Alex A. Cardoni

Risperidone: Review and Assessment of Its Role in the Treatment of Schizophrenia

Objective: To review pharmacologic, pharmacokinetic, therapeutic, and safety information for the antipsychotic agent risperidone and to evaluate its place in the treatment of schizophrenia. Data Sources: MEDLINE and Exerpta Medica databases; Janssen Pharmaceuticals; Food and Drug Administration Psychopharmacology Advisory Committee; PJB Publications; published articles and abstracts; unpublished research reports and abstracts. Study Selection: In vivo animal studies (pharmacology); volunteer studies (pharmacokinetics); clinical case reports, open clinical studies, and controlled clinical studies (clinical efficacy and adverse effects; long-term studies; studies in special populations. Data Extraction: Relevant data were extracted from published and unpublished source documents, evaluated, and summarized in tables for comparative review. Abstracts were used in 6 of 8 pharmacokinetic studies, 4 of 8 open clinical studies, and 2 of 9 controlled clinical studies. Use of abstracts limits the extent of data extracted. Data Synthesis: Risperidone is an effective treatment for positive symptoms of schizophrenia and may be effective for negative symptoms. Efficacy in treatment-resistant patients is inconclusive. In patients in whom low-to-moderate dosage is effective, there should be fewer and less severe adverse effects with risperidone than with haloperidol. Optimal dosage for schizophrenia appears to be 6 mg/d. Although data are limited, risperidone may be toxic on overdose. Conclusions: Risperidone is a useful addition to the antipsychotic drug armamentarium, but it should not be viewed as an atypical antipsychotic agent. It is reasonable to consider a trial of risperidone in treatment-resistant schizophrenic patients prior to the use of clozapine and as a first-line treatment for newly diagnosed patients with schizophrenia.

New Drug Evaluations: Metronidazole (Flagyl IV®, Searle):

Metronidazole is a narrow spectrum antibiotic with undoubted efficacy against common anaerobic bacteria; resistance is unusual. Therapeutic concentrations of the drug are attained throughout most body compartments after either oral or intravenous administration. The limited side effects of metronidazole are generally tolerable, transient, or reversible. Clinically, metronidazole is as effective as clindamycin and probably chloramphenicol against anaerobes. It has a definite advantage over clindamycin in CNS infections since clindamycin does not penetrate the CSF well. Metronidazole has no irreversible hematologic toxicities, nor has pseudomembranous colitis been definitely attributed to intravenous use of the drug. Metronidazole may replace chloramphenicol for use in anaerobic infections since it lacks the predictable hematologic toxicity of the latter drug. It should also be useful in patients who fail to respond to clindamycin or who develop pseudomembranous colitis while receiving clindamycin. Problems with metronidazole include a complicated preparation procedure, and the high cost of the drug. The single major drawback to the use of metronidazole is uncertainty about its carcinogenic potential in humans. Metronidazole is carcinogenic in animals and mutagenic in vitro, but has not increased the incidence of cancer in humans followed for relatively short periods. Thus, the risk appears to be small. Still, the question will not be resolved for years because of the long latency periods involved in carcinogenesis. Until that time, metronidazole should be used conservatively.

Alprazolam (Xanax®, the Upjohn Company)

Alprazolam is a triazolobenzodiazepine, a derivative of the benzodiazepines. Comparison studies of alprazolam and diazepam or chlordiazepoxide in patients suffering from clinical anxiety secondary to anxiety neurosis or chronic alcohol withdrawal suggest an equal efficacy of those agents. Studies examining the use of alprazolam for the treatment of “primary depression” suggest that it is as effective as imipramine in the treatment of exogenous (reactive) depression. Although alprazolam may be effective in patients with exogenous depression, no extrapolation can be made to the treatment of endogenous depression. Mechanisms of action have not been fully elucidated, but probably are similar to those of other benzodiazepines. Peak blood levels are reached in 0.7–1.6 hours and the elimination half-life after steady state is approximately 19 hours. Daily dosages established from clinical studies ranged from 1 to 6 mg. Clinically, alprazolam appears to be ten times more potent than diazepam. Drowsiness, headaches, lightheadedness, dry mouth, and depression appear to be the most common side effects of the drug. It is concluded that alprazolam offers no striking therapeutic advantage over currently marketed benzodiazepines.

Cefoperazone (Cefobid, Pfizer)

Cefoperazone is a new β-lactam antibiotic that possesses a broad spectrum of activity against gram-positive and gram-negative organisms. Cefoperazone differs from all previous cephalosporins in that it has exceptional activity against P. aeruginosa. The other distinguishing feature of cefoperazone is its high rate of biliary excretion, which will allow for treatment of biliary tract infections. Renal elimination accounts for only 20 percent of the agents elimination; dosage modification is not necessary in decreased renal function. The clinical response rate of infections to cefoperazone is similar to that of moxalactam, cefotaxime, or the cephalosporins in general. The overall incidence of side effects was 14 percent in U.S. trials, with skin rash, fever, or urticaria occurring in 1 percent; phlebitis and injection-site pain in 2 percent; and diarrhea in 5 percent. As with the other third-generation cephalosporins, cefoperazone requires close scrutiny because of its expected high cost and the lack of comparative trials with standard antibiotic regimens.

