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PubMed2005

Structural characteristics and crystal polymorphism of three local anaesthetic bases crystal polymorphism of local anaesthetic drugs: part VII.

Benzocaine (BZC), butambene (BTN) and isobutambene (BTI) are basic local anaesthetic agents of the ester type, preferentially used for surgery and dental procedures. The compounds, official in the USP (BZC and BTN) and Ph. Eur. (BZC), were each found to exist in two polymorphic crystal forms and their solid state characteristics have been determined by thermomicroscopy, differential scanning calorimetry (DSC), FTIR-, FT-Raman-spectroscopy as well as X-ray powder diffractometry. This work further emphasizes the comparison of solid state characteristics of three compounds with closely related structural features on molecular level, leading to opportunities for the investigation of structure-property relationships. Mod. I0 is the particular thermodynamically stable form at room temperature in all of the three systems. This form is present in commercial products and can be crystallized from solvents at room conditions. Mod. II can be obtained by annealing the supercooled melt or fast cooling of a saturated solution, respectively. The endothermic transformation of mod. II to mod. I0 upon heating confirms that mod. I0 is thermodynamically stable at ambient conditions (heat of transition rule) whereas mod. II is enantiotropically related to mod. I0, i.e. is metastable at temperatures above the transition temperature. The metastable forms show different kinetic stabilities at room temperature.

Anesthetics, Local↗
PubMed2006

Solid-state characterization of non-stoichiometric hydrates of ester-type local anaesthetics. Part XI. Crystal polymorphism of local anaesthetic drugs.

Three structurally closely related local anaesthetic drugs, hydroxyprocaine hydrochloride (4-butylamino-2-hydroxybenzoic acid 2-dimethylaminoethyl ester hydrochloride, HPCHC), tetracaine hydrochloride (4-butylamino-2-hydroxybenzoic acid 2-dimethylaminoethyl ester hydrochloride, TCHC) and hydroxytetracaine hydrochloride (4-butylamino-2-hydroxybenzoic acid 2-dimethylaminoethyl ester hydrochloride, SLCHC) are found to form hydrated crystals. Those were characterized by thermal analysis (hot stage microscopy, differential scanning calorimetry, thermogravimetry), vibrational spectroscopic methods (FTIR-, FT-Raman-spectroscopy), powder X-ray diffractometry, solid-state NMR and water sorption/desorption analysis. The formation and the stability of the hydrated solid phases are evaluated by sorption isotherms derived from different sorption/desorption analytic methods. The three substances investigated show conformational polymorphism with the anhydrated phases including a high temperature form mod. I, which is highly hygroscopic and isostructural with the hydrate. The hydrated form is present in commercial products at various contents. These hemihydrates crystallize from water, whereas the anhydrates crystallize from all other tested organic solvents. Different methods of water sorption/desorption analysis indicate the formation of non-stoichiometric hydrates. Different methods of drying lead to the same results. Solid-state NMR spectra were used to obtain both structural and molecular level mobility information.

Adsorption↗
PubMed1992

Local anesthesia for extracorporeal shock wave lithotripsy: a study comparing eutetic mixture of local anesthetics cream and lidocaine infiltration.

A study of the anesthetic efficacy of a eutetic mixture of local anesthetics (EMLA cream) versus lidocaine infiltration in extracorporeal shock wave lithotripsy (ESWL) was done. A total of 46 patients had 30 gm. of EMLA cream applied to the skin over the kidney and 45 had subcutaneous infiltration anesthesia with 20 ml. 1% lidocaine with epinephrine. All patients received an intravenous dose of morphine just before ESWL. The patients were comparable with regard to age, sex, weight, morphine dosage, number of shock waves given and duration of treatment. Median pain score and the amount of supplementary analgesics were not significantly different between the 2 groups. There were no significant differences between the groups with regard to post-ESWL skin changes. Therefore, EMLA cream can be recommended for ESWL provided it is applied correctly.

Adolescent↗
PubMed2002

Determination of the sensitising activity of the rubber contact sensitisers TMTD, ZDMC, MBT and DEA in a modified local lymph node assay and the effect of sodium dodecyl sulfate pretreatment on local lymph node responses.

