Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.

BACKGROUND: Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). PATIENTS AND METHODS: We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. RESULTS: Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. CONCLUSIONS: GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. CLINICAL TRIAL NUMBER: This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer.

BACKGROUND: We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC). PATIENTS AND METHODS: Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS). RESULTS: Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37-0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54-1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47-1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group. CONCLUSION: The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting. CLINICAL TRIALS NUMBER: Japan Pharmaceutical Information Center: JapicCTI-111554.

Oxygen at high pressures: a theoretical approach to monoatomic phases.

We have studied the ζ-phase of solid oxygen using the generalized gradient approximation in the density functional approach. Calculations of total energies and pressures have been carried out for the prototype of diatomic ζ-phase and other hypothetical monoatomic crystal structures. The diatomic phase was found to be stable over a wide range of pressure (100-2000 GPa). The stacking of molecular layers is discussed in comparison with the available experimental data.

Relationship between microtubule-binding repeats and morphology of neurofibrillary tangle in Alzheimer's disease.

OBJECTIVE: The present study was performed to compare the distributions of three-repeat (3R) and four-repeat (4R) neurofibrillary tangles (NFT) with those of pretangles (p-NFT), intracellular NFT (i-NFT), and extracellular NFT (e-NFT) in the hippocampus of Alzheimer's disease brains. METHODS: NFT labeling was performed using anti-tau antibodies: pSer262 for p-NFT, pSer422 for i-NFT, AT8 for e-NFT, RD3 for 3R, and RD4 for 4R tau, and Gallyas impregnation for the NFT population. RD4- and pSer422-positive NFT were detected predominantly in sectors from CA2 to CA4, while RD3- and pSer262-positive NFT were predominantly present in CA1, the entorhinal cortex, and the subiculum. The tau epitope recognized by pSer262 belongs to 4R tau but it showed a strong correlation with RD3- and AT8-positive NFT. CONCLUSIONS: Sectors CA2-CA4 showed predominantly 4R-NFT containing the pSer422 epitope. pSer262 may detect the process of transformation from p-NFT to i-NFT, and e-NFT consisted predominantly of 3R tau.

High-sensitivity analysis of serum C-reactive protein in young patients with lumbar disc herniation.

We measured the serum concentration of C-reactive protein (CRP) by a high-sensitive method in patients with lumbar disc herniation. There were 48 patients in the study group and 53 normal controls. The level and type of herniation were evaluated. The clinical data including the neurological findings, the angle of straight leg raising and post-operative recovery as measured by the Japanese Orthopaedic Association (JOA) score, were recorded. The high-sensitive CRP (hs-CRP) was measured by an ultrasensitive latex-enhanced immunoassay. The mean hs-CRP concentration was 0.056 +/- 0.076 mg/dl in the patient group and 0.017 +/- 0.021 mg/dl in the control group. The difference was statistically significant (p = 0.006). There was no other correlation between the hs-CRP concentration and the level and type of herniation, or the pre-operative clinical data. A positive correlation was found between the concentration of hs-CRP before operation and the JOA score after. Those with a higher concentration of hs-CRP before operation showed a poorer recovery after. The significantly high concentration of serum hs-CRP might indicate a systemic inflammatory response to impingement of the nerve root caused by disc herniation and might be a predictor of recovery after operation.

Progression of ossification of the posterior longitudinal ligament following en bloc cervical laminoplasty.

BACKGROUND: Ossification of the posterior longitudinal ligament often causes compressive myelopathy. Ossification is a progressive disease, and it has been reported that the area of ossification increases after decompressive surgery. However, it is uncertain how the progression of ossification affects the long-term outcome after cervical laminoplasty. This study was performed to clarify the relationship between the progression of ossification of the posterior longitudinal ligament and the clinical results following en bloc cervical laminoplasty. METHODS: Forty-five patients who were followed for more than ten years after laminoplasty participated in this study. Radiographs and tomograms of the cervical spine of each patient were made before and after the operation and at the time of the latest follow-up. The extent of ossification in the longitudinal and sagittal axes was evaluated. Neurological function was graded with use of the Japanese Orthopaedic Association scoring system. The relationship between the progression of ossification and the score-based rate of recovery was analyzed. RESULTS: Thirty-three (73%) of the patients had progression of ossification of the posterior longitudinal ligament after laminoplasty. Progression was frequent in patients with the mixed type of ossification and in those with the continuous type, whereas it was rare in patients with the segmental type. The patients with progression of the ossification were significantly younger than those without progression (p = 0.018). The Japanese Orthopaedic Association score improved rapidly within one year and continued to improve up to five years after surgery. The score tended to decrease thereafter. For thirteen patients, the score had worsened at the time of the latest follow-up. Three patients had neurological deterioration following an increase in the thickness of the ossification. CONCLUSIONS: Progression of ossification of the posterior longitudinal ligament was often observed during the long-term follow-up period after laminoplasty. Young patients with mixed and continuous types of ossification had the greatest risk for progression. Preventive measures, such as the use of a wider laminar opening during the laminoplasty, should be considered for patients who are at risk for progression of ossification.

