Estimating the size of the effects of co-medications on plasma clozapine concentrations using a model that controls for clozapine doses and confounding variables.

AIM: The purpose of this study was to estimate the effect sizes of drug interactions on plasma clozapine concentrations, adjusting for potentially confounding factors such as smoking. METHODS: The estimation was performed by using a mixed model, and a combination of unpublished (N=83) and published (N=172) data that included patients taking phenobarbital, valproic acid, fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram and reboxetine, and patients not taking co-medications. RESULTS: The 255 patients provided a total of 415 steady-state trough plasma clozapine concentrations. Each patient provided 1 to 15 measures of plasma clozapine concentrations. Total plasma clozapine concentration, defined as the sum of plasma clozapine and norclozapine concentrations, was also investigated. A random intercept linear model of the natural log of plasma clozapine concentration with the natural log of dose and other variables as independent variables was built. The model confirmed that phenobarbital induces clozapine metabolism (effect size, E=-28%), and that fluoxetine (E=+42%), fluvoxamine (E=+263%) and paroxetine (E=+30%) inhibit it. Valproic acid appeared to inhibit clozapine metabolism in non-smokers (effect size, E=+16%), whereas it appeared to induce clozapine metabolism in smokers (E=-22%). The effect sizes of smoking on plasma clozapine concentration were -20% in patients not taking valproic acid, and -46% in patients taking valproic acid. Thus, smoking induces clozapine metabolism, and this induction may be stronger when the patient is taking valproic acid. The effect sizes allowed the computation of clozapine dose-correction factors for phenobarbital, 1.4 [95% confidence interval, CI, (1.1, 1.7)]; paroxetine, 0.77 (0.67, 0.89); fluoxetine, 0.70 (0.64, 0.78); fluvoxamine, 0.28 (0.22, 0.35); and valproic acid [0.86 (0.75, 1.0) in non-smokers, and 1.3 (0.96, 1.73) in smokers]. Sertraline, reboxetine and citalopram had no obvious effects. DISCUSSION: The results for total plasma clozapine concentrations are similar to those for plasma clozapine concentrations. The main limitations of this study were that the computed effect sizes reflect only the doses and treatment-durations of the co-medications studied, and that the substantial "noise" of the clinical environment may make it difficult to detect the effects of some variables, particularly those with small effect sizes. Gender was not significant probably due to its relatively small effect size in the studied population, and age was not significant probably due to the limited age variability. CONCLUSION: This article contributes to the clozapine literature by describing a possible interaction between taking valproic acid and smoking, which modifies plasma clozapine concentrations, by estimating the effect sizes of other compounds on plasma clozapine concentrations after correcting for confounders, and by providing dose-correction factors for clinicians.

Oleic acid-associated bronchiolitis obliterans-organizing pneumonia in beagle dogs.

Accidental intra-airway exposure of dogs with pure oleic acid produced bronchiolitis obliterans and bronchopneumonia. Pulmonary changes included multifocal to coalescing necrosis of bronchioles and adjacent alveoli, hemorrhage, inflammation, and exudation of fibrin. Hyperplasia of bronchiