Efficacy of aflibercept on exudative age-related macular degeneration in patients exhibiting complete ranibizumab resistance and tachyphylaxis / Eficácia do aflibercept em pacientes portadores de degeneração macular relacionada à idade exsudativa com resistência completa e taquifilaxia ao ranibizumab

ABSTRACT Purpose: The present study compared the efficacy of aflibercept for neovascular age-related macular degeneration (NV-AMD) in patients with complete ranibizumab resistance and tachyphylaxis. Methods: Forty-four eyes of 38 neovascular age-related macular degeneration patients were evaluated. Eyes were divided into a complete resistance group (n=23 eyes) and tachyphylaxis group (n=21 eyes). Results: After three injections, eight (38.1%) patients in the tachyphylaxis group and nine (39.1%) in the complete resistance group presented with macular dryness. After the first injection of aflibercept, the mean visual acuity improved significantly in the tachyphylaxis group (p=0.018) but remained unchanged in the complete resistance group (p=0.37). There was a non-significant trend towards improved mean visual acuity in both groups after the second and third injections relative to the acuity at the final visit for ranibizumab treatment. In the tachyphylaxis group, the presence of subfoveal pigmented epithelium detachment (PED) decreased significantly after intravitreal aflibercept treatment. Conclusions: Although treatment with aflibercept yielded generally positive anatomical results in both groups, no significant increase in visual acuity was achieved.

RESUMO Objetivo: O presente estudo comparou a eficácia do aflibercept na degeneração macular neovascular relacionada à idade (NV-AMD) com de resistência completa ao ranibizumab e taquifilaxia ao ranibizumab. Método: Quarenta e quatro olhos de 38 pacientes com degeneração macular neovascular relacionada à idade foram inscritos. Eles foram divididos em dois grupos: grupo de resistência completa (n=23 olhos) e grupo taquifilaxia (n=21 olhos). Resultados: Depois de três injeções, 8 (38,1%) olhos no grupo de taquifilaxia e 9 (39,1%) olhos no grupo de resistência completa, apresentaram mácula seca. Após a primeira injeção de aflibercept, a acuidade visual média melhorou significativamente no grupo taquifilaxia (p=0,018) e manteve-se inalterada no grupo de resistência completa (p=0,37). Houve uma tendência de melhora da acuidade visual média em ambos os grupos após a segunda e terceira injeções em comparação com a última visita do tratamento com ranibizumab, mas isso não foi estatisticamente significativo. A presença de descolamento do epitélio pimentado subfoveal (PED) em olhos com taquifilaxia ao ranibizumab diminuiu significativamente após o tratamento aflibercept intravítreo. Conclusões: Embora o tratamento com aflibercept tenha mostrado resultados anatômicos positivas em ambos os grupos, não foi obtida melhora significativa da acuidade visual.

Cyanide toxicity during cardiopulmonary bypass with small dose of nitroprusside: a case report / 대한마취과학회지

Sodium nitroprusside (SNP) is an anti-hypertensive drug, commonly used to decrease the systemic vascular resistance and lower the blood pressure. When the amount of cyanide generated by the SNP exceeds the metabolic capacity for detoxification, cyanide toxicity occurs. Under general anesthesia and cardiopulmonary bypass (CPB), it may be difficult to detect the development of cyanide toxicity. In cardiac surgical patients, hemolysis, hypothermia and decreased organ perfusion, which emphasize the risk of cyanide toxicity, may develop as a consequence of CPB. In particular, hemolysis during CPB may cause an unexpected overproduction of cyanide due to free hemoglobin release. We experienced a patient who demonstrated SNP tachyphylaxis and cyanide toxicity during CPB, even though the total amount of SNP administered was much lower than the recommended dose. We therefore report this case with a review of the relevant literature.

Effects of repeated injection of local anesthetic on sciatic nerve blocks response / 华中科技大学学报（医学）（英德文版）

