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The pharmacological profile of ASP2205 fumarate (ASP2205), a novel 5-HT2Creceptor agonist, was evaluated in vitroand in vivo. ASP2205 showed potent and selective agonistic activity for the human 5-HT2Creceptor, with an EC50of 0.85 nM in the intracellular Ca2+mobilization assay. Rat 5-HT2Creceptor was also activated by ASP2205 with an EC50of 2.5 nM. Intraduodenal administration (i.d.) of ASP2205 (0.1–1 mg/kg) significantly elevated the leak point pressure (LPP) in anesthetized rats in a dose-dependent manner. This ASP2205 (0.3 mg/kg i.d.)-induced LPP elevation was inhibited by SB242084 (0.3 mg/kg i.v.), a selective 5-HT2Creceptor antagonist. Urethral closure responses induced by intravesical pressure loading in rats were enhanced by ASP2205 (0.3 mg/kg i.v.), which was abolished by pretreatment with SB242084 (0.3 mg/kg i.v.) and bilateral transection of the pudendal nerve. In contrast, ASP2205 (0.3 mg/kg i.v.) did not change the resting urethral pressure in rats. These results indicate that ASP2205 can enhance the pudendal nerve-mediated urethral closure reflex via the 5-HT2Creceptor, resulting in the prevention of involuntary urine loss.

The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib, in a real-world clinical setting.

Studying membrane protein function using Xenopus laevis oocytes has been proven to be a successful toolsince its introduction more than three decades ago. Due to their great availability, large size and ease of handling, X. laevisoocytes are often superior when compared to other expression systems such as Escherichia coli or eukaryote expressionsystems. The Xenopus laevis oocyte expression system is able to efficiently transcribe and translate injected geneticinformation and to assemble, process, and target protein products. Protein characterization studies in intact whole cellinjected oocytes are done using established techniques such as electrophysiology, transport assays, and calcium imaging.Recently Xenopus oocytes have been analyzed using in-vivo NMR spectroscopy, and we wondered if it would be possibleto use Raman spectroscopy for non-invasive analysis of single oocytes. We present here evidence that it is possible toidentify Raman bands arising from heterologous expressed membrane proteins in stage VI oocytes. This opens thepossibility for integrating the Raman analysis with already established protein expression methods in order to yieldcomplementary information about membrane protein structure and function.

In this work, we investigate the usability of layered polymer - inorganic composite waveguides for label-free sensing of surface bound bioreactions in an aqueous environment. The waveguide structure consists of a nanoimprint fabricated polymeric inverted rib waveguide with a sputtered Ta2O5thin film on top. The interaction of the optical field with the surface is increased as a consequence of the mode profile localization near the surface, when high-index coating is deposited on a low-index waveguide. Young interferometer configuration with reference and sensors waveguide arms was utilized in sensor chips. Light from a laser source was end-fire coupled into the chips and interference pattern produced by the outcoupled light was investigated. External -fluidic pump was used to produce the analyte flow. Ambient refractive index change was characterized by applying DI-water with varying glucose concentration on waveguides. With the waveguide length of 1 cm a detection limit in the order of 10-7- 10-6refractive index unit (RIU) was achieved. Specific binding reactions on the surface were investigated with C - reactive protein (CRP) antibodies and antigens.

This paper presents research activities carried out at VTT Technical Research Centre of Finland in the field of hybrid integration of optics, electronics and mechanics. Main focus area in our research is the manufacturing of electronic modules and product structures with printed electronics, film-over-molding and polymer sheet lamination technologies and the goal is in the next generation of smart systems utilizing monolithic polymer packages. The combination of manufacturing technologies such as roll-to-roll -printing, injection molding and traditional component assembly is called Printed Hybrid Systems (PHS). Several demonstrator structures have been made, which show the potential of polymer packaging technology. One demonstrator example is a laminated structure with embedded LED chips. Element thickness is only 0.3mm and the flexible stack of foils can be bent in two directions after assembly process and was shaped curved using heat and pressure. The combination of printed flexible circuit boards and injection molding has also been demonstrated with several functional modules. The demonstrators illustrate the potential of origami electronics, which can be cut and folded to 3D shapes. It shows that several manufacturing process steps can be eliminated by Printed Hybrid Systems technology. The main benefits of this combination are small size, ruggedness and conformality. The devices are ideally suited for medical applications as the sensitive electronic components are well protected inside the plastic and the structures can be cleaned easily due to the fact that they have no joints or seams that can accumulate dirt or bacteria.

