Anticonvulsant combination therapy: rational concepts versus real effectiveness

Primary drug treatment of epilepsies is usually a monotherapy with an antiepileptic drug. This procedure causes less side effects as polytherapy and probably shows the same efficacy. Two third of patients with focal epilepsies are sufficiently treated with a single antiepileptic drug: 60% of patients with Grand mal and 22-30% of patients with complex focal seizures remain seizures free. An alternative monotherapy will suppress seizures in another 30% of patients. With polytherapy this is achieved in only 12% of the remaining patients, furthermore, side effects increase in polytherapy. Generalized epilepsies are usually treated with valproate monotherapy. Patients remain seizure free from absence in 60-90%, from myoclonic-impulsive seizures in 75-97% and from Grand mal in about 85%. Alternative monotherapy is less common because of the limited efficacy and possible side effects of drugs: ethosuximide does not control Grand mal and phenobarbitone may cause sedation. Thus, polytherapy is commonly initiated when monotherapy fails to control seizures (lamotrigine is often chosen as comedication). Rational polypharmacy is a term suggesting rational concepts in planning antiepileptic polytherapy leading to a superior anticonvulsant effect. However, this consideration is not based on or supported by clinical data. Yet, a combination of drugs which have no or little pharmacokinetic interactions seems to be a clinically relevant recommendation. Thus, newly developed drugs such as vigabatrin, lamotrigine or gabapentin are more frequently used as comedication with standard antiepileptic drugs.     

Comparative clinical pharmacology of rocuronium, cisatracurium, and their combination

BACKGROUND: The comparative clinical pharmacology of cisatracurium and rocuronium and their combinations has not been reported. In this study, the authors compared the relative potency and the clinical profile and characterized the interaction of both drugs. METHODS: Two hundred twenty adults classified as American Society of Anesthesiologists physical status I and anesthetized with propofol-fentanyl-nitrous oxide were studied. In part 1, the neuromuscular-blocking effects of cisatracurium and rocuronium were assessed after administration of bolus doses of 20-50 microg/kg and 100-300 microg/kg, respectively. In part 2, we compared the time course of 1xED50, 1, 1.5, and 2xED95 doses of both drugs (where ED50 and ED95 are, respectively, the doses producing 50% and 95% depression of the first twitch height [T1]). In part 3, equieffective combinations of both drugs were studied to characterize their interaction. RESULTS: The calculated ED50 values and their 95% confidence intervals were 111 (107-115) and 26.2 (25.8-26.5) microg/kg [corrected] for rocuronium and cisatracurium, respectively. Compared with equipotent doses of cisatracurium, rocuronium had a faster onset, and a faster spontaneous T1 and train-of-four recovery times that were significant except at maximum recovery with the 2xED95 dose. The interaction between rocuronium and cisatracurium was synergistic, and the time profile of the combination group was different from that of the single-dose groups. CONCLUSIONS: Cisatracurium is four to five times more potent than rocuronium. Rocuronium had a faster onset of action, a shorter clinical duration, and a faster spontaneous recovery rate compared with equipotent doses of cisatracurium.     

Switch therapy with beta-lactam/beta-lactamase inhibitors in patients with community-acquired pneumonia

BACKGROUND: Antimicrobial drugs are prescribed inappropriately nearly 50% of the time. To address this problem, a hospital antimicrobial team was formed integrating the talents of infectious disease physicians, pharmacists, microbiologists, infectious control practitioners, and nurses. The primary goal of the team is to provide optimal, cost-effective antimicrobial therapy. OBJECTIVE: To review the principles of streamlining antimicrobial therapy, with an emphasis on antibiotic switch therapy. DISCUSSION: With appropriate guidelines, switch therapy appears to be an important means to provide optimal antimicrobial therapy complementing the many social pressures placed on patients, while positively impacting on the overall cost of treatment. The use of beta-lactam/beta-lactamase inhibitor combinations as the antibiotics for initial intravenous medication to oral combination switch therapy is a viable approach to the treatment of hospitalized patients with community-acquired pneumonia. Preliminary data from our institution were obtained with such a therapeutic approach to assess the clinical efficacy, patient satisfaction with their care, and calculated dollar savings in the overall cost of care. The results of this evaluation strongly support the validity and desirability of such an approach. CONCLUSIONS: The prospective use of a program that incorporates the use of beta-lactam/beta-lactamase inhibitor combinations for intravenous and switch-to-oral drug administration is a cost-effective means of providing optimal antimicrobial therapy for patients with community-acquired pneumonia.     

