Dose Determination Study Research Articles

Low-dose xenogeneic mesenchymal stem cells target canine osteoarthritis through systemic immunomodulation and homing

BackgroundAs current therapies for canine osteoarthritis (OA) provide mainly symptomatic improvement and fail to address the complex pathology of the disease, mesenchymal stem cells (MSCs) offer a promising biological approach to address both aspects of OA through their immunomodulatory properties.MethodsThis study aimed to investigate the safety and efficacy of xenogeneic MSCs in dogs with OA at different dose levels after intravenous injection. OA was surgically induced in the right stifle joint. Thirty-two male and female dogs were divided into three treatment groups and a control group. Regular general physical examinations; lameness, joint, radiographic, and animal caretaker assessments; pressure plate analyses; and blood analyses were performed over 42 days. At study end, joint tissues were evaluated regarding gross pathology, histopathology, and immunohistochemistry. In a follow-up study, the biodistribution of intravenously injected 99mTc-labeled equine peripheral blood-derived MSCs was evaluated over 24h in three dogs after the cruciate ligament section.ResultsThe dose determination study showed the systemic administration of ePB-MSCs in a canine OA model resulted in an analgesic, anti-inflammatory, and joint tissue protective effect associated with improved clinical signs and improved cartilage structure, as well as a good safety profile. Furthermore, a clear dose effect was found with 0.3 × 106 ePB-MSCs as the most effective dose. In addition, this treatment was demonstrated to home specifically towards the injury zone in a biodistribution study.ConclusionThis model-based study is the first to confirm the efficacy and safety of systemically administered xenogeneic MSCs in dogs with OA. The systemic administration of a low dose of xenogeneic MSCs could offer a widely accessible, safe, and efficacious treatment to address the complex pathology of canine OA and potentially slow down the disease progression by its joint tissue protective effect.

Phase 1b OMNIVERSE trial: Safety and tolerability of oral azacitidine (Oral-AZA) in combination with venetoclax (VEN) for treatment of acute myeloid leukemia.

e19011 Background: Safer and more effective lower-intensity treatment (Tx) options are needed for patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). The combination of VEN, an oral BCL-2 inhibitor, and injectable AZA (Inj AZA), a hypomethylating agent, is indicated in IC-ineligible pts with newly diagnosed (ND) AML and has shown significantly improved response and survival rates vs. Inj AZA alone (DiNardo et al., N Engl J Med 2020). Oral-AZA allows for extended dosing schedules vs. Inj AZA. Methods: OMNIVERSE (NCT04887857) is an ongoing, phase 1b, multicenter, open-label, dose-determination study evaluating Oral-AZA + VEN in pts with relapsed/refractory (R/R; part 1) and ND AML (part 2). This abstract presents data from part 1. Eligible pts are adults with R/R AML (WHO 2016 criteria) not eligible for further IC, with an ECOG performance status of ≤ 2. The Oral-AZA starting dose is 300 mg QD × 14 days (d) per 28d cycle (dose level [DL] −1), which can be de-escalated to 200 mg QD × 14d depending on dose-limiting toxicities (DLTs); VEN 400 mg QD is taken continuously (or 21d per cycle; DL −2). Dosing decisions are guided by a modified toxicity probability interval 2 (mTPI-2) design. The primary endpoint is to evaluate safety/tolerability and establish the maximum tolerated dose (MTD) of Oral-AZA + VEN in R/R AML (starting dose for part 2). Secondary endpoints are to assess preliminary investigator-determined response rates per ELN 2017 AML response criteria (Döhner et al., Blood 2017) for complete remission (CR), CR with partial hematologic recovery, CR with incomplete blood count recovery (CRi), morphologic leukemia-free state, overall response, and measurable residual disease (plus conversion rate). Results: Pt enrollment began in December 2021 and is ongoing; data from part 1 are available for 5 pts (3 female; aged 51–80 years). 3 pts had 1 prior line of Tx and 2 pts had 2. Oral-AZA + VEN was given for 1–12 cycles. Of the 5 pts, 3 reported ≥ 1 any grade (Gr) drug-related adverse event, the most common of which were Gr 1–3 diarrhea (2 pts) and Gr 1–2 nausea (2 pts). Gr 3 febrile neutropenia, which was not deemed drug related, was reported in 4 pts (6 episodes total). In 1 pt, Oral-AZA was reduced to 200 mg QD x 14d from cycle 4 due to Gr 1 diarrhea and VEN to 70 mg QD x 28d from cycle 3 due to co-Tx with a strong CYP3A inhibitor (per protocol). 3 pts died after Tx discontinuation. No DLTs were observed and MTD of Oral-AZA + VEN was determined to be Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d. As of January 2023, 2 pts remained on Tx and best response achieved was CRi in 2 pts and stable disease in 3 pts. Conclusions: These results indicate that a MTD of Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d has a manageable safety profile consistent with known profiles of the 2 agents. Further evaluation in AML is warranted. Clinical trial information: NCT04887857 .