The role of an uncommon type of oral streptococcus sanguis in the etiology of behcet's disease.

The relationships of Behcet's disease (BD) with oral diseases and the prevalence of an uncommon type of oralStreptococcus sanguis (Str. sanguis) in the oral cavity were investigated in a case-control study. BD patients were compared to patient controls (collagen disease) and healthy controls.An interview questionnaire survey of BD and oral diseases showed that during the pre-onset, onset, and post-onset periods, the incidences of tonsillitis and dental caries, or the history of dental treatment, were greater in BD cases. Typological analysis showed a higher prevalence of an uncommon type ofStr. sanguis, differing from the common type, among BD cases compared to control groups. These results, showing a higher incidence of tonsillitis and dental caries during the presymptomatic period, a greater frequency of dental treatments during the symptomatic period, and the presence of an uncommon type ofStr. sanguis, indicate thatStr. sanguis of an uncommon type is related to increased risk of BD, and the possibility of a causal role is suggested.

Changes in the period of no respiratory sensation and total breath-holding time in successive breath-holding trials.

1. Immediately after breath-holding at end-expiratory level, there is a certain period of no particular respiratory sensation which is terminated by the onset of an unpleasant sensation and followed by progressive discomfort during breath-holding. This period, defined as the time from the start of voluntary breath-holding to the point where the onset of an unpleasant sensation occurs, is designated "the period of no respiratory sensation'. Although it has been shown that the maximum breath-holding performance is improved with successive trials, it is not clear whether this training effect exerts a similar influence on the period of no respiratory sensation during breath-holding. 2. Since the training effect seems to be associated with the stresses of breath-holding, we hypothesized that the initial period of no respiratory sensation during breath-holding might be less influenced by the training effect. 3. We studied 13 normal subjects who performed repeated breath holds while continuously rating their respiratory discomfort using a visual analogue scale. In addition, we measured the hypercapnic ventilatory response of each individual and obtained the relationship between the slope of the hypercapnic response curve and breath-holding periods. 4. Our results showed that there was little training effect on the period of no respiratory sensation and that the period of no sensation during breath-holding is inversely related to the slope of the hypercapnic ventilatory response curve. 5. The period of no respiratory sensation was also measured in eight patients with chronic obstructive pulmonary disease. The values of the period of no respiratory sensation in patients with chronic obstructive pulmonary disease were apparently lower than those obtained in normal subjects. 6. These findings suggest that measurement of the period of no respiratory sensation can be a useful clinical test for the study of genesis of dyspnoea.

Analysis of the double occlusion which provides four pressure gradients.

The arterial, double and venous occlusions are used to partition pulmonary vascular resistance into four segments. In this study, we tested whether the same can be accomplished from one double occlusion. In an isolated canine lung left lower lobe perfused with blood (flow rate = 500 mL.min-1), the pulmonary arterial and venous pressures (Pa and Pv, respectively) were measured directly. Arterial, double, and venous occlusions were performed and analysed as usual (Method 1) to measure pressures in small arteries and small veins (Pa' and Pv', respectively) and capillary pressure (Pc). Alternatively, one double occlusion was analysed (Method 2), not only for Pa, Pv and Pc, but also as independent arterial and venous occlusions to measure Pa' and Pv'. Method 1 yielded Pa, Pa', Pc, Pv', and Pv (Baseline) of 14.2 +/- 1.7, 10.8 +/- 1.6, 8.9 +/- 1.9, 7.3 +/- 1.5 and 1.3 +/- 0.6 mmHg, respectively (1 mmHg = 0.133 kPa). Method 2 yielded values for the same five pressures equal to 14.7 +/- 2.1, 11.0 +/- 2.2, 8.9 +/- 1.9, 7.3 +/- 1.3 and 1.3 +/- 0.6 mmHg, respectively. There was no significant difference in the pressure profile obtained using the two methods, nor were there differences during hypoxia and angiotensin infusion. These results suggest that a more thorough analysis of the double occlusion can provide the same information about distribution of vascular resistance as provided by a combination of the three occlusions. The advantage of the new approach is that fewer occlusions are needed and resistance distribution can be assessed during a transient response. Because all pressures are derived from one occlusion, the pressures would be more accurate relative to each other.

