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In search of a backup M(2) muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models. The improvement of oral efficacy was achieved by modulating both the molecular weight and lipophilicity of the lead compounds.
Whilst the "effect" of a drug can be observed or deduced from observational data, the concept of "therapeutic efficacy" represents mainly a theoretical construction of a high degree of abstraction which is inconceivable without reciprocal combination with other theoretical constructs. The "therapeutic efficacy" of drugs can be investigated only via clinical-pharmacological or clinical models. Several examples are given. The strength of evidence of models is discussed as well as the necessity to continually test them empirically.
In many clinical trials, subjects are followed for two stages of outcomes, and it is of interest to compare the incidence of each outcome between two randomized groups. The outcome of the first stage may influence the outcome of the second stage. Moreover, the relative risks of the two outcomes may be linked, with the time-dependent profile of relative risk for the second outcome functionally dependent on that of the first. For example, during exposure to HIV, virologic and host factors simultaneously impact the probability of infection and the subsequent viral trajectories, and the efficacy of a tested vaccine to prevent infection and to prevent viral failure may work in concert. We address this problem by modeling the relationship between the stage two hazard function and covariates via Cox's proportional hazards model (Cox, 1972), with the stage one log-hazard ratio theta(*) at the first event time Tl, included as a covariate. With theta(*) estimated using three methods, 1) nonparametric kernel smoothing; 2) locally parametric penalized splines; and 3) fully parametric cubic linear splines, we subsequently develop inference procedures for the regression parameter in the stage two Cox model based on each of the estimator of theta(*). The inferential procedures are studied in simulations and are illustrated with application to data from the world's first preventive HIV vaccine efficacy trial.
BACKGROUND: Chronic cough that persists despite medical treatment may respond to speech pathology intervention, but the efficacy of such treatment has not been investigated in prospective randomised trials. The aim of this study was to determine the efficacy of a speech pathology intervention programme for chronic cough. METHODS: A single blind, randomised, placebo controlled trial was conducted in 87 patients with chronic cough that persisted despite medical treatment. Patients were randomly allocated to receive either a specifically designed speech pathology intervention or a placebo intervention. Participants in both groups attended four intervention sessions with a qualified speech pathologist. RESULTS: Participants in the treatment group had a significant reduction in cough (8.9 to 4.6, p<0.001), breathing (7.9 to 4.7, p<0.001), voice (7.3 to 4.6, p<0.001) upper airway (8.9 to 5.9, p<0.001) symptom scores and limitation (2.3 to 1.6, p<0.001) ratings following intervention. There was also a significant reduction in breathing (6.8 to 5.6, p = 0.047), cough (7.6 to 6.3, p = 0.014), and limitation (2.3 to 2.0, p = 0.038) scores in the placebo group, but the degree of improvement was significantly less than in the treatment group (p<0.01). Clinical judgement of outcome indicated successful ratings in 88% of participants in the treatment group compared with 14% in the placebo group (p<0.001). CONCLUSION: Speech pathology is an effective management intervention for chronic cough which may be a viable alternative for patients who do not respond to medical treatment.