Efficacy of a novel chewable tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio\u2122) against four common tick species infesting dogs in Europe

BackgroundTick infestations can cause direct deleterious effects to dogs as a result of tick blood-feeding, and indirectly ticks can transmit disease agents that can be detrimental to the health of both dogs and humans. Six laboratory studies were conducted to support dosage selection and efficacy confirmation of a novel combination of sarolaner, moxidectin and pyrantel against four tick species that commonly infest dogs in Europe.MethodsTwo studies were conducted against Dermacentor reticulatus (one of which was a dose determination study), two against Ixodes ricinus, and one each against Ixodes hexagonus and Rhipicephalus sanguineus (sensu lato). In each study, eight purpose-bred Beagle or mix-breed dogs were randomly allocated to each treatment group and infested with 50 unfed adult ticks on Days-2, 5, 12, 19, 26 and 33. On Day 0 dogs were treated orally with placebo or the combination product. In the dose determination study, dogs received sarolaner at point dosages of 0.6 mg/kg, 1.2 mg/kg or 2.4 mg/kg in combination with moxidectin and pyrantel, and in all other studies dogs received Simparica Trio™ to provide minimum dosages of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel (as pamoate salt). Efficacy was assessed based on live tick counts conducted 48 hours after treatment and each weekly infestation.ResultsThere were no treatment-related adverse events in any study. In the dose determination study, 1.2 mg/kg sarolaner was the lowest dosage evaluated that provided > 90% efficacy for at least 28 days and therefore was selected as the dosage to provide tick control for at least one month following a single oral treatment. In the dose confirmation studies, a single oral dose of Simparica Trio™ provided ≥ 99.2% efficacy against existing infestations of all tick species, and against re-infestations efficacy was ≥ 97.2% against D. reticulatus for 28 days and against all other species for 35 days.ConclusionsThese studies support the sarolaner dose selected and confirm the efficacy of a single oral dose of Simparica Trio™ against existing infestations and re-infestations of the common tick species infesting dogs in Europe for at least one month.

AS1-KL-1 DEVELOPMENT OF HIGH-DOSE CHEMOTHERAPY INCLUDING THIOTEPA COMBINED WITH AUTOLOGOUS PERIPHERAL BLOOD STEM CELL RESCUE

Thiotepa is a classic alkylating agent that was launched in 1958 in Japan. We have consistently developed thiotepa-containing HDC since 1992, inspired by the fact that thiotepa was used as an alternative to melphalan as a high-dose chemotherapy (HDC) drug for neuroblastoma in the United States. Thiotepa is considered to be a drug suitable for brain tumor treatment because of its good BBB permeability, equal concentration in cerebrospinal fluid and blood, and the characteristics of alkylating agents that enhance the effect by log ratio of dose. Melphalan, which is also an alkylating agent as a central agent of HDC, has a strong antitumor effect, so we planned to use both at the maximum tolerated dose for each. Therefore, in order to reduce toxicity, it was decided to divide it into two doses at weekly intervals and to administer thiotepa for 24 hours in order to prevent hepatic sinus obstruction syndrome (SOS). Since 1993, a dose determination study was conducted, and the doses of thiotepa and melphalan were determined to be 800 mg/m2 and 280 mg/m2, respectively. Autologous peripheral blood stem cell transplantation using this regimen was performed as a consolidation therapy for metastatic pediatric medulloblastoma in 28 and 15 patients, respectively, in 2 series. Five-year progression-free survival rates of 82.1 ± 7.2% and 92.9 ± 6.9% were obtained. After that, the supply was stopped in 2009. This time, a domestic study was conducted with the dose of melphalan reduced to 210 mg/m2, and this year, a new indication (pretreatment for autologous hematopoietic stem cell transplantation in childhood malignant solid tumors) was acquired and launched. By this dose reduction, reduced gastrointestinal toxicity such as mucosal damage is expected. The JCCG clinical trials incorporating HDC will be conducted in medulloblastoma, ATRT, and refractory germ cell tumors.

