THP Group Research Articles

Efficacy of Oral Trihexyphenidyl Plus Clonazepam Versus Trihexyphenidyl for the Treatment of Dystonia in Children With Dystonic Cerebral Palsy: An Open-Label Randomized Controlled Trial

BackgroundTrihexyphenidyl and clonazepam are commonly used to treat dystonia in children with cerebral palsy (CP). However, there is a notable gap in the literature when it comes to studies that combine these first-line agents for the management of dystonia. MethodsThis open-label, randomized controlled trial aimed to compare the efficacy of adding oral clonazepam to trihexyphenidyl (THP + CLZ) versus using trihexyphenidyl alone (THP) in reducing the severity of dystonia, as measured by the Barry-Albright Dystonia (BAD) score. The study was conducted over a 12-week therapy period in children with dystonic CP aged two to 14 years. ResultsEach group enrolled 51 participants. The THP + CLZ group showed significantly better improvement in dystonia severity at 12 weeks compared with the THP group alone (−4.5 ± 2.9 vs −3.4 ± 1.7, P = 0.02). Furthermore, the THP + CLZ group exhibited superior improvement in the severity of choreoathetosis, upper limb function, pain perception by the child, and quality of life, with P values of 0.02, 0.009, 0.01, and 0.01, respectively. The number of participants experiencing treatment-emergent adverse events was comparable in both groups (P = 0.67). Importantly, none of the participants in any of the groups reported any serious adverse events. ConclusionA combination of oral THP + CLZ proves to be more efficacious than using THP alone for the treatment of dystonic CP in children aged two to 14 years in terms of reducing the severity of dystonia.

Prognostic value of baseline neutrophil/lymphocyte ratio in HER2-positive metastatic breast cancer: exploratory analysis of data from the CLEOPATRA trial

PurposeThis study aimed to evaluate the prognostic role of the baseline neutrophil/lymphocyte ratio (NLR) in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab/pertuzumab.Experimental designData from 780 patients from the CLEOPATRA trial and 248 local patients were collected. Patients were divided into the low and high NLR subgroups by the NLR cutoff value. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methods were used to control bias. Associations between the NLR and progression-free survival (PFS) and overall survival (OS) were analyzed.ResultsThe baseline characteristics of the subgroups were well balanced after PSM and IPTW. A low baseline NLR was associated with better PFS and OS in the trastuzumab and docetaxel (TH) group in the unadjusted, PSM and IPTW models. After IPTW, a low NLR, versus a high NLR, was associated with improved PFS (HR 1.35, 95% CI 1.07–1.70, P = 0.012) and OS (HR 1.47, 95% CI 1.12–1.94, P = 0.006) in the TH group. In patients undergoing treatment with trastuzumab and pertuzumab and docetaxel (THP), a low baseline NLR was also correlated with better PFS but not OS across the three models. After IPTW, a low NLR was associated with better PFS (HR 1.52, 95% CI 1.20–1.93, P = 0.001) than a high NLR in the THP group. Multivariate analyses showed that a low baseline NLR was a predictor for PFS and OS in the TH group and for PFS in the THP group in all three models. In the real-world setting, a low baseline NLR was a predictor of better PFS among patients treated with docetaxel plus trastuzumab without or with pertuzumab in the multivariate model (P = 0.015 and 0.008, respectively).ConclusionsA low baseline NLR is associated with better survival outcomes among HER2-positive MBC patients receiving docetaxel plus trastuzumab/pertuzumab as first-line therapy.

Synthesis of SGLT2 Inhibitors by Means of Fukuyama Coupling Reaction.