The efficacy of modified M-VAC chemotherapy was evaluated in twenty-two patients with advanced urothelial carcinoma (18 cases of transitional cell carcinoma, 3 of transitional cell associated with squamous cell carcinoma and 1 of squamous cell carcinoma). Among the 22 patients, 14 underwent two or more courses of modified M-VAC chemotherapy and had lesions suitable for the evaluation. Three of the 14 patients achieved complete response and 6 partial response, resulting in a 64.3% response rate. With regard to the direct effect according to the site of the lesion, the response rate was 75% for the urinary bladder, 100% for lung, 100% for subcutaneous tissues, and 75% for lymph nodes metastasis, whereas the chemotherapy was ineffective for metastasis in the bone and muscle. With this neoadjuvant chemotherapy the primary tumor of the urinary bladder was downstaged from T2 to T0 in one patient who showed complete response. In 4 of 5 patients achieving partial response, the primary tumors were downstaged from T2 to T1. Of 9 patients given this chemotherapy for metastatic lesions, 2 achieved complete response and are alive, whereas all 3 without response died of cancer within the 1 year following the chemotherapy. Since most of the cases associated with the squamous cells carcinoma component showed no response to the therapy, it seems that the level of serum squamous cell carcinoma-associated antigen may be helpful for predicting the efficacy of modified M-VAC chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Our aim was to determine the efficacy of HIV-1 voluntary counselling and testing (VCT) in reducing unprotected intercourse among individuals and sex-partner couples in Nairobi (Kenya), Dar es Salaam (Tanzania), and Port of Spain (Trinidad). METHODS: Individual or couple participants were randomly assigned HIV-1 VCT or basic health information. At first follow-up (mean 7.3 months after baseline) health-information participants were offered VCT and all VCT participants were offered retesting. Sexually transmitted infections were diagnosed and treated at first follow-up. The second follow-up (mean 13.9 months after baseline) involved only behavioural assessment, and all participants were again offered VCT. FINDINGS: 3120 individuals and 586 couples were enrolled. The proportion of individuals reporting unprotected intercourse with non-primary partners declined significantly more for those receiving VCT than those receiving health information (men, 35% reduction with VCT vs 13% reduction with health information; women, 39% reduction with VCT vs 17% reduction with health information), and these results were maintained at the second follow-up. Individual HIV-1-infected men were more likely than uninfected men to reduce unprotected intercourse with primary and non-primary partners, whereas HIV-1-infected women were more likely than uninfected women to reduce unprotected intercourse with primary partners. Couples assigned VCT reduced unprotected intercourse with their enrolment partners significantly more than couples assigned health information, but no differences were found in unprotected intercourse with non-enrolment partners. Couples in which one or both members were diagnosed with HIV-1 were more likely to reduce unprotected intercourse with each other than couples in which both members were uninfected. These changes were replicated by those in the health-information group diagnosed with HIV-1 at first follow-up. INTERPRETATION: These data support the efficacy of HIV-1 VCT in promoting behaviour change.
Inhibitors of angiogenesis are potential anti-cancer agents in that they deprive tumors of the blood necessary for growth and metastasis. The anti-angiogenic efficacy of tinzaparin, a known anticoagulant low molecular weight heparin (LMWH), was examined in vitro in endothelial cell tube formation assay and in vivo in the chick chorioallantoic membrane model. The observed anti-angiogenic effects of tinzaparin were shown to be dose-related and dependent on the relatively higher molecular weight tinzaparin fragments. These experiments demonstrated that tinzaparin is a potent inhibitor of angiogenesis (ED90-100 range, 0.05-0.1 mg) regardless of the angiogenic factor and suggest that its effect is mediated via cellular release of tissue factor pathway inhibitor (TFPI). This was evident by the reversal of either tinzaparin or r-TFPI anti-angiogenesis efficacy by a specific monoclonal TFPI antibody. The ED90-100 for the inhibition of angiogenesis for r-TFPI ranged from 0.01 to 0.03 mg in the chorioallantoic membrane model regardless of the proangiogenic factor. In addition, either tinzaparin or r-TFPI inhibited the growth of colon carcinoma tumors, human fibrosarcoma tumors, and human lung carcinoma in the chorioallantoic membrane tumor implant model. Thus, the LMWH tinzaparin, in addition to its anticoagulant effects, may offer important benefits in treatment of cancer and other disorders supported by pathologic angiogenesis.
BACKGROUND & OBJECTIVE: The trans-anal local excision for lower rectal cancer of early stage may achieve the same therapeutic effect as abdominal resection. This study was to evaluate efficacy of local resection for lower rectal cancer of early stage. METHODS: Records of 23 patients with lower rectal cancer of early stage received local excision from Feb. 1989 to Apr. 1999 in our hospital were analyzed retrospectively. RESULTS: Of the 23 patients,12 were adenocarcinoma, and 11 were canceration of adenoma; 17 with tumor of stage T0, and 6 with tumor of stage T1. Three patients had local recurrence, 2 of 3 were salvaged by trans-anal local excision, and 1 of 3 was treated by abdominoperineal resection. All patients were followed-up for more than 5 years with a 5-year survival rate of 95.65%. CONCLUSION: So long as carefully considering indications of trans-anal local excision in treating patients with lower rectal cancer of early stage, good efficacy may be achieved.