In order to examine whether repeated sciatic nerve blocks showed tachyphylaxis and continuity of sciatic nerve with spinal cord affected development of tachyphylaxis when assayed in vivo by duration of depression compound action potentials (CAP), rats were anesthetized with halothane, ventilated, monitored and supported with stable hemodynamics and temperature. Posterior tibial nerve distally and sciatic nerve in thigh were exposed, placed on bipolar silver electrodes for stimulation and recording respectively. Three sequential sciatic nerve blocks were performed between these electrodes using 0.15 ml of 3% chloroprocaine. Nine rats were chosen to observe the effects of repeated sciatic nerve blocks on CAP. In another 18 rats, a second investigator exposed the sciatic nerve near its origin at spinal cord and randomly performed nerve cut and sham (n=9), and closed the incision blinding the electrophysiologic investigator. The results showed that electrical stimulated tibial nerve induced sciatic nerve Aalpha/beta, Adelta, C fiber mediated CAP waves. CAP amplitudes were remained stable during whole experimental procedure. CAP amplitudes were decreased completely with 3% chloroprocaine blocked sciatic nerve and recovered fully. The duration of CAP depression were reduced with repeated blocks. There were no selective blocked effects on Aalpha/beta, Adelta, C fiber mediated CAP. With sciatic nerve cut proximally, there was no statistical significant tachyphylaxis with 3% chloroprocaine repeated blocked sciatic nerve, and the duration of first and third blocked Adelta fiber mediated CAP was 108+/-20 and 92+/-14 min respectively (P>0.05). In normal rats the duration of first and third blocked Adelta fiber mediated CAP was 110+/-20 and 75+/-16 min respectively (P<0.05). It was suggested that tachyphylaxis to local anesthetics can occur in rats repeated blocked sciatic nerve when assayed in vivo by duration of depression CAP. The continuity of sciatic nerve with spinal cord is one of the important factors affecting the development of tachyphylaxis.

Effects of repeated injection of local anesthetic on sciatic nerve blocks response / 华中科技大学学报（医学）（英德文版）

In order to examine whether repeated sciatic nerve blocks showed tachyphylaxis and continuity of sciatic nerve with spinal cord affected development of tachyphylaxis when assayed in vivo by duration of depression compound action potentials (CAP), rats were anesthetized with halothane, ventilated, monitored and supported with stable hemodynamics and temperature. Posterior tibial nerve distally and sciatic nerve in thigh were exposed, placed on bipolar silver electrodes for stimulation and recording respectively. Three sequential sciatic nerve blocks were performed between these electrodes using 0.15 ml of 3% chloroprocaine. Nine rats were chosen to observe the effects of repeated sciatic nerve blocks on CAP. In another 18 rats, a second investigator exposed the sciatic nerve near its origin at spinal cord and randomly performed nerve cut and sham (n=9), and closed the incision blinding the electrophysiologic investigator. The results showed that electrical stimulated tibial nerve induced sciatic nerve Aalpha/beta, Adelta, C fiber mediated CAP waves. CAP amplitudes were remained stable during whole experimental procedure. CAP amplitudes were decreased completely with 3% chloroprocaine blocked sciatic nerve and recovered fully. The duration of CAP depression were reduced with repeated blocks. There were no selective blocked effects on Aalpha/beta, Adelta, C fiber mediated CAP. With sciatic nerve cut proximally, there was no statistical significant tachyphylaxis with 3% chloroprocaine repeated blocked sciatic nerve, and the duration of first and third blocked Adelta fiber mediated CAP was 108+/-20 and 92+/-14 min respectively (P>0.05). In normal rats the duration of first and third blocked Adelta fiber mediated CAP was 110+/-20 and 75+/-16 min respectively (P<0.05). It was suggested that tachyphylaxis to local anesthetics can occur in rats repeated blocked sciatic nerve when assayed in vivo by duration of depression CAP. The continuity of sciatic nerve with spinal cord is one of the important factors affecting the development of tachyphylaxis.

Efecto de la capsaicina sobre la proliferación y ciclo celular de fibroblastos pulpares humanos / The effect of capsaicin on proliferation and cell cycle of human pulp fibroblasts

La capsaicina es un vanilloide natural que controla la inflamación neurogénica disminuyendo los neuropeptidos en la sinapsis neuronal. Nosotros determinamos el efecto de la capsaicina sobre la proliferación y el ciclo celular de fibroblastos pulpares humanos en cultivo (FPH). La dosis con la que se obtuvo el más alto porcentaje de células en proceso de división celular fue la capsaicina 10-16 M a las 24 y 96 horas. Sin embargo, con esta dosis también se observó una ruptura de la monocapa y una disminución significativa en el conteo de células, especialmente a las 24 horas. Estos mismos cambios, aunque en menor proporción, también fueron observados con capsaicina 10-8M. Con relación al tiempo, hubo un aumento significativo en el número de cèlulas en fase 24 y 72 horas. Estos efectos sobre el receptor para vanillides (VR1) dependientes del tiempo han sido descritos anteriormente en neuronas tratadas con capsaicina y se ha denominado taquifilaxis

Mechanism of epibatidine-induced catecholamine secretion in the rat adrenal gland