Nestin is a class 6 intermediate filament protein expressed in stem/progenitor cells during CNS development. Nestin expression has been detected in many kinds of tumors and was reported in a recent small-scale study in non-small cell lung cancer (NSCLC). We investigated the relationships between nestin expression and clinicopathologic parameters and determined its prognostic significance concerning survival in patients with resected NSCLC.

The present study, aiming to elucidate ion channel mechanisms underlying muscarinic receptor–induced depolarization, has characterized membrane currents induced by carbachol in single guinea-pig urinary bladder myocytes. Application of carbachol to cells that were voltage-clamped at − 50 mV produced an atropine-sensitive, biphasic inward current consisting of an initial peak followed by a smaller sustained phase. Replacing the extracellular Na+and intracellular Cl−with impermeable tris+and glutamate−, respectively, demonstrated that the biphasic current is entirely composed of cation currents. Its initial peak phase was abolished by buffering intracellular Ca2+to a constant level of 100 nM or depleting intracellular Ca2+stores, and it was mimicked by the Ca2+releaser caffeine. Ca2+entry evoked by voltage steps in the sustained phase induced no noticeable change, indicating that this phase of cation current is insensitive to a rise of [Ca2+]i. These results demonstrate that muscarinic receptor stimulation invokes the openings of two types of cation channel, a Ca2+-activated and a receptor-operated type; the former channels are gated by a rise in [Ca2+]iupon intracellular Ca2+release, and the latter are gated through other muscarinic receptor–coupled signal transduction mechanisms.

Previous studies have indicated that NO plays a crucial role in the metastasis of tumor cells and that tumor cells produce nitric oxide (NO) via inducible nitric oxide synthase (iNOS). Since the deformability of tumor cells is an important factor governing their metastatic potential, in this study we investigated the regulation of tumor cell deformability by NO. Lewis lung tumor cells (3LL cells) were also incubated with a cytokine mixture (IL‐1β, IFNγ, and TNFα). The nitrite/nitrate content of the supernatant was then measured by the Griess method, and iNOS expression was evaluated by RT‐PCR in vitro. Nitrite/nitrate was produced in response to administration of the cytokine mixture, and iNOS mRNA was expressed in the cytokine‐treated cells. The deformability of the 3LL cells was evaluated by measuring the peak pressure generated during their passage through a microfilter at a constant flow rate. Both the cytokine mixture and NO donor (NOC 18) significantly increased the filtration pressure, and the staining of the cells with rhodamine‐phalloidin revealed assembly of F‐actin in the cell membrane. In conclusion, NO plays a role in the decreased deformability of tumor cells, suggesting that NO is one of the factors that regulates metastasis.

An early phase II study of topotecan produced favorable results in a small number of untreated and previously treated patients with small-cell lung cancer (SCLC). This multicenter study was conducted in patients with relapsed SCLC at 19 medical institutions in Japan. Topotecan 1.0 mg/m2/day was administered for 5 consecutive days every 3 weeks. Fifty-three patients were enrolled in the study. One patient was withdrawn before the commencement of study treatment, and 2 patients were unable to continue study treatment due to an interruption in the supply of study medication. The response rate was 26.0% in 13 of the 50 evaluable patients who were eligible and completed protocol-specified treatment and procedures. The median time to progression and overall survival were 133 days and 262 days, respectively. The most frequently reported toxicity was reversible myelosuppression, such as leukopenia, neutropenia, anemia (decreased hemoglobin), and thrombocytopenia. Nonhematological toxicity was also reported but the incidence of grade 3/4 symptoms was low. The results of this study indicate that topotecan is effective against relapsed SCLC with good tolerability.