Disclosed herein is a novel and efficient synthesis of dapagliflozin and canagliflozin, the most advanced sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors), for the treatment of type 2 diabetes mellitus (T2DM). Per Ac-protected thioester was prepared by the treatment of per Ac d-gluconolactone with 1-dodecanethiol and iPrMgCl without affecting labile Ac-protecting groups. Aryl bromide (ArBr) was synthesized through reduction of diaryl ketone to diaryl methane by the TiCl4/NaBH4/DME-MeOH reduction system. Fukuyama coupling of the thioester with aryl zinc reagent prepared from ArBr gave a multifunctional aryl ketone at 40 °C in a high yield where the use of a limited amount of a mixed solvent (7.2 volumes (v), THF:toluene:DMF = 3v/4v/0.2v) was crucial to achieve the higher yield. After cleavage of the THP group, hydroxy ketone obtained was treated with methanesulfonic acid (MSA) in MeOH to give a methoxy-cyclized product in a single step and in a quantitative yield, which was allowed to silane reduction to furnish dapagliflozin in an excellent yield. By following the same procedure, canagliflozin was synthesized. The current synthetic method is featured by high yields, mild reaction conditions, and the use of inexpensive reagents and readily cleavable protecting groups.

Neoadjuvant docetaxel with or without carboplatin plus dual HER2 blockade for HER2-positive breast cancer: a retrospective multi-center Chinese study

This study aimed to compare the real-world efficacy and safety of the TCbHP regimen (docetaxel, carboplatin, trastuzumab and pertuzumab) and the THP regimen (docetaxel, trastuzumab and pertuzumab) as neoadjuvant therapy for Chinese patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We compared efficacy and safety outcomes from 72 Chinese patients with HER2-positive breast cancer who underwent neoadjuvant dual HER2 blockade plus TCb or T chemotherapy and surgery between March 2019 and June 2020. All 72 patients were women (32-76 years old) and the overall pathological complete response (pCR) rate was 70.8% (51/72). The pCR rates were 76.1% (35/46) for the TCbHP regimen and 61.5% (16/26) for the THP regimen (P=0.28). Univariate analyses revealed that pCR was associated with clinical T classification (P=0.024), AJCC stage (P=0.042), estrogen receptor (ER) status (P=0.002), progesterone receptor (PR) status (P=0.035), Ki-67 index (P<0.001), and immunohistochemical HER2 status (P<0.001). Multivariate analyses revealed that pCR was independently predicted by ER status (OR: 0.227, 95% CI: 0.053-0.852; P=0.032) and immunohistochemical HER2 status (OR: 43.673, 95% CI: 6.801-875.86; P<0.001). The common adverse events for both regimens included neutropenia, anemia, thrombocytopenia, nausea, and diarrhea. Relative to the THP group, the TCbHP group had higher frequencies of grade 3-4 thrombocytopenia (17% vs. 0%, P=0.044) and grade 3-4 diarrhea (15% vs. 0%, P=0.044). Both regimens had very good cardiac safety. These results suggest that both TCbHP and THP regimens may be useful neoadjuvant treatments for high-risk early or locally advanced HER2-positive breast cancer. Both regimens had generally good safety outcomes, although clinicians should be aware of the risks of grade 3-4 thrombocytopenia and diarrhea during TCbHP treatment. Elderly patients who require neoadjuvant therapy may benefit from 6 cycles of THP treatment, based on its good efficacy and mild adverse events.

Direct AlCl3-catalyzed transformation of benzyl THP ethers and allyl benzyl ethers

THP and allyl groups are frequently used for the protection of alcohols. In this study, novel direct transformations of benzyl THP ethers and allyl benzyl ethers, protected forms of alcohols, are reported. TMSN3 and AlCl3 were employed as key azide reagent and catalyst to perform direct conversion of benzyl THP ethers and allyl benzyl ethers to azido compounds. In addition, direct nucleophile additions of carbon nucleophiles to benzyl THP ethers and allyl benzyl ethers were successfully accomplished in the presence of catalytic AlCl3. The results indicate that this novel method could be applied to various direct transformations of benzyl THP ethers and allyl benzyl ethers such as azidation, allylation, and alkynylation.

Randomized Study of Postoperative Single Intravesical Instillation With Pirarubicin and Mitomycin C for Low-risk Bladder Cancer.