The present study was attempted to investigate the characteristics of epibatidine on secretion of catecholamines (CA) from the isolated perfused model of the rat adrenal gland, and to establish the mechanism of action. Epibatidine (3X10(-8) M) injected into an adrenal vein produced a great inhibition in secretory response of CA from the perfused rat adrenal gland. However, upon the repeated injection of epibatidine (3X10(-8) M) at 15 min-intervals, CA secretion was rapidly decreased after second injection of epibatidine. However, there was no statistical difference between CA secretory responses of both 1st and 2nd periods by the successive administration of epibatidine at 120 min-intervals. Tachyphylaxis to releasing effects of CA evoked by epibatidine was observed by the repeated administration. Therefore, in all subsequent experiments, epibatidine was not administered successively more than twice only 120 min-intervals. The epibatidine-induced CA secretion was markedly inhibited by the pretreatment with atropine, chlorisondamine, pirenzepine, nicardipine, TMB-8, and perfusion of Ca2+/-free Krebs solution containing EGTA, while was not affected by diphenhydramine. Moreover, the CA secretion evoked by ACh for 1st period (0apprx4 min) was greatly potentiated by the simultaneous perfusion of epibatidine (1.5X10(-8) M), but followed by time-dependently gradual reduction after 2nd period. The CA release evoked by high potassium (5.6+/-10(-8) M) for 1st period (0apprx4 min) was also enhanced by the simultaneous perfusion of epibatidine, but those after 2nd period were not affected. Taken together, these experimental data suggest that epibatidine causes catecholamine secretion in a calcium dependent fashion from the perfused rat adrenal gland through activation of neuronal cholinergic (nicotinic and muscarinic) receptors located in adrenomedullary chromaffin cells. It also seems that epibatidine-evoked catecholamine release is not relevant to stimulation of histaminergic receptors.

The Effect of Erythromycin on Gastric Antrum and Low Esophageal Sphincter in the Newborn Rabbit

PURPOSE: We studied smooth muscle strips from rabbit gastric antrum and low esophageal sphincter (LES) to explore the difference between newborn and adult rabbit on erythromycin (EM)- induced contractions. Another aim of this study was to determine the mechanism of LES contractile activities induced by erythromycin (EM). METHODS: Muscle strips prepared from newborn and adult rabbits were stimulated with agonists such as KCl, motilin and EM, and the isometric tensions were measured. To study the underlying mechanism of EM-stimulated contraction of LES, the receptor antagonsts, including tetrodotoxin, hexamethonium, atropine, propranolol and phentholamine, were used. A high concentration of motilin (1 micrometer) was employed to provoke tachyphylaxis. RESULTS: Antral smooth muscle and LES from newborn rabbits developed less active force than those from adult rabbits when stimulated with KCl, motilin and erythromycin, however, the effective concentrations (EC50s) were similar in both age groups. Antral smooth muscle strips showed both tonic and phasic contractions but LES muscle strips showed only tonic contractions. These findings were observed in both newborn and adult rabbits. The contraction force of antral smooth muscle strips in response to agonists was greater than that of LES. The contractile response of LES to repeated motilin or EM administration was markedly decreased. EM- induced contractions of LES were markedly decreased by motilin tachyphylaxis but were unaffected by tetrodotoxin, hexamethonium, atropine or propranolol plus phentolamine. CONCLUSOIN: The data suggest that the contractilities of antrum and LES smooth muscle from newborn rabbit are less than those from adult ones, however, the effective concentratons of EM (EC50) are not different between the two age groups. The results also suggest that erythromycin induces the contraction of rabbit LES via motilin receptor in vitro.

Mechanism of vasoactive intestinal polypeptide-induced catecholamine secretion from the rat adrenal medulla

The present study was attempted to investigate the effect of vasoactive intestinal polypeptide (VIP) on secretion of catecholamines (CA) and to establish whether there is the existence of a noncholinergic mechanism in adrenomedullary CA secretion from the isolated perfused rat adrenal gland. The perfusion into an adrenal vein of VIP (3 X 10-6 M) for 5 min or the injection of acetylcholine (ACh, 5.32 X 10-3 M) resulted in great increases in CA secretion. Tachyphylaxis to releasing effect of CA evoked by VIP was not observed by the repeated perfusion. The net increase in adrenal CA secretion evoked by VIP still remained unaffected in the presence of atropine or chlorisondamine. However, the CA release in response to ACh was greatly inhibited by the pretreatment with atropine or chlorisondamine. The releasing effects of CA evoked by either VIP or ACh were depressed by pretreatment with nicardipine, TMB-8, and the perfusion of Ca2+-free medium. Moreover, VIP- as well as ACh-evoked CA secretory responses were markedly inhibited under the presence of (Lys1, Pro2.5, Arg3.4, Tyr6)-VIP or naloxone. CA secretory responses induced by ACh and high K+ (5.6 X 10-2 M) were potentiated by infusion of VIP (3 X 10-6 M for 5 min). Taken together, these experimental results indicate that VIP causes CA release in a fashion of calcium ion-dependence, suggesting strongly that there exists a noncholinergic mechanism that may be involved in the regulation of adrenomedullary CA secretion through VIP receptors in the rat adrenal gland, and that VIP may be the noncholinergic excitatory secretagogue present in the chromaffin cells.