Combination chemotherapy is the cornerstone of treatment of small cell lung cancer, leading to a meaningful survival benefit for these patients. However, there have been no major advances in therapy in the last decade. Therefore, more effective new treatments are necessary to improve the outcome of therapy. Irinotecan is one of the new active agents that provide hope for more effective therapies in the 21st century. A Phase III trial carried out in Japan clearly demonstrated a survival advantage of a combination of cisplatin and irinotecan over the standard regimen of cisplatin and etoposide. This review outlines the treatment results of irinotecan as a single agent as well as in combination with other cytotoxic agents.

Pharmacologic profiles of YM934, a newly synthesized 1,4-benzoxazin derivative K channel opener were evaluated in in vitro and in vivo experiments. In isolated rat portal vein, YM934 and a benzopyran derivative K channel opener lemakalim inhibited the frequency of spontaneous rhythmic contractions concentration de-pendently, with IC50values of 14 and 38 n Mrespectively. These inhibitory effects were competitively antagonized by glibenclamide (an ATP-sensitive K channel blocker; 10-7-3 x 10-6M).In isolated rabbit aorta, YM934 (10-810-6M)and lemakalim (10-8-10-6M)relaxed the contractions induced by 20 mMKC1 concentration dependency but were ineffective against the contractions induced by 50 mMKC1. YM934 (10-8-3 x 10-6M)and lemakalim (3 x 10-8-10-5M),but not the calcium antagonist nifedipine, relaxed the contractions induced by norepinephrine (NE 10 -6M) or prostaglandin F2α(PGF2α3 x 10-6M)in the aorta. In pentobarbital-anesthetized dogs, YM934 (1–10 μg/kg intravenously, i.v.) dose-dependently increased coronary artery blood flow (CBF), and decreased total peripheral resistance (TPR) and mean blood pressure (MBP). YM934 selectively increased CBF, but had little effect on vertebral, carotid, mesenteric, renal and femoral artery BF. These vasodilatory effects of YM934 were antagonized by glibenclamide. YM934 is a potent K channel opener and possesses potent vasodilatory effects, with particularly pronounced effects on the coronary artery. These effects of YM934 may, like lemakalim, be mediated by opening of ATP-sensitive K channels.

Microbial transformation of cholic acid and chenodeoxycholic acid by anaerobic mixed cultures of human fecal microorganisms was investigated, and the results were examined in relation to the bile acid transforming activities of 75 bacterial strains isolated from the same fecal cultures. The reactions involved in the mixed cultures were dehydrogenation and dehydroxylation of the 7α‐hydroxy group in both primary bile acids and epimerization of the 3α‐hydroxy group in all metabolic bile acids. Extensive epimerization of the 7α‐hydroxy group of chenodeoxycholic acid yielding ursodeoxycholic acid was also demonstrated by certain fecal samples. 7α‐Dehydrogenase activity was widespread among the fecal isolates (88% of 16 facultative anaerobes and 51% of 59 obligate anaerobes), and 7α‐dehydroxylase activity was revealed in one of the isolates, an unidentified gram‐positive nonsporeforming anaerobic bacterium. 3α‐Epimerization was effected by seven strains assigned to Eubacterium lentum, which were also active for 3α‐ and 7α‐dehydrogenations. No microorganism accounting for 7α‐epimerization was recovered among the isolates. Splitting of conjugated bile acid was demonstrated by the majority of obligate anaerobes but the activity was rare among facultative anaerobes.

Deconjugation of bile salts by four strains of Bacteroidesand four strains of Clostridiumwas studied by use of resting cells and cell‐free culture supernatants. Bacteroidesstrains yielded active cells but showed relatively low bile salt hydrolase (BSH) activity in the culture supernatants while the reverse was the case for the spore‐forming clostridial strains.

A dose-escalation study of daily etoposide and carboplatin was carried out on 23 patients with advanced lung cancer using a starting dose of 40 mg/m2/day etoposide given orally for 21 days and 250 mg/m2carboplatin given intravenously (IV) on day 1. A total of 41 courses were given. Myelosuppression was the major dose-limiting toxicity. The maximum tolerated dose was reached at the fourth level with 40 mg/m2/day etoposide for 21 days and 400 mg/m2carboplatin on day 1, once every 4 weeks. Non-hematological toxicities were generally mild or reversible. The recommended doses of this combination chemotherapy are 40 mg/m2/day etoposide for 21 days and 350 mg/m2carboplatin on day 1. The response rate for non-small cell lung cancer and small cell lung cancer was 16.7% and 60% (95% confidence intervals of 3.6% to 41.4%, and 14.7% to 94.7%), respectively. A phase II study is necessary to define the efficacy and safety of this combination chemotherapy.