Half-life of nitric oxide in aqueous solutions with and without haemoglobin.

Nitric oxide (NO) has been linked to many regulatory functions in mammalian cells. Studies of NO release are hampered by the short half-life of the molecule. In the blood, NO disappears within seconds because it binds avidly with haemoglobin (Hb). The relationship between Hb concentration and NO disappearance, however, has not been described. In this study we utilized an amperometric NO sensor (WPI, Sarasota, FL) to monitor continuously the disappearance of NO from an aqueous solution when Hb (free or as red blood cells) was added. The calibration and linearity of the NO sensor was checked frequently using a chemical reaction to generate a known concentration of NO. An aliquot of NO solution (prepared from authentic gas) was added to a glass beaker containing 20 ml saline to generate NO concentration of approximately 1200 nM. Under our experimental conditions (PO2 = 40 mmHg), NO concentration fell slowly over 20 min with a half-life of 445 s. However, when haemoglobin was added, NO disappeared rapidly in proportion to Hb concentration. The results suggest that rapid binding of NO to Hb occurs in a 4:1 ratio. The maximum rate constant of NO disappearance due to binding with Hb was 2 x 10(5) M-1 s-1. The 4:1 binding ratio between NO:Hb may be used as a tool to quantitate NO release in some biological assays. The study supports the notion that NO acts as an autocoid because it disappears rapidly in the presence of Hb and is not likely to act as a circulating humoral substance. The NO sensor was useful for monitoring of NO concentration in Hb free solutions, but its response time limits its use in blood.

Site of action of endogenous nitric oxide on pulmonary vasculature in rats.

The effect of endogenous nitric oxide (NO) on the pulmonary hypoxic vasoconstriction was studied in isolated and blood perfused rat lungs. By applying the occlusion technique we partitioned the total pulmonary vascular resistance (PVR) into four segments: (1) large arteries (Ra), (2) small arteries (Ra'), (3) small veins (Rv'), and (4) large veins (Rv). The resistances were evaluated under baseline (BL) conditions and during; hypoxic vasoconstriction and acetylcholine (Ach) which was injected during hypoxic vasoconstriction. After recovery from hypoxia and Ach, Nomega-nitro-L-arginine (L-NA) was added to the reservoir and the responses to hypoxia and Ach were reevaluated. Before L-NA, hypoxia caused significant increase in the resistances of all segments (P < 0.05), with the largest being in Ra and Ra'. Ach-induced relaxation during hypoxia occurred in Ra, Ra' and Rv' (P < 0.05). L-NA did not change the basal tone of the pulmonary vasculature significantly. However, after L-NA, hypoxic vasoconstriction was markedly enhanced in Ra, Ra', and Rv' (P < 0.01) compared with the hypoxic response before L-NA. Ach-induced relaxation was abolished after L-NA. We conclude that, in rat lungs, inhibition of NO production during hypoxia enhances the response in the small arteries and veins as well as in the large arteries. The results suggest that hypoxic vasoconstriction in the large pulmonary arteries and small vessels is attenuated by NO release.

Sulfolobus hakonensis sp. nov., a novel species of acidothermophilic archaeon.

We characterized a microbial strain that was isolated from a hot spring at a geothermal area in Hakone, Japan. This isolate, whose lobed-shaped cells were about 1.0 micron in diameter, was a facultative chemolitho-autotroph that required aerobic conditions for growth. The optimum pH was 3.0 (pH range, 1.0 to 4.0), and the optimum temperature was 70 degrees C (temperature range, 50 to 80 degrees C). Lithotrophically, this strain grew on elemental sulfur and reduced sulfur compounds. The G+C content of the genomic DNA was 38.4 mol%. This organism contained calditoglycerocaldarchaeol, which is characteristic of members of the Sulfolobaceae. The levels of 16S rRNA sequence similarity between the new isolate and Sulfolobus acidocaldarius, Sulfolobus solfataricus, and Sulfolobus shibatae were less than 89.8%. Unlike S. acidocaldarius, S. solfataricus, and S. shibatae, the new isolate utilized sugars and amino acids poorly as sole carbon sources, and the levels of DNA-DNA hybridization between the new isolate and these Sulfolobus species were very low. Phenotypically, the new isolate was also distinct from the obligately lithotrophic organism Sulfolobus metallicus. We concluded that the new organism belongs to a new Sulfolobus species, for which we propose the name Sulfolobus hakonensis.

