Use Of Drugs In Patients Research Articles

Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-β1 Signaling in Endothelial Cells

Hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal-dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations in internal organs. Patients show severe epistaxis, and/or gastrointestinal bleeding, both of which notably interfere with their quality of life. There are two predominant types of HHT caused by mutations in endoglin (ENG) and ACVRL1/activin receptor-like kinase 1 (ALK1) genes, named HHT1 and HHT2, respectively. ENG and ALK1 code for proteins involved in the transforming growth factor (TGF)-β1 signaling pathway, and it is widely accepted that HHT pathogenicity results from haploinsufficiency. No cure for HHT has been found, so identification of drugs able to increase the expression of these genes is essential when proposing new therapies. We report the efficacy of tacrolimus (FK506) in increasing ENG and ALK1 expression. The rationale comes from a case report of a patient with HHT who received a liver transplantation after hepatic failure due to a liver arteriovenous malformation. The liver was transplanted, and the immunosuppressor FK506 was used to prevent the rejection. After the first month of FK506 treatment, the internal and external telangiectases, epistaxes, and anemia disappeared. Here, we find that the immunosuppressor FK506 increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells and enhances the TGF-β1/ALK1 signaling pathway and endothelial cell functions like tubulogenesis and migration. These results suggest that the mechanism of action of FK506 involves a partial correction of endoglin and ALK1 haploinsufficiency and may therefore be an interesting drug for use in patients with HHT who undergo transplantation.

Ranolazin – ein ergänzendes Antianginosum

Ranolazine is a new drug for use in patients with stable angina pectoris. Unlike other antianginal drugs ranolazine does not alter heart rate or systemic blood pressure. Inhibition of the persistent or late sodium current (I(Na,late)) by ranolazine reduces [Na(+) ](i)-dependent Ca(2+) overload and the effects of ischaemia. Moreover, ranolazine holds potential promise to be effective in treatment of atrial fibrillation and diastolic heart failure.

Influence of Mirtazapine on the Hypotensive Activity of Enalapril and Propranolol in Spontaneously Hypertensive Rats

Mirtazapine is a noradrenergic and specific serotonergic antidepressant. The influence of the drug on the cardiovascular system has not been definitely determined. Therefore, we made an attempt to evaluate the influence of chronic administration of mirtazapine on the hypotensive action of a single administered dose of propranolol and enalapril in spontaneously hypertensive rats. The animals were divided into eight experimental groups. Mirtazapine (5 and 10 mg/kg) was administered intraperitoneally for 14 days. Twenty-four hours after the last administration of the drug, the rats received a single intraperitoneal dose of hypotensive drugs (propranolol 5 mg/kg or enalapril 10 mg/kg) or 1% solution of methylcellulose. Mirtazapine administered chronically did not affect the hypotensive effect of a single dose of propranolol or enalapril in spontaneously hypertensive rats. It seems that mirtazapine could be a useful drug in patients with depression accompanied by hypertension.

Janumet™: a combination product suitable for use in patients with Type 2 diabetes

Inhibition of the enzyme dipeptidyl peptidase-4 represents the latest pharmacologic intervention to become available to assist patients with Type 2 diabetes to achieve glycemic control. A combination tablet of sitagliptin (Januvia®) and metformin HCl (Glucophage®) is now available from Merck (Janumet™). The FDA has approved this drug for use in patients who are not adequately controlled by taking either sitagliptin or metformin HCl alone or for patients who are at present taking both simultaneously. Sitagliptin has been shown to be safe and effective at 100 mg daily doses. When given in combination with metformin the effect on glycemic control is thought to be complementary and possibly additive.

Apaziquone for non-muscle invasive bladder cancer: a critical review

Objective: To describe clinical needs in non-muscle invasive bladder cancer (NMIBC) and review the potential of apaziquone in this respect. Methods: Epidemiology and clinical practice in NMIBC, as well as new drugs and strategies are reviewed. Results: Bladder cancer is a heterogeneous and frequent disease. Clinical risk factors help in determining additional therapy after initial resection. However, current treatments have clear limitations with regard to efficacy and/or toxicity. New drugs and strategies have been tested recently and are in (pre)clinical use. Intravesical apaziquone (EOquin™) is a new drug. It has theoretical advantages for intravesical use, has proven safety and is presently under further clinical evaluation. Conclusion: Apaziquone is a promising drug for intravesical use in patients with NMIBC.

