Safety Of Oral Treatment Research Articles

CANNA-TICS: Efficacy and safety of oral treatment with nabiximols in adults with chronic tic disorders – Results of a prospective, multicenter, randomized, double-blind, placebo controlled, phase IIIb superiority study

Preliminary data suggest that cannabis-based medicines might be a promising new treatment for patients with Tourette syndrome (TS)/chronic tic disorders (CTD) resulting in an improvement of tics, comorbidities, and quality of life. This randomized, multicenter, placebo-controlled, phase IIIb study aimed to examine efficacy and safety of the cannabis extract nabiximols in adults with TS/CTD (n = 97, randomized 2:1 to nabiximols:placebo). The primary efficacy endpoint was defined as a tic reduction of ≥ 25% according to the Total Tic Score of the Yale Global Tic Severity Scale after 13 weeks of treatment. Although a much larger number of patients in the nabiximols compared to the placebo group (14/64 (21·9%) vs. 3/33 (9·1%)) met the responder criterion, superiority of nabiximols could formally not be demonstrated. In secondary analyses, substantial trends for improvements of tics, depression, and quality of life were observed. Additionally exploratory subgroup analyses revealed an improvement of tics in particular in males, patients with more severe tics, and patients with comorbid attention deficit/hyperactivity disorder suggesting that these subgroups may benefit better from treatment with cannabis-based medication. There were no relevant safety issues. Our data further support the role of cannabinoids in the treatment of patients with chronic tic disorders.

Setting research priorities for management and treatment of hyperhidrosis: the results of the James Lind Alliance Priority Setting Partnership.

SummaryBackgroundHyperhidrosis is a common skin condition characterized by excessive sweating, which can negatively impact on quality of life. It is under‐researched compared with other conditions of similar prevalence.AimTo generate a Top 10 list of research priorities for the treatment and management of hyperhidrosis, with equal input from people with hyperhidrosis and healthcare professionals (HCPs).MethodsA priority setting partnership (PSP) was established and processes from the James Lind Alliance Handbook were followed. An online survey asked participants what questions they would like research to answer. These questions were grouped into ‘indicative questions’, which were ranked in a second survey of 45 indicative questions. The top 23 questions were then taken to a final workshop event attended by key stakeholders, and ranked to generate the Top 10 list of research priorities.ResultsThere were 592 questions submitted by 268 respondents for the first survey. For the second survey, 286 participants ranked the indicative questions in order of priority. At the final workshop, the Top 10 list was generated. The top three priorities were: (i) Are there any safe and effective permanent solutions for hyperhidrosis? (ii) What is the most effective and safe oral treatment (drugs taken by mouth) for hyperhidrosis? and (iii) What are the most effective and safe ways to reduce sweating in particular areas of the body?ConclusionsThere are many unanswered research questions that both people with hyperhidrosis and HCPs would like to see answered. The results from this PSP will help to ensure future research funding can be directed to these areas of priority.

CANNA-TICS: Efficacy and Safety of Oral Treatment with Nabiximols in Adults with Chronic Tic Disorders – Results of a Prospective, Multicenter, Randomized, Double-Blind, Placebo Controlled, Phase IIIb Superiority Study

CANNA-TICS: Efficacy and Safety of Oral Treatment with Nabiximols in Adults with Chronic Tic Disorders – Results of a Prospective, Multicenter, Randomized, Double-Blind, Placebo Controlled, Phase IIIb Superiority Study

Clinical safety of zafirlukast treatment during a foreign body inflammatory reaction in nile tilapias, oreochromis niloticus