Effect of slow versus fast desaturation on the ventilatory response to hypoxia.

The ventilatory response to progressive hypoxia was studied in 15 healthy adult males by employing two different rates of desaturation. In a slow hypoxic ramp, peripheral oxygen saturation was gradually reduced to 70% over 10-13 min, while in a fast ramp the saturation was reduced over 3-5 min. The ventilatory response to hypoxia was evaluated as the slope of the regression between oxygen desaturation and minute ventilation (l/min/%). There was no significant difference in the slope between the slow and fast ramps. The subjects were further divided into two subgroups; namely high and low responders, according to the value of their slopes. A slope of 0.6 l/min/% was considered the cut-off limit for this classification. In the group of high responders, the hypoxic ventilatory response was significantly higher with the slow ramp than with the fast ramp (p < 0.05). In the low responders, the response was significantly higher with the fast ramp (p < 0.05). We conclude that the hypoxic ventilatory responses are influenced by the rate of desaturation and they appear to be related to the individual sensitivity to hypoxia. These responses are reversed in the low compared with the high responders.

Intestinal protein loss and bleeding assessed by fecal hemoglobin, transferrin, albumin, and alpha-1-antitrypsin levels in patients with colorectal diseases.

Four fecal proteins (hemoglobin, transferrin, albumin, and alpha 1-antitrypsin) were measured by enzyme-linked immunosorbent assay (ELISA) in patients with colorectal diseases. Levels of all 4 proteins were significantly increased in patients with colonic cancer and ulcerative colitis (UC) compared to levels in control subjects, while fecal alpha 1-antitrypsin was particularly elevated in colonic Crohn's disease (CD). That is, the fecal protein pattern of CD was distinct from those of colonic polyps, colonic cancer, and UC. To investigate whether levels of these fecal proteins reflect disease activity in UC and CD, comparative evaluation of fecal proteins in the active and inactive phases was performed. In UC, differences in the fecal concentrations of all 4 proteins were significant between the active and inactive phases of the disease. In CD, however, the difference in alpha 1-antitrypsin concentration was significant. Our results suggest that measurements of these 4 fecal proteins would be useful in the screening of colorectal diseases. In addition, these markers can also be used as indicators of disease activity in inflammatory bowel diseases.

Thoracic epidural anesthesia causes rib cage distortion in anesthetized, spontaneously breathing dogs.

The effects of thoracic epidural anesthesia on the performance of the parasternal intercostal muscles were investigated by measuring electromyographic activity and length changes of the parasternals (EMG activities and length, respectively, of the parasternals) in seven pentobarbital anesthetized, spontaneously breathing dogs. Epidural injection of 0.1 mL/kg of 2% lidocaine decreased tidal volume and minute ventilation during unstimulated breathing. These changes were accompanied by complete abolishment of EMG activities of the parasternals and passive elongation of the parasternals during inspiration. At equivalent end-tidal PCO2 values (70 and 80 mm Hg) during CO2 rebreathing, tidal volume and minute ventilation were lower after epidural block compared to the corresponding values before the block. Thoracic epidural anesthesia impaired contraction of the parasternals and conceivably other respiratory muscles in the rib cage as well and could induce a distortion of the rib cage. The authors conclude that respiratory muscles in the rib cage contribute considerably to the maintenance of ventilation in anesthetized dogs.

Bronchospirometry and separate measurement of occlusion pressure before and after lung resection using a double-lumen endotracheal tube.

To assess the distribution of ventilation to each lung, we measured ventilation and maximum negative airway pressure during occluded inspiratory effort (Pmax) of the individual lungs in eight male patients immediately before and after right upper lobectomy using a double-lumen endotracheal tube at a constant depth of enflurane anesthesia (end-tidal concentration 1.7%). Compared with the breathing pattern observed immediately before surgery, minute ventilation, Pmax, and respiratory frequency significantly increased immediately after the surgery, whereas tidal volume was unchanged. Bronchospirometry revealed that tidal volumes on the nonoperated side significantly increased after the operation. In contrast, tidal volumes on the operated side significantly decreased after the operation and were associated with significantly smaller Pmax obtained from unilateral airway than those of the nonoperated side postoperatively. These results indicate that there are considerable differences in ventilatory function between the lungs on the operated side and nonoperated side. The lung on the nonoperated side can partially compensate for the impaired ventilatory function on the operated side.

Differential effects of vecuronium on diaphragm and geniohyoid muscle in anaesthetized dogs.