The Impact of Atypical Antipsychotic Medications on the Use of Health Care by Patients with Schizophrenia

Objectives Using data in real-world clinical practice, this study aims to compare the health-care use patterns of patients with schizophrenia who use oral antipsychotics. Methods A total of 219,504 episodes of antipsychotic drug therapy initiated during the period from 2000 to 2002 were identified using data from the California Medicaid program. Four types of episodes were analyzed based on the patient's drug use history as far back as 1994: restarting therapy after a break in therapy using the same drug used in the preceding episode; switching therapy after a break in treatment using a different medication; switching therapy without a break in therapy; and augmentation. Health-care use patterns over a 1-year post-treatment period were analyzed using ordinary least squares (OLS) regressions, Cox proportional hazards models, and logistic regression. Results The impact of atypical antipsychotics on health-care use in the first post-treatment year varies by episode type. Patients switching to atypical medications generally cost significantly more than similar patients switching to a conventional antipsychotic. Olanzapine and risperidone, however, were associated with reductions in total costs relative to conventional antipsychotics when used in restart and augmentation episodes. Differences across all three second-generation antipsychotics were relatively small. Conclusions Small differences across the atypical antipsychotics suggest that these drugs are interchangeable, raising the question of whether drug costs could be reduced through selectively contracting for a preferred drug. Potential savings may be limited by several factors. First, most episodes of treatment are restart episodes. Switching these patients to a preferred drug may have clinical risk. Second, patients with schizophrenia switch and augment therapies frequently, thus quickly reducing the population of patients who could be effectively treated with a single preferred drug.

Management of the hepatitis B virus in the liver transplantation setting: A European and an American perspective

Management of the hepatitis B virus in the liver transplantation setting: A European and an American perspective

The Right of Minors to Confidentiality and Informed Consent

Doctor-patient confidentiality is a precept of adolescent medicine. In general, physicians honor the privacy of adolescents unless there is evidence that the youngster is engaging in dangerous activities. An otherwise healthy 16 year old was referred for headache evaluation. During the portion of the interview conducted outside the presence of his mother, the patient revealed using marijuana and cocaine regularly and LSD (lysergic acid diethylamide), hallucinogenic mushrooms, and "Ecstasy" (3,4-methylenedioxymethamphetamine) occasionally. Given this information, and as allowed by North Carolina's General Statutes, the patient was offered confidential treatment for illegal substance abuse; he declined the offer. He also turned down the request to forgo his right to privacy so that his parents could be made aware of his addiction. As a result of the patient's drug use and disregard of its consequences, it was determined that notification of a parent was essential to his life or health; thus, confidentiality was breached. Although substance abuse is a behavior that threatens the abuser's health and life, state and federal laws vary regarding the rights of minors to confidential evaluation and treatment. For this article, laws that govern minors' rights to consent to confidential treatment for illegal substance abuse were reviewed. The aforementioned case is used as a catalyst for discussion.

Hypertrichosis of the eyelashes caused by bimatoprost

The phenyl-substituted analog of prostaglandin F 2alpha , latanoprost (Xalatan; Pfizer, Inc, New York, NY) is an intraocular pressure (IOP)-lowering drug for use in patients with glaucoma and ocular hypertension. Latanoprost has been shown to stimulate eyelash hypertrichosis and has recently been proposed as a possible treatment for alopecia areata involving the eyelashes. We report a case of hypertrichosis of the eyelashes caused by the prostamide bimatoprost (Lumigan; Allergan, Inc, Irvine, Calif), a new IOP-lowering drug.

Pharmacology Review

Cefepime is the only fourth-generation cephalosporin licensed for use in the United States. It is being used increasingly for treatment of infections caused by resistant gram-negative bacteria in older infants and children. Some hospitals have replaced antipseudomonal third-generation cephalosporin antibiotics (eg, ceftazidime) with cefepime because of high rates of infection caused by resistant gram-negative bacteria. Although cefepime generally is not used to treat infections in neonates, it is important for neonatologists to be familiar with the characteristics of the drug because there are a few circumstances in which cefepime may be appropriate therapy for an older infant hospitalized in a neonatal intensive care unit. It is important to understand the unique differences of the drug compared with older cephalosporins. The cephalosporin antibiotics are derivatives of cephalosporin C, a natural antibiotic derived from the fungus Emericellopsis minimum . Cephalosporins have a beta-lactam ring as their major structural component, and their spectrum of activity varies, depending on substitutions at the 3 and 7 positions of the cephalosporin nucleus. Traditionally, these antibiotics are grouped by their spectrum of activity against antimicrobial organisms (Table 1). First-generation cephalosporins are active against most gram-positive bacteria (except enterococci and Listeria ) and have limited activity against some gram-negative organisms. Second-generation cephalosporins have increased activity against gram-negative organisms. Cephamycins, which generally are classified with the second-generation cephalosporins, have enhanced activity against anaerobic bacteria. The third-generation cephalosporins have extended potency against gram-negative bacteria but are generally less active against susceptible staphylococci. Cefepime hydrochloride is a newer semisynthetic, broad-spectrum fourth-generation cephalosporin antibiotic. The other antibiotic in this class is cefpirome, which is not available for use in the United States. | | First Generation | Second Generation | Third Generation | Fourth Generation | |:----------:| ---------------- | ----------------- | ---------------- | ----------------- | | Oral | Cefadroxil | Cefaclor | Cefdinir | | | | Cephalexin | Cefprozil | Cefpodoxime | | | | Cephradine | Cefuroxime axetil | | | | | | Loracarbef | | | | Parenteral | Cefazolin | Cefamandole | Cefoperazone | Cefepime | | | Cephalothin | Cefuroxime | Cefotaxime | | | | Cephapirin | | Ceftizoxime | | | | | Cephamycins | Ceftriaxone | | | | | Cefotetan | Ceftazidime | | | | | Cefoxitin | | | Table 1. Generations of Cephalosporins Cefepime differs from the third-generation cephalosporins by having a quaternized N-methylpyrrolidine substitution at the C3 position of the cephem nucleus and an alkoxyimino group at the C7 position …