The aim of our study was to evaluate the efficacy and safety of 3-drugs regimen: T 75 mg/m2 d2 + P 75 mg/m2 d2 + F 500 mg/m2 x 3h d 1-3 every 28 days. 31 patients (pts) with morphologically proven advanced gastric cancer of the age 29-77 years (median 61.0) have been treated with this regimen. They received 138 cycles (1-10, median 4.0 cycles per pt). The response rate was evaluated in pts received > or =2 cycles: CR 1/27 (3.7%), PR 12/27 (44.4%), SD 7/27 (25.9%), PD 7/27 (25.9%). The median duration of CR+PR--4.5 mon (1.1-9.9), of SD--6.8 mon (3.0-10.7). Median TTP--5.5 mon. Overall survival: median--11.5 mon, 1-year--46.6%. PS improvement was observed in 54.8%pts, symptomatic improvement--in 71% pts. Toxicity per pt (per cycle) was moderate. There were 11 elderly among these pts. We didn't receive any significant differences in efficacy and severe toxicity in this group compared to non-elderly pts. We observed 55.6% PR, 33.3% SD, 11.1% PD, TTP--4.6 mon, median OS-7.5 mon. in elderly and 5.6% CR, 38.9% PR, 22.2% SD, 33.3 % PD, TTP--6.1 mon, median OS-12.3 mon for non-elderly pts. But dose reduction was performed more frequently in the elderly then non-elderly: 63.6% vs 30.0% pts (p = 0.07) in 64.8% vs 19.1% cycles (p < 0.0001). We consider this regimen to be effective and well tolerated both for elderly and for non-elderly patients.
A phase IV trial evaluated the efficacy and safety of a monophasic oral contraceptive formulation, ethynodiol diacetate, 1 mg, plus ethinyl estradiol, 35 micrograms (EDA 1 mg with EE 35 micrograms) (Demulen 1/35). Nine hundred eighty-three community-based obstetrician-gynecologists treated a total of 7,759 patients with EDA 1 mg with EE 35 micrograms for one to eight months. Clinical evaluation forms on 6,382 patients were amenable to analysis for safety (including breakthrough bleeding, ovarian cyst formation and complexion changes); 5,412 patients were evaluable for efficacy (prevention of pregnancy), with a total of 21,440 cycles recorded. The study results were interpreted in terms of the impact on clinical management of oral contraceptive users and the methods, strengths and weaknesses of phase IV trials, particularly as they relate to confirmation of the results reported here.
The anthelmintic efficacy of a 44.5% paste formulation of cambendazole was evaluated in a critical trial performed on 5 horses and a donkey. A dosage of 20 mg/kg showed reduction of mean parasite burdens as follows: Strongylinae greater than 99%; Cyathostominae 94%; immature and adult Oxyuris equi 89 and greater than 99%; Probstmayria vivipara greater than 99% and Habronema muscae 97%. Parascaris equorum and Anoplocephala perfoliata were present in small numbers in individual animals only, and while all were removed by treatment, the small numbers did not justify calculation of a percentage efficacy for these 2 parasites.
Through co-expression of the human beta 1 and beta 2 adrenergic receptors in a single tester cell (the murine L fibroblast) and through assaying the effect of the beta 1 and beta 2 selective blockers CGP 20712A and ICI 118551 on isoproterenol-stimulated adenylyl cyclase, it is shown that the maximal stimulation achievable with a given cell density of beta 1 adrenergic receptor is less than that obtained with the same density of the beta 2 adrenergic receptor. It is concluded that the efficacy of the 2 receptors differs in that the beta 1 adrenergic receptor has a lower efficacy (or intrinsic activity) than does the beta 2 adrenergic receptor.