Farmacología de los anestésicos locales / Pharmacology of the local anaesthetics

El conocimiento básico de la farmacología de las drogas promueve un uso más racional de las mismas por parte del anestesiólogo. En la presente revisión se actualizan conceptos farmacodinámicos y farmacocinéticos.

Influence of GABAergic Receptors on Catecholamine Secretion in the Isolated Rat Adrenal Glands

BACKGROUND: The influence of gamma-aminobutyric acid(GABA), which is well-known as a major inhibitory neurotransmitter in central nervous system, on secretion of catecholamines(CA) was investigated in the isolated perfused rat adrenal gland. METHODS: Mature male Sprague-Dawley rats were anesthetized with ether. Ther adrenal gland was isolated by the methods f Wakade. A cannula used for perfusion of the adrenal gladn was inserted into the distal end of the renal vein. The adrenal gland, along with ligated blood vessels and the cannula, was carefully removed from the animal and placed on a platform of a leucite chamber. RESULTS: GABA given into an adrenal vein of the rat produced markedly secretion of CA from the adrenal gland. Tachyphylaxis to the relesing effect of CA evoked by GABA was observed. The secretory effect of CA evoked by GABA was attenuated singnificantly by pretreatment with mecamylamine or atropine. Ouabain inhibited greatly the secretory response of GABA. When omitting the external potassium ion, the basal release of CA was increased. During this period GABA no longer revealed the increase in CA release. CA secretion evoked by GABA was blocked significantly by perfusion of calcium-free Krebs solution containing 5mMEGTA for 30-min. Pretreatment with bicuculline or picrotoxin inhibited CA secretion evoked by GABA as well as ACh. ACh-evoked CA release was potentiated by GABA infusion(400ug/30min). CONCLUSION: The experimental findings suggest that GABA causes the secretory effect of CA in a fashion of external calcium and potassium iosn-dependence, and that this releasing effect of CA induced by GABA may be exterted by stimulation of GABAergic A-reccptors located on adrenomedullary chromaffine cell, which is likely associated with cholinergic receptor activation evoked CA secretion.

The Study of Continuous Infusion Rates of Sodium Nitropusside in Deliberate Hypotensive Anesthesia / 대한마취과학회지

Sodium nitroprusside(SNP) is used to induce hypotension for a wide variety of indica- tions. Ordinarily, blood pressure responds sensitively to infusion of SNP in low doses, but occasioally resistance is seen, and actual tachyphylaxis during SNP infusion has been reported. To investigste the continuous infusion rates of SNP, we retrospectively reviewed 144 cases of spinal fusion operations which had been performed under deliberate hypotensive anesthesia (mean arterial pressure at 50-60 mmHg). To produce deliberate hypotension, The mean dose of SNP was 17.16 mg, the mean infusion time 283.85 minutes, and the average infusion rates 1.05 ug/kg/min. Patients who received csptopril required less SNP than untreated patients(0.95 vs 1.23 ug /kg/min., p<0.05). Isovolemic hemodilution also reduced aversge infusion rates of SNP (0. 87 vs 1.22ug/kg/min., p<0.05). There were, however, no significant differences in preoperative hypertention vs normotension, mild hypothermia vs. normothermia during the operation, and male vs. female. In addition, the average infusion rates of SNP were significantly correlated with body mass index(r=0.3329, p<0.01). But those were not correlated with age, infusion time of SNP, weight, volume of transfusion, height/age, and height.

Comparative effects of mast cell degranulators on perfused systemic blood vessels of Bufo melanostictus and Rana tigrina.

Three agents known to induce release of mast cell constituents, viz. polymyxin, compound 48/80 and polysorbate-80, were evaluated for effect on perfused blood vessels of R. tigrina and B. melanostictus. The mast cell degranulators caused vasoconstriction in frog and toad, except that for P-80 whose responses in toad were equivocal. Toads showed a general low responsiveness in comparison to frogs. Pharmacologic intervention with pheniramine, metergoline, hydergine, atropine and mecamylamine, respectively ruled out role of histamine, 5-HT, catecholamine or acetylcholine or even autonomic mechanisms in the above phenomena. The observations are suggestive of phylogenetic differences in biochemical profile of mast cells in amphibian species.