Pharmacologic profiles of YM934, a newly synthesized 1,4-benzoxazin derivative K channel opener were evaluated in in vitro and in vivo experiments. In isolated rat portal vein, YM934 and a benzopyran derivative K channel opener lemakalim inhibited the frequency of spontaneous rhythmic contractions concentration de-pendently, with IC50values of 14 and 38 μM, respectively. These inhibitory effects were competitively antagonized by glibenclamide (an ATP-sensitive K channel blocker; 10-7-3 x 10-6M).In isolated rabbit aorta, YM934 (10-8-10-6M)and lemakalim (10-8-l0-6M)relaxed the contractions induced by 20 mAf KC1 concentration dependency but were ineffective against the contractions induced by 50 mM KC1. YM934 (108-3 x KT6M)and lemakalim (3 x 10-8-10-5M), but not the calcium antagonist nifedipine, relaxed the contractions induced by norepinephrine (NE 10-6M) or prostaglandin F2α(PGF2α3 x 106M)in the aorta. In pentobarbital-anesthetized dogs, YM934 (1–10 μg/kg intravenously, i.v.) dose-dependently increased coronary artery blood flow (CBF), and decreased total peripheral resistance (TPR) and mean blood pressure (MBP). YM934 selectively increased CBF, but had little effect on vertebral, carotid, mesenteric, renal and femoral artery BF. These vasodilatory effects of YM934 were antagonized by glibenclamide. YM934 is a potent K channel opener and possesses potent vasodilatory effects, with particularly pronounced effects on the coronary artery. These effects of YM934 may, like lemakalim, be mediated by opening of ATP-sensitive K channels.

Irinotecan (CPT-11), a new derivative of camptothecin, showed schedule-dependent antitumor activity and toxicity in preclinical animal studies. We carried out a phase I study of weekly CPT-11 infusion, which indicated that the recommended dose for phase II studies was 100 mg/ m2. In a phase II trial, CPT-11 achieved a response rate of 32% for non-small cell lung cancer (NSCLC). In two phase II trials, CPT-11 achieved objective response rates of 37% and 47% for small cell lung cancer (SCLC). The high activity of CPT-11 in these phase II studies suggested that the next rational step was to investigate combination chemotherapy. The first phase I trial of CPT-11 combined with cisplatin achieved an encouraging response rate of 54% in 27 patients with previously untreated NSCLC, and the recommended schedule for phase II studies was 60 mg/m2 of CPT-11 (days 1, 8, and 15) plus 80 mg/m2 of cisplatin (day 1) given at 4-week intervals. Given the high single-agent activity of CPT-11 against SCLC and NSCLC, a regimen with a higher dose of this agent and a lower dose of cisplatin seemed likely to be more effective. In the second trial, the cisplatin dose was accordingly reduced from 80 to 60 mg/m2, and the recommended dose of CPT-11 was concluded to be 80 mg/m2. Thus, reduction of the cisplatin dose to 60 mg/m2 allowed the safe administration of CPT-11 at 80 mg/m2 (33.3% dose intensification compared with the original regimen). The most recent trial of this combination with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support demonstrated that the recommended dose is 80 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin. Thus, we could raise the CPT-11 dose 33% above that given in the original regimen while maintaining the original cisplatin dose by the use of rhG-CSF support. Further trials are needed to evaluate the effect of CPT-11 given in combination with other active agents for the treatment of lung cancer.

