Anti-Leishmania effect of intralesional procaine and dibucaine in hamsters

Se compara el efecto terapéutico de los anestésicos locales "caínicos" Procaína y Dibucaína administrados intralesionalmente (IL), con el del tratamiento intramuscular (IM) convencional con Glucantime®, para lograr la cura clínica y parasitológica sobre lesiones dérmicas en la base de la cola de hámsters machos heterocigotos experimentalemente infectados con 4 x 10³ amastigotes de Leishmania (Viannia) braziliensis. Los resultados revelaron que todas las drogas ensayadas reducen significativamente (P<0,01) los tamaños promedio de las lesiones granulomatosas, cuando se comparan con los aninales controles sin tratamiento. El tratamiento local con la Dibucaína fue tan eficaz clínicamente como el Glucantime® administrado sistémicamente, y tuvo mejor eficacia para la resolución clínica de las lesiones que la Procaína IL. Se detectó la presencia de amastigotes viables en nódulos granulomatosos o cicatrices en su totalidad de los hámsters evaluados, después de 75-165 días de haberse finalizado los tratamientos, mediantes los métodos de frotis directo, histopatología convencional, medios de cultivo (NNN) y la técnica de la inmunoperoxidasa, lo que sugiere que la medición de las lesiones cutáneas por sí solo no es un método totalmente confiable y válido para evaluar la eficacia quimioterapéutica en la LC experimental. La eficiencia clínica de los anestésicos locales parece estar relacionada con sus tiempos de vida media y lipofilia relativa. De una manera preliminar, estos resultados parecieran apoyar la inclusión de los anestésicos locales "caínicos" como parte del armamentarium alternativo para el tratamiento de las LC animal y humana

[Cauda equina syndrome following intrathecal dibucaine].

We report three cases of cauda equina syndrome following spinal anesthesia with dibucaine. In two cases, the lumbar puncture was repeated and additional doses of dibucaine were administered to obtain adequate sensory blockade. In the last case, spinal anesthesia worked well with single injection of dibucaine. In all cases patients complained of varying degrees of bladder and bowel dysfunction, perineal sensory loss and lower extremity motor weakness on the next day, and the diagnosis of cauda equina syndrome was made. With only one case, the symptom disappeared four months later, but the rest of the patients suffered from sensory disturbance and defecation for more than four months after the surgery. One possible cause is a direct neurotoxic effect of high concentration dibucaine due to its maldistribution within the subarachnoid space. We have to consider the neurotoxicity and dose of the local anesthetic for obtaining a safer method and for preventing this complication.

[Spinal anesthesia with bupivacaine for a patient with a history of severe leg pain after intrathecal dibucaine].

An 87-year-old man was scheduled for the 11th transurethral bladder tumor resection (TURBT). He had a history of non-active syphilis for 21 years, diabetes mellitus for 7 years, and severe emphysema. Preoperative physical examination of the lower extremities, revealed loss of knee-jerk reflex, and loss of vibratory and proprioceptive perception. Four years previously, he underwent TURBT twice under spinal anesthesia with dibucaine, which caused severe leg pain during anesthesia. Therefore, subsequent TURBTs (eight times) were performed under general anesthesia with tracheal intubation, which frequently caused postoperative respiratory distress. Recently, bupivacaine, less neurotoxic than dibucaine, was on the market in Japan for use in spinal anesthesia. Therefore we planned spinal anesthesia using 0.5% bupivacaine, 2.0 ml. This time, he did not complain of leg pain during anesthesia, and postoperative conditions were satisfactory. We can conclude that bupivacaine is very useful for spinal anesthesia especially in patients with a history of leg pain by spinal anesthesia with dibucaine.

[Anaphylactoid reaction to dibucaine during spinal anesthesia].

A 71-year-old man with a history of allergic rhinitis for 6 years received spinal anesthesia using 2 ml of 0.3% dibucaine for transurethral prostatectomy. Two months previously he had undergone prostate biopsy and cystoscopy under spinal anesthesia with isobaric bupivacaine uneventfully. Forty five minutes after injection of dibucaine he complained of itching in the periorbital area, and developed tremor and muscle rigidity followed by loss of consciousness. Soon after, his blood pressure decreased to 40 mmHg, and erythema appeared over his body. Symptoms were relieved by epinephrine, hydrocortisone and antihistamine agents, but ten minutes after the treatment he again developed hypotension and erythema. Continuous infusion of epinephrine was needed for complete relief of symptoms. An intradermal test with 0.3% dibucaine carried out 6 days after surgery demonstrated a 12 x 8 mm wheal with flare. Although anaphylactic reaction to an amide local anesthetic has been reported to be quite rare, this is the 7th case report of anaphylactic reaction to dibucaine used for spinal anesthesia in Japan.

[Dibucaine for spinal anesthesia is a probable risk for cauda equina syndrome].

A 64-year-old man was scheduled for transure thral resection of the prostate. The patient's medical history showed borderline diabetic state and two uncomplicated surgeries under spinal anesthesia. Spinal anesthesia was performed at the L 3/4 interspace using hyperbaric 0.24% dibucaine 2.2 ml, which was followed by general anesthesia because the anesthesia level had spread only to the lower left side of the body. On the next day, he complained of difficulty of defecation and urination combined with hypesthesia around the anus, which was diagnosed as cauda equina syndrome. The symptoms had not changed for three weeks. Then, there was a gradual recovery but slight hypesthesia remained even four months after the surgery. Speculation of this clinical etiology suggests that high concentration of dibucaine, having maldistributed inside the intrathecal space, affected cauda equina, which resulted in irreversible nerve damage. There were other risk factors for cauda equina syndrome in this patient such as lithotomy position, history of frequent spinal anesthesia, diabetes and advanced age. None of these are contraindication for spinal anesthesia. Many elderly patients particularly undergoing urological surgeries are likely to have such risk factors. Therefore at least dibucaine should be avoided for spinal anesthesia because of its high neurotoxicity compared with other local anesthetics.