Seeking to understand the defense mechanisms of tilapia to assist in the sanitary management of fish farms, this study aimed to evaluate the clinical safety of Nile tilapia (Oreochromis niloticus) submitted to oral treatment with 500μg of zafirlukast/Kg of body weight during chronic inflammation, through the implantation of round glass coverslips in the subcutaneous tissue. For this study, 63 male tilapiawere randomly distributed in 9 aquariums to compose the following treatments: Control submitted to inflammatory stimulus without treatment; CT – Conventional treatment; PT – Prolonged treatment. Seven animals were evaluated per treatment in three periods: 2, 4 and 8 days post-implantation (DPI).Tilapia during foreign body reaction showed a decrease in erythrocyte counts and hematocrit values, as well as macrocytic changes, these effects were mitigated by treatment with zafirlukast. Control tilapia showed a gradual increase over time in serum values of total protein, cholesterol, and triglycerides. Serum values of ALT, AST and alkaline phosphatase of control tilapia showed an increase in the late phase of the chronic inflammatory process (8 DPI). Therefore, it was possible to conclude that tilapia treated with 500µg of zafirlukast showed attenuation of hematological changes resulting from fluid-electrolyte imbalance during a foreign body inflammation, as well as ameliorated serum biochemical disorders, demonstrating the clinical safety of oral treatment with this cys-leukotriene blocker.

Kirenol inhibits RANKL-induced osteoclastogenesis and prevents ovariectomized-induced osteoporosis via suppressing the Ca2+-NFATc1 and Cav-1 signaling pathways

BackgroundOsteoporosis is a threat to aged people who have excessive osteoclast activation and bone resorption, subsequently causing fracture and even disability. Inhibiting osteoclast differentiation and absorptive functions has become an efficient approach to treat osteoporosis, but osteoclast-targeting inhibitors available clinically remain rare. Kirenol (Kir), a bioactive diterpenoid derived from an antirheumatic Chinese herbal medicine Herba Siegesbeckiae, can treat collagen-induced arthritis in vivo and promote osteoblast differentiation in vitro, while the effects of Kir on osteoclasts are still unclear. PurposeWe explore the role of Kir on RANKL-induced osteoclastogenesis in vitro and bone loss in vivo. MethodsThe in vitro effects of Kir on osteoclast differentiation, bone resorption and the underlying mechanisms were evaluated with bone marrow-derived macrophages (BMMs). In vivo experiments were performed using an ovariectomy (OVX)-induced osteoporosis model. ResultsWe found that Kir remarkably inhibited osteoclast generation and bone resorption in vitro. Mechanistically, Kir significantly inhibited F-actinring formation and repressed RANKL-induced NF-κB p65 activation and p-p38, p-ERK and c-Fos expression. Moreover, Kir inhibited both the expression and nuclear translocation of NFATc1. Ca2+ oscillation and caveolin-1 (Cav-1) were also reduced by Kir during osteoclastogenesis in vitro. Consistent with these findings, 2–10 mg/kg Kir attenuated OVX-induced osteoporosis in vivo as evidenced by decreased osteoclast numbers and downregulated Cav-1 and NFATc1 expression. ConclusionsKir suppresses osteoclastogenesis and the Cav-1/NFATc1 signaling pathway both in vitro and in vivo and protects against OVX-induced osteoporosis. Our findings reveal Kir as a potential safe oral treatment for osteoporosis.

Broad Spectrum and Safety of Oral Treatment with a Promising Nitrosylated Chalcone in Murine Leishmaniasis.

The oral efficacy and safety of a leishmanicidal nitrochalcone (CH8) were studied in BALB/c mouse infections with Leishmania amazonensis and Leishmania infantum Although 10-fold-higher doses of CH8 were needed to produce the same antiparasitic effect as that seen with the reference drug miltefosine, the latter was nephrotoxic, whereas CH8 restored disease toxicity markers to normal. This study shows the therapeutic potential of an orally active and hepato-/nephroprotective chalcone against cutaneous and visceral leishmaniases.

Prevention and treatment of cardiovascular complications of oral therapy

Acute cardiovascular event is common acute complication in oral therapy. This article describes how to assess risk of cardiovascular complications before oral treatment, and elabrates the prevention and treatment of angina, acute myocardial infarction, arrhythmia, cardiac arrest, cardiopulmonary resuscitation and other cardiovascular complications. Detailed assessment and comprehensive management of patients are important guarantee for safe oral treatment.