To assess the prophylactic efficacy of postoperative single intravesical instillation with pirarubicin (THP) and mitomycin C (MMC) for low-risk non-muscle-invasive bladder cancer (NMBC). A total of 103 clinically low-risk NMBC patients were preoperatively randomized into either THP (n=49) or MMC (n=54) groups. The primary endpoint was recurrence-free survival. The median follow-up periods of the THP and MMC groups were 955 and 1008 days, respectively (p=0.76). Twelve patients (24.5%) in the THP group and 7 (13%) in the MMC group had bladder cancer recurrences. The two-year recurrence-free survival of the THP group and the MMC group was 77.8% and 86.4%, respectively (p=0.20). Neither groups had severe toxicity. In low-risk NMBC, the prophylactic effect against postoperative single intravesical instillation with THP was not superior to that with MMC.

Qishen Huanwu capsule reduces pirarubicin-induced cardiotoxicity in rats by activating the PI3K/Akt/mTOR pathway

One of the common adverse reactions to anthracyclines, a group of chemotherapeutics, is cardiotoxicity. Cancer patients receiving anthracycline-based chemotherapeutic regimens often discontinue treatment due to cardiotoxicity. How to prevent and reduce the cardiotoxicity of anthracyclines is one of the hot topics in the field of onco-cardiology. Traditional Chinese medicine can reduce the toxic side effects of chemotherapeutics. The present study aimed to investigate the protective effect of Qishen Huanwu capsule (QSHWC) on pirarubicin (THP)-induced myocardial injury in rats and the underlying mechanisms. Forty-eight male Sprague-Dawley (SD) rats were randomly divided into six groups: control group, THP, low-dose QSHWC, moderate-dose QSHWC, high-dose QSHWC, and LY294002 [phosphatidylinositol 3-kinase (PI3K) inhibitor] (n=8 each). Echocardiographic examination was performed to examine heart structure and function. Hematoxylin and eosin (HE) staining was conducted to examine histopathological changes in myocardial tissue. Immunofluorescence staining was carried out to examine the expression of the autophagosome-specific marker protein microtubule-associated protein 1 light chain 3 (LC3). Western blot was performed to analyze the expression of LC3-I, LC3-II, PI3K, phosphorylated (p)-PI3K, protein kinase B (Akt), p-Akt, mammalian target of rapamycin (mTOR), and p-mTOR. Compared with the control group, the THP group had a higher left ventricular end-systolic diameter (LVESD), lower left ventricular ejection fraction (LVEF), lower left ventricular fractional shortening (LVFS), and inferior heart function. In addition, compared with the control group, the THP group had significantly higher LC3 protein expression, a significantly higher LC3-II/LC3-I ratio (P<0.05), and significantly lower p-PI3K, p-Akt, and p-mTOR (P<0.05). QSHWC attenuated the THP-induced decline in heart function, downregulated LC3 protein in rat myocardial tissue, decreased the LC3-II/LC3-I ratio, and increased p-PI3K, p-Akt, and p-mTOR. In the LY294002 group, the above effects of QSHWC were reversed. QSHWC alleviated THP-induced myocardial injury. The underlying mechanism was related to the activation of the PI3K/Akt/mTOR pathway and the mitigation of the excessive autophagy of cardiomyocytes caused by THP.

Variations in Health Care Utilization Patterns Among Inflammatory Bowel Disease Patients at Risk for High Medical Service Utilization Enrolled in High Deductible Health Plans.

High-deductible health plans (HDHPs) are increasing in prevalence as a cost control device for slowing health care cost growth by reducing nonessential medical service utilization. High cost-sharing associated with HDHPs can lead to significant financial distress and worse disease outcomes. We hypothesize that chronic disease patients are delaying or foregoing necessary medical care due to health care costs. A retrospective cohort analysis of IBD patients at risk for high medical service utilization with continuous enrollment in either an HDHP or THP from 2009 to 2016 were identified using the MarketScan database. Health care costs were compared between insurance plan groups by Kruskal-Wallis test. Temporal trends in office visits, colonoscopies, emergency department (ED) visits, and hospitalizations were evaluated using additive decomposition time series analysis. Of 605,862 patients with a diagnosis of IBD, we identified 13,052 eligible patients. Annual out-of-pocket costs were higher in the HDHP group (n = 524) than the THP group (n = 12,458) ($2870 vs $1,864; P < 0.001) without any difference in total health care expenses ($23,029 vs $23,794; P = 0.583). Enrollment in an HDHP influenced colonoscopy, ED visit, and hospitalization utilization timing. Colonoscopies peaked in the fourth quarter, ED visits peaked in the first quarter, and hospitalizations peaked in the third and fourth quarter. High-deductible health plan enrollment does not change the cost of care; however, it shifts health care costs onto patients and changes the timing of the care they receive. High-deductible health plans are incentivizing delays in obtaining health care with a potential to cause worse disease outcomes and financial distress. Further evaluation is warranted.