A modified local lymph node assay (LLNA) was used to determine the sensitising activity of four chemicals used for the production of natural rubber latex products. Tetramethylthiuramdisulfide (TMTD), 2-mercaptobenzothiazole (MBT) and zincdimethyldithiocarbamate (ZDMC), three moderate human sensitisers, and diethylamine (DEA) a known human sensitiser, were epicutaneously administered on the ear and the proliferating activity in the draining (auricular) lymph node (LN) was determined by ex vivo (3)H-thymidine incorporation. Consistent results were obtained for TMTD and ZDMC with stimulation indices (SI) above 3, identifying these compounds as sensitiser, while for DEA and MBT inconsistent results were obtained. For all parameters determined such as LN weight, LN cell number, cell proliferation per 2 x 10(6) cells, and cell proliferation per LN statistical significant increases were observed. The SI, expressed as cellular proliferation per LN or per animal (left and right LN combined), was the most sensitive parameter with an optimum at day 5 after start of treatment.Furthermore, we investigated whether the use of sodium dodecyl sulfate (SDS) was able to enhance weak responses in the LLNA. SDS treatment with dosages of 10% and higher resulted in a SI above 3, while a dosage of 1% SDS showed no activity. Pretreatment with 1% SDS 1 h before application of the rubber chemicals enhanced the responses to these chemicals consistently, identifying also DEA and MBT as sensitisers. Our results indicate that SDS had synergistic activity on the LN responses of the administered rubber chemicals in the LLNA. For the moderately responding sensitisers TMTD and ZDMC both IFN-gamma and IL-4 production was observed. For the weakly responding sensitisers DEA and MBT both IFN-gamma and IL-4 cytokine production was only observed after pretreatment of the animals with 10% SDS. For 10% and 20% SDS, inducing approximately a SI of 20 in the LLNA, no induction of cytokines was observed.

Allergens↗
PubMed2003

Immediate cortical reorganization after local anesthetic block of the thumb: source localization of somatosensory evoked potentials in human subjects.

Psychophysical observations after anesthesia of the thumb raise the question whether the functional border between the thumb and the index is functionally distinct. We present a source localization study using equivalent current dipole modeling of somatosensory evoked potentials (SEPs) following mechanical air-puff stimulation of the first, second and third digits before and during anesthesia of the thumb. Source reconstruction was based on 96-channel SEP recordings. During anesthesia of the thumb the distance between the cortical representation of the thumb and the second and third digits immediately decreased. This indicates a shift of the cortical representation of the second and third digits towards the deafferented area of the anesthetized thumb. Thus, the present results did not confirm the hypothesis of a functional border of the cortical representation between thumb and index finger in this particular task.

Adult↗
PubMed2001

Isolated late local recurrences with high mitotic count and early local recurrences following breast-conserving therapy are associated with increased risk on distant metastasis.

PURPOSE: Local recurrence (LR) after breast-conserving therapy (BCT) is associated with an increased risk for the development of distant metastasis. We studied risk factors for distant metastasis risk (DMR) and poor prognosis within a group of patients with LR as first event. PATIENTS AND METHODS: From a cohort of 1481 breast carcinomas treated with BCT in the period 1980-1994, a total of 68 pT1-3 N0-1 patients developed LR as first event. We have studied risk factors for the development of distant metastasis within this group of patients with LR. In addition to clinical factors (age at BCT and LR, mode of detection, location of LR, and treatment of LR), the histology slides of the primary and the recurrent tumor were reviewed. Immunohistochemical staining was performed for the following proteins: bcl-2, cyclin D1, E-cadherin, EGF receptor, ER, PR, Ki-67, c-erbB-2/neu, and p53. Statistical analyses were performed using conditional logistic regression. RESULTS: At a median follow-up after LR of 5.6 years, the 5-year DMR was 53%. In univariate analysis, none of the factors of the primary tumor was found to be associated with DMR after LR. Of the recurrent tumor the following factors were found to be risk factors for high DMR after LR: interval between treatment of the primary tumor and LR at 2 years or less (relative risk, 2.38; 95% confidence interval, 1.22-4.76; p = 0.008) and high mitotic count (relative risk, 2.51; 95% confidence interval, 1.03-6.15; p = 0.04). All patients with noninvasive recurrent tumor were alive at the time of analysis. Patients with an interval of greater than 2 years and a recurrent tumor with high mitotic count were found to have an equally poor prognosis compared to patients with LRs detected after a short interval. CONCLUSION: LR after BCT is associated with higher DMR and poor prognosis. Patients with LR within 2 years after BCT are especially at high risk. Late recurrences with high mitotic count have the same poor prognosis as early recurrences. For these patients, systemic treatment at time of the detection of LR should be considered.