Ex-vivo gene therapy using cytokine-transduced tumor vaccines: molecular and clinical pharmacology

Whether the current generation of cytokine gene-transduced tumor vaccines will show clinical efficacy is under study. Fortunately, the large safety profile so far observed with gene-transduced tumor vaccines can allow outpatient testing in large populations of patients in the adjuvant therapy situation. This will allow large studies statistically powered to see potentially important adjuvant therapy effects in the range that are observed for tamoxifen in breast cancer. For example, the outpatient, adjuvant therapy safety context has been established in the use of GM-CSF gene-transduced autologous prostate cancer vaccines following radical prostatectomy. Similar adjuvant therapy clinical trial efforts are anticipated with allogeneic breast, colon, pancreatic, and ovarian cancer in addition to prostate, renal cell carcinoma, and melanoma. The reverse translation of early clinical data back to basic laboratory research also suggests the field of cytokine gene-transduced tumor vaccine research will remain vibrant. Efforts are currently being directed on optimizing DC activation with polycistronic constructs of cytokine genes, and overexpressing the most relevant tumor-associated peptides. As in the case of antineoplastic drug development, not all lead compounds will become approved drugs in medical oncology. Rigorous yet innovative clinical trial designs will be key to the accelerated identification of cytokine gene-transduced vaccines that improve survival in cancer patients.     

Early transition to oral antibiotic therapy for community-acquired pneumonia: duration of therapy, clinical outcomes, and cost analysis

Our objective was to compare therapeutic outcome and analyse cost-benefit of a 'conventional' (7-day course of i.v. antibiotic therapy) vs. an abbreviated (2-day i.v. antibiotic course followed by 'switch' to oral antibiotics) therapy for in-patients with community-acquired pneumonia (CAP). We used a multicenter prospective, randomized, parallel group with a 28 day follow-up, at the University-based teaching hospitals: The Medical Center of Louisiana in New Orleans, LA and hospitals listed in the acknowledgement. Ninety-five patients were randomized to receive either a 'conventional' course of intravenous antibiotic therapy with cefamandole 1 g i.v. every 6 h for 7 days (n = 37), or an abbreviated course of intravenous therapy with cefamandole (1 g i.v. every 6 h for 2 days) followed by oral therapy with cefaclor (500 mg every 8 h for 5 days). No difference was found in the clinical courses, cure rates, survival or the resolution of the chest radiograph abnormalities among the two groups. The mean duration of therapy (6.88 days for the conventional group compared to 7-30 days for the early oral therapy group) and the frequencies of overall symptomatic improvement (97% vs. 95%, respectively) were similar in both groups. Patients who received early oral therapy had shorter hospital stays (7.3 vs. 9.71 days, P = 0.01), and a lower total cost of care ($2953 vs. $5002, P < 0.05). It was concluded that early transition to an oral antibiotic after an abbreviated course of intravenous therapy in CAP is substantially less expensive and has comparable efficacy to conventional intravenous therapy. Altering physicians' customary management of hospitalized patients with CAP can reduce costs with no appreciable additional risk of adverse patient outcome.     

The therapy of peripheral obstructive arteriopathies: rational bases

The authors underline the relations among the anatomical lesion progression, the appearance of the clinical signs (claudicatio) of tissue ischaemia and the thromboembolic event in vascular districts like myocardium and brain, at high morbidity and mortality risk. They widely state the pathogenetic mechanism of the atherosclerotic arterial disease and the compensative mechanisms that may prevent the ischaemic effects of the vascular obstruction. It has been considered the importance of the hemorheologic changes and their influence on the development of the ischaemic syndrome. The therapeutic choice in relation to physiopathologic and hemorheologic events in the peripheral obstructive arterial disease is considered.     

Why rational-emotive therapy to rational emotive behavior therapy?

Describes the reasoning behind renaming rational-emotive therapy (RET), first introduced in 1955 by the author as rational therapy, to rational emotive behavior therapy (REBT). The theory of REBT holds that human disturbance is complicated by biological and environmental factors that exacerbate irrational beliefs. REBT is based on the view that thinking, feeling, and behaving are integrated and holistic processes. The cognitive, emotional, and action techniques of REBT address these processes and also provide therapists with ways of overcoming client resistance. REBT has been a pioneering cognitive-emotive-behavioral therapy, in spite of originally being named rational therapy and RET. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The pharmacology of FMRFamide-related neuropeptides in nematodes: new opportunities for rational anthelmintic discovery?