1-Sarcosine - Angiotensin II tachyphylaxis in helical strips and everted rings of rabbit aorta

The development of tachyphylaxis to [1-sarcosine]-angiotensin II was studied in helical strips and everted rings of rabbit aorta. Strips, but not everted rings, developed marked (>50%) tachyphylaxis to the peptide, when challenged repeatedly at 1-h intervals. Measurements of the membrane potential showed no difference between the two preparations, but strips were more sensitive to KC1 than everted rings. These results suggest that the strips are more depolarized than the everted rings due to lesions caused by the spiral cutting. This partial depolarization may underlie the tachyphylactic phenomenon

Influence of Verapamil Pretreatment on Hemodynamic Responses & Pulmonary Gas Exchange during Sodium Nitroprusside Induced Hypotension in Isoflurane-N2O Anesthetized Man / 대한마취과학회지

Controlled hypotension induced with sodium nitroprusside (SNP) has been most widely used to facilitate the surgical procedure and to reduce blood loss. However, major problem with its clinical use is cyanide toxicity, which is dose related. And resitance and tachyphylaxis, probably being mediated by sympathoadrenal response to lowered blood pressure, is known to increase dose requirements. Accordingly, several attempts have been made to attenuate sympathetic activity and therefore to reduce dose requirement of SNP. Verapamil, a representative calcium channel blocker, exerts inotropic and chronotropic effect, as well as vasodilation. And it is, also, known to impair pulmonary gas exchange. The purpose of these experiments was to evaluate hemodynamic and gas exchange effects of verapamil, and also its efficacy for reducing the amount of SNP during induced hypotension in patients anesthetized with isoflurane and N2O. Twenty five patients, scheduled to undergo general anesthesia with hypotension, were randomly assigned to two groups. Twelve patients were pretreated with verapamil (160mg, SOD: verapamil group) and the other thirteen were not (control group). The results were as follows: 1) Cardiac index remained unchanged in both groups and did not differ significantly between groups at all times. 2) Heart rate was significatly lower in verapamil group than in control group in the hypotensive period. (113+/- 3.3 vs 103+/- 2.7, p < 0.05) 3) Hypotension induced by SNP resulted from a marked decrease in systemic vascular resistance in both groups. 4) MPAP, PCWP, CVP, SVR and PVR significantly decreased after SNP infusion in both groups, but they did not differ significantly between the groups at all times. 5) SNP dose requirements to attain the same MAP reduction did not differ significantly between groups. (5.5+/-0.8vs 4.1+/-0.8mcg/kg/min, NS) 6) Verapamil pretreatment produced no significant change in intrapulmonary shunt fraction at all times. 7) SNP caused a signficant decrease in arterial oxygen tension in both group, but there were no significant difference between groups at all times. From the above results, it might be concluded 1) that verapamil, in clinical doses, does not blunt a reflex increase in sympathetic activity in response to SNP induced vasodilation, since it produced only a minor influence on SNP induced hemodynamics and the SNP dose requirements, and that verapamil does not inhibit hypoxic pulmonary vasoconstriction during isoflurane-N2O anesthesia. Thus, verapamil could not be a valuable adjunct of SNP in enhancing the hypotensive effect in spite of preserved arterial oxygenation.

A Clinical Effect of Pilocarpine Gel(Pilogel(R) HS) in Glaucoma: Alternative Effect of 4% Pilocarpine Solution

In order to research the clinical utility of Pilogel(R), we administered Pilogel(R) to 13 POAG(primary open angle glaucoma) patients once daily for four weeks and measured the degree of intraocular pressure reduction and accompanying side effects three days after; one week after; two weeks after; three weeks after and four weeks administration. 1. Administration of Pilogel(R) single dose at bed time produced the same effect of intraocular pressure reduction as that of 4% Pilocarpine eye drop four times a day. 2. Up to four weeks of daily administration of Pilogel(R) did not produced tachyphylaxis. 3. Degree of intraocular pressure reduction after administration of Pilogel(R) was maintained at the almost same level from days 3 up to 4 weeks. 4. The intraocular pressure reduction effect with pilogel(R) was maintained at the constant level for 18 hours following administration of it. 5. Once a day regimen of Pilogel(R) was proven to be more comfortable than the 4 times a day regimen of pilocarpine eye drop. And the side effect of Pilogel(R) was no greater than that of pilocarpine eye drop.