Analysis of Variance↗
PubMed2006

Nuclear localization signal receptor affinity correlates with in vivo localization in Saccharomyces cerevisiae.

Nuclear localization signals (NLSs) target proteins into the nucleus through mediating interactions with nuclear import receptors. Here, we perform a quantitative analysis of the correlation between NLS receptor affinity and the steady-state distribution of NLS-bearing cargo proteins between the cytoplasm and the nucleus of live yeast, which reflects the relative import rates of various NLS sequences. We find that there is a complicated, but monotonic quantitative relationship between the affinity of an NLS for the import receptor, importin alpha, and the steady-state accumulation of the cargo in the nucleus. This analysis takes into consideration the impact of protein size. In addition, the hypothetical upper limit to an NLS affinity for the receptors is explored through genetic approaches. Overall, our results indicate that there is a correlation between the binding affinity of an NLS cargo for the NLS receptor, importin alpha, and the import rate for this cargo. This correlation, however, is not maintained for cargoes that bind to the NLS receptor with very weak or very strong affinity.

Active Transport, Cell Nucleus↗
PubMed1995

Local anesthetic effects in the presence of chronic osteomyelitis (necrosis) of the mandible: implications for localizing the etiologic sites of referred trigeminal pain.

The aims of this study were: (1) to demonstrate how reproducible variations in incomplete anesthesia of the inferior alveolar nerve can be used as a guide to locate the etiologic sites of referred trigeminal pain emanating from the mandible; (2) to describe the salient histopathologic features of a lowgrade, nonsuppurative osteomyelitis seen in this patient population. Forty-six patients with idiopathic facial pain were subjected to a specific protocol of local anesthetic injections to sequentially block branches of the mandibular nerve to determine the effects on his/her pain. If this significantly reduced or altered the pain on three separate appointments, then exploratory surgery was conducted near identified zones of unanesthetized gingiva. Blocking (92%), bridging (4%), and divergence (4%) were observed patterns of anesthetic resistance of the mucogingival tissues used to categorize the incomplete anesthesia. A 100% correlation was found between the identified zones of unanesthetized gingiva and the discovery of intramedullary pathology. Medullary fibrosis with ischemic and degenerative changes in the cancellous bone were common findings, along with chronic inflammatory cell infiltrates and clusters of lymphocytes. It is concluded that Ratner's method of diagnostic anesthesia be implemented when searching for occult pain producing pathology of the jaws.

Adult↗
PubMed1999

Enhancement of polylysine-mediated transferrinfection by nuclear localization sequences: polylysine does not function as a nuclear localization sequence.

Polylysine (pLy) has been used successfully as a DNA carrier in receptor-mediated gene transfer, enhancement of transfection having been proposed to be in part through efficient nuclear targeting stemming from the resemblance of pLy to the nuclear localization sequence (NLS) from simian virus SV40 large tumor antigen (T-ag). In this study we test whether pLy carrying covalently attached peptides comprising the T-ag NLS (the pLyP101 derivative) can enhance transferrin-pLy-mediated transfection ("transferrinfection"). Unlike pLy itself or a pLy derivative (pLyP101T) carrying cross-linked T-ag NLS mutant peptides, pLyP101 significantly enhanced transferrinfection of a beta-galactosidase-expressing reporter plasmid. The basis of this was shown to be the ability of the pLyP101-plasmid DNA complex to be recognized with high affinity by the NLS-binding importin subunits, in contrast to pLyP101T- and pLy-plasmid complexes. Confocal laser scanning microscopy was used to determine the nuclear import kinetics of fluorescently labeled pLyP101 and pLyP101T in the presence of complexed plasmid, indicating that pLyP101 and not pLyP101T complexes accumulated rapidly in the nucleus. We conclude that pLy itself does not function as an NLS and that the addition of exogenous NLSs conferring interaction with the cellular nuclear import machinery can increase transferrinfection by enhancing the nuclear targeting of pLy-DNA complexes.

Amino Acid Sequence↗
PubMed1975

Pharmacology of local anaesthetic agents. Pharmacokinetics of local anaesthetic agents.

Information derived from measurements of blood concentrations of local anaesthetics can be extended by the application of pharmacokinetic anaylsis. A better understanding of quantitative aspects of the disposition and absorption of these drugs should assist the anaesthetist in deciding the optimal agent and dosage for regional block techniques.

Absorption↗
PubMed1992

[Local anesthetics. CVII. Local anesthetic effects of phenylcarbamates--the effect of connecting chain modification].