Integration of diagnosis and treatment of sleeping sickness in primary healthcare facilities in the Democratic Republic of the Congo.

Control of human African trypanosomiasis (HAT) in the Democratic Republic of Congo (DRC) has always been a vertical programme, although attempts at integration in general health services were made in recent years. Now that HAT prevalence is declining, the integration question becomes even more crucial. We studied the level of attainment of integration of HAT case detection and management in primary care centres in two high-prevalence districts in the province of Bandundu, DRC. We visited all 43 first-line health centres of Mushie and Kwamouth districts, conducted structured interviews and inspected facilities using a standardised checklist. We focused on: availability of well trained staff - besides HAT, we also tested for knowledge on tuberculosis; availability of equipment, consumables and supplies; and utilisation of the services. All health centres were operating but most were poorly equipped, and attendance rates were very low. We observed a median of 14 outpatient consultations per facility (IQR 8-21) in the week prior to our visit, that is two patients per day. The staff had good knowledge on presenting symptoms, diagnosis and treatment of both HAT and tuberculosis. Nine centres were accredited by the national programme as HAT diagnosis and treatment centres, but the most sensitive diagnostic confirmation test, the mini-anion exchange centrifugation technique (mAECT), was not present in any. Although all nine were performing the CATT screening test, only two had the required cold chain in working order. In these high-prevalence districts in DRC, staff is well-acquainted with HAT but lack the tools required for an adequate diagnostic procedure. Attendance rates of these primary care centres are extremely low, making timely recognition of a resurgence of HAT unlikely in the current state of affairs.

Direct comparison of the efficacy and safety of oral treatments with oleylphosphocholine (OlPC) and miltefosine in a mouse model of L. major cutaneous leishmaniasis.

BackgroundCutaneous leishmaniasis (CL) represents a range of skin diseases caused by infection with Leishmania parasites and associated with tissue inflammation and skin ulceration. CL is clinically widespread in both the Old and New World but lacks treatments that are well tolerated, effective and inexpensive. Oleylphosphocholine (OlPC) is a new orally bioavailable drug of the alkylphosphocholine family with potent antileishmanial activity against a broad range of Leishmania species/strains.Methodology/principal findingsThe potential of OlPC against Old World CL was evaluated in a mouse model of Leishmania (L.) major infection in BALB/c mice. Initial dose-response experiments showed that an oral daily dose of 40 mg/kg of OlPC was needed to impact time to cure and lesion sizes. This dose was then used to directly compare the efficacy of OlPC to the efficacy of the antileishmanial drugs miltefosine (40 mg/kg/day), fluconazole (160 mg/kg/day) and amphotericin B (25 mg/kg/day). OlPC, miltefosine and fluconazole were given orally for 21 days while amphotericin B was administered intraperitoneally for 10 days. Ulcer sizes and animal weights were followed up on a weekly basis and parasitemia was determined by means of a real-time in vivo imaging system which detects luminescence emitted from luciferase-expressing infecting L. major parasites. Amphotericin B and OlPC showed excellent efficacy against L. major lesions in terms of reduction of parasitic loads and by inducing complete healing of established lesions. In contrast, treatment with miltefosine did not significantly affect parasitemia and lesion sizes, while fluconazole was completely ineffective at the dose regimen tested.Conclusions/SignificanceGiven the data showing the outstanding efficacy and tolerability of OlPC, our results suggest that OlPC is a promising new drug candidate to improve and simplify current clinical management of L. major CL.