Abstract: Purpose: To compare the response rates, toxicities and survival durations of elderly patients (70 years of age or more) with those of younger patients ( less than 70 years of age) with non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. Patients and methods: We analyzed retrospectively the data of 203 assessable patients entered on a prospective randomized trial of cisplatin-based combination chemotherapy. Chemotherapy consisted of three dosage regimens: (1) vindesine and cisplatin (VP); (2) mitomycin, vindesine and cisplatin (MVP); or (3) etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM). Results: A greater proportion of elderly patients had localized disease and more squamous cell carcinoma than non-elderly patients. The overall response rates were 44% in the elderly group and 28% in the non-elderly group. In the EP/VM arm, the response rate was significantly better in the elderly group than in the non-elderly group. The frequency of grade 4 leukocytopenia in the MVP and EP/VM arms in the elderly group was significantly greater than in the non-elderly group (P < 0.05). No differences were found in nonhematological toxicities between the two groups. There was no difference in overall survival between the groups. Conclusion: Elderly patients treated with mitomycin-containing regimens have higher hematologic toxicities than younger patients. The results of this study are consistent with the previously reported pharmaco logic data on mitomycin suggesting altered pharmacokinetics in elderly patients. The improved response rate in the elderly patients was probably because more elderly patients had earlier disease, squamous cell carcinoma and better performance status. Cisplatin-based chemotherapy was tolerable for most elderly NSCLC patients with good performance status.

(E)-2′-deoxy-2′-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3–4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.

Abstract The importance of the dose intensity of chemotherapy in achieving maximal therapeutic effect has recently been reported for several chemosensitive malignant diseases, with Murray et al. reporting that intensive weekly chemotherapy using the cisplatin, vincristine, doxorubicin, and etoposide (CODE) regimen in small-cell lung cancer (SCLC) is very effective. However, leukopenia is the major obstacle to delivering the planned dose in intensive regimens. Therefore, we investigated whether recombinant human granulocyte colony-stimulating factor (rhG-CSF) could allow full drug doses to be given as scheduled, thereby improving the final outcome. Extensive-stage (ES) SCLC patients were randomized to receive either CODE alone or CODE with rhG-CSF, with the CODE regimen consisting of cisplatin given i.v. at 25 mg/m² weekly for 9 weeks; vincristine given i.v. at 1 mg/m² during weeks 1, 2, 4, 6, and 8; and doxorubicin given i.v. at 40 mg/m² and etoposide given i.v. at 80 mg/m² for 3 days during weeks 1, 3, 5, 7, and 9. rhG-CSF at 50 μg/m² was given s.c. on the days on which cytotoxic drugs were not given. From May 1989 to September 1991, 64 patients were enrolled in the study, of whom 63 were analyzable (31 for CODE alone and 32 for CODE with rhG-CSF). No difference in any of the patients’ characteristics except gender was found between the two groups. The complete response (CR) rate was 34% in the CODE with rhG-CSF group and 23% in the CODE alone group; the median survival was 59 and 32 weeks, respectively, in these groups (P = 0.004). Therefore CODE with rhG-CSF improved the survival of ES SCLC patients. On the basis of these results a phase III study to determine whether CODE with rhG-CSF would increase survival as compared to the standard regimen in ES SCLC was designed by the Japan Clinical Oncology Group.

The role of extracellular Ca2+ in the toniccontractile response to muscarinic receptor stimulation was investigated in isolated detrusor smooth muscle from the pig urinary bladder.

To facilitate the studies in cell biology and drug sensitivity of non-small cell lung cancer, cell samples from 55 patients have been used to establish cell lines in culture using a chemically defined medium (ACL-4). A total of 20 cell lines (36 percent) were directly established and characterized: 14 (44 percent) from pleural effusions, five (29 percent) from resected primary tumors, and one (25 percent) from ascitic fluids. They comprised 16 adenocarcinoma, two large cell carcinoma, one squamous cell carcinoma, and one malignant mesothelioma. Each cell line had distinct gross morphologic features and population doubling times from 21 to 75 h. The plating efficiency was 0.01 to 9.51 percent. The modal chromosome number varied from 45 to 108. Secretion of tumor markers (carcinoembryonic antigen, sialyl Lewis Xi, CA 50, CA 125, and CA 19-9) into the medium was also different in each cell line. Most of the cell lines have been xenografted into nude mice and found to be tumorigenic. Survival of 20 patients whose tumor cell specimens continually grew in culture at any time during their clinical course was significantly shorter than that of 35 patients with no in vitrotumor growth (median survival time of 28 weeks vs 53 weeks, p = 0.0093). Our study indicates that in vitrotumor cell growth appears to be an adverse prognostic factor in patients with non-small cell lung cancer.