The preceding study of the effect of the branching of the connecting chain by the metoxymethyl-, ethoxymethyl- and propoxymethyl group on the alpha carbon on local anaesthetic activity was a stimulus for the preparation of 16 drugs of the group of 1-ethoxyethoxymethyl-2-(1-pyrrolidinyl-), 2-piperidino- and 2-(1-perhydroazepinyl) ethyl esters of o-, m- and p-alkoxyphenylcarbamic acids. The discontinuation of the substituent on the alpha carbon of the connecting chain by another oxygen atom (introduction of an ethoxyethoxymethyl group) has a positive effect on surface and infiltration anaesthesia. Of the prepared agents, 2-piperidino- and 2-(1-perhydroazepinyl-) derivatives with a hexyl or heptyloxy group in the o-position of the benzene ring were most effective; they exceeded the standards cocaine and procaine more than one hundred times. p-Derivatives were least effective; in some cases their indices of effectiveness did not achieve the effectiveness of the standards in both surface and infiltration anaesthesia under study. Acute toxicity of all drugs lies within the range of the toxicities of the standards.

Anesthetics, Local↗
PubMed2003

Patient satisfaction during the administration of local anesthesia using a computer controlled local anesthetic delivery system.

Patients undergoing a surgical procedure first must be properly anesthetized prior to the procedure to minimize discomfort. The effectiveness of a Computer Controlled Local Anesthetic Delivery System (CCLADS) known as the "wand," was evaluated. Patient anxiety and pain associated with the injection of anesthesia both decreased using this method.

Anesthetics, Local↗
PubMedDate not supplied

Is radiotherapy needed after adequate local excision of localized DCIS?

Despite the fact that mastectomy remains the safest treatment for ductal carcinoma in situ, breast conserving surgery is still a frequent option. Three randomized trials (NSABP B17- EORTC 10853- UK DCIS) have confirmed a statistically significant reduction of LR rate by the addition of a whole breast irradiation at 50 Gy (RT). The rate of LR, both in situ and invasive, has been reduced by 45-55% with RT, e.g. in the NSABP B-17 trial, with a 129-month follow-up, the overall LR rate decreased from 31.7% to 15.7% (p = 0.001). The RT benefit was confirmed in all subgroups of patients, even with a lack of advantage on survival. Two large retrospective studies (in France and California) also confirmed the benefit of RT after lumpectomy, but with small differences in the subgroup with large excision (and margin width > or = 10 mm). On the other hand, invasive LR can give a 15-20% subsequent metastasis rate. Today, the current whole breast RT using megavoltage photons and provisional CT-scan-based dose distribution is resulting in less than 1% of complications. Until now, no studies have clearly identified patients with a sufficiently low LR risk to justify the lack of RT after lumpectomy. Finally, DCIS treatment requires a close multidisciplinary collaboration; moreover surgery and radiotherapy should be used jointly to obtain optimal long-term local control, such as for so many tumors.

Breast Neoplasms↗
PubMed2005

[Five cases of locally advanced rectal cancer or local recurrence performed intra-arterial infusion chemotherapy via the internal iliac artery].

Intra-arterial infusion chemotherapy via the internal iliac artery was performed in 5 patients with locally advanced rectal cancer or recurrent rectal cancer. Arterial infusion chemotherapy was conducted into the internal iliac artery via bilateral femoral artery following a blood flow change with a coil. 5 FU 500 mg and l-leucovorin 125 mg/m2 were injected weekly. An average time of injections or its duration was 40 (17-74) times or 12.8 (5-23) months, respectively. Disappearance or improvement of symptoms was observed in 4 cases. A decrease of tumor size observed by CT was in 2 cases and a decrease of blood CEA level was in 3 cases. As for the complication of arterial infusion chemotherapy, dermatopathy was found in all of the cases, and sensory disturbance of lower extremities was in 3 cases, infection was in 2 cases and catheter obstruction was in 2 cases. A decrease of dosage or abundance of continuation was done during the course due to complications. Two patients with primary cancer died 1-3 years after the treatment, and 2 patients with recurrence died 7 months to 1 year after the treatment. One patient with primary cancer is continuing the treatment for the last 2 years though multiple metastatic diseases have been confirmed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Pleural permeability to local anesthetics--the influence of concentration, pH, and local anesthetic combinations.