BACKGROUND: Diabetic dyslipidemia is characterized by high triglyceride levels; low high-density lipoprotein cholesterol levels; small, dense low-density lipoprotein particles; and high free fatty acid levels. Niacin reduces concentrations of triglyceride-rich and small low-density lipoprotein particles while increasing high-density lipoprotein cholesterol levels. It also lowers levels of free fatty acids and lipoprotein(a). However, the use of niacin in patients with diabetes has been discouraged because high doses can worsen glycemic control. We evaluated the efficacy and safety of once-daily extended-release (ER) niacin in patients with diabetic dyslipidemia. METHODS: During a 16-week, double-blind, placebo-controlled trial, 148 patients were randomized to placebo (n = 49) or 1000 (n = 45) or 1500 mg/d (n = 52) of ER niacin. Sixty-nine patients (47%) were also receiving concomitant therapy with statins. RESULTS: Dose-dependent increases in high-density lipoprotein cholesterol levels (+19% to +24% [P<.05] vs placebo for both niacin dosages) and reductions in triglyceride levels (-13% to -28% [P<.05] vs placebo for the 1500-mg ER niacin) were observed. Baseline and week 16 values for glycosylated hemoglobin levels were 7.13% and 7.11%, respectively, in the placebo group; 7.28% and 7.35%, respectively, in the 1000-mg ER niacin group (P=.16 vs placebo); and 7.2% and 7.5%, respectively, in the 1500-mg ER niacin group (P=.048 vs placebo). Four patients discontinued participation because of inadequate glucose control. Rates of adverse event rates other than flushing were similar for the niacin and placebo groups. Four patients discontinued participation owing to flushing (including 1 receiving placebo). No hepatotoxic effects or myopathy were observed. CONCLUSION: Low doses of ER niacin (1000 or 1500 mg/d) are a treatment option for dyslipidemia in patients with type 2 diabetes.
The efficacy of contrast-enhanced magnetic resonance imaging (MRI) for detecting and characterizing, or excluding, hepatic masses was assessed in 404 patients, following the intravenous administration of mangafodipir trisodium (MnDPDP) injection, a hepatic MRI contrast agent. An initial contrast-enhanced computed tomography (CT) examination was followed by unenhanced MRI, injection of MnDPDP (5 micromol/kg IV), and enhanced MRI at 15 minutes post injection. Agreement of the radiologic diagnoses with the patients' final diagnoses was higher for enhanced MRI and for the combined unenhanced and enhanced MRI evaluations than for unenhanced MRI alone or enhanced CT using the clinical diagnosis as the gold standard. Mangafodipir-enhanced MRI uniquely provided additional diagnostic information in 48% of the patients, and patient management was consequently altered in 6% of the patients. MnDPDP-enhanced MRI was comparable or superior to unenhanced MRI and enhanced CT for the detection, classification, and diagnosis of focal liver lesions in patients with known or suspected focal liver disease.
The analgesic efficacy of a combination of pentazocine and aspirin (PA) in the ration 1:13 was compared with that of 650 mg of aspirin alone (A650) and with placebo (PBO), in 98 patients with postoperative pain. Two dose levels of the combination were compared: the lower dose (PA-L) consisted of pentazocine 25 mg and aspirin 325 mg, while the higher dose (PA-H) consisted of pentazocine 50 mg and aspirin 650 mg. All active treatments performed significantly better than PBO. PA-L performed as well as A650, while PA-H performed significantly better than A650. In addition to the usual subjective measures of analgesia, we obtained in 74 patients an evaluation of the overall (GLOBAL) performance of the treatment. This was rated on an ordinal scale of 1 ("poor") to 5 ("excellent"). On the GLOBAL scale, PBO had a mean score of 2.4 (fair-good); A650 and PA-L had scores of 3.6 and 3.9 respectively (good-very good): and PA-H had a score of 4.5 (very good-excellent). In five of six comparisons between treatment means, GLOBAL had the best discriminating power of all six measures. In the two comparisons of greatest interest (A650 against PBO and PA-H against A650), GLOBAL was more than twice as efficient as the TOTAL (summed pain score) measure. In comparing the statistical efficiency of different measures of the same analgesic effect, there is a problem in determining what are "clinically equivalent differences" on the various analgesic scales employed. We propose the use of the observed sample differences and the safeguard of repeating the comparisons over several studies to minimize the effect of random-origin bias.