Teriflunomide for the Treatment of Relapsing Multiple Sclerosis

To review the pharmacology and clinical data for teriflunomide in relapsing multiple sclerosis (MS). A literature search from 1966 to May 2013 using PubMed/MEDLINE, Web of Science, International Pharmaceutical Abstracts, Academic Search Premiere, Science Citation Index, and the national clinical trials registry was performed using the terms teriflunomide, HMR1726, and A771726. All articles containing human clinical trial data and relevant pharmacologic information were reviewed. Phase 2 and phase 3 clinical trials for teriflunomide were evaluated. All peer-reviewed articles with clinically relevant information were reviewed. Priority for inclusion was placed on randomized controlled trials. Three phase 2 and three phase 3 clinical trials have evaluated teriflunomide as monotherapy or as adjunctive therapy in approximately 3000 patients with relapsing forms of MS. The phase 3 studies used annualized relapse rate, magnetic resonance imaging changes, and Expanded Disability Status Scale scores as outcome measures. One additional Phase 3 clinical study is ongoing. The annualized relapse rates and magnetic resonance imaging findings were improved compared to those with placebo and similar to or improved compared with those with subcutaneously administered interferon-β-1a 44 µg thrice weekly. Durability of response is supported by open-label extension studies. Common adverse events include increased liver function enzymes, alopecia, diarrhea, influenza, nausea, and paresthesias. Treatment discontinuation was not common and occurred in approximately 10% of patients in phase 3 studies. Teriflunomide is an effective and safe oral treatment option for relapsing MS. It can be used as monotherapy or added to an interferon or glatiramer acetate. It reduces the rate of relapse and may slow disease progression. The advantages of this drug are the convenience of oral administration and good tolerability. The disadvantage is the lack of long-term safety data and data about the benefit of combination therapy.

Effectiveness and safety of fumaric acid esters in children with psoriasis: a retrospective analysis of 14 patients from the Netherlands

Fumaric acid esters (FAE) are used as an effective and safe oral treatment for plaque psoriasis in adult patients, but little is known about their efficacy and safety in children with psoriasis. To assess the effectiveness and safety of FAE in the treatment of paediatric psoriasis. This is a retrospective analysis of 14 paediatric patients with psoriasis (age <18 years) treated with FAE between 2004 and 2012 at several Dutch university and regional clinics. Patients were identified through databases or registries. The median age at the start of FAE treatment was 15 years (range 8-17 years). The median duration of FAE treatment was 10 months (range 1-80 months), and the median maintenance dosage per day was 360 mg dimethylfumarate (range 240-600 mg). Five patients (36%) achieved a complete clearance of their psoriasis, one patient (7%) had a good improvement, three patients (21%) had a partial response and five patients (36%) were nonresponders. FAE treatment was well tolerated, but two patients (14%) discontinued FAE, one with severe diarrhoea and one with flushes. Five patients (36%) had transient, slightly abnormal laboratory values of liver-function tests or leucocytes that did not necessitate FAE dosage reduction or treatment discontinuation. No serious adverse events occurred. In this retrospective case series FAE seemed to be an effective and safe treatment for children with psoriasis. FAE may be an attractive therapeutic alternative to the currently used systemic immunosuppressive agents for paediatric patients with psoriasis. Further studies are needed to evaluate the suitability of FAE in paediatric psoriasis.

Apremilast as a treatment for psoriasis

Introduction: Psoriasis is a common skin disorder characterized by chronic inflammatory lesions that are frequently vexing for patients and difficult for physicians to treat. Although multiple therapeutic options are available, all have limitations. Topical preparations have issues with patient adherence, as compared to oral routes of administration. Currently available oral medications, such as methotrexate, possess unfavorable toxicity profiles that limit use. There is a large unmet need for an effective, safe oral treatment for psoriasis. Apremilast is an oral medication that inhibits the activity of multiple inflammatory markers involved in the pathogenesis of psoriasis.Areas covered: The present review article presents the pharmacokinetic properties of apremilast, as well as available preliminary pre-clinical and clinical trial data, and gives an overview of its safety and efficacy.Expert opinion: Apremilast has been well tolerated in phase I and II clinical trials. It has favorable safety and toxicity profiles at doses that are also effective for the treatment of plaque psoriasis. Phase III clinical trials are currently underway and will better elucidate appropriate dosing of apremilast and further illuminate its side effect profile. In future studies, a comparison of apremilast to other psoriasis medications administered through different routes would be beneficial, to document whether patient adherence is better with an oral medication. Depending on the price of the agent, efficacy and perhaps most importantly its safety profile, apremilast may fill a key need as a safe, first-line oral treatment for patients with psoriasis.

