Daniel A. Hussar

Aspects of the epimerization of certain tetracycline derivatives

The epimerization of several tetracycline derivatives was examined at several pH values using varying conditions of temperature and buffer strength. Rate coefficients for the epimerization of tetracycline and demethylchlortetracycline are reported and factors associated with the epimerization of chlortetracycline and oxytetracycline are discussed. Under the conditions used calcium had no effect on the rate of epimerization and copper promoted degradation other than epimerization.

Metal binding tendencies of various antibiotics

A method to determine the presence of metal‐drug complexes in dilute solutions is described. Using this method cycloserine was found to complex with cupric, nickelous, zinc and cobalt ions; streptomycin and novobiocin complexed with cupric ions; erythromycin complexed with cobalt ions, and chloramphenicol exhibited no metal binding tendencies. Various penicillins were found to interact with zinc and cupric ions. Preliminary investigations suggest that cupric ions, rather than simply complexing with penicillin as suggested by previous workers, promote the degradation of penicillin to penicilloic acid. Evidence is presented to confirm the presence of penicilloic acid in reaction mixtures initially containing penicillin G or V and cupric ions, and to establish that the reaction follows second order kinetics and ceases when all available cupric ion has been consumed. Good correlation was noted for these results and previous work which showed the effects of metal ions on the antibacterial properties of penicillin.

New Drugs of 2003

OBJECTIVES To provide information regarding the most important properties of the new therapeutic agents marketed in 2003. DATA SOURCES Product labeling supplemented selectively with published studies and drug information reference sources. STUDY SELECTION By the author. DATA EXTRACTION By the author. DATA SYNTHESIS The 28 new therapeutic agents marketed in the United States during 2003 are reviewed in this article: adalimumab, agalsidase beta, alefacept, alfuzosin hydrochloride, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, bortezomib, daptomycin, efalizumab, eletriptan hydrobromide, emtricitabine, enfuvirtide, eplerenone, gefitinib, icodextrin, laronidase, memantine hydrochloride, mequinol/tretinoin, miglustat, nitazoxanide, omalizumab, palonosetron hydrochloride, pegvisomant, rosuvastatin calcium, tadalafil, tositumomab and iodine I 131 tositumomab, and vardenafil hydrochloride. Indications and information on dosage and administration for these agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. When possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION A number of the new therapeutic agents marketed in 2003 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.

New drugs of 1999.

OBJECTIVE To provide information regarding the most important properties of the new therapeutic agents marketed in 1999. DATA SOURCES Published studies, drug information reference sources, and product labeling. DATA SYNTHESIS In 1999, 28 new therapeutic agents were marketed. The indications and information on dosage and administration for each new agent are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSIONS A number of the new therapeutic agents marketed in 1999 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health care professionals regarding these drugs.

New drugs: Denosumab, dienogest/estradiol valerate, and polidocanol

Agent for osteoporosis Osteoporosis is characterized by decreased bone mass and an increased risk of fracture, most often at the spine, hip, and wrist. Because of the reduction in estrogen production that occurs following menopause, women are more likely than men to experience osteoporosis, and one of every two women older than 50 years will experience a bone fracture as a consequence. Bisphosphonates such as alendronate (e.g., Fosamax), ibandronate (Boniva), and risedronate (Actonel) have been widely prescribed for the treatment and prevention of osteoporosis. These agents are administered orally, and ibandronate is also available in a formulation that is administered intravenously every 3 months. Another bisphosphonate, zoledronic acid (Reclast), is administered intravenously once a year for the treatment (and every 2 years for prevention) of osteoporosis in postmenopausal women. Denosumab (Prolia—Amgen) is a human monoclonal antibody that binds to receptor activator of nuclear factor kappa-B ligand (RANKL), a protein that is essential for the formation, function, and survival of osteoclasts, the cells that are responsible for bone resorption. Denosumab prevents RANKL from activating its receptor on the surface of osteoclasts and their precursors, with a resultant decrease in bone resorption and increase in bone mass and strength. Denosumab is administered subcutaneously and is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture, or of patients who have failed or are intolerant to other available therapies for osteoporosis. The effectiveness of the new drug was demonstrated in placebocontrolled studies, in which it reduced the incidence (identified as new fractures at year 3 for the denosumab and placebo groups, respectively) of vertebral (2.3%, 7.2%), nonvertebral (6.5%, 8%), and hip (0.7%, 1.2%) fractures. Treatment with denosumab significantly increased bone mineral density (BMD) at all anatomic sites measured at 3 years. Following discontinuation of treatment, BMD returned to approximately baseline levels within 12 months. Whereas the labeled indication for denosumab is for the treatment of women who are considered to be at high risk of fracture, the indications for alendronate, ibandronate, risedronate, and zoledronic acid include the prevention, as well as treatment, of osteoporosis in postmenopausal women, and the indication is not limited to those at high risk of fracture. The indications for alendronate, risedronate, and zoledronic acid also include the treatment of osteoporosis in men, glucocorticoid-induced osteoporosis in men and women, and Paget’s disease in men and women. Denosumab is also being evaluated to determine whether it may reduce the risk of fractures in patients with certain cancers (e.g., prostate cancer) that have metastasized to bone tissue or whether it may prevent tumors from metastasizing to bone. However, these are not labeled indications at the present time. The use of denosumab may exacerbate hypocalcemia, and it is contraindicated in patients with hypocalcemia. Preexisting hypocalcemia should be corrected before initiating treatment with the new drug. In patients who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g., history of hypoparathyroidism, malabsorption syndromes, severe renal impairment), concentrations of calcium and minerals (e.g., phosphorus, magnesium) should be monitored. Supplementation with calcium and vitamin D should be provided during treatment. In the clinical studies, serious infections (e.g., skin, abdominal, urinary tract, ear, endocarditis) that necessitated hospitalization were reported more frequently in patients treated with denosumab than in those receiving placebo. Patients who are also being treated with immunosuppressive agents or who have impaired immune function should be considered at greater risk for serious infection. Patients should be advised to promptly report signs or symptoms of severe infection. Denosumab has been reported to cause dermatologic adverse events (e.g., dermatitis, eczema, rash) at a significantly higher incidence than was observed in the placebo group. The discontinuation of treatment should be considered if severe symptoms occur. As with the bisphosphonates, some patients treated with denosumab have experienced osteonecrosis of the jaw (ONJ) that may be related, in part, to suppression of bone remodeling. A routine oral exam should be performed by the prescriber before initiating treatment. In patients with risk factors for ONJ (e.g., tooth extraction, oral surgery, poor oral hygiene), a dental examination with appropriate preventive dentistry should be considered. Patients should be advised to inform their dentists that they are taking denosumab before having dental work done. The most frequently experienced adverse events with denosumab include back pain (35%), pain in extremity (12%), musculoskeletal pain (8%),