In this study, the systemically administered anti-human T-leukemia immunotoxins (ITs) are shown to be effective for tumor suppression in Ichikawa T-leukemia-bearing nude mice. In addition, their antitumor efficacy was markedly potentiated by recombinant human IFN-alpha. The combination of ITs and IFN-alpha effectively killed the tumor in the majority of the treated mice; 9 of the 12 treated mice survived tumor-free for as long as they were followed, i.e. for 140 days. Two different ITs, SN1-ricin A chain (RA) and SN2-RA, were used together to minimize the problem of tumor heterogeneity; monoclonal antibodies SN1 and SN2 are directed toward two different human T-leukemia associated cell surface antigens. In the biodistribution experiments, the paired label technique was used to include a reliable internal control. In an experiment, equal amounts of 125I-SN1-RA and 131I-labelled isotype-matching control IgG (IgG1-kappa)-RA were mixed and administered i.v. into tumor-bearing nude mice. In a separate experiment, a mixture of equal amounts of 125I-SN2-RA and 131I-control IgG-RA was administered i.v. This technique allowed us to distinguish the immunospecific uptake from the non-immunospecific uptake of ITs into individual organs. The present results clearly show that both SN1-RA and SN2-RA are specifically localized in tumors after systemic administration. For instance, 24 h after the administration of a radiolabelled mixture, the ratio of 125I/131I in the tumor was 7.0 and 23.5, respectively, for the SN1-RA/control IgG-RA mixture and the SN2-RA/control IgG-RA mixture. Such high ratios of 125I/131I were detected in the tumors throughout the experiments between 30 min and 24 h after the administration of the paired label mixture.
We investigated the effect of smaller dose, weight-adjusted heparin with earlier monitoring of activated partial thromboplastin time on the incidence of ischemic and hemorrhagic complications in patients with ST-elevation myocardial infarction treated with full-dose tenecteplase. We compared the outcomes of patients enrolled in the Second Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT-2; n = 8,461) who received heparin stratified by weight (patients weighing >67 kg received a 5,000-U bolus plus infusion at 1,000 U/hour; those weighing < or =67 kg received a 4,000-U bolus plus infusion at 800 U/hour) with patients in ASSENT-3 who received weight-adjusted heparin (60-U/kg bolus, maximum 4,000 U/hour, followed by a 12-U/kg/hour infusion, maximum 1,000 U/hour). Compared with patients in ASSENT-2, those in ASSENT-3 had similar rates of 30-day mortality, recurrent infarction, and intracranial hemorrhage, less major bleeding (2.2% vs 4.7%, p <0.001), and less refractory ischemia (6.5% vs 8.6%, p <0.001). After adjustment for baseline characteristics, patients in ASSENT-3 had similar rates of 30-day mortality (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.77 to 1.19) and intracranial hemorrhage (OR 1.02, 95% CI 0.61 to 1.69) but less major bleeding (OR 0.49, 95% CI 0.35 to 0.67) than did patients in ASSENT-2. These findings support the use of smaller dose, weight-adjusted heparin in patients with ST-elevation myocardial infarction treated with tenecteplase.
The description of drug effects on receptor proteins is based on models and equations used to describe mass-action kinetics of molecules and inert surfaces. These models provide an adequate description of drug affinity, that is, how well a molecule binds to a receptor protein, but the way in which ligands change receptor populations to impart signals to cells remains to be determined. In the first of two articles, Terry Kenakin discusses a basic question in receptor pharmacology, namely the nature of ligand efficacy.