Ketamine and its isomers have equipotent relaxant effects on tracheal smooth muscle contracted by tachykinins

Recent studies indicate that not only inflammatory cells but also neural mechanisms by which tachykinins such as substance P (SP) and neurokinin A (NKA) are released from vagal afferent C-fiber contribute to asthma. Although ketamine (K) has been used in the anesthetic management of asthmatic patients, the mechanism by which K relaxes the airway smooth muscle is still uncertain, and no information exists on any differential effect of K and its isomers. We determined the spasmolytic effect of racemic [R(±)]K and its isomers S(+) K and R(−) K on SP and NKA-induced contraction of tracheal smooth muscle in guinea pigs. Strips of guinea pig trachea were mounted in an organ bath filled with Tyrode's solution at 37°C bubbled with 95% O₂/5% CO₂. Strip tension was measured isometrically with a force displacement transducer. Strip contraction was elicited with SP 10⁻⁶ M or NKA 5×10⁻⁷ M.R(±), R(−), or S(+) K (4.5−18.0×10⁻⁴M) was cumulatively administered into the bath. The calculated ED₅₀ values (the concentration that relaxed the contraction by 50%) of R(±), R(−) and S(+) K were 7.6±0.5, 7.8±0.6, and 7.6±0.5 (10⁻⁴M), respectively, when the contraction was elicited with SP, and 8.0±1.0, 8.2±1.2, and 7.9±1.3 (10⁻⁴M), respectively, when NKA was used. We concluded that K and its isomers have equipotent spasmolytic effects on airway smooth muscle precontracted with tachykinins.     

Preparation of drug: hydroxypropylcyclodextrin complexes by a method using ethanol or aqueous ammonium hydroxide as co-solubilizers

The dissolution of lipophilic drugs in aqueous solutions of hydroxypropylcyclodextrins can be accelerated by the addition of co-solubilizers such as ethanol or ammonia. These co-solubilizers can be removed later, together with water, by evaporation or freeze-drying, leaving drug: hydroxypropylcyclodextrin complexes. The co-solubilizer method was used successfully with steroid drugs (5-anrostene-3β,17β-diol, 4-androstene-3,17-dione, dehydroepiandrosterone, dexamethasone, 5-dihydrostestosterone, 6-methylprednisolone and testosterone), peptides (gramicidin S) and a macrocylic antibiotic (amphotericin B). The complexes prepared in this manner were amorphous and of satisfactory stability and solubility.     

Two cases of nonrecurrent inferior laryngeal nerve--different branching levels from vagus nerve

We observed two cases of nonrecurrent inferior laryngeal nerve (NRILN). Case 1, a 71 year old man was diagnosed as having papillary carcinoma. NRILN was found during his operation. It directly branched from the right cervical trunk of the vagus nerve at the level of the cricoid cartilage and then entered the larynx after running behind the thyroid gland. Case 2, a 64 year old woman was diagnosed as having primary hyperparathyroidism. In this patient, the NRILN branched at the level of the inferior pole of the thyroid gland, rose up beside the tracheal wall and entered the larynx. In both patients, preoperative CT scan and postoperative MR angiography revealed the aberrant right subclavian artery. A postoperative barium swallow test showed the compression of the esophagus by this anomalous artery in case 1. Although it is possible to predict the presence of NRILN by preoperative imaging tests, the branching level from the vagus nerve is unpredictable. Surgery must be performed with this point in mind, if the presence of NRILN is suspected.     

The relationship between salivary biomarkers and state-trait anxiety inventory score under mental arithmetic stress: a pilot study

Measurement of stress hormones is a common objective method for assessment of mental stress. However, the stress of blood sampling alone may also increase stress hormone levels. In the present study, we sampled salivary biomarkers from healthy volunteers under noninvasive conditions and determined their efficacy to assess mental stress. Specifically, we examined the relationship between State Anxiety Inventory score (STAI-s) in subjects exposed to arithmetic stress and salivary chromogranin-A, alpha-amylase, or cortisol. The STAI-s was significantly correlated to salivary alpha-amylase (r = 0.589; P < 0.01) but not to salivary chromogranin-A or cortisol. Therefore, salivary alpha-amylase is a useful indicator of psychosocial stress.     

In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone

The in vitro and in vivo activity of T-3912, a novel non-fluorinated topical quinolone, was compared with that of nadifloxacin, ofloxacin, levofloxacin, clindamycin, erythromycin and gentamicin. The in vitro activity of T-3912 against methicillin-susceptible Staphylococcus aureus, ofloxacin-resistant and methicillin-resistant S. aureus, Staphylococcus epidermidis, ofloxacin-resistant S. epidermidis, penicillin-resistant Streptococcus pneumoniae and Propionibacterium acnes was four-fold to 16 000-fold greater than that of other agents at the MIC90 for the clinical isolates. The activity of T-3912 was not influenced by grlA mutation in S. aureus, and the degree of MIC increase of T-3912 for grlA-gyrA double and triple mutants was lowest among the quinolones tested (nadifloxacin, levofloxacin and ofloxacin). The inhibitory activity of T-3912 was compared with other quinolones for DNA gyrase and topoisomerase IV of S. aureus SA113. T-3912 showed the greatest inhibitory activity for both enzymes among the quinolones tested. The isolation frequency of spontaneous mutants resistant to T-3912 was < 1.7 x 10(-9) and < 2.0 x 10(-9) for S. aureus SA113 and P. acnes JCM 6425, respectively. Furthermore, resistance to T-3912 could not be clearly detected in the 28th transfer by the serial passage method. T-3912 exhibited more potent bactericidal activity against S. aureus and P. acnes than nadifloxacin and clindamycin in a short time period. T-3912 in a 1% gel formulation showed good therapeutic activity against a burn infection model caused by S. aureus SA113, P. acnes JCM6425 and multidrug-resistant S. aureus F-2161. These results indicate that T-3912 is potentially a useful quinolone for the treatment of skin and soft-tissue infections and that its potent bactericidal activity might be able to shorten the treatment period.     