A First-in-human Study of Tenalisib (RP6530), a Dual PI3K δ/γ Inhibitor, in Patients With Relapsed/Refractory Hematologic Malignancies: Results From the European Study

BackgroundTenalisib (RP6530) is a novel, highly specific, dual phosphoinositide-3 kinases (PI3K) δ/γ inhibitor with nano-molar potency. Material and MethodsThis was a phase I, open-label, 3 + 3 dose escalation, maximum tolerated dose determination study to evaluate the safety, pharmacokinetics, and efficacy of tenalisib in patients with relapsed/refractory hematologic malignancies. Tenalisib was administered orally twice/thrice daily in 28-day cycles with starting dose of 25 mg twice daily. ResultsThirty-five patients were enrolled across 11 dose levels. No dose limiting toxicity was reported at any of the dose levels. The most common treatment-emergent adverse events irrespective of causality were asthenia and cough in 15 (43%) patients and pyrexia in 13 (37%) patients. The most frequently reported related treatment-emergent adverse events were diarrhea, nausea, and vomiting. Related grade 3/4 adverse events were limited to events of hypertriglyceridemia, neutropenia, and diarrhea.Pharmacokinetics showed rapid absorption. Based on maximum plasma concentration and area under the plasma-concentration time curve, dose proportionality was observed up to 400 mg dose. Of 31 patients included in the efficacy analysis, complete response was seen in 2 (7%) patients and partial response in 4 (13%) patients, with an overall response rate of 19% and a disease-control rate of 61%. The median duration of response was 5.7 months. Responders demonstrated a marked downregulation of phospho-AKT on C1D8. ConclusionTenalisib demonstrated acceptable safety up to 1200 mg twice a day with no dose-limiting toxicities. Consistent clinical response was seen at doses 200 mg BID and above. Pharmacodynamics correlated well with clinical outcome. Further phase I/II studies are being undertaken to evaluate efficacy across different histologies.

In vitro anti-LPS dose determination of ketorolac tromethamine and in vivo safety of repeated dosing in healthy horses.

Flunixin meglumine (FM) is a commonly used Nonsteroidal anti-inflammatory drug (NSAID) in horses, but clinical efficacy is often unsatisfactory. Ketorolac tromethamine (KT) demonstrates superior efficacy compared to other NSAIDs in humans, but its anti-inflammatory effects have not been investigated in the horse. Safety of repeated dosing of KT has not been evaluated. The first objective was to conduct a dose determination study to verify that a previously described dosage of KT would inhibit Lipopolysaccharide (LPS)-induced eicosanoid production in vitro, and to compare KT effects of this inhibition to those of FM. Then, a randomized crossover study was performed using nine healthy horses to evaluate plasma concentrations of KT and FM following IV administration. Administered dosages of KT and FM were 0.5mg/kg and 1.1mg/kg, respectively. Safety following six repeated doses of KT was assessed. Ketorolac tromethamine and FM suppressed LPS-induced Thromboxane B2 (TXB2 ) and Prostaglandin E2 (PGE2 ) production in vitro for up to 12hr. Intravenous administration produced plasma concentrations of KT and FM similar to previous reports. No adverse effects were observed. A KT dosage of 0.5mg/kg IV inhibited LPS-induced eicosanoids in vitro, and repeated dosing for up to 3days appears safe in healthy horses. Investigation of in vivo anti-inflammatory and analgesic effects of KT is warranted.

Use of Sitagliptin With Closed-Loop Technology to Decrease Postprandial Blood Glucose in Type 1 Diabetes.