Safety and efficacy of intensive instillation of low-dose pirarubicin vs. bacillus Calmette-Guérin in patients with high-risk non-muscle-invasive bladder cancer

ObjectivesTo evaluate the safety and efficacy of intensive intravesical instillation of low-dose pirarubicin (THP) for 6 times vs. bacillus Calmette-Guérin (BCG) without maintenance therapy after transurethral resection of bladder tumor (TURBT) in patients with primary high-risk non-muscle-invasive bladder cancer (NMIBC). Materials and MethodsWe retrospectively evaluated 370 patients with primary high-risk NMIBC who underwent TURBT from November 1993 to April 2019. The patients were divided into 2 groups: patients treated with intravesical instillation of BCG without maintenance therapy (BCG group) and intensive intravesical instillation of low-dose (20 mg) THP for 6 times within 10 days after TURBT (THP group). Safety was assessed using the Common Terminology Criteria for Adverse Events version 5.0. Background-adjusted multivariate analyses were performed to evaluate the effect of intensive intravesical instillation of low-dose THP on oncological outcomes, including intravesical recurrence-free survival (RFS), upper urinary tract RFS, muscle-invasive bladder cancer-free survival, metastasis-free survival, cancer-specific survival, and overall survival. ResultsOf the 370 patients with primary high-risk NMIBC, 180 (49%) and 190 (51%) were stratified into the BCG and THP groups, respectively. The incidence rate of adverse events of any grade in the BCG group was significantly higher than that in the THP group (P < 0.001). In the background-adjusted multivariate analyses, no significant differences were observed in oncological outcomes between the BCG and THP groups. ConclusionsIntensive intravesical instillation of low-dose THP for 6 times may be one of the treatment options in view of safety and efficacy after TURBT in patients with primary high-risk NMIBC.

Randomized study of intravesical pirarubicin chemotherapy with low and intermediate-risk nonmuscle-invasive bladder cancer in Japan: Comparison of a single immediate postoperative intravesical instillation with short-term adjuvant intravesical instillations after transurethral resection.

Purpose:The objective of this study was to evaluate the efficacy, defined by the 3-year tumor recurrence-free survival rate, of intravesical chemotherapy using pirarubicin (THP) in patients with low or intermediate-risk nonmuscle-invasive bladder cancer (NMIBC).Patients and methods:Between October 2010 and January 2015, 206 patients were enrolled, and finally 113 were randomized to receive either a single immediate postoperative intravesical instillation of THP (30 mg) (Group A), or 8 additional weekly intravesical instillations of THP (30 mg) after a single postoperative instillation (Group B). The patients were examined by performing cystoscopy and urine cytology every 3 months after transurethral resection to determine bladder tumor recurrence. The primary endpoint was 3-year-recurrence-free survival rate.Results:All 113 patients were bacillus Calmette–Guérin (BCG)-naïve. The 3-year recurrence free survival rate was 63.7% for Group A and 85.3% for Group B (log-rank test, P = .0070). In patients with intermediate recurrence risk, the 3-year recurrence-free survival rate was 63.4% in Group A and 86.1% in Group B (log-rank test, P = .0036). Cox regression analysis revealed that only additional instillation of THP was a significant independent factor for recurrence-free rate in patients with intermediate risk. No patient with progression was noted during this period. Frequent adverse effects (AEs) were frequent urination and micturition pain, and no severe AEs (Grade 3 or more) occurred.Conclusion:Additional instillation of THP (30 mg) weekly for 8 weeks reduced the risk of tumor recurrence without severe AEs in BCG-naïve NMIBC patients with intermediate risk.