Temazepam (Restoril, Sandoz Pharmaceuticals)

Temazepam is a benzodiazepine derivative indicated for the treatment of insomnia. Pharmacokinetic studies of the hard capsule formulation indicate that the mean time to peak is 2.99 hours and the mean elimination half-life is 14.7 hours. Sleep laboratory studies have demonstrated improvements in all sleep parameters except sleep onset latency. Clinically, patients report improvements in all sleep parameters including sleep onset latency. The efficacy of temazepam compares favorably with barbiturates, glutethimide, nitrazepam, lorazepam, oxazepam, and flurazepam. It has not been compared with diazepam in the clinical setting. Side effects include drowsiness, dizziness, and lethargy. The incidence of hangover effects from 15- and 30-mg doses is relatively low. Temazepam has no proven advantages over other benzodiazepine hypnotics. The major issues that need further clarification include temazepams sleep induction properties and the relative incidence of hangover and rebound insomnia when compared with longer-acting benzodiazepines.

Cefaclor (Ceclor® - Eli Lilly and Company)

CEFACLOR ( 3-chloro-7-D-[2-phenylglycinamido]-3-cephem-4-carboxylic acid) is a semisynthetic, orally administered cephalosporin derivative which is chemically similar to cephalexin (Figures 1 and 2 ) . Experiments have shown that cefaclor is less stable in aqueous solution than it is in the crystalline form, and that the stability of the solution is pH-dependent. coccus aureus and S. pyogenes; lower respiratory infections, including pneumonia caused by susceptible strains of S. pneumoniae, H. influenzae, and S. pyogenes; and upper respiratory infections, including tonsillitis and pharyngitis caused by susceptible strains of S. pyogenes.

Nomifensine Maleate (Merital, Hoechst-Roussel)

Nomifensine is an isoquinoline antidepressant that inhibits the reuptake of dopamine at central synapses. It also inhibits norepinephrine reuptake but is only a weak inhibitor of 5-hydroxytryptamine. Open and controlled trials comparing nomifensine with placebo and other standard antidepressants have shown it to be an effective antidepressant in divided doses up to 200 mg/d. The full dosage range of 50–200 mg/d is well tolerated, and doses can be selected to suit patient disease, age, and therapeutic response. Minimal anticholinergic and sedative side effects and no impairment of psychomotor performance make nomifensine a suitable drug for use in a wide variety of ambulatory outpatients, including the elderly. A relative lack of cardiotoxicity and epileptogenic activity add to this profile; the safety of the drug, when taken in overdose, has been documented. However, the place of nomifensine in the treatment of depression, relative to other antidepressants, is still unclear.

New drug evaluations amiloride (Midamor, Merck, Sharp and Dohme).

Amiloride is a potassium-sparing diuretic that is pharmacologically similar to triamterene. It has been widely used abroad for several years, alone and in combination with hydrochlorothiazide. As a potassium-sparing agent, amiloride appears to be approximately as effective as triamterene and spironolactone and to have a longer duration of action than triamterene, allowing once daily dosing. The diuretic effect of amiloride is mild, as are all agents that act at distal tubular sites. Amiloride appears to have an antihypertensive effect approximating that of the thiazides and spironolactone – an advantage over triamterene, which is devoid of antihypertensive effects. Amiloride will probably be most useful as a potassium-sparing agent in combination with the thiazide and loop diuretics. It should be kept in mind, however, that many patients on thiazide diuretics do not need supplemental potassium or potassium-sparing agents if they have no other complicating factors, such as digitalis therapy. When hypokalemia causes symptoms, a potassium-sparing agent may have advantages over oral potassium supplements in patient tolerance and compliance. Because of the possibility of tumorigenicity and estrogenic side effects, spironolactones popularity has been decreasing in recent years. Amiloride will probably be a strong competitor of triamterene and spironolactone because of its longer duration of action than triamterene and, from early indications (cf. ticrynafen), more benign side effects than spironolactone. The drug should be used with great caution, if at all, in patients with impaired renal function, however. The benefits of amiloride will have to be weighed against the cost of the drug in individual patients.

Clinical Pharmacy Education in New England: A Report of the Whispering Pines Conference

Clinical pharmacy practice as it relates to the future of the pharmacy profession has been examined at Hilton Head in 1985 and at regional conferences throughout the U.S. between 1986 and 1988. However, clinical pharmacy education and its role in the future of the profession had not been the focus of this type of “futuristic” conference. In 1988, the clinical pharmacy faculties from the four colleges of pharmacy in New England met to discuss the “Directions for Clinical Pharmacy Education in New England.” Through a series of workshops, and stimulated by challenges from keynote speakers, the participants focused on the current status of clinical pharmacy education in New England, the barriers to change, and the strategies required to accomplish these changes. Consensus on prioritization of changes and their strategies was reached, and those that could be implemented in the near future were identified. Since the conference, changes have occurred and the professional networking that began at the conference has continued. This paper is a summary of the proceedings of this conference.

A Course in Psychotropic Drug Therapy for First-Year Psychiatry Residents

A course in psychotropic drug therapy for first-year psychiatry residents at the University of Connecticut Health Center is described. The course is taught by a pharmacist with training and experience in the psychiatric patient care setting. During the 8-week, 16-hour course, emphasis is placed on the practical aspects of selection and use of psychotropic drugs, including antipsychotic agents, antidepressants, and anti-anxiety agents. A major objective of the course is to familiarize the residents with current psychotropic drug literature. Within the context of this course offering, the role of the pharmacist as an educator of the physician is discussed.