Involvement of calmodulin inhibition in analgesia induced with low doses of intrathecal trifluoperazine

We examined which of the known properties of trifluoperazine, including calmodulin inhibition, are involved in its analgesic effect. Furthermore, we tried to find any possible interaction between opioidergic system and calmodulin inhibition-induced analgesia. Intrathecal trifluoperazine (1, 10, 100 microg) showed a biphasic effect in the formalin test; i.e., analgesia at relatively low doses (1, 10 microg) and hyperalgesia at a high dose (100 microg). No analgesic effects were observed after intrathecal injection of sulpiride (1, 10, 100 microg), atropine (0.1, 1, 10 microg), phentolamine (0.1, 1, 10 microg) and brompheniramine (0.1, 1, 10 microg). Meanwhile, intrathecal calmidazolium (10, 50, 250 microg) induced a dose-dependent analgesia. Histamine (1 microg), physostigmine (1 microg), bromocriptine (1 microg) and norepinephrine (1 microg) did not affect trifluoperazine-induced analgesia. Calcium (20 microg) attenuated the antinociceptive effect of trifluoperazine and inhibited the analgesic effect of calmidazolium. Finally, naloxone (2 mg/kg) decreased trifluoperazine-induced antinociception but did not have any effects on calmidazolium-induced analgesia. We concluded that calmodulin inhibition may be involved in the analgesia produced by trifluoperazine. With increasing doses of trifluoperazine, the algesic effect seems to overcome the analgesic effect. It is also suggested that the opioidergic system does not interact with calmodulin inhibition-induced analgesia even though this system has a possible role in trifluoperazine-induced analgesia.     

Design and Evaluation of an Osmotic Pump Tablet (OPT) for Chlorpromazine Using (SBE)7m-β-CD

Purpose. The purpose of this study was to develop a controlled-porosity osmotic pump tablet (OPT) which exhibits pH-independent release profiles for a basic drug using a sulfobutyl ether--cyclodextrin, (SBE)_7m--CD, which acts as both a solubilizer and as an osmotic agent. Methods. Chlorpromazine free base (CLP) was chosen as a model drug for this study. The release of CLP from osmotic pump tablets was studied in vitro. In vivo absorption of CLP from the OPT was evaluated in male beagle dogs. Results. The CLP release profile from an OPT prepared from a core tablet composed of a 1:10 molar ratio of CLP to (SBE)_7m--CD was pH-independent, and was controlled by modulating the membrane thickness of the OPT. Another cyclodextrin, hydroxypropyl--cyclodextrin (HP--CD), and a sugar mixture of lactose and fructose resulted in pH-dependent release at the same molar ratio. An in vivo absorption study in dogs with an OPT containing (SBE)_7m--CD correlated very well with the in vitro release profiles using the Japanese Pharmacopoeia dissolution method. Conclusions. In addition to serving as a solubilizer and osmotic agent, (SBE)_7m--CD can also serve as the controlling agent for pH independent release of CLP from OPTs. This system successfully modified the in vivo input rate of CLP without compromising oral bioavailability.     

Design and Evaluation of an Osmotic Pump Tablet (OPT) for Prednisolone,a Poorly Water Soluble Drug,Using (SBE)7m-β-CD

Purpose. The purpose of this study was to develop a controlled-porosity osmotic pump tablet (OPT) for poorly water soluble drugs using a sulfobutyl ether--cyclodextrin, (SBE)_7m--CD or Captisol, which acted as both a solubilizer and as an osmotic agent. Methods. Prednisolone (PDL) was chosen as a model drug for this study. The release of PDL from osmotic pump devices and tablets was studied. In vivo absorption of PDL from OPT was evaluated in male beagle dogs. Results. PDL release from the osmotic pump tablet with (SBE)_7m--CD was complete. Another cyclodextrin, hydroxypropyl--cyclodextrin (HP--CD), and a sugar mixture of lactose and fructose resulted in incomplete release. Although PDL release from the OPT with (SBE)_7m--CD and the sugar formulation displayed mainly zero-order release characteristics, the tablet utilizing HP--CD showed apparent first-order release characteristics. An in vivo absorption study in dogs correlated very well with the in vitro release profiles using the Japanese Pharmacopoeia dissolution method. Conclusions. The present results confirm that (SBE)_7m--CD can serve as both the solubilizer and the osmotic agent for OPT of PDL, and modify the input rate of PDL without compromising oral bioavailability.