Effect of triple therapy with bladder perfusion chemotherapy on recurrence risk, survival time and laboratory parameters of patients with superficial bladder cancer after TURBT

Objective To investigate the effect of triple chemotherapy including bacillus calmette guerin (BCG) and hydroxycamptothecin (HCPT) and pirarubicin (THP) with bladder perfusion on recurrence risk, survival time and laboratory parameters of patients with superficial bladder cancer after (transurethral resection of bladder cancer, TURBT). Methods A total of 130 patients with superficial bladder cancer after TURBT were chosen from January 2011 to August 2013 in our hospital and randomly divided into two groups, control group with HCPT+ THP and observation group with BCG+ HCPT+ THP, 65 cases each group. and the recurrence rate with follow-up, the long-term survival rate, the levels of tumor marker and vascular endothelial growth factor (VEGF) and adverse reaction incidence of both groups were compared between two groups. Results The recurrence rate with follow-up of observation group was significantly lower than control group(P 0.05). Conclusions Triple chemotherapy with bladder perfusion on recurrence risk, survival time and laboratory parameters of patients with superficial bladder cancer after TURBT can efficiently reduce the recurrence risk, prolong the survival time, down-regulate the levels of tumor markers and VEGF and not increase the risk of adverse reactions. Key words: Urinary Bladder Neoplasms; Neoplasm Recurrence, Local; BCG Vaccine; Camptothecin

Transeterification of the Intermediate Chloro-ester Compounds in the Sequence for Obtaining Corey Aldehyde Protected as Cyclic Acetals

Transesterification of the TBDMS-bis-protected compounds 10-1a and 10-2a with K2CO3 in methanol takes place with the cleavage of the secondary TBDMS group to compounds 13-1 and 13-2. The same compounds were obtained as proof of the transesterification of the bis-benzoate compounds 10-1b and 10-2b. In case of bis-THP protected compounds 10-1c and 10-2c, the secondary THP group, stable in base conditions, was expected not to be removed in transesterification conditions, resulting the compounds rezultind compusii 13-1c and 13-2c.

Tetrahydropyranyl: A Non-aromatic, Mild-Acid-Labile Group for Hydroxyl Protection in Solid-Phase Peptide Synthesis.

The use of the tetrahydropyranyl (Thp) group for the protection of serine and threonine side‐chain hydroxyl groups in solid‐phase peptide synthesis has not been widely investigated. Ser/Thr side‐chain hydroxyl protection with this acid‐labile and non‐aromatic moiety is presented here. Although Thp reacts with free carboxylic acids, it can be concluded that to introduce Thp ethers at the hydroxyl groups of N‐protected Ser and Thr, protection of the C‐terminal carboxyl group is unnecessary due to the lability of Thp esters. Thp‐protected Ser/Thr‐containing tripeptides are synthesized and the removal of Thp studied in low concentrations of trifluoroacetic acid in the presence of cation scavengers. Given its general stability to most non‐acidic reagents, improved solubility of its conjugates and ease with which it can be removed, Thp emerges as an effective protecting group for the hydroxyl groups of Ser and Thr in solid‐phase peptide synthesis.

ChemInform Abstract: Synthesis of Ethers via Reaction of Carbanions and Monoperoxyacetals.

AbstractA series of monoperoxy acetals, especially those bearing a ‐Thp group, reacts with organo‐lithium and organo‐magnesium reagents to afford different types of ethers which, in part, are difficult to prepare by other methods.

ChemInform Abstract: Efficient Functionalization of 2‐Amino‐6‐chloropurine Derivatives at C‐8 via 8‐Lithiated Species.

AbstractThe protection of the amino group in 2‐amino‐6‐chloropurines using a THP group allows introduction of a variety of halogen and carbon substituents at the purine 8‐position.

Neoadjuvant chemotherapy of breast cancer with pirarubicin versus epirubicin in combination with cyclophosphamide and docetaxel.