Postprandial hyperglycemia poses a challenge to closed-loop systems. Dipeptidyl peptidase-4 (DPP-4) inhibitors, like sitagliptin, reduce postprandial glucose concentrations in patients with type 2 diabetes. The objective of this study was to assess sitagliptin's role in type 1 diabetes (T1DM) as an adjunct therapy in reducing postprandial blood glucose with an insulin-only closed-loop system. This was a randomized, double-blinded, placebo controlled, crossover design trial. The participants were18-35 years old, had T1DM, and an HbA1c of ≤ 8.5%. A dose determination study included eight subjects with T1DM. There were three study visits. Four hours after receiving study drug (placebo, sitagliptin 50 mg, sitagliptin 100 mg), subjects underwent a mixed meal tolerance test with assessment of hormone concentrations. In a second study, 15 subjects underwent two visits receiving either placebo or 100 mg of sitagliptin plus an insulin only closed-loop system for 25 hours with timed meals. Blood glucose and other hormone concentrations were analyzed using repeated measures ANOVA. For the dose determination study, sitagliptin 100 mg resulted in reduced postprandial blood glucose ( P = .006). For the closed-loop study, glucose concentrations were lower in the treatment group, most prominently during the first two study meals ( P = .03). There was no difference in glucagon concentrations, but insulin concentrations and insulin delivery were lower in the treatment group. Sitagliptin may be considered as an adjunct therapy in a closed-loop setting. Larger studies are needed to determine the role of oral agents like sitagliptin to lower postprandial hyperglycemia with closed loop.

Abstract OT3-06-01: KARISMA, The karma intervention study. - A tamoxifen dose determination trial

Abstract Background: Breast cancer incidence is increasing throughout the world. Despite remarkable risk reducing effects demonstrated in preventive randomised endocrine trials; primary preventive strategies are scarcely part of clinical routine. Putative reasons for reluctance may be inadequate tools for identification of women at high risk of breast cancer and reluctance to prescribe pharmaceuticals with considerable side effects in the preventive setting. Trial Design: A randomized, double blinded, six-armed placebo controlled dose determination study to investigate the optimal dose of tamoxifen with the most favorable side effect spectra. To reduce the number of participants, costs and to shorten the trial period; change in mammographic density will be used as clinical outcome. After randomization and baseline mammography, women will be treated with placebo, 1mg, 2.5mg, 5mg, 10mg or 20mg of tamoxifen for six months where after a subsequent mammogram is performed. Eligibility criteria: 1) Attending the national Swedish mammography screening program, 2) Having a measurable mammographic density, i.e. ≥4.5 % density (volumetric) measured by Volpara. Specific aims: The primary aim is to identify the minimum dose of tamoxifen non-inferior in its ability to reduce mammographic density and with fewer side effects compared to 20 mg of tamoxifen. Secondarily, to study the associations between different doses of tamoxifen and changes in circulating levels of a number of proteins, lipids, hormones, and tamoxifen metabolites, including the impact of polymorphisms in the CYP2D6 gene. A translational aim is to study molecular changes in the healthy breast tissue as a result of tamoxifen exposure. Statistical Methods: Previous studies have shown that ∼ 50% of women treated with 20mg of tamoxifen have a reduction in density and respond to therapy. We therefore use the median density decrease in women treated with 20mg tamoxifen as the predefined response threshold. The primary efficacy endpoint is thus the proportion of responders that reaches this threshold. We will test for non-inferiority after treatment with placebo, 1mg, 2.5mg, 5mg, and 10mg compared to the group of women treated with 20mg tamoxifen. Per definition 50% of the women in the 20mg group are responders. The non-inferiority margin is defined to be 16.7 percentage points; that is the fraction of responders is not less than one third of the treated individuals (50% minus 16.7% = 33.3%).The null hypothesis is thus that the proportion of responders in women treated with placebo, 1mg, 2.5mg, 5mg, and 10mg is 33.3% or higher. Power calculations have determined a need of 1200 participants corresponding to 200 participants in each treatment arm. Present accrual and target accrual: The trial will start recruiting as of September 2016. Eligible women are identified from the Swedish mammographic screening cohort, i.e. women age 40-74 years invited for biennial screening. Contact information for people with a specific interest in the trial: Signe.Borgquist@med.lu.se & Per.Hall@ki.se. Citation Format: Borgquist S, Eriksson M, Czene K, Hall P. KARISMA, The karma intervention study. - A tamoxifen dose determination trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-06-01.

Efficacy of a new combination of fipronil and permethrin (Effitix®) against Phlebotomus perniciosus in dogs