The transpleural passage of lidocaine, bupivacaine-lidocaine mixtures, and of bupivacaine, with and without epinephrine, was studied in vitro using pleural from piglets. Our objective was to ascertain whether changing physical parameters of local anesthetics such as pH, concentration, and addition of epinephrine might influence the transfer. Rate of transfer is linearly related to concentration at a given pH, but raising the pH increases the rate for bupivacaine. No change in rate was detectable when the pH of lidocaine was increased or in the rate of transfer of bupivacaine when bupivacaine and lidocaine were mixed. The mixture did however facilitate lidocaine flux. Epinephrine [1:200,000] lowers the pH of the solution dramatically but does not statistically change the transpleural passage of bupivacaine. We conclude that the onset of interpleural blockade may be shortened by using more concentrated solutions of bupivacaine whose pH have been modified by the addition of alkali, by using the higher concentrations of lidocaine or by mixing lidocaine with bupivacaine.

Anesthetics, Local↗
PubMed1988

Laser-induced pain for evaluation of local analgesia: a comparison of topical application (EMLA) and local injection (lidocaine).

High-energy lasers are suitable for experimental pain stimulation because they selectively activate the polymodal nociceptors. Argon laser light penetrates deep into the skin and makes this laser type preferable for simulating pain arising from surgical skin incisions. Short argon laser pulses were applied to the skin and three parameters were quantified before and during analgesia; sensory threshold, pain threshold, and the pain-related cortical response (latency and amplitude). Determination of sensory and pain thresholds made it possible to distinguish between two levels of analgesia; the pain block, where no pain was felt but other sensations were still perceived; and total sensory block, where the laser stimulus elicited no sensations of any type. The analgetic effects of cutaneous injections of lidocaine and topical application of EMLA (eutectic mixture of local anesthetics) cream were evaluated and compared by means of the introduced parameters. Lidocaine produced total sensory block almost immediately after injection, which was associated with the absence of cortical response to cutaneous laser stimulation. When the EMLA cream was applied for 15 minutes, both sensory and pain thresholds increased. During the next 30 minutes after removal of the cream, the thresholds increased further. The increase in analgetic effect after removal of the cream was studied using different times (15, 30, 60, 80, 100, and 120 minutes) for topical EMLA cream application. Total sensory block was reached 20 minutes after removal of application for 80 minutes or immediately after removal of the cream after it was applied for 100 or 120 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1992

Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis. Implications for local actions of tumor necrosis factor alpha.

OBJECTIVE: We have previously described the location of tumor necrosis factor alpha (TNF alpha)-producing cells in synovial tissue and cartilage-pannus junction in rheumatoid arthritis (RA). To further understand the local actions of TNF alpha, we investigated the expression of TNF receptors (TNF-R) on cells in the same compartments in patients with RA. METHODS: The expression of both p55 TNF-R and p75 TNF-R was determined using alkaline phosphatase-conjugated mouse anti-alkaline phosphatase (APAAP) and double immunofluorescence staining techniques with monoclonal antibodies. RESULTS: In RA synovial membrane, both p55 TNF-R and p75 TNF-R were detectable in up to 90% of the cells in the lining layer, and were demonstrated on cells in deeper layers of the membrane, including vascular endothelial cells. Cells in lymphoid aggregates expressed both TNF-R, but with a predominant expression of p75 receptor. At the cartilage-pannus junction, the majority of pannus cells, especially those invading cartilage, expressed both the p55 and the p75 TNF-R. Sequential section and double immunofluorescence staining showed that the TNF-R-expressing cells were in the vicinity of TNF alpha-containing cells, and some TNF alpha-containing cells also expressed TNF-R. TNF-R-expressing cells were also detected in osteoarthritic and normal synovial tissue, but in smaller numbers and at a lower intensity. CONCLUSION: These results provide histologic evidence that both p55 TNF-R and p75 TNF-R are expressed by a variety of cell types in RA synovial tissue, reflecting the fact that a wide range of cells are potential targets for TNF alpha in this tissue. This study further supports the hypothesis that TNF alpha plays a major role in the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed1989

High field localized proton spectroscopy in small volumes: greatly improved localization and shimming using shielded strong gradients.

The availability of shielded gradients facilitates accurate single-voxel spectroscopy. Exact localization (90-99%) of volumes as small as 2 x 2 x 2 mm is demonstrated using a modified stimulated echo sequence. Strong gradient pulses (up to 200 mT/m) are employed to clear the stimulated echo of unwanted magnetization, enabling superior (single-scan) shimming of the selected volume. In vivo and in vitro proton NMR results at 4.7 T are presented.

Animals↗