Spinal anesthesia hypotension in elective cesarean section in parturients wearing extra-strong compression stockings.

We have routinely applied an extra-strong graduated compression stocking to cesarean section patients to reduce the incidence of spinal anesthesia hypotension. Because bupivacaine has recently become available in Japan, we compared the incidence of spinal hypotension using either 2.0 ml of hyperbaric 0.3% dibucaine or 0.5% bupivacaine. There were 98 full-term parturients wearing the stocking who received 2.0 ml injection of dibucaine or bupivacaine for elective cesarean section. When systolic blood pressure decreased to 90-100 mm Hg or to less than 70% of the pre-anesthesia value, ephedrine was injected intravenously. There was no significant difference in systolic blood pressure or heart rate during spinal anesthesia between the dibucaine and bupivacaine groups. Although the demographic data and various data related to anesthesia or surgery were similar in the groups, the fluid volume and the dose and incidence of ephedrine injection during anesthesia showed significant differences: the mean dose was 3.6 and 1.5 mg and the incidence was 41% and 19% in the dibucaine and bupivacaine groups, respectively. Spinal anesthesia using bupivacaine results in a lower incidence of spinal hypotension compared with dibucaine and, in combination with fitting the extra-strong stockings onto both legs, is clinically useful for cesarean sections.

Blood concentrations of tetracaine and its metabolite following spinal anesthesia.

Blood concentrations of tetracaine and its metabolite, p-butylaminobenzoic acid, were measured after spinal anesthesia with tetracaine which had been administered to patients under going orthopedic surgery. Tetracaine, an ester anesthetic, was given to 10 patients, the dose was 8-14mg, and blood samples were collected 1, 2 and 6h after the injection of tetracaine. We used gas chromatography/mass spectrometry for purposes of analysis. Tetracaine was not detected in any blood sample, but the metabolite was detected in each sample with the mean concentrations of 126.5, 97.9 and 43.3ng/ml at 1, 2 and 6h, respectively. This data will be useful in determination of the cause of death after spinal anesthesia with tetracaine.

Thermal destabilization of transmembrane proteins by local anaesthetics.

Local anaesthetics, in addition to anaesthesia, induce the synthesis of heat shock proteins (HSPs), sensitize cells to hyperthermia, and increase the aggregation of nuclear proteins during heat shock. Anaesthetics are membrane active agents, and anaesthesia appears to be due to altered ion channel activity; however, the direct effect of heat shock is protein denaturation. These observations suggest that local anaesthetics may sensitize cells to hyperthermia by interacting with and destabilizing membrane proteins such that protein denaturation is increased. It is shown, using differential scanning calorimetry (DSC), that the local anaesthetics procaine, lidocaine, tetracaine and dibucaine destabilize the transmembrane domains of the Ca2+ -ATPase of sarcoplasmic reticulum and the band III anion transporter of red blood cells. The transmembrane domain of the Ca2+ -ATPase has a transition temperature (Tm) of denaturation of 61 degrees C which is decreased, for example, to 53 degrees C by 15 mM lidocaine. The degree of destabilization (deltaTm) by each anaesthetic is proportional to the lipid to water partition coefficient, and the increased sensitization by anaesthetics with larger partition coefficients and at higher pH suggests that the uncharged forms of the anaesthetics are responsible for destabilization. A Hill analysis of deltaTm for the Ca2+ -ATPase as a function of the concentration of anaesthetic in water gives dissociation constants (Kd) on the order of 10(-4) M, if binding occurs directly from the aqueous phase. This demonstrates moderate affinity binding. However, dissociation constants of 1-3 M are obtained, if binding occurs through the lipid phase, which demonstrates low affinity binding. Thus, the interaction of local anaesthetics with the Ca2+ -ATPase may be moderately specific or non-specific depending on the mechanism of interaction. The observation that local anaesthetics also destabilize the transmembrane domain of the band III protein of erythrocytes suggests that destabilization of transmembrane proteins is a general property of anaesthetics, which is at least in part a mechanism of sensitization to hyperthermia.

[Severe lightning limb pain induced by spinal anesthesia].

We report a case in which spinal anesthesia induced a severe lightning limb pain. A 71-year-old man presented for prostate biopsy. Preanesthetic examinations revealed slight hypesthesia in the L 5-S 1 dermatomal segments in the right leg. The patient reported that he had received "local anesthetic" in the lumbar spine 16 years previously because of severe lumbago, and that his hyposthesia had originated from the "local anesthetic". Unfortunately we had no way to know the anesthetic technique performed 16 years ago. The spinal anesthesia was uneventfully introduced with a 25 G Quincke needle at the L 3-4 interspace using 2.0 ml 0.3% hyperbaric dibucaine in the left lateral positions. As soon as the patient was put into the supine position, he started to complain about severe lightning pain in the region of his hyposthesic segments. Severe lightning pain completely diminished 4 hours later when the effect of spinal anesthesia disappeared.

Chemical, pharmaceutical and clinical standardization of the TRUE Test caine mix.

The development of the caine mix patch of the TRUE TestTM involved extensive formulation work to obtain optimal release, stability and clinical function. Hydroxypropyl cellulose, ordinarily used in the TRUE TestTM, induced crystallization and inadequate release of benzocaine. Addition of the crystal poison glucose caused rapid degradation of the caines. Polyvinylpyrrolidone (PVP) proved to be a vehicle which incorporated the caines in a stable preparation on the patch. Rapid release of the caines from this vehicle when applied on membranes was confirmed by in vivo patch test studies.