-administration of aspirin and self-referral were carried out. All participating physicians were asked to register consecutive cases of ACS (20 each) presenting to their clinics before and after the intervention programme. The pre- and post-intervention data were compared. RESULTS: The use of aspirin at discharge increased from 89.7% to 96.8% (p < 0.05) and that of heparin from 57.6% to 66.3% (p < 0.05). The use of beta-blockers increased from 48.6% to 63.4% (p < 0.05) and that of lipid-lowering therapy from 74.1% to 96.3% (p < 0.05). There was a significant reduction in the use of calcium channel blockers from 21.6% to 8.1% (p < 0.05). The time to thrombolysis decreased significantly (median difference of 54 minutes, p < 0.05) after the intervention programme. CONCLUSION: Structured quality improvement programmes aimed at both patients and providers can be successful in secondary care settings of developing countries.

Nimodipine is more effective than nifedipine in attenuating morphine tolerance on chronic co-administration in the rat tail-flick test.

Opioids, when co-administered with L-type calcium channel blockers (L-CCBs) show morphine like higher antinociceptive effect. This antinociceptive effect has been further investigated using a different experimental paradigm. The effect of two different L-CCBs (nifedipine and nimodipine) on morphine-induced antinociception was studied by the tail-flick test (40 min after morphine administration) in adult Wistar rats. A fixed-dose of nimodipine or nifedipine (2 mg/kg, once daily) was combined with a fixed dose of morphine (10 mg/kg, twice daily) for 10 days. Co-administration of L-CCBs significantly increased the antinociceptive effect of morphine, even 12 hr after administration. Also, nimodipine was more effective than nifedipine. Nimodipine was further studied using a higher and escalating doses of morphine (20-30 mg/kg twice daily for 14 days). Nimodipine increased the antinociceptive effect of morphine in the latter part of the study (days nine to fourteen) though significant difference was observed on 11th evening and 12th morning. No obvious adverse effects were observed in the present study. The results show for the first time that nimodipine is more effective than nifedipine and that these L-CCBs continue to be effective, even 12 hr after administration in the tail-flick test.

Fisura anal, opciones terapéuticas actuales: [revisión] / Anal fissure, actually treatment options: [review]

La fisura anal es una patología frecuente y probablemente la causante de la mayor parte de las proctalgias agudas severas. Esta revisión tiene por objetivo, evaluar los procedimientos actualmente utilizados para el tratamiento de esta enfermedad. En principio se describen algunos aspectos ligados a la etiopatogenia y a la evolución natural con la intención de comprender la utilización de las distintas modalidades terapéuticas. Posteriormente se analizan las características de cada método en particular, como así también sus beneficios, efectos adversos y resultados. Al final del trabajo, se expone el algoritmo de tratamiento seguido por los autores.

The anal fissure is a frequent pathology and probably the cause of most of the severe acute proctalgias. This revision has by objective, to evaluate the procedures at the moment used for the treatment of this disease. In principle some aspects related to etiopatogenia are described and to the natural evolution, with the intention to understand the use of different therapeutic modalities. Later the characteristics of each method in individual are analyzed, like thus also their benefits, adverse effects and results. At the end of the work, the algorithm of treatment followed by the authors is exposed.

Combinación de un inhibidor de la enzima convertidora de la angiotensina con un antagonista del calcio versus la monoterapia con el IECA: eficacia terapéutica en hipertensión arterial esencial y regresión de la hipertrofia cardíaca / Combination of a converting enzyme inhibitor (ACEI) with a calcium antagonist versus monotherapy with an ACEI: therapeutic efficacy in essential hypertension and regression of ventricular hypertrophy