Should evidence-based proof of efficacy as defined for a specific therapeutic agent be extrapolated to encompass a therapeutic class of agents?

Our task as clinicians would be simple if all we had to do was to follow the logical sequence of identifying a biological target, finding a drug or treatment specifically affecting that target, testing the efficacy of the drug or treatment in appropriately designed clinical trials, and then prescribing only those drugs or treatments with proven efficacy and an acceptable safety profile. Drugs that affect a given biological target could be considered as a “class,” with those that show “efficacy” in clinical trials considered as therapeutic alternatives within that class. Unfortunately, the real world is not that simple. Defining precisely what we mean by class effect and efficacy becomes increasingly problematic, for example, as we have recently witnessed with calcium channel blockers, β-blockers, angiotensin-converting enzyme inhibitors, HMG CoA reductase inhibitors, glycoprotein IIb/IIIa antagonists, low-molecular-weight heparins, and direct thrombin antagonists.1 If we identify a drug that demonstrates efficacy, are the benefits of that drug generalizable to all drugs with similar biological targets?2 If benefits are present in one clinical circumstance, are those benefits generalizable to all circumstances in which that class of drugs can be applied?3 In the modern cost-conscious arena, can we substitute less expensive, mechanistically similar agents that may not have the same weight of clinical evidence support or even the same degree of clinical benefit? When is it acceptable to generalize to a class effect, or should we adhere strictly to evidence-based therapy with individual compounds? These issues can be viewed from both scientific and clinical perspectives. ### Definition of Biological Target As our scientific knowledge grows, our traditional grouping of drugs has become, to a large extent, obsolete. For example, there are 9 different calcium channel blockers that are approved for clinical use in the United States, which can be divided into 5 general groups on the basis of …

Effect of different doses of cisatracurium on intraocular pressure in sedated patients

Background and objective: The aim was to examine the course of intraocular pressure after relaxation with different doses of cisatracurium. Methods: The investigation was carried out as a prospective, randomized double-blind study in a crossover design in 30 postoperative patients with stable haemodynamic and respiratory function (ASA I and II). To exclude any disrupting factors, patients remained intubated and continuously sedated. Twenty patients received an intubation dose (2 × ED95) of cisatracurium (0.1 mg kg−1) compared with atracurium (0.5 mg kg−1). In a second series, 10 patients were given an effective dose, ED95 (0.05 mg kg−1), and a repeat dose (0.02 mg kg−1) of cisatracurium. The intraocular pressure was determined before (T0) as well as 1 (T1), 5 (T5), 10 (T10), 15 (T15), 20 (T20) and 45 (T45) min after bolus administration. Results: Intraocular pressure decreased after an intubation dose of either cisatracurium or atracurium, and reached a minimum after 10 min (6.7 ± 2.2 and 7.9 ± 2.1 mmHg, respectively). There was no significant difference between either muscle relaxant (P = 0.27). When lower doses of cisatracurium (0.05 and 0.02 mg kg−1) were applied, the intraocular pressure also decreased, albeit to a lesser extent and with a delayed onset (8.4 ± 1.9 mmHg after 10 min, 9.9 ± 3.4 mmHg after 15 min). There was no significant difference between dosages (P = 0.44). Conclusions: Cisatracurium is a useful drug in patients when a decrease of intraocular pressure is wanted and where muscle relaxation is necessary and acceptable.