Successful Outcomes with Oral Fluoroquinolones Combined with Rifampicin in the Treatment of Mycobacterium ulcerans: An Observational Cohort Study

BackgroundThe World Health Organization currently recommends combined streptomycin and rifampicin antibiotic treatment as first-line therapy for Mycobacterium ulcerans infections. Alternatives are needed when these are not tolerated or accepted by patients, contraindicated, or neither accessible nor affordable. Despite in vitro effectiveness, clinical evidence for fluoroquinolone antibiotic use against Mycobacterium ulcerans is lacking. We describe outcomes and tolerability of fluoroquinolone-containing antibiotic regimens for Mycobacterium ulcerans in south-eastern Australia.Methodology/Principal FindingsAnalysis was performed of prospectively collected data including all primary Mycobacterium ulcerans infections treated at Barwon Health between 1998 and 2010. Medical treatment involved antibiotic use for more than 7 days; surgical treatment involved surgical excision of a lesion. Treatment success was defined as complete lesion healing without recurrence at 12 months follow-up. A complication was defined as an adverse event attributed to an antibiotic that required its cessation. A total of 133 patients with 137 lesions were studied. Median age was 62 years (range 3–94 years). 47 (34%) had surgical treatment alone, and 90 (66%) had combined surgical and medical treatment. Rifampicin and ciprofloxacin comprised 61% and rifampicin and clarithromycin 23% of first-line antibiotic regimens. 13/47 (30%) treated with surgery alone failed treatment compared to 0/90 (0%) of those treated with combination medical and surgical treatment (p<0.0001). There was no difference in treatment success rate for antibiotic combinations containing a fluoroquinolone (61/61 cases; 100%) compared with those not containing a fluoroquinolone (29/29 cases; 100%). Complication rates were similar between ciprofloxacin and rifampicin (31%) and rifampicin and clarithromycin (33%) regimens (OR 0.89, 95% CI 0.27–2.99). Paradoxical reactions during treatment were observed in 8 (9%) of antibiotic treated cases.ConclusionsAntibiotics combined with surgery may significantly increase treatment success for Mycobacterium ulcerans infections, and fluoroquinolone combined with rifampicin-containing antibiotic regimens can provide an effective and safe oral treatment option.

Miltefosine induces programmed cell death in Leishmania amazonensis promastigotes

In the current study, we evaluated the mechanism of action of miltefosine, which is the first effective and safe oral treatment for visceral leishmaniasis, in Leishmania amazonensis promastigotes. Miltefosine induced a process of programmed cell death, which was determined by the externalization of phosphatidylserine, the incorporation of propidium iodide, cell-cycle arrest at the sub-G0/G1 phase and DNA fragmentation into oligonucleosome-sized fragments. Despite the intrinsic variation that is detected in Leishmania spp, our results indicate that miltefosine causes apoptosis-like death in L. amazonensis promastigote cells using a similar process that is observed in Leishmania donovani.

Immunosuppressive oral prednisone after percutaneous interventions in patients with multi-vessel coronary artery disease. The IMPRESS-2/MVD study.