Two controlled clinical trials were carried out to assess the anti-feeding and adulticidal effects of a spot-on combining fipronil and permethrin (Effitix®, Virbac, Carros, France) against Phlebotomus perniciosus in dogs. The first study (Exp. A) was a dose-determination study in which 3 doses of permethrin (30mg/kg, 60mg/kg and 120mg/kg) were compared. The second study (Exp. B) was an efficacy study using commercial dose of permethrin contained in Effitix® (the minimum dose of permethrin applied to dogs was 60mg/kg). Twenty four and twelve Beagle dogs with equal sensitivity to sandflies were included in Exp. A and in Exp. B, respectively. Dogs were challenged with female sandflies (50 per dogs in Exp. A and 80 in Exp. B) for 60±5min on Days – 7, 1, 7, 14, 21 and 28 (Day 0 being treatment day). Counts and engorgement determination of dead and alive sandflies were performed after each exposure to treated and untreated dogs. Dead sandflies were also counted 24h after exposure. In Exp. A, the repellency induced by an administration of 30mg/kg of permethrin to dogs was above 91% for the first two weeks and then dropped to 82.2, 83.1 and 81.1% on Days 14, 21 and 28, respectively. For dogs receiving 60mg/kg of permethrin, the repellency was a bit higher with 95.8, 97.6, 92.1, 91.4, and 86.8%, for Days 1, 7, 14, 21 and 28, respectively. The repellency induced by 120mg/kg of permethrin was significantly higher than that induced by 60mg/kg of permethrin on Day 14 only. In Exp. B the anti-feeding effect of the spot-on formulation was 94.1, 97.8, 96.3, 90.8 and 87% on Days 1, 7, 14, 21 and 28, respectively. The mortality effect was 98.9, 99.1, 99.8, 97.0 and 89.7% on Days 1, 7, 14, 21 and 28, respectively. At each challenge point, the mortality and anti-feeding effects on sandflies were significantly different between control and treatment group (p<0.05). The results indicate that a monthly administration of this new combination of permethrin and fipronil could be used as an effective sandfly control strategy in dogs and therefore recommended for use in an integrated leishmaniosis prevention program.

한약 및 천연물의 항암 임상연구 방법론에 대한 고찰

Objectives : The cancer incidence and cancer burden is increasing. In addition, the use of botanical agents in cancer care is increasing. This article aims to review a research strategy for botanical agents. Methods : The clinical studies of anticancer botanical agents and the papers about clinical research methodology of botanical agents were reviewed. Results : In phase I study, safety confirmation, optimal dose determination and drug interaction study are important. Most botanical agents have low toxicity and some have non-monotone dose response. Therefore, dose-response curve must be evaluated separately from the dose-toxicity curve to determine optimal dose. Although anticancer botanical agents can't shrink tumor size rapidly, they do extend survival. So, in phase II study, response should be evaluated by the survival. Conclusions : Clinical research of botanical agents in cancer is different from traditional methods and strategies. Considering the characteristics of botanical agents and experimental mechanism is necessary in conducting botanical based clinical trials.

Broad spectrum antiviral activity of favipiravir (T-705): protection from highly lethal inhalational Rift Valley Fever.

BackgroundDevelopment of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705), which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV). RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route.Methodology/Principal FindingsWistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92%) survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease.Conclusions/SignificanceCurrently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug.

Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug

BackgroundDose selection is an important step in pharmacokinetic (PK) studies of hemodialysis patients. We propose a simulation-based dose-selection method for PK studies of hemodialysis patients using a subpharmacological dose of oseltamivir as a model drug.MethodsThe concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured by liquid chromatography-tandem mass spectrometry. To determine a low oseltamivir dose exhibiting PK linearity, a pilot low dose determination investigation (n = 4) was performed using a single administration dose-escalation study. After the dose was determined, a low dose study (n = 10) was performed, and the optimal dose required to reach the hypothetical target OC exposure (area under the concentration-time curve [AUC] of 60,000 ng · hr/mL) was simulated using a nonparametric superposition method. Finally, observed PKs at the optimal dose were compared to the simulated PKs to verify PK predictability.ResultsIn the pilot low dose determination study, 2.5 mg of oseltamivir was determined to be the low dose. Subsequently, we performed a single-dose PK study with the low oseltamivir dose in an additional group of 10 hemodialysis patients. The predicted AUClast of OC following continuous oseltamivir doses was simulated, and 35 mg of oseltamivir corresponded to the hypothetical target AUClast of OC. The observed PK profiles of OC at a 35-mg oseltamivir dose and the simulated data based on the low dose study were in close alignment.ConclusionThe results indicate that the proposed method provides a rational approach to determine the proper PK dose in hemodialysis patients.