Bimatoprost and Travoprost: A Review of Recent Studies of Two New Glaucoma Drugs

Bimatoprost (Lumigan™ [Allergan, Inc, Irvine CA]) and travoprost (Travatan™ [Alcon, Ft Worth, TX]) are two new intraocular pressure (IOP)-lowering drugs for use in patients with glaucoma and ocular hypertension. This review evaluates recent studies comparing these new drugs with timolol and with latanoprost. In each study, the statistical analyses support the conclusion that these agents were more effective than timolol and as effective as latanoprost in terms of their ability to reduce IOP. The side effect profiles for bimatoprost, latanoprost, and travoprost were similar, but with statistically higher occurrences of hyperemia and eyelash growth for bimatoprost or travoprost versus latanoprost or timolol.

Respiratory pharmacology of airway nerves

The advent of computer-based prescribing in general practice has made it possible to study a patient's drug use in detail. This study compared the use of inhaled therapy in 100 patients with chronic disease by examining every prescription issued during the year before and the year after initial consultation at a nurse-run asthma clinic. The majority were poorly controlled in that 79% scored high on the Jones Morbidity Index at their first visit.The number of patients on inhaled corticosteroid and salmeterol xinafoate rose from 87 to 100% and 6 to 28%, respectively, while those instructed to take their β-agonist ‘when required’ as opposed to a regular dose rose from 26 to 82%.The daily median intake of short-acting β-agonist fell from 5·0 to 3·8 doses (P<0·0001).In the 87 patients on inhaled corticosteroid throughout, the mean daily dose increased from 532·1 to 793·1 μg (P<0·0001), and compliance (defined as the total dose issued in 1 year expressed as a percentage of that recommended) increased from 61·5 to 69·3% (P=<0·05).Attendance at a nurse-run asthma clinic was associated with a number of significant alterations in inhaled therapy. These changes conformed to the British Thoracic Society's guidelines.

Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial

Purpose: This study was to evaluate the efficacy and safety of topiramate (TPM) in patients with severe myoclonic epilepsy in infancy (SMEI) and refractory seizures. Methods: We performed a prospective multicentric open label add-on study in 18 patients (age 2–21 years, mean 9 years) with SMEI and refractory seizures of different types. TPM was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. Results: TPM was initiated at a daily dose of 0.5–1 mg/kg, followed by a 2-week titration at increments of 1–3 mg/kg/24 h up to a maximum daily dose of 12 mg/kg. After a mean period of 11.9 months (range 2–24 months), three patients (16.7%) had 100% fewer seizures and ten patients (55.5%) had a more than 50% seizure decrease. In no patient there was a seizure worsening. Mild to moderate adverse events were present in four patients (22.2%), represented by weight loss, hypermenorrhoea, renal microlithiasis, nervousness and dysarthric speech. Conclusion: TPM may be a useful drug in patients with SMEI, being particularly effective against generalized tonic–clonic seizures. Further studies are needed to evaluate the early use of this drug in such a severe syndrome.

Pharmacological and clinical profile of nifekalant (shinbit injection), a class III antiarrhythmic drug

Nifekalant (shinbit, MS-551) is a pure class III antiarrhythmic drug (Vaughan Williams' classification), which was approved in Japan in June 1999. This drug prolongs the action potential duration (APD) and the effective refractory period (ERP) in cardiac myocytes mainly by blocking the IKr (the rapid component of delayed rectifier K+ current). The antiarrhythmic efficacy depends on prolongation of ERP. The importance of this drug is to save patients from the life-threatening arrhythmias ventricular tachycardia (VT) and fibrillation (VF). Nifekalant was effective against reentrant arrhythmias such as VT and VF in postinfarction dogs. This drug does not have the negative inotropic effect that has been observed with other antiarrhythmic drugs. In clinical therapy, this drug was remarkably effective on patients who were unresponsive to therapy with other drugs or who were not able to receive other drugs due to decreased cardiac function. There has been no case of drug-induced worsening of the cardiac function. The significant adverse reaction is proarrhythmia such as ventricular tachycardia including TdP. Nifekalant is expected to be a useful drug for patients who could not be rescued from life-threatening arrhythmia by conventional therapies.

Paclitaxel-based combination chemotherapy in advanced non-small cell lung cancer

Paclitaxel has proven to be a useful drug for patients with advanced non-small cell lung cancer (NSCLC). Paclitaxel-based combination chemotherapy, particularly with carboplatin, has become a very popular combination in the US. This article will review the conclusions of several studies regarding paclitaxel-based chemotherapy. The data provide evidence that this therapy produces good palliation and prolongation of survival for patients with NSCLC and is superior to older cisplatin-based chemotherapy. These results in patients with advanced disease have important implications for neoadjuvant and/or adjuvant approaches in patients with lower stages of disease, and several studies are ongoing.

