Direct conversion from tramadol to tapentadol prolonged release for moderate to severe, chronic malignant tumour-related pain.

BACKGROUND: A recent randomized-withdrawal, active- and placebo-controlled, double-blind phase 3 study showed that tapentadol prolonged release (PR) was effective and well tolerated for managing moderate to severe, chronic malignant tumour-related pain in patients who were opioid naive or dissatisfied with current treatment (Pain Physician, 2014, 17, 329-343). This post hoc, subgroup analysis evaluated the efficacy and tolerability of tapentadol PR in patients who previously received and were dissatisfied with tramadol for any reason and who had a pain intensity ≥5 (11-point numerical rating scale) before converting directly to tapentadol PR. METHODS: In the original study, eligible patients had been randomized (2:1) and titrated to their optimal dose of tapentadol PR (100-250 mg bid) or morphine sulphate-controlled release (40-100 mg bid) over 2 weeks. The present report focuses on results during the titration period for a subgroup of patients randomized to tapentadol PR after having been on tramadol treatment prior to randomization in the study (n = 129). Results for this subgroup are compared with results for all 338 patients who received tapentadol PR during titration (overall tapentadol PR group). RESULTS: Responder rates (responders: completed titration, mean pain intensity <5 [0-10 scale] and ≤20 mg/day rescue medication during last 3 days) were slightly better for the tramadol/tapentadol PR subgroup (69.8% [90/129]) vs. the overall tapentadol PR group (63.9% [214/335]). Tolerability profiles were comparable for both groups. CONCLUSIONS: Results of this subgroup analysis indicate that patients with cancer pain could safely switch from prior treatment with the weak centrally acting analgesic tramadol directly to the strong centrally acting analgesic tapentadol PR, for an improved analgesic therapy for severe pain. WHAT DOES THIS STUDY ADD?: Results of this post hoc analysis show that patients who had received prior tramadol therapy could switch directly to tapentadol PR, with the majority (˜70%) experiencing improved efficacy.

Acute postoperative pain relief with immediate-release tapentadol: randomized, double-blind, placebo-controlled study conducted in South Korea.

OBJECTIVE: To broaden the ethnic groups in which tapentadol IR is evaluated for treating acute postoperative pain to include Asians. METHODS: In this phase 3, multicenter, double-blind, randomized study, 352 Korean adults with moderate-to-severe pain following hallux valgus surgery received tapentadol IR 50 or 75 mg or placebo orally every 4-6 hours for 72 hours. Patients requesting other (rescue) analgesics during this period were discontinued for lack of efficacy. The primary endpoint, sum of pain intensity difference (SPID) over 48 hours, was evaluated based on the difference between tapentadol IR and placebo in least squares (LS) mean change from baseline using analysis of covariance (ANCOVA). Secondary endpoints included the time to first rescue medication use and the distribution of responder rates. RESULTS: A treatment effect, favoring tapentadol IR, was observed for SPID48 (p < 0.001 for both doses vs. placebo, ANCOVA). The between-group difference (vs. placebo) in LS means of SPID48 was 76.4 (95% CI: 51.0, 101.7) for tapentadol IR 50 mg and 90.6 (95% CI: 65.1, 116.1) for tapentadol IR 75 mg. Time to first rescue medication use was delayed for tapentadol IR (p < 0.001 for both doses vs. placebo; log-rank test). The distribution of responders at 12, 24, 48, and 72 hours favored tapentadol IR (p ≤ 0.001 for both doses vs. placebo; Cochran-Mantel-Haenszel test). Dizziness, nausea, and vomiting were each reported in ≥ 10% tapentadol-treated patients and at an incidence ≥ 2-fold higher vs. placebo. The study findings may be limited by study drug dosing every 4 to 6 hours and frequent monitoring during treatment, neither of which mimic pain treatment in clinical practice. However, any potential bias based on this systematic monitoring of patients would be mitigated by the randomized, double-blind nature of the study, with all treatment groups similarly affected by such biases, if any. CONCLUSIONS: Tapentadol IR reduced acute pain intensity, significantly more than placebo, after orthopedic surgery in Korean patients. CLINICAL TRIAL REGISTRATION: NCT01516008.

Dosimetric calculations for uranium miners for epidemiological studies.