Fractionated Scheme of Oral Vinorelbine as Single-Agent Therapy or in Combination With Cisplatin Concomitantly With Thoracic Radiotherapy in Stage III Non–Small-Cell Lung Cancer: Dose-Escalation Phase I Trial

IntroductionA dose-determination study was conducted in untreated stage III non–small-cell lung cancer to assess continuous exposure to fractionated oral vinorelbine (NVBo), a radiosensitizer, during the radiotherapy period, either alone (first cohort) or in combination with cisplatin (second cohort). Patients and MethodsThree patients with stage IIIAN2/IIIB were expected at each dose level, with 3 additional patients in case of dose-limiting toxicity (DLT). Concomitantly with a 60-Gy total dose of radiotherapy, NVBo was given from 60 mg up to 180 mg total dose per week split on days 1, 3, and 5. Once the maximum tolerated dose (MTD), defined as 2 DLTs in a dose level, was determined and the recommended dose of NVBo alone was established, the trial assessed its recommended dose in combination with cisplatin 80 mg/m2 every 3 weeks. ResultsIn the first cohort, 26 patients were enrolled. MTD was 160 mg/wk; there were 3 cases of grade 3 esophagitis and 1 of grade 3 pneumonia as DLT out of 5 patients in this dose level. In the recommended dose level (150 mg/wk), only 1 of 6 patients experienced a DLT. In the second cohort, 11 patients received NVBo weekly doses from 130 mg to 150 mg with cisplatin. Only 2 patients received 150 mg/wk NVBo; the trial closed before MTD was determined. The confirmed response rates were 42% and 55% in the first and second cohort, respectively. ConclusionThe recommended dose of this fractionated NVBo scheme as single-agent therapy concomitantly with radiotherapy for 6 weeks is 50 mg on days 1, 3, and 5 (150 mg/wk); combined with cisplatin 80 mg/m2 every 3 weeks, the dose should be 140 to 150 mg/wk adapted on hematology. The response rate is promising.

Chinese herbal medicine (Ma Zi Ren Wan) for functional constipation: study protocol for a prospective, double-blinded, double-dummy, randomized controlled trial

BackgroundFunctional constipation is a common clinical complaint. Although the effectiveness of Ma Zi Ren Wan for alleviating functional constipation symptoms has been proven in a previous randomized placebo-controlled study, further evidence is needed to make clinical recommendations about Chinese herbal medicine. In particular, a comparison with conventional western medicine for functional constipation patients is needed.Methods/DesignThis is a prospective, double-blinded, double dummy, randomized, controlled trial. After a 2-week run-in period, eligible patients (Rome III) with excessive traditional Chinese medicine syndrome will randomly be assigned to the Chinese medicine arm (Ma Zi Ren Wan and western medicine placebo), western medicine arm (senna and Chinese medicine placebo) or placebo arm (Chinese medicine placebo and western medicine placebo). Patients will undergo an 8-week treatment and an 8-week follow-up. The primary outcome is the responder rate for complete spontaneous bowel movement (CSBM) during treatment. Patients with a mean increase of CSBM ≧1/week in comparison with their baselines are defined as responders. The secondary outcomes include responder rate during follow-up, changes of colonic transit as measured with radio-opaque markers, individual and global symptom assessments, and reported adverse effects.DiscussionThis study is the first study to compare a Chinese Herbal Medicine (Ma Zi Ren Wan) with a laxative that is commonly used in the clinical practice of western medicine, and with a placebo. This study will complete the investigation of Ma Zi Ren Wan for functional constipation, and should, therefore, suggest recommendations for clinical practice. Furthermore, the process of first conducting a systematic review, then implementing a dose determination study followed by a placebo-control trial, and finally, comparing traditional Chinese medicine with an active conventional medicine in a controlled trial can be a reference to other researches on Chinese medicine interventions in the future.Trial registrationNCT01695850