Summary In order to evaluate the preventive efficacy, safety and usefulness of mesna (Sodium 2-mercaptoethane sulfonate) against ifosfamide-induced urinary disorders, a placebo-controlled double-blind comparative study was performed. Ifosfamide was administered by intravenous drip infusion at a daily dose of 2 g/m2 for 5 consecutive days, and mesna was intravenously administered at 20% of the ifosfamide dose, three times daily for 5 consecutive days. The results obtained are as follows. (a) Of 101 accrued patients, 91 patients were evaluated consisting of 45 for the mesna group and 46 for the placebo group. There was no intergroup difference in the number of the evaluated cases and patient characteristics. (b) Micturition pain and feeling of residual urine graded as moderate or severe were not observed for the mesna group, but were observed for the placebo group with incidences of 19.6% (9/46) for micturition pain and 15.2% (7/46) for feeling of residual urine; the intergroup differences in the appearance of these urinary symptoms were statistically significant (P=0.0003 for micturition pain;P=0.0009 for feeling of residual urine). The incidence of hematuria graded as moderate or severe was 6.7% (3/45) in the mesna group, which was significantly lower than the 32.6% (15/46) in the placebo group (P=0.0008). (c) No side-effect attributable to mesna was observed. (d) A judgment of “useful” was obtained in 80.0% (36/45) of the patients treated with mesna, which was significantly higher than the 34.8% (16/46) of the patients treated with placebo (P= near 0). On the basis of the above results, we conclude that the preventive efficacy, safety and usefulness of mesna against ifosfamide-induced urinary disorders have been well demonstrated in this study.

Abstract: Cell-cycle-dependent phosphorylation of the tumor-suppressor protein product of the retinoblastoma gene (RB) is mediated by a family of cyclin-dependent kinases and cyclins. We examined the expressions of RB protein and cyclin A protein in 13 small-cell lung cancer (SCLC) lines and 14 non-small-cell lung cancer (NSCLC) lines by immunoblotting. RB protein was not present or was of a mutant type in 77% of the SCLC lines (10/13) but was present in all the NSCLC lines. Cyclin A was expressed in 38% of the SCLC lines (5/13) and in 86% of the NSCLC lines (12/14). A positive correlation (P = 0.0034) between expression of cyclin A and wild-type RB protein was found by Fisher's exact probability test. Densitometric analysis of the expression of RB protein in RB(+) lung cancer lines showed that the phosphorylated form was predominant in 2/3 of the SCLC and 8/14 of the NSCLC lines. The positive correlation between the expressions of RB protein and cyclin A suggests that RB protein in most RB(+) lung cancer cell lines is a target of cyclin-A-dependent kinase and that the tumor-suppressor function may be inactivated by phosphorylation.

The detrusor muscle contains β‐adrenoceptors (β‐AR) and three subtypes, such as β1‐AR, β2‐AR, and β3‐AR, which have been identified in most species. There is a predominant expression of β3‐AR messenger RNA in human bladder tissue when compared with the β1‐AR and β2‐AR subtypes. Moreover, the presence of β1, β2, and β3‐AR in the human urothelium has been identified. It has also been demonstrated in animals that relaxation mediated through βs‐AR is achieved solely by cAMP‐dependent mechanisms in non‐contracted detrusor muscles, whereas in KCl precontracted detrusor muscles, cAMP‐dependent and ‐independent mechanisms by way of calcium‐activated K +(BK Ca) channels may be involved in β‐adrenergic relaxation. In addition, a recent phase II proof‐of‐concept study using a novel selective β3‐adrenoceptor agonist (YM178) has shown clinical efficacy in the treatment of overactive bladder (OAB) symptoms, suggesting that β3‐AR should be used as a therapeutic target for the treatment of OAB disorders.