We have examined the sensitivity of the geniohyoid, an upper airway dilating muscle, to vecuronium in 12 anaesthetized dogs undergoing mechanical ventilation of the lungs and compared it with that of the diaphragm. Dogs were allocated randomly to two groups: pentobarbitone alone (group 1, n = 7); pentobarbitone combined with 0.2 MAC (0.44%) of enflurane anaesthesia (group 2, n = 5). Supramaximal single twitch stimulations (0.1 Hz) were applied to the phrenic nerves in the upper thorax and the geniohyoid branches of the hypoglossal nerves at the neck. The evoked responses were assessed by the transdiaphragmatic pressure (Pdi) and the isometric force of the geniohyoid muscles (Tgh) until complete recovery of these variables after i.v. administration of vecuronium 0.02 mg kg-1. In both groups, the magnitude of the depression of twitch response was greater and time required to reach control amplitude was longer in the geniohyoid than the diaphragm. The depression of Tgh was significantly greater in group 2 than in group 1, whereas no change was observed in Pdi between the two groups. We conclude that the geniohyoid is more sensitive to vecuronium than the diaphragm and the differential effects of vecuronium are facilitated by a low concentration of enflurane.

Effects of tracheal irritation and hypercapnia on tracheal smooth muscle in humans.

Both hypercapnia and tracheal irritation are known to constrict the airways in animals. To see whether similar responses occur in humans, we investigated tracheal smooth muscle (TSM) responses to hypercapnia and tracheal irritation with water in 14 paralyzed and anesthetized humans. TSM tone was monitored by measuring the pressure in the saline-filled cuff of the endotracheal tube. Although, tracheal irritation caused TSM constriction in 10 of 14 patients, 4 patients showed no TSM response. Administration of intravenous atropine attenuated the TSM constriction response. Hypercapnia did not cause any change in TSM tone in any of the 14 patients. These results indicate that in paralyzed and anesthetized humans, there exist interindividual differences in the TSM responses to tracheal irritation and that hypercapnia cannot be an effective stimulus for the TSM constriction.

Respiratory effects of expiratory flow-resistive loading in conscious and anesthetized humans.

The response of breathing patterns to increased expiratory resistance is not only of physiologic interest, with respect to the control of breathing, but also of clinical interest because of its clinical relevance to obstructive diseases such as asthma and emphysema. To elucidate the response of breathing patterns to increased expiratory resistance during anesthesia, the respiratory effects of expiratory flow-resistive loading on breathing patterns were studied in 15 conscious and 10 lightly anesthetized subjects. Inspiratory time, expiratory time, respiratory frequency, inspiratory duty cycle, tidal volume, minute ventilation, and mean inspiratory flow rate were determined from a respiratory inductive plethysmograph. End-tidal CO2 was continuously recorded. In awake subjects, respiratory frequency was reduced without change in tidal volume or mean inspiratory flow rate, and minute ventilation was significantly decreased; the synchrony between rib cage and abdomen wall motion was well maintained during the loads. In contrast, in anesthetized subjects, respiratory frequency was reduced with remarkable increases in tidal volume, mean inspiratory flow rate, and minute ventilation, whereas coordination between rib cage and abdomen compartments was disturbed. End-tidal CO2 did not change in conscious subjects, but it increased in anesthetized subjects during the loads. These results indicate that there are differences between conscious and anesthetized subjects in breathing patterns during expiratory loading, and suggest that the ability to coordinate rib cage-abdomen wall motion is easily disturbed during anesthesia in patients with expiratory flow limitation.

Effects of i.v. lignocaine on airway reflexes elicited by irritation of the tracheal mucosa in humans anaesthetized with enflurane.

We have investigated the effects of bolus administration of lignocaine 1.5 mg kg-1 i.v. on respiratory responses to airway irritation induced by instillation of distilled water into the trachea in 10 patients anaesthetized with enflurane (1.5% end-tidal). Before administration of lignocaine, airway irritation elicited not only the cough reflex, but also other respiratory reflexes such as expiration, apnoea and spasmodic panting. Immediately after administration of i.v. lignocaine, when plasma concentrations of lignocaine exceeded 4.7 micrograms ml-1, tracheal irritation elicited only brief apnoea. Other reflex responses were suppressed completely; they recovered gradually with progressive decrease in plasma concentration of lignocaine. The apnoeic reflex was not eliminated at plasma lignocaine concentrations greater than 7.0 micrograms ml-1, whereas the expiration reflex, cough reflex and spasmodic panting were eliminated effectively by plasma concentrations of lignocaine greater than 3.5, 2.8 and 2.2 micrograms ml-1, respectively.