To assess efficacy and safety of oral treatment with prednisone at immunosuppressive dose after percutaneous coronary interventions (PCI) in patients with multi-vessel coronary artery disease (CAD). Eighty-six consecutive patients with multi-vessel CAD were successfully treated with multiple PCI. Forty-three patients (115 coronary stenoses), with C-reactive protein >3mg/L 48 hours after PCI and in absence of contra-indications received 45-day high-dose oral prednisone treatment (study-group). Forty-three patients (106 coronary stenoses), did not receive prednisone (control-group). The primary clinical endpoint was 12-month event-free survival rate (defined as freedom from death, myocardial infarction, and the need for target vessel revascularisation). Angiographic restenosis at 8 months was assessed in the study group only. Event-free survival rates were 93 and 69.8% in the study and the control group, respectively (relative risk 0.34, 95%CI: 0.12 to 0.96, p=0.006). Target vessel revascularisation rate in the study group was 7% compared to 27.9% in the control group (p=0.01). Quantitative coronary angiography performed on 104 lesions of 39 prednisone-treated patients (91%) showed 4 restenotic lesions (3.8%). The mean late lumen loss was 0.61+/-0.35mm and loss index 31.3+/-21.6%. Oral immunosuppression with prednisone effectively reduces clinical restenosis in patients undergoing complex, multi-vessel PCI.

Acute Treatment of Psychotic Agitation

Standard treatment for acute psychotic agitation often involves intramuscular administration of the benzodiazepine lorazepam and the antipsychotic haloperidol. This study compared the efficacy and safety of oral treatment with the atypical antipsychotic risperidone plus lorazepam with those of standard intramuscular treatment. We hypothesized that the efficacy and speed of action of both treatments would be similar. In a prospective, parallel-group, randomized, rater-blinded noninferiority study conducted at 24 sites in the United States, 162 patients exhibiting agitation associated with active psychosis were randomly assigned to receive either oral treatment with 2 mg of risperidone plus 2 mg of lorazepam (N = 83) or intramuscular treatment with 5 mg of haloperidol plus 2 mg of lorazepam (N = 79). The change scores on a 5-item acute-agitation cluster from the Positive and Negative Syndrome Scale (hallucinatory behavior, excitement, hostility, uncooperativeness, and poor impulse control) were the main outcome measure. The study was conducted from January 8 to August 8, 2001. Mean acute-agitation cluster scores were similar in the 2 groups at baseline. Mean score improvements at 30, 60, and 120 minutes after dosing were significant at each timepoint in both groups (p <.0001) and were similar in both groups (p >.05). Both treatments were well tolerated. A single oral dose of risperidone plus lorazepam was as effective as parenterally administered haloperidol plus lorazepam for the rapid control of agitation and psychosis. These findings suggest that this oral regimen is an acceptable alternative to the current intramuscular treatment for acute psychotic agitation.

Clinical experience with thioctacid (thioctic acid) in the treatment of distal symmetric polyneuropathy in Korean diabetic patients

Objective: This open-label study was performed to evaluate the efficacy and safety of oral treatment with the antioxidant α-lipoic acid (ALA, thioctic acid) in Korean diabetic patients with distal symmetric polyneuropathy (DSP). Subjects and Methods: Thioctic acid was administered orally using 600 mg once daily for 8 weeks in 61 diabetic patients with symptomatic polyneuropathy. Neuropathic symptoms (pain, burning sensation, paresthesia, and numbness) were scored at baseline as well as at 4 and 8 weeks following treatment. In addition, neurological assessment was carried out before and after 8 weeks of treatment, and an overall evaluation was performed at the end of treatment. The primary endpoint was the response rate after 8 weeks of treatment, defined as an improvement in the Total Symptom Score (TSS) of ≥30%. Results: Efficacy was evaluated in 38 patients who had completed the study according to the protocol. Safety was evaluated in all 61 patients who had taken the study medication. Fasting blood glucose and HbA 1c did not change during the study. The response rate after 8 weeks was 71.4%. At 4 weeks, the response rate was 47.4%. The TSS significantly decreased at 4 weeks, which decreased further at 8 weeks ( P<.05). All the individual scores for neuropathic symptoms (pain, burning sensation, paresthesia, and numbness) were also significantly reduced at 4 weeks and further decreased at 8 weeks ( P<.05). The duration of diabetes, severity and duration of diabetic polyneuropathy, and all the other demographic and metabolic parameters did not demonstrate an effect on the response rate. The parameters of neurological assessment (ankle reflexes, pin-prick test, 10-g monofilament test) and quantitative sensory tests (vibration, warm and cold sensation) were not influenced by 8 weeks of treatment with 600 mg of oral thioctic acid per day. Overall efficacy rated as “good/fair” was 86.8% by the physician and 76.3% by the patients at the end of an 8-week treatment period. Eleven episodes (18.0%) of adverse events (possibly, probably, definitely related) were reported in seven patients (11.5%). Conclusion: These findings indicate that oral treatment with thioctic acid at a dose of 600 mg/day for 8 weeks improved symptoms of polyneuropathy in Korean diabetic patients without causing serious adverse events.