The chemotherapeutic control of helminth parasites is compromised by the limited number of classes of anthelmintic drugs. Discovery of novel anthelmintics is impeded by the lack of novel screening technologies that overcome the difficulties inherent in screens based on whole organism toxicity. The development and implementation of mechanism-based screens for new anthelmintics offers great promise for the revitalization of antiparasitic drug discovery. However, mechanism-based screens must be based on a thorough understanding of the proteins or processes that offer the best chance for selective chemotherapeutic intervention. Basic research on the characterization of nematode FMRFamide-related peptides (FaRPs) has revealed that these peptides are ubiquitously distributed in helminths. Chemical identification of a number of nematode FaRPs has been achieved, and these peptides have potent and profound effects on the nematode neuromuscular system. Physiological processes mediated by nematode FaRPs (and other helminth neuropeptides) offer potential targets for the discovery of novel anthelmintics.     

The clinical pharmacology of amoxicillin and clavulanic acid

Recent clinical reports have shown that intrathecal administration of thyrotropin-releasing hormone (TRH) can induce 2 to 3 day remissions of major depression more reliably than i.v. administration. Although clinically impractical, these remissions are rapid, occur within hours, and they survive at least one night's sleep. TRH and related peptides have regulatory effects in the limbic forebrain. Electroconvulsive shock (ECS) in rats induces synthesis of TRH in multiple subcortical limbic and frontal cortical regions, which are known in humans to be involved in both depression and in sleep. The increases in TRH and related peptides are regionally specific. The quantitative TRH increases in individual limbic regions have been correlated with the amount of forced-swimming done by the individual animal after ECS. Intraperitoneal TRH also gives a positive response in this test, as do all effective antidepressants. This article provides a heuristic framework for interdisciplinary neuroscientific study of the interrelated fields of depression and sleep, with a focus on TRH. Preclinical data suggest that glutamatergic, subcortical limbic circuits contain TRH and related peptides as inhibitory cotransmitters that may normally restrain glutamatergic hyperactivity. It is suggested that, in depression, pathologically overdriven glutamatergic circuits escape inhibitory regulation by TRH. This escape is especially pronounced during rapid eye movement (REM) sleep, and these phenomena may explain the prolonged latency of antidepressant treatment.     

Microtubule inhibitors: structure-activity analyses suggest rational models to identify potentially active compounds

Trifluralin, a dinitroaniline microtubule inhibitor currently in use as an herbicide, has been shown to inhibit the proliferation of Plasmodium falciparum, Trypanosoma brucei, and several species of Leishmania, in vitro. As a topical formulation, trifluralin is also effective in vivo (in BALB/c mice) against Leishmania major and Leishmania mexicana. Although trifluralin and other dinitroaniline herbicides show significant activity as antiparasitic compounds, disputed indications of potential carcinogenicity will probably limit advanced development of these substances. However, researchers have suggested that the activity of trifluralin is due to an impurity or contaminant, not to trifluralin itself. We have pursued this lead and identified the structure of the active impurity. This compound, chloralin, is 100 times more active than trifluralin. On the basis of its structure, we developed a rational structure-activity model for chloralin. Using this model, we have successfully predicted and tested active analogs in a Leishmania promastigote assay; thus, we have identified the putative mechanism of action of this class of drugs in Leishmania species. Potentially, this will allow the design of noncarcinogenic, active drugs.     

Mediators and pharmacology of visceral sensitivity: from basic to clinical investigations

Over the last decade, the role of visceral sensitivity has been largely recognized in the pathophysiology of functional digestive disorders, particularly in the irritable bowel syndrome. These studies have highlighted the role of afferent pathways arising from the gut as a possible target for new treatments intended to relieve pain or modify altered reflexes present in such patients. These pharmacological targets have been identified mainly by studies on animal models of visceral hyperalgesia of various origins including local inflammation. Locally, several mediators are of paramount importance for sensitization of nerve endings: 5-hydroxytryptamine, bradykinin, tachykinins, calcitonin gene-related peptide, and neurotrophins. Selective antagonists to various subtypes of their receptors are currently available and have been shown to be active in these animal models. Other substances, such as somatostatin, opiold peptides, cholecystokinin, oxytocin, and adenosine, modulate the transmission of nociceptive inputs from the gut to the brain and are of clinical interest. This article reviews the current understanding of these mediators. Although these agents seem to be promising tools for the treatment of visceral hyperalgesia and its consequences (abdominal pain and disturbed reflexes), their clinical efficacy remains to be shown. A better understanding of the nature and the location of the defect in the sensory pathways may permit the selection of subgroups of patients for treatment according to the pharmacological properties of these new therapeutic agents.     