Objetivo: Evaluar la eficacia y la tolerancia, así como su acción sobre la regresión de la hipertrofia ventricular izquierda, de la combinación de benazepril más amlodipina (B + A) versus la monoterapia con benazepril (B). Material y métodos: Se incluyeron 33 hipertensos esenciales. Durante 6 meses de tratamiento, 18 de ellos recibieron B + A (9 varones, 55 ± 2 años) y los 15 restantes recibieron B (10 varones, 49 ± 2 años). Se realizó una presurometría (MAPA) al comienzo y a los 3 y a los 6 meses de tratamiento. En un subgrupo de 23 pacientes se calculó la masa ventricular izquierda (MVI) y el índice de MVI (IMVI) al inicio y al final del tratamiento. Resultados: A los 3 meses de tratamiento, los valores de la presión arterial (PA) fueron significativamente menores (p < 0,05) en los pacientes tratados con B + A que con B (24 horas: 123 ± 1,7 / 77 ± 1,8 versus 132 ± 1,5 / 85 ± 1,6 mm Hg; día: 127 ± 1,9 / 81 ± 1,8 versus 137 ± 1,8 / 91 ± 1,9 mm Hg; noche: 115 ± 2,0 / 68 ± 2,1 versus 122 ± 2,0 / 76 ± 1,7 mm Hg). Esto se logró con una dosis menor y hubo mejor tolerancia. En el grupo B + A, la MVI y el IMVI disminuyeron de 225,3 ± 47,4 g y 125,5 ± 19,3 g/m², a 187,2 ± 45,1 g y 104,7 ± 27,2 g/m2 (p < 0,05), mientras que en el grupo B la disminución no resultó estadísticamente significativa. Al finalizar el tratamiento, sólo en los pacientes tratados con B + A se observó una correlación positiva entre el descenso de la PAS y la MVI (r = 0,56, p < 0,025) y el IMVI (IMVI: r = 0,60; p < 0,01). Conclusión: La combinación B + A mostró una reducción de la PA más precoz. Se requirió una dosis menor y se obtuvo mejor tolerancia clínica que con B solo. En relación con la MVI y el IMVI, estos parámetros disminuyeron en forma significativa sólo en B + A.

Enhanced analgesic effect of morphine-nimodipine combination after intraspinal administration as compared to systemic administration in mice.

Calcium plays an important role in the pathophysiology of pain. A number of studies have investigated the effect of L-type calcium channel blockers on the analgesic response of morphine. However, the results are conflicting. In the present study, the antinociceptive effect of morphine (2.5 microg) and nimodipine (1 microg) co-administered intraspinally in mice was observed using the tail flick test. It was compared to the analgesic effect of these drugs (morphine - 250 microg subcutaneously; nimodipine - 100 microg intraperitoneally) after systemic administration. Nimodipine is highly lipophilic and readily crosses the blood brain barrier. Addition of nimodipine to morphine potentiated the analgesic response of the latter when administered through the intraspinal route but not when administered through systemic route. It may be due to direct inhibitory effect of morphine and nimodipine on neurons of superficial laminae of the spinal cord after binding to mu -opioid receptors and L-type calcium channels respectively.

Pre-electroconvulsive shock administration of calcium channel blockers reduces retrograde amnesia induced by ECS.

Effect of pre-electroconvulsive shock (ECS) administration of calcium channel blockers (CCBs) like verapamil, diltiazem, nifedipine, nimodipine, flunarizine and cinnarizine on retrograde amnesia induced by ECS was examined using passive avoidance paradigm in rats. The groups (Gr 1-7) of adult, male Wistar rats received true ECS with CCBs (5mg/kg; i.p) or vehicle (10 ml/kg; ip) and other groups (Gr 8-14) received sham ECS with CCBs (5mg/kg; i.p) or vehicle (10 ml/kg; i.p). The anti-amnestic activity of CCBs were evaluated using the passive avoidance paradigm in rats. Results showed that, the baseline latencies for all the groups did not differ significantly. Rats receiving true ECS produced significantly lower latencies. There was increase in the post ECS step through latencies of the rats administered CCBs before ECS. Therefore, pre-ECS administration of calcium channel blockers might reduce retrograde amnesia produced by ECS without altering seizure duration.