Recent understanding in the treatment of visceral leishmaniasis.

Visceral leishmaniasis (VL) is a severe disease associated with infection of the reticuloendothelial system by Leishmania species. The infection is acquired through sandfly bites. Recent large scale epidemics of VL in east Africa and India and the emergence of a HIV epidemic make VL a priority for the World Health Organization. Pentavalent antimonials have been cornerstone of treatment for the last six decades. The appearance of antimonial-resistance and the development of lipid formulations of amphotericin B have changed the pattern of VL treatment. Within the past five years, miltefosine has been demonstrated as the first effective and safe oral treatment against VL. The price of miltefosine is yet to be determined. However, miltefosine will certainly be cheaper than lipid formulations of amphotericin B, which are beyond the financial capacity of the poor countries. Because it can be administered orally, miltefosine is suited for the treatment of large number of patients who get affected during epidemics, particularly in regions where the parasites are resistant to the currently used agents. Here, we recommend different treatment schedules according to the resistance pattern and the region-specific socio-economical and cultural factors.

Activity of biphenyl matrix metalloproteinase inhibitor BAY 12-9566 in a human breast cancer orthotopic model.

Matrix metalloproteinases (MMPs) have been implicated in the invasion, metastasis, and angiogenesis associated with human cancer by mediating the degradation of extracellular matrix components. In this paper, we report data that show that BAY 12-9566, a novel inhibitor of MMPs, inhibits angiogenesis, tumor regrowth, and the growth of lung metastases. BAY 12-9566, at 15-100 microM, inhibited tubule formation by human endothelial cells in an in vitro model, but did not prevent the proliferation of endothelial and human breast cancer cells. In the MDA-MB-435 human mammary carcinoma xenograft model, in which the primary tumor is transplanted into the murine mammary fat pad, BAY 12-9566, administered daily at a dose of 100 mg/kg/day p.o. after resection of the primary tumor, inhibited local tumor regrowth by 58% without causing any toxic effect. In addition, BAY 12-9566 treatment inhibited the number and volume of lung metastases by 57 and 88%, respectively. These effects were highly correlated with the serum concentration of BAY 12-9566 at the end of treatment. The serum of the treated animals, harvested 24 h after the last treatment, and the tumor regrown at the site of tumor transplant in the treated animals, contained less protein with MMP-9 activity (as measured in a gelatin zymography assay) than the corresponding controls. However, no difference in the activity of MMP-2 was observed. Although all clinical trials in cancer involving BAY 12-9566 have been halted, this MMP inhibitor has never been used in clinical trials in breast cancer. These results suggest that the novel MMP inhibitor BAY 12-9566 maybe a useful and safe oral treatment for breast cancer, adjunctive to surgery.

Vardenafil: The clinical trial experience

Vardenafil is a new phosphodiesterase 5 inhibitor designed specifically to be an effective and safe oral treatment for erectile dysfunction (ED). The present review provides a broad overview, with emphasis placed on results from key studies that will impact patient and physician choice of an appropriate treatment for ED. In addition to being highly selective for phosphodiesterase 5, vardenafil shows strong efficacy in the broad range of ED patients, regardless of age, etiology or severity, or concomitant disorders (eg, diabetes). This, combined with a good cardiovascular safety profile and the added features of minimal interactions with food and alcohol, indicates that vardenafil is very likely to play an important role in the overall management of ED.