New drugs: Asenapine, iloperidone, and bepotastine besilate

Antipsychotic agents Asenapine (Saphris—Schering) and iloperidone (Fanapt—Vanda) are new atypical antipsychotic agents that join an already large class of these drugs that includes aripiprazole (Abilify), clozapine (e.g., Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and risperidone (e.g., Risperdal) and its active metabolite paliperidone (Invega). Both new drugs have been approved for the acute treatment of schizophrenia in adults, and asenapine has also been approved for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. The labeled indications for asenapine and iloperidone are more limited than those of their predecessors, with which long-term experience and additional studies have resulted in an extension of the indications for which they were initially approved. Although much remains to be learned regarding the mechanisms through which the antipsychotic agents provide benefit in the treatment of schizophrenia, it is thought that their efficacy is mediated through a combination of antagonist activity at dopamine type 2 and serotonin type 2 receptors. Most of the warnings and precautions associated with using asenapine and iloperidone are similar to those of the other atypical antipsychotic agents. The labeling for all of these agents includes a boxed warning regarding increased mortality in elderly patients with dementia-related psychosis, as well as the statement that these agents have not been approved for treating patients with dementia-related psychosis. Other shared warnings and precautions include the potential for cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, hyperglycemia/diabetes, weight gain, orthostatic hypotension/syncope, hyperprolactinemia, seizures, cognitive and motor impairment, dysphagia, problems associated with body temperature regulation, and leukopenia, neutropenia, and agranulocytosis. The possibility of suicide is inherent in psychiatric illness, and these drugs should be prescribed in the smallest quantities consistent with good patient management to reduce the possibility of overdosage. The labeling for both asenapine and iloperidone, as well as that for selected other atypical antipsychotic agents (e.g., paliperidone, ziprasidone), includes a warning regarding prolongation of the QT interval and the associated risk of cardiac dysrhythmias. Accordingly, the use of these agents should be avoided in patients with congenital long QT syndrome, hypokalemia and/or hypomagnesemia, or a history of cardiac dysrhythmias, as well as in patients being treated with other medications that are known to cause QT prolongation, including Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antidysrhythmic agents, antipsychotic agents (e.g., chlorpromazine, thioridazine, ziprasidone), and antimicrobial agents (e.g., moxifloxacin [Avelox]). Both asenapine and iloperidone are classified in Pregnancy Category C and should only be used during pregnancy if the anticipated benefit outweighs the risk to the fetus. Although it is not known whether the new drugs or their metabolites are excreted in human milk, it is recommended that women treated with either of these agents should not breast feed. The effectiveness and safety of asenapine and iloperidone in patients younger than 18 years of age have not been established. Asenapine and iloperidone are considered on an individual basis below.

New drugs of 2001

OBJECTIVE To provide information regarding the most important properties of the new therapeutic agents marketed in 2001. DATA SOURCES Published studies, drug information reference sources, and product labeling. DATA SYNTHESIS In 2001, 26 new therapeutic agents were marketed. The indications and information on dosage and administration for the new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION A number of the new therapeutic agents marketed in 2001 have important advantages over older medications. An understanding of the properties of these agents is important if the pharmacist is to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.

New drugs of 2000.