In vitro activity of 9 antibiotics and 3 beta-lactamase inhibitors against 107 clinical isolates of Acinetobacter baumanii

Twenty eight of 227 patients undergoing restorative proctocolectomy for inflammatory bowel disease, familial adenomatous polyposis or functional disease were over the age of 50 years: ages 50 to 60 (n = 13), 60 to 70 (n = 10), and over 70 (n = 5). Major complications occurred in 5 patients over the age of 50 (18%) compared with 43 patients under the age of 50 (23%). Three patients above the age of 50 had their pouch excised (11%) compared with 23 under the age of 50 (12%). Functional outcome was assessed with a 12 point symptom score. This was similar in all age bands: under 50 years (mean = 2.2; sd +/- 2.2; n = 109), 50 to 60 years (mean = 2.5; sd +/- 2.5; n = 12), 60 to 70 years (mean = 2.8; sd +/- 2.3; n = 7) and over 70 years (mean = 4.0; sd +/- 3.7; n = 5): P > 0.05). When analysed for ulcerative colitis alone, no significant differences were seen between the two age groups. Restorative proctocolectomy in the elderly gives results which are comparable to the younger population.     

The taxoids. Comparative clinical pharmacology and therapeutic potential

Paclitaxel and docetaxel are 2 compounds from the new taxoid class of anti-cancer agents. Both drugs are very similar in preclinical activity, mechanism of action and spectrum of clinical activity. Some subtle differences in the intracellular retention of docetaxel may account for its lack of schedule-related myelosuppression and greater potency, and may be relevant to the skin toxicity and oedema which it produces. Early data suggest that there may be differing behaviour of anthracycline/taxoid combinations with respect to cardiotoxicity. Paclitaxel has been studied in several first-line combination therapy trials in ovarian cancer. Here, paclitaxel in combination with a platinum compound seems to have proven itself as a standard regimen. It is uncertain if docetaxel will be evaluated in this context. An abundance of clinical data is available for both analogues in the advanced, metastatic setting of breast cancer. Both also have been compared as single agents with doxorubicin with the results suggesting paclitaxel in a 3-hour infusion is inferior to the anthracycline (in terms of response rate), and those of docetaxel suggesting it is superior to the same dose of doxorubicin. This indirect comparison favours the activity of docetaxel; however, it is clear that in the dose/schedules studied, the taxoid compounds are not equitoxic. Either agent by itself, in the treatment of metastatic breast cancer, remains appropriate; however, lack of cumulative toxicity may make paclitaxel more attractive in some situations where prolonged administration is foreseen. Lung cancer trials have also confirmed the activity of both agents, although docetaxel appears to have slightly more promising activity in previously treated patients than paclitaxel. Paclitaxel in combination with cisplatin has been evaluated in randomised trials as first-line treatment of non-small-cell lung cancer (NSCLC). The results of these trials taken together suggest that this combination has an impact on survival similar to other new regimens now considered 'standard' in the front-line setting in this disease. Unfortunately, despite all the phase II data generated in numerous tumour types, little else can be said about the role of either taxoid in the 'standard' management of malignant disease. It will be some years yet before taxoid-based combinations have been evaluated sufficiently in randomised trials such that the impact of this novel class can be adequately assessed in terms of survival and cure rates.     

Susceptibilities of 97 strains of Xanthomonas maltophilia to antibiotics and the effect of beta-lactamase inhibitors

An agar dilution technique and the 'E' test were used to compare the antimicrobial activities of ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, meropenem, biapenem, imipenem, levofloxacin, ofloxacin, ciprofloxacin, ceftazidime and cefepime against 97 clinical isolates of Xanthomonas maltophilia. Intermediate susceptibility breakpoints for members of the family Enterobacteriaceae were used. Results were analysed as minimum inhibitory concentrations for 50 and 90% of the strains tested and as percentages of strains susceptible at the breakpoint. Good correlation between the two techniques was observed, with ticarcillin-clavulanate clearly the most active agent by both methods with 64 to 66% followed by levofloxacin with 63 to 65% of the strains being susceptible. Biapenem and imipenem showed weak activity with none of the strains being susceptible. Ceftazidime had better activity than cefepime when they were compared by the two methods. There was no significant difference in the results between the two susceptibility techniques used.