Anticoccidial effects of a novel triazine nitromezuril in broiler chickens

The anticoccidial efficacy of 2-(3-methyl-4-(4-nitrophenoxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (nitromezuril, NZL), a novel triazine compound, was evaluated in three different studies under experimental conditions. The anticoccidial efficacy was chiefly evaluated using the anticoccidial index (ACI). The resistance level was determined by calculating ACI, percentage optimum anticoccidial activity (POAA), reduction in lesion scores (RLS) and relative oocyst production (ROP). In the dose determination study (study A), NZL was added to the diet at doses of 1, 2, 3, 4, 5 and 6mg/kg to test its efficacy against coccidiosis caused by Eimeria tenella. Groups treated with NZL 1mg/kg feed could observe the faecal dropping scores and caecal lesions. ACIs of NZL-treated groups reached 179–199. In the study on the anticoccidial efficacy of 3mg/kg NZL in the diet (study B), only a few faecal oocysts and slight lesions were observed. NZL significantly promoted weight gain (WG) and reduced lesion scores (LS) compared to controls receiving diclazuril (DZL) (P<0.05). ACIs of NZL-treated groups were 193, 192, 191 and 163 for E. tenella, Eimeria necatrix, Eimeria acervulina and Eimeria maxima, respectively, whereas those of DZL-treated groups were 185, 176, 176 and 148. In the cross-drug resistance study (study C), ACIs of NZL and toltrazuril (TZL)-treated groups ranged from 188 to 204, which were significantly higher than those of DZL-treated groups (P<0.05). NZL- and TZL-treated groups were sensitive to experimentally induced DZL-resistant E. tenella, whereas DZL-treated groups showed complete resistance. No cross-resistance was observed between DZL and NZL or TZL. Based on the abovementioned studies, it was concluded that diets containing 3mg/kg NZL had an excellent efficacy in preventing coccidiosis in broiler chickens. The activity of 3mg/kg NZL in the diet was equal or superior to that of 1mg/kg DZL. These results are of great significance for the future applications of NZL; however, its actual mechanism of action remains unknown. NZL is a potential novel anticoccidial agent suitable for further development.

Oral vinorelbine (NVBo) at 3-weekly flat-dose intakes (FDI) as single agent or with cisplatin (CDDP) concomitantly with thoracic radiotherapy (RT) in stage III NSCLC: Escalation-dose phase I trial results.

7045 Background: In vitro, vinorelbine (NVB) has shown to be a powerful radiosensitizer. Based on the bioavailability of NVBo, a dose-determination study was implemented in patients (pts) with untreated locally advanced or inoperable stage III NSCLC assessing continuous exposure to NVBo through 3 times a week (w) FDI during the RT period, either alone (1st part of the trial) or in combination with CDDP (2nd part). Methods: 3 pts with stage IIIAN2/IIIB NSCLC were expected at each dose-level (L) with 3 additional pts in case of a dose-limiting toxicity (DLT): age 18-70 years, adequate bone marrow, hepatic and renal function, KPS ≥80%. NVBo was given concomitantly with 60 Gy RT (2 Gy/day; 5 days/w) from 60 mg up to 180 mg total-dose/w splited on days (D) 1, 3 and 5 during 6 w. Based on the maximal tolerated dose (MTD) defined as 2 DLT in a L and the recommended dose (RD) of NVBo alone, the trial assessed its RD in combination with CDDP 80 mg/m2 D1 every 3 w (q3w) in a 2nd cohort. Results: In the 1st cohort, ...

Efficacy of a Chinese Herbal Proprietary Medicine (Hemp Seed Pill) for Functional Constipation

Functional constipation (FC) is a common clinical complaint. Despite a lack of consolidated evidence, Chinese herbal medicine (CHM) has become a popular alternative treatment for this condition. The aim of this study was to assess, with a rigidly designed study, the efficacy and safety of a CHM proprietary medicine, Hemp Seed Pill (HSP), in optimal dosage for treating FC. This study comprised two parts: trial I, a dose determination study, and trial II, a placebo-controlled clinical study. In trial I, the optimal dosage of HSP was first determined from among three doses (2.5, 5.0, and 7.5 g b.i.d.). In trial II, a randomized double-blind study, the efficacy and safety of HSP for FC patients (Rome III criteria) in excessive syndrome as defined by traditional Chinese medicine (TCM) theory were compared with placebo. All participants in trials underwent a 2-week run-in, an 8-week treatment, and an 8-week follow-up. The primary end point was the responder rate for complete spontaneous bowel movement (CSBM) during treatment. Participants with a mean increase of CSBM ≧ 1/week compared with their baselines were defined as responders. Secondary outcome measures included responder rate during follow-up, individual and global symptom assessments, and reported adverse effects (AEs). The dose of 7.5 g b.i.d. showed better therapeutic effect than that of 2.5 and 5.0 g b.i.d. among 96 subjects (32 per arm) in trial I and was therefore selected for comparison with placebo in trial II. In trial II, 120 subjects were randomized into two arms (60 per arm). Responder rates for the HSP and placebo groups were 43.3 and 8.3% during treatment and 30.0 and 15.0% in the follow-up period, respectively (P<0.05). Those in the HSP group showed benefit in terms of increased CSBM, relief in the severity of constipation and straining of evacuation, and effective reduction in the use of rescue therapy when compared with placebo. No serious AE was reported. HSP (7.5 g b.i.d.) is safe and effective for alleviating FC for subjects in excessive syndrome. Optimal dose determination may be crucial for all CHM studies.