OBJECTIVE To provide information regarding the most important properties of the new therapeutic agents marketed in 2000. DATA SOURCES Published studies, drug information reference sources, and product labeling. DATA SYNTHESIS In 2000, 33 new therapeutic agents were marketed. The indications and information on dosage and administration for the new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION A number of the new therapeutic agents marketed in 2000 have important advantages over older medications. An understanding of the properties of these agents is important if the pharmacist is to effectively counsel patients about their use and to serve as a valuable source of information for other health care professionals regarding these drugs.

Mechanisms of Drug Interactions

Feel lonely? What about reading books? Book is one of the greatest friends to accompany while in your lonely time. When you have no friends and activities somewhere and sometimes, reading book can be a great choice. This is not only for spending the time, it will increase the knowledge. Of course the b=benefits to take will relate to what kind of book that you are reading. And now, we will concern you to try reading mechanisms of drug interactions as one of the reading material to finish quickly.

New drugs: simeprevir, sofosbuvir, and dolutegravir sodium

combination regimens for the treatment of chronic HCV infection that include neither interferon nor, in the not-so-distant future, ribavirin. The new regimens offer the hope of being more effective, better tolerated, and shorter in duration. Simeprevir and sofosbuvir are considered on an individual basis in the following discussions. Simeprevir is a direct-acting antiviral agent against HCV. Like boceprevir and telaprevir, it is an inhibitor of the HCV NS3/4A protease that is necessary for replication of the virus. It is indicated for the treatment of chronic HCV infection as a component of a combination antiviral treatment regimen, and its efficacy has been established in combination with peginterferon alfa and ribavirin in HCV-genotype-1-infected patients with compensated liver disease (including cirrhosis). It must not be used as monotherapy. Simeprevir was evaluated in studies designed to measure whether a patient’s HCV was no longer detected in the blood at least 12 weeks after finishing treatment (i.e., SVR). Of treatment-naive patients treated with simeprevir, peginterferon alfa, and ribavavirin, 80% achieved an SVR, compared with 50% of those treated with peginterferon alfa and ribavirin alone. In a study involving prior relapse patients, 79% treated with the three-drug regimen achieved an SVR, compared with 37% of those treated with just peginterferon alfa and ribavirin. In another study, the regimen including simeprevir improved response rates in both partial responders and those who did not respond to prior therapy (null responders). However, the new drug has not been evaluated in patients who have previously failed therapy with a treatment regimen that includes an HCV protease inhibitor. Antiviral agents Agents for hepatitis C virus infection Hepatitis C virus (HCV) infection is characterized by inflammation of the liver, which can lead to reduced liver function and liver failure. Following the initial infection with HCV, most people develop chronic HCV infection. Many patients with the infection do not experience symptoms until liver damage occurs, which may take several years. Some develop cirrhosis of the liver, which can lead to liver damage with complications such as bleeding, jaundice, fluid accumulation in the abdomen, infections, and/or liver cancer. Liver disease resulting from HCV infection is the most frequent reason for liver transplants in the United States. More than 3 million Americans have chronic HCV infection, but approximately one-half are unaware of their status. HCV genotype 1 infection—the most common form—is experienced by approximately 80% of patients. For a number of years, the standard of treatment for chronic HCV infection was a combination regimen of peginterferon alfa and ribavirin for 48 weeks. This treatment provided sustained virologic responses (SVRs) characterized by undetectable plasma HCV RNA 24 weeks following discontinuation of therapy, which is considered a cure of the infection. However, SVRs were attained in fewer than 50% of patients. Additionally, peginterferon alfa must be injected and often causes adverse events (e.g., flu-like symptoms, fatigue, depression), and ribavirin must not be used during pregnancy due to the risk of birth defects and fetal death. In 2011, the approval and marketing of two new antiviral agents provided an important advance in the treatment of chronic HCV infection. Boceprevir (Victrelis) and telaprevir (Incivek) were the first medications to act directly on HCV (i.e., direct-acting agents), and both are classified as HCV protease inhibitors. By inhibiting the HCV nonstructural protein NS3/4A serine protease, they interfere with actions that are necessary for the replication of HCV. Both drugs are administered orally and are indicated for the treatment of chronic hepatitis C genotype 1 infection in combination with peginterferon alfa and ribavirin. The three-drug regimens that include an HCV protease inhibitor are more effective (i.e., a considerably higher percentage of patients experience an SVR) and permit a shorter course of treatment for many patients. However, boceprevir and telaprevir may cause some serious adverse events, interact with numerous medications, and have a short duration of action that necessitates administration three times a day and twice a day, respectively. In late 2013, the Food and Drug Administration (FDA) approved simeprevir (Olysio—Janssen) and sofosbuvir (Sovaldi—Gilead). These agents are administered orally once a day as part of a combination regimen, increase the effectiveness of treatment, and reduce the duration of treatment in some patients. Sofosbuvir is the first agent that permits the use of combination regimens for some patients that do not include interferon. This represents an important advance in the development of New drugs: simeprevir, sofosbuvir, and dolutegravir sodium