Epidemiological studies on uranium miners are being carried out to quantify the risk of cancer based on organ dose calculations. Mathematical models have been applied to calculate the annual absorbed doses to regions of the lung, red bone marrow, liver, kidney and stomach for each individual miner arising from exposure to radon gas, radon progeny and long-lived radionuclides (LLR) present in the uranium ore dust and to external gamma radiation. The methodology and dosimetric models used to calculate these organ doses are described and the resulting doses for unit exposure to each source (radon gas, radon progeny and LLR) are presented. The results of dosimetric calculations for a typical German miner are also given. For this miner, the absorbed dose to the central regions of the lung is dominated by the dose arising from exposure to radon progeny, whereas the absorbed dose to the red bone marrow is dominated by the external gamma dose. The uncertainties in the absorbed dose to regions of the lung arising from unit exposure to radon progeny are also discussed. These dose estimates are being used in epidemiological studies of cancer in uranium miners.

Is radiation protection for the unborn child guaranteed by radiation protection for female workers?

ICRP Publication 88 recommends doses to the embryo and fetus from intakes of radionuclides by the mother for various intake scenarios. Mainly by answering the question 'Is radiation protection for the unborn child guaranteed by radiation protection for female workers?' it has been assessed if the intake scenarios given in ICRP Publication 88 are adequate for radiation protection purposes. This is generally the case, but the consideration of an additional chronic intake scenario for early pregnancy would be helpful. It is demonstrated that following chronic intake by inhalation, for most radionuclides radiation protection for (female) workers is also adequate for protection of the unborn child, considered as a member of the public. However, there are a number of radionuclides for which possible intakes in routine operations should be more restricted (up to 1% of the annual limits on intake for workers in the case of nickel isotopes) to ensure radiation protection for the unborn child.

Determination of dose coefficients and urinary excretion function for inhalation of carbon-14-labelled benzene.

Based on existing pharmacokinetic models for benzene, the distribution and retention of activity after inhalation of 14C-labelled benzene in humans were studied. Six different benzene concentrations from 0.1 to 10,000 ppm (corresponding to activity concentrations between 9.6 x 10(6) and 9.6 x 10(11) Bq m(-3)) and five exposure times from 0.1 to 1000 min were considered. The cumulated activities in the different organs and tissues and the urinary excretion rates were observed to depend non-linearly on the activity intake. The fraction of activity removed via urine varies between 52 and 10% of the intake. Nevertheless, for times that are long compared to the exposure duration the urinary excretion rate is determined by the activity clearance from adipose tissue and thus decreases at a constant rate. This decrease is common for all exposure conditions examined and thus allowed determining a mean urinary excretion rate and corresponding dose coefficients for committed equivalent doses as well as for the effective dose. The uncertainty of the dose coefficients is estimated to be about 50% for the exposure range covered. A 14-day interval for the incorporation monitoring by urine activity counting seems to be reasonable.

Studies on an immunologically induced synovitis model in pigs and sheep.

Chronic synovitis was induced in seven sheep and nine pigs to investigate the potential applicability of laser treatment in arthroscopic synovectomy. Systemic sensitization was accomplished using chicken egg or turkey egg albumin antigens with Freund's incomplete adjuvant, enriched with killed and dried Mycobacterium tuberculosis. Ten days after the second immunizing dose, skin sensitization testing was undertaken. After a satisfactory systemic reaction had been observed, the respective antigen was injected once or twice into the left knee of each animal at 2-week intervals. After chicken egg albumin sensitization at varying systemic immunization and joint injection doses, sheep (five of five) showed neither strong morphologic nor continuous synovitis, despite a positive systemic reaction. In pigs (three of three) the inflammatory signs also were unsatisfactory for the manifestation and characterization of a synovitis model. In contrast, the application of turkey egg albumin to pigs (six of six) during the 4-month study provided a persistent, clearly manifested synovitis that developed visible villi formation and an amber to gray synovial fluid and microscopically showed follicular aggregations of lymphocytes and plasma cells. In similarly immunized sheep (two of two), only a light synovitis developed with occasional perivascular inflammatory foci.

Onset and duration of action of levocabastine nasal spray in atopic patients under nasal challenge conditions.

BACKGROUND: Although prior studies have documented the rapid onset of action of topical intranasal levocabastine (LEV), little is known about its duration of action under nasal challenge conditions. OBJECTIVES: We sought to assess the onset and duration of action of escalating doses of LEV nasal spray by using a nasal allergen challenge (NAC) model. METHODS: Eighteen asymptomatic subjects with histories of seasonal allergic rhinitis were enrolled into a randomized, single-blind, placebo-controlled, dose-ranging crossover study. Each patient was randomly assigned to receive single doses of placebo and intranasal LEV 0.1, 0.2, and 0.4 mg during 2 parts of the study. In part 1 (onset of action), NAC consisted of a single dose of allergen administered 5 minutes after study drug treatment. In part 2 (duration of action), NAC consisted of increasing doses of allergen administered 0.5, 6, 12, and 24 hours on separate days after study drug treatment. Nasal symptom scores (NSSs) and nasal peak expiratory flow rates were measured after NAC in both phases of the study. Blood samples for plasma LEV concentrations were drawn after each NAC. RESULTS: In part 1, NSSs were significantly lower after the administration of LEV 0.1, 0.2, and 0.4 mg compared with placebo (P <.05). In part 2, NSSs were significantly lower after LEV doses of 0.2 and 0.4 mg compared with placebo at 0.5, 6, 12, and 24 hours after treatment (P <.05). The mean provocative dose of allergen required to elicit a positive nasal reaction was increased after LEV doses of 0.2 and 0.4 mg at 0.5, 6, and 12 hours after treatment. Nasal peak expiratory flow rates demonstrated no significant differences between LEV and placebo for any doses at any time points. Mean plasma LEV concentrations were low (range, 0 to 3. 7 ng/mL) after all doses and did not correlate with drug efficacy. CONCLUSIONS: Single intranasal LEV doses of 0.1, 0.2, and 0.4 mg significantly reduced the severity of the immediate nasal response to allergen when administered 5 minutes before NAC. This protective effect against NAC continued to be present 24 hours after administration of LEV doses of 0.2 and 0.4 mg. Efficacy in blocking the reaction to NAC did not correlate with plasma LEV levels, suggesting that the inhibitory effect was due largely to topical rather than systemic effects.

Efficacy and safety of levocabastine nasal spray for seasonal allergic rhinitis.

This multicenter, double-blind, placebo-controlled trial evaluated the efficacy and safety of levocabastine nasal spray, a potent and selective H1-receptor antagonist, in the control of histamine-mediated symptoms of seasonal allergic rhinitis. Adults with > or = 2 year history of allergic rhinitis due to Mountain Cedar were randomized to treatment with levocabastine nasal spray (0.2 mg twice daily) or placebo for 28 days during the 1994-1995 Mountain Cedar allergy season. Patients assessed the severity of their rhinitis symptoms on a four-point scale twice daily. At the end of the trial, patients also performed a global evaluation of treatment efficacy on a five-point scale. Overall for the 4-week treatment period, levocabastine nasal spray significantly reduced major nasal (runny nose and sneezing) and primary rhinitis (runny nose, sneezing, and itchy/gritty eyes) symptoms compared with placebo on both repeated measures (p = 0.023; p = 0.01) and ANOVA (p = 0.003; p < 0.001) analyses. Global evaluations of treatment efficacy at the end of the trial significantly favored levocabastine over placebo (p = 0.002). Overall, the incidence of adverse events was similar for both treatment groups. In general, most adverse events were mild in intensity, with sinusitis (17% each group), headache (17% placebo, 14% levocabastine), and rhinitis (8% placebo, 2% levocabastine) most commonly reported. Levocabastine nasal spray 0.2 mg twice daily was significantly more effective than placebo in the relief of histamine-mediated symptoms in patients with seasonal allergic rhinitis and was well tolerated over the 28-day treatment period.

[Holmium laser versus mechanical cartilage resection. Comparative studies in the rabbit arthrosis model]. / Holmiumlaser versus mechanische Knorpelabtragung. Vergleichende Untersuchungen am Arthrosemodell bei Kaninchen.

The aim of this work was to investigate and evaluate the tissue reactions after sham operation and after mechanical and holmium laser chondral debridement in a rabbit model at different postoperative intervals. In 27 rabbits an arthrosis was induced by implantation of a piece of polyethylene sheeting in one knee joint. After 5 months, distinct arthritic changes had developed. Nine animals each were randomized for sham operation, mechanical debridement, and holmium laser chondral debridement. At 1 day, 1 month, and 3 months postoperatively, three animals in each group were sacrificed and their joints examined grossly and microscopically. At 3 months after mechanical debridement the articular surface was relatively smooth, and tears and defects were filled with fibrous repair tissue. After holmium laser debridement chondral necroses were regularly found, occasionally with damage to the subchondral bone and distinct inflammation in the marrow space. The articular surface remained rough and uneven. These preliminary results suggest that use of the holmium laser is not superior to mechanical methods for remodelling and smoothing of fairly large chondral areas.

X-ray induced DNA double-strand breakage and rejoining in a radiosensitive human renal carcinoma cell line estimated by CHEF electrophoresis.

Cell intrinsic radiosensitivity is of great importance in radiation therapy, but its molecular basis is still uncertain. Since DNA double strand breakage is considered to be the most important lesion related to cell death induced by ionizing radiation, the relationship between DNA double-strand breakage, repair and cell survival was investigated in three cell lines: Chinese hamster cell (CHO-K1), human fibroblast and human renal carcinoma (Tu 25). The D0 values after X-irradiation were 1.73, 1.23, and 0.89 Gy, respectively, showing that Tu 25 was the most sensitive among them. DNA double-strand breaks were measured by CHEF electrophoresis, the initial yield of double-strand break per dose in the three cell lines was almost the same, and no correlation to cell survival was found. However, the rejoining capacity for DNA double-strand break differed. After a dose of 20 Gy, the repair rate was markedly lower in Tu 25, with a half repair time of 40 min, as compared with the other two cell lines with half repair times of 15 min. The results strongly supported the correlation between the repair capacity for DNA double-strand break and cell survival. It was concluded that DNA repair capacity is one of the determinants of cell radiosensitivity. Estimation of DNA double-strand break rejoining by CHEF was suggested as a predictive assay for radiosensitivity of human tumor cells.

[Potentialities and limitations of combined radiotherapy-surgical treatment of large orofacial T3/T4 tumors]. / Möglichkeiten und Grenzen der kombiniert radiotherapeutisch-chirurgischen Behandlung grosser orofazialer T3-/T4-Tumoren.

The possibilities, limits and good cosmetic and functional results of combined radiotherapy-surgical treatment of large orofacial tumors (T3) are prescribed. The pre- and postoperative split radiotherapy with operation in between is favoured. The radical en-bloc-resection with radical neck dissection is the surgical therapy of choice. The defects have been reconstructed with osteomusculocutaneous flaps.

[Comparative experimental studies of mechanical and holmium laser synovectomy]. / Vergleichende experimentelle Untersuchungen zur mechanischen und Holmiumlaser-Synovektomie.

The goal of this study was to evaluate tissue reactions in rabbit knees following laser synovectomy using a holmium:YAG laser (wavelength: 2.1 microns) and to compare these results with those found after conventional mechanical abrasion treatment. Chronic arthritis was immunologically induced in one knee joint each of 48 rabbits. Twelve served as controls, 12 were sham-operated, 12 were exposed to laser radiation, and 12 others were treated according to conventional methods. In the laser group, a pulse length of 1 ms at a repetition rate of 3 Hz resulted in a pulse energy of 600 mJ. After periods of 1 day, 1 week and 1 and 3 months, respectively, three animals from each group were sacrificed and the synovialis was examined macroscopically and histologically using light and electron microscopy. Edema, acute inflammation, and coagulation necrosis occurred immediately following laser therapy. After 1 week, the synovial layer showed slight fibrosis, which was comparable to that found in the controls. One month later the surface appeared to be smooth. The mechanical abrasion caused hemorrhage and necrosis. Fibrosis was pronounced in all capsular layers, and after 3 months the surface appeared coarse and villous in this group. Based on these preliminary findings, holmium-laser synovectomy may offer an alternative to existing therapeutic techniques in the treatment of rheumatoid arthritis. The arthroscopic approach could prevent additional capsular fibrosis associated with mechanical irritation.

[The prevention of mucosal lesions during oropharyngeal irradiation with a dental-filling shield]. / Prävention lokaler Schleimhautläsionen während Oropharynx-Bestrahlung durch einen Plombenschutz.

In patients with metallic dental fillings radiation therapy to the oral cavity can cause mucous membrane lesions, which are more severe than expected. They appear as circumscribed erosions, opposite to metallic fillings and are caused by an increase in radiation dose through secondary radiation due to the higher density and atomic number of the filling material. This dose increase can be directly measured with 0.1 mm thin sheets of graphite-loaded TLD's (LiF, Vinten). For Co-60 gamma rays a commercial amalgam filling caused a dose increase by a factor of 1.7. The half value layer for this additional radiation was measured to be approximately 0.4 mm tissue. In order to avoid painful mucous membrane ulcerations which are even more a problem if hyperfractionated treatment schedules are used, we constructed individual dental shields for each patient. As shielding material we used a dental impression material (Optosil P+1 Bayer). This method was tested in 35 patients, in all of them circumscribed mucous membrane ulcerations could be avoided. The method proved to be fast and simple and was very well tolerated by all patients.

[The value of transrectal sonography in assessing radiogenic rectal changes]. / Wertigkeit der Transrektalsonographie in der Erfassung radiogener Rektumveränderungen.

The clinical value of TRS in diagnosis and staging of radiogenic rectal disorders is discussed. TRS was performed on 120 patients with tumours of lower pelvis who were treated by radiotherapy. They were divided in this trial into 2 groups. Group I (n = 113, with a mean interval to radiotherapy of 2 years) including patients who were under a routine control. Group II (n = 7, with a mean interval to radiotherapy of 13 years) including patients with strong local pain of the radiotherapy zone. The sonographic changes were divided into 4 grades (0-III) and verified histologically in group II patients by means of biopsy. A control group (n = 35) was also examined by TRS. The patients of this group were not treated radiotherapeutically. We concluded in our study that TRS in radiogenic rectal disorders, give us a very precise grading of the tumours which in turn, is of great importance in the further therapeutic procedure and in the evaluation of tumour recidives and second malignomas of the rectal wall.

[Therapy monitoring and after care of irradiated anorectal cancer using transrectal sonography]. / Therapie-Monitoring und Nachsorge bestrahlter anorektaler Karzinome mittels Transrektalsonographie.

Pretherapeutic staging before radiotherapy and peri- and posttherapeutic endosonographic screening was carried out on 33 patients with anorectal carcinoma. The results showed the transrectal endosonography to be essential for staging and for the differential diagnosis of tumor recurrence/post irradiation changes during follow up. The sonomorphological criteria of tumor recurrences and post irradiation bowel wall changes are discussed.

[Oxygen consumption during photodynamic therapy in vitro]. / Sauerstoffverbrauch bei photodynamischer Therapie in vitro.

The consumption of dissolved molecular oxygen was measured during photodynamic therapy in vitro. Aqueous solutions of hematoporphyrin derivative (HpD) containing different concentrations of serum or numbers of cells were prepared. Decrease in oxygen in the solution and cell suspensions was monitored during light-irradiation (at a wavelength of 610 to 640 nm). The rate of oxygen consumption increased with increasing concentrations of HpD, serum levels or numbers of cells. Upon repeated irradiation of the same solutions (after restitution of the initial pO2 of 100 mm Hg), the rate of oxygen consumption decreased indicating a disaggregation process of HpD. The rate of oxygen content of the solutions decreased independently of the actual oxygen partial pressure. Even at a low pO2 below 10 mm Hg, oxygen consumption was unimpeded until the solutions were free of oxygen. No O2-consumption was noted in aqueous solutions of HpD (up to 40 g/ml) without serum or cells during irradiation.

A new spacing material for interstitial implantation of radioactive seeds.

Poly-p-dioxanon sutures (PDS) have been common in surgery as an absorbable material for years. After hardening by a particular procedure we use PDS pins as spacer material in interstitial I-125 implantations. The advantages of PDS are the mechanical qualities in contrast to catgut which causes hazards because of its soft consistency. PDS supports the efforts in optimization of seed distribution and dose application in interstitial radiotherapy.