Breast cancers (BC) are treated with surgery, radiotherapy, and chemotherapy. Neoadjuvant chemotherapy (NACT) is an emerging treatment option in many cancers and is given before primary therapy to shrink tumor size. The efficacy of NACT in varied settings of BC, such as inoperable tumors, borderline resectable tumors, and breast-conserving surgery, has been debated extensively in literature, and the results remain unclear and depended on a wide variety of factors such as cancer type, disease extent, and the specific combination of chemotherapy drugs. This study was performed to examine the efficacy, toxicity, and tolerability of pirarubicin (THP) and epirubicin (EPI) in combination with docetaxel and cyclophosphamide in a NACT setting for BC. A total of 48 patients with stage II or III breast cancers were randomly divided into two groups: THP group and EPI group. The patients in THP group received 2-4 cycles of neoadjuvant chemotherapy with DTC regimen (docetaxel, THP, cyclophosphamide), while patients in the EPI group received 2-4 cycles of DEC regimen (docetaxel, EPI, cyclophosphamide) before surgery. The incidence of adverse reactions and the efficacy of the treatment regimen were compared between the two groups. Prognostic evaluation indexes were estimated by Kaplan-Meier survival analysis, including the 5-year disease-free survival (DFS) and overall survival (OS). The overall response rate in THP group was 83.3 %, and the EPI group showed a response rate of 79.2 %, with no statistically significant difference in response rate between the two groups. The incidence of cardiac toxicity, myelosuppression, nausea, and vomiting in the THP group was significantly lower than the EPI group (all P < 0.05). The incidence of hepatic toxicity, alopecia, and diarrhea in the THP group was also lower than the EPI group, but these differences were not statistically significant. The 5-year DFS and OS in THP versus EPI groups were 80 versus 76 % (DFS) and 86 versus 81 % (OS), respectively. Our study found that NACT with DTC regimen and DEC regimen were both very effective in treatment of BC. However, THP-based combination therapy was associated with significantly lower incidence of cardiac toxicity, myelosuppression, nausea, and vomiting.

Phase Behavior of Poly(4-hydroxystyrene-block-styrene) Synthesized by Living Anionic Polymerization of an Acetal Protected Monomer

We have synthesized a series of poly(4-(2-tetrahydropyranyloxy)styrene) [P(OTHPSt)] homopolymers by living anionic polymerization of the protected monomer (OTHPSt) in tetrahydrofuran at −78 °C, with excellent control over molecular weight and dispersity. The high Tg of P(OTHPSt) led to facile purification and isolation of the polymer as a powder. Characterization of the POTHPSt homopolymer by nuclear Overhauser effect spectroscopy confirms the strong preference for the axial position of the relatively sterically demanding alkoxy phenyl group. By sequential monomer addition, a series of low to high molecular weight P(OTHPSt-b-styrene) BCPs with narrow dispersities were synthesized. Quantitative deprotection of the THP groups yielded poly(4-hydroxystyrene-b-styrene) with tunable molecular weights and compositions. The solid-state and melt-phase self-assembly of these diblocks was investigated using synchrotron small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). Mean-field theory analysis of the temperature-dependent correlation-hole scattering for a disordered diblock was used to determine the interaction parameter as χHS/S(T) = (4.39 ± 0.83)/T + (0.109 ± 0.002), which is approximately 4 times larger than that of poly(styrene-b-methyl methacrylate) with the same disproportionately high contribution of entropy to the free energy of mixing.

Prospective Randomized Phase II Trial of a Single Early Intravesical Instillation of Pirarubicin (THP) in the Prevention of Bladder Recurrence After Nephroureterectomy for Upper Urinary Tract Urothelial Carcinoma: The THP Monotherapy Study Group Trial

We evaluated the efficacy of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). From December 2005 to November 2008, 77 patients clinically diagnosed with UUT-UC from 11 institutions participating in the Tohoku Urological Evidence-Based Medicine Study Group were preoperatively enrolled in this study. Patients were randomly assigned to receive or not receive a single instillation of THP (30 mg in 30 mL of saline) into the bladder within 48 hours after nephroureterectomy. Cystoscopy and urinary cytology were repeated every 3 months for 2 years or until the occurrence of first bladder recurrence. Seventy-two patients were evaluable for efficacy analysis, 21 of whom had a subsequent bladder recurrence. Significantly fewer patients who received THP had a recurrence compared with the control group (16.9% at 1 year and 16.9% at 2 years in the THP group v 31.8% at 1 year and 42.2% at 2 years in the control group; log-rank P = .025). No remarkable adverse events were observed in the THP-treated group. Based on multivariate analysis, THP instillation (hazard rate [HR], 0.26; 95% CI, 0.07 to 0.91; P = .035) and open surgery (HR, 0.28; 95% CI, 0.09 to 0.84; P = .024) were independently predictive of a reduced incidence of bladder recurrence. In this prospective randomized phase II study, a single intravesical instillation of THP seemed to reduce bladder recurrence after nephroureterectomy. A phase III, large-scale, multicenter study is needed to confirm these observations.