Sarpogrelate reduces mechanical hemolysis in patients with heart valve prostheses.

We evaluate the clinical efficacy of sarpogrelate, an antiplatelet drug that improves red blood cell deformability, to reduce the intravascular hemolysis problems suffered frequently by patients implanted with heart valve prostheses. Subjects were 34 patients undergoing mechanical heart valve replacement and having serum lactate dehydrogenase concentrations 20% above the maximum normal range. Sarpogrelate was given daily, 100 mg orally for the first 6 months and 200 mg thereafter. Average serum lactate dehydrogenase decreased significantly from 423 +/- 108 IU/l, to 391 +/- 83 IU/l with the 100 mg dose, and to 361 +/- 86 IU/l with the 200 mg dose. The percentage of reticulocytes decreased from 15.5 +/- 5.3/1000 to 15.3 +/- 5.7/1000 at the 100 mg dose and 13.1 +/- 4.0/1000 at the 200 mg dose. Serum iron concentrations increased significantly from 63.2 +/- 24.8 micrograms/dl to 76.2 +/- 16.2 micrograms/dl at the 100 mg dose, and to 70.9 +/- 26.2 micrograms/dl with the 200 mg dose. Sarpogrelate is a useful drug for patients with implanted heart valve prostheses and subsequent high serum lactate dehydrogenase because it works as an antiplatelet drug and reduces mechanical hemolysis.

Protective effect of a traditional Japanese medicine, Bu-zhong-yi-qi-tang (Japanese name: Hochu-ekki-to), on the restraint stress-induced susceptibility against Listeria monocytogenes

In this study, the effect of traditional Japanese (Chinese) medicine, Bu-zhong-yi-qi-tang (Japanese name: Hochu-ekki-to, HOT), on the restraint stress treatment (RST)-induced susceptibility against Listeria monocytogenes (L. monocytogenes) was examined. When RST was performed every day for 10 h from the day of infection, the bacterial numbers were increased at 3 and 5 days after the infection. Oral pretreatment with HOT for 7 days prevented such increases. Pretreatment with HOT prevented the suppression of antigen-specific IFN-γ production by RST. HOT also prevented suppression of macrophage accumulation, including MHC-class II positives, in the peritoneal cavity and their bactericidal activity by RST. HOT suppressed the serum corticosterone level elevated by RST in infected mice. Taken together, the suppression of corticosterone using HOT participates in the prevention of suppressions of the bactericidal activity of macrophages, migration of macrophages and antigen-specific IFN-γ production of Th1 cells by RST. Our findings suggest that HOT is a useful drug for patients suffering from stress disease to reduce the susceptibility to bacterial infection.

Safety and efficacy of vigabatrin and carbamazepine in ne wly diagnosed epilepsy: a multicentre randomised double-blind study

Vigabatrin is a newly licensed drug for use in patients with epilepsy. We investigated whether this drug was comparable to standard first-line monotherapy in efficacy and incidence of adverse events. We enrolled 459 patients with newly diagnosed, previously untreated partial epileptic seizures from 44 European centres and randomly assigned them carbamazepine 600 mg daily (n=230) or vigabatrin 2 g daily (n=229). After initial maintenance doses were reached, doses were adjusted downwards (in the case of adverse events) or upwards (in the case of seizures) by the clinician. The primary outcome was time to withdrawal because of lack of efficacy or adverse events. Secondary outcomes included efficacy (time to 6-month remission of seizures, time to first seizure after initial dose stabilisation), and adverse events (incidence and severity). Analysis was by intention to treat. Time to withdrawal for lack of efficacy or adverse events did not differ between groups (p=0.318). Vigabatrin was better tolerated than carbamazepine with fewer withdrawals, but was more frequently associated with psychiatric symptoms (58 [25%] vs 34 [15%]) and weight gain (25 [11%] vs 12 [5%]). Carbamazepine was associated with rash (22 [10%] vs seven [3%]). All efficacy outcomes favoured carbamazepine and failed to show equivalence between the two drugs. No significant difference was found for time to achieve 6 months of remission from seizures (p=0.058), but the most powerful outcome, time to first seizure after the first 6 weeks from randomisation, showed carbamazepine to be significantly more effective than vigabatrin (p=0.0001). Vigabatrin seems less effective but better tolerated than carbamazepine, which is the first-choice drug for the treatment of partial epilepsies. Vigabatrin cannot therefore be recommended as a first-line drug for monotherapy in this group of patients.