Efficacy of Emodepside plus Praziquantel Tablets (Profender® Tablets for Dogs) against Mature and Immature Adult Trichuris vulpis Infections in Dogs

This paper reports on the efficacy of a novel flavoured tablet formulation of emodepside plus praziquantel (Profender tablets for dogs) against mature and immature adult whipworms (Trichuris vulpis) at the proposed minimum dose of 1 mg emodepside and 5 mg praziquantel per kg body weight in dogs. Three randomised, blinded and controlled laboratory studies with naturally or experimentally infected dogs were performed. The first study was conducted as a dose determination study in experimentally infected dogs using three different dose levels, i.e., 0.5x, 1x and 2x the minimum therapeutic dose. Two further studies confirmed the efficacy of emodepside plus praziquantel tablets against mature and immature adult T. vulpis at the recommended minimum dose. In all three studies, the efficacy against mature and immature adult T. vulpis was >99%. No side effects of the treatment were observed. It is concluded that the emodepside plus praziquantel tablet is an effective and safe treatment against mature and immature adult stages of T. vulpis in dogs.

RecombinantMycobacterium bovisBCG Prime-Recombinant Adenovirus Boost Vaccination in Rhesus Monkeys Elicits Robust Polyfunctional Simian Immunodeficiency Virus-Specific T-Cell Responses

While mycobacteria have been proposed as vaccine vectors because of their persistence and safety, little has been done systematically to optimize their immunogenicity in nonhuman primates. We successfully generated recombinant Mycobacterium bovis BCG (rBCG) expressing simian immunodeficiency virus (SIV) Gag and Pol as multigenic, nonintegrating vectors, but rBCG-expressing SIV Env was unstable. A dose and route determination study in rhesus monkeys revealed that intramuscular administration of rBCG was associated with local reactogenicity, whereas intravenous and intradermal administration of 10(6) to 10(8) CFU of rBCG was well tolerated. After single or repeat rBCG inoculations, monkeys developed high-frequency gamma interferon enzyme-linked immunospot responses against BCG purified protein derivative. However, the same animals developed only modest SIV-specific CD8(+) T-cell responses. Nevertheless, high-frequency SIV-specific cellular responses were observed in the rBCG-primed monkeys after boosting with recombinant adenovirus 5 (rAd5) expressing the SIV antigens. These cellular responses were of greater magnitude and more persistent than those generated after vaccination with rAd5 alone. The vaccine-elicited cellular responses were predominantly polyfunctional CD8(+) T cells. These findings support the further exploration of mycobacteria as priming vaccine vectors.

A feasibility study on biweekly administration of docetaxel for patients with recurrent ovarian cancer☆

Objective A recent study demonstrated that docetaxel (DTX) was an effective agent for second line chemotherapy against ovarian cancer. Weekly administration of taxane compounds had been more effective compared with a 3 week interval administration in ovarian cancer. The role of biweekly administration of DTX has been unknown. We conducted a dose determination and feasibility study of biweekly DTX administration in patients with ovarian cancer. Methods Patients with histologically confirmed epithelial ovarian cancer who received one or more regimens of prior chemotherapy with more than 4 weeks of treatment-free interval were eligible. DTX was administered as 1-h intravenous infusion every two weeks for at least four courses. The starting dose was 40 mg/m 2 (level 1) and the dose was escalated to 50 mg/m 2 (level 2) and 60 mg/m 2 (level 3) in consequent patient cohorts. Results Nine patients were examined in this study. The treatments were completely performed in all cohorts. Mean treatment delay ranged from 0 to 2.0 days. Dose level did not affect treatment delay. At the first dose level, no patients experienced grade 3/4 neutropenia. Two patients in level 2 experienced grade 3/4 neutropenia. In level 3, all patients had grade 4 neutropenia. Nonhematologic toxicities were tolerable. Of eight patients with measurable disease, all patients in level 1 showed progressive disease, and all patients in level 2 were no-change. There were two responders showing complete response and partial response and one case was no-change in level 3. Conclusion The present study showed that biweekly administration of 60 mg/m 2 DTX was feasible for recurrent ovarian cancer.