Study Toward the Total Synthesis of Pyrenophorin

Macrodiolides are macrocyclic compounds containing two ester groups in a cyclic chain. Of this class of compounds, Pyrenophorin ( 1 ) shows antifungal activity, and is produced from the pathogenic fungus Pyrenophora avenae. As this substance, derived from nature, is isolated in small quantities, an asymmetric synthesis using a simple and efficient methodology would be of great interest. The proposed synthetic route starts with the protection of propargyl alcohol 3 using DHP and feldspar as catalyst. Compound 5 obtained in this reaction was then subjected to acid-base reaction between the acetylenic proton and 1 eq. n-BuLi, leading to formation of the acetylide 5A . The 1,2- addition reaction between 5A and g -valerolactone ( 6 ) leads to the formation of alkinone 7 in 67% yield. Subsequently, compound 7 was subjected to a ketalization reaction using the same feldspar catalyst. Ketal 8 was formed under concomitant removal of the THP group. The product of this reaction ( 8 ) was then submitted to a reduction reaction of the triple bond to form olefin 9 with E configuration. Currently, the conditions for obtaining 10 by oxidation using Jones reagent, are being optimized. Compound 10 , obtained as described, is being subjected to a macrolactonization reaction. Various conditions including the use of enzymes are being studied. In addition, a study involving the enantioselective synthesis of (R,R)-(-)-pyrenophorin, using enzymatic kinetic resolution of the racemic mixture of compound 8 , is in progress in the group

In vitro and in vivo studies of pirarubicin-loaded SWNT for the treatment of bladder cancer

Intravesical chemotherapy is an important part of the treatment for superficial bladder cancer. However, the response to it is limited and its side effects are extensive. Functional single-walled carbon nanotubes (SWNT) have shown promise for tumor-targeted accumulation and low toxicity. In the present study, we performed in vivo and in vitro investigations to determine whether SWNT-based drug delivery could induce high tumor depression in rat bladder cancer and could decrease the side effects of pirarubicin (tetrahydropyranyl-adriamycin, THP). We modified SWNT with phospholipid-branched polyethylene glycol and constructed an SWNT-THP conjugate via a cleavable ester bond. The cytotoxicity of SWNT-THP against the human bladder cancer cell line BIU-87 was evaluated in vitro. Rat bladder cancer in situ models constructed by N-methyl-N-nitrosourea intravesical installation (1 g/L, 2 mg/rat once every 2 weeks for 8 weeks) were used for in vivo evaluation of the cytotoxicity of SWNT and SWNT-THP. Specific side effects in the THP group including urinary frequency (N = 12), macroscopic hematuria (N = 1), and vomiting (N = 7) were identified; however, no side effects were observed with SWNT-THP treatment. Flow cytometry was used to assess the cytotoxicity in vitro and in vivo. Results showed that SWNT alone did not yield significant tumor depression compared to saline (1.74 ± 0.56 and 1.23 ± 0.42%) in vitro. SWNT-THP exhibited higher tumor depression than THP-saline in vitro (74.35 ± 2.56 and 51.24 ± 1.45%) and in vivo (52.46 ± 2.41 and 96.85 ± 0.85%). The present findings indicate that SWNT delivery of THP for the treatment of bladder cancer leads to minimal side effects without loss of therapeutic efficacy. Therefore, this nanotechnology may play a crucial role in the improvement of intravesical treatment of bladder cancer. Key words: Single-walled carbon nanotubes; Bladder cancer; Drug vehicle; THP; Intravesical chemotherapy