Low-loss polymeric optical waveguides were fabricated by UV-nanoimprinting. With this technique the waveguides are directly patterned by imprinting of the UV-curable optical polymer materials, i.e. no etching processes are needed. By properly manufactured imprinting molds, very smooth waveguide surfaces are achieved and the optical loss is dominated by the material attenuation. The advantages of the manufacturing technology include the potential scalability onto large substrate areas and applicability for fabrication on various substrate materials. For instance, printed circuit boards are interesting substrates for high-bit-rate optical interconnection applications requiring long waveguides, and glass and plastic sheets are interesting for sensor applications. The technology also promises for low overall costs, as it is a relatively simple high-throughput replication process. Both ridge-type and inverted-rib-type single-mode waveguides were fabricated using Ormocer hybrid polymer materials having low optical attenuation. Very low loss waveguides were demonstrated by fabrication long waveguides in a spiral shape. The optical attenuation was characterized of 27 cm-long inverted-rib waveguide spirals having 2 m-wide cores. The measured average attenuation was 0.25 and 0.56 dB/cm at the wavelengths of 638 and 1310 nm, respectively.

For Abstract see ChemInform Abstract in Full Text.

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We studied tumor samples from 39 patients, who entered our study from January 1989 to May 1990, to assess whether the ability to establish a continually growing tumor cell line from fresh tumor specimens can be associated with decreased survival times in patients with small-cell lung cancer. The tumor samples were used to establish cell lines in culture using a serum-free medium supplemented with hydro-cortisone, insulin, transferrin, estrogen, and selenium (HITES). Thirty-three of these specimens were obtained by fiberoptic bronchoscopy from primary sites during routine diagnostic procedures. A total of 11 (28%) cell lines were established: seven (21%) from 33 primary tumors and four (80%) from five peripheral lymph nodes. Survival times of the 11 patients whose tumor cell specimens continually grew in culture at any time during their clinical course were significantly shorter than those of the 28 patients whose tumor cell specimens did not grow in vitro (median survival time of 26 weeks versus 73 weeks; P = .0068). Coxs proportional hazards model, including sex, age, Eastern Cooperative Oncology Group performance status, stage, source of specimen, treatment, and in vitro tumor cell growth in the overall patient group, showed that cell line establishment (P = .0017) and no therapy (P = .0015) were the most important factors indicating poor survival time. For the subgroup of 23 primary tumor patients, the important factors (in decreasing order) that indicated decreased order) that indicated decreased survival times were the establishment of a cell line (P = .0112) and treatment with cyclophosphamide-doxorubicin-vincristine alternating with cisplatin-etoposide, versus cisplatin-vincristine-doxorubicin-etoposide therapy (P = .0463). Our study demonstrates that in vitro tumor cell growth is an adverse predominant prognostic factor in patients with small-cell lung cancer. [J Natl Cancer Inst 83:1743–1748, 1991]

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) is a novel camptothecin derivative that has been selected for clinical evaluation because of its broad spectrum of anti-tumor activity in animal models and its unique inhibitory effects on mammalian DNA topoisomerase I. Seventeen patients with advanced non-small-cell lung cancer were treated with CPT-11 at weekly dose levels ranging from 50 to 150 mg/m2. At least three weekly doses were given to all patients except four, and a total of 74 weekly doses were given to the 17 patients. The dose-limiting toxic effects were myelosuppression (predominantly leukopenia) and unpredictable diarrhea. Gastroin-testinal toxic effects were severe and not well controlled by standard therapy in some patients. Interpatient variability of toxic effects was substantial (including two deaths) and did not correlate with the pharmacokinetic parameters of CPT-11 and 7-ethyl-10-hydroxycamptothecin, its major metabolite. Two previously untreated patients, who received doses of 100 and 125 mg/m2, had partial responses lasting 3.2 and 4.0 months, respectively. The maximum tolerated dose on this schedule was 100 mg/m2, which we also recommend as a starting dose for phase II studies. This schedule appears to allow a CPT-11 dose intensity which is double the dose intensity possible on a once-a-month schedule. However, careful supervision to assess gastrointestinal toxic effects and myelosuppression is indispensable because of wide individual differences in drug tolerance. [J Natl Cancer Inst 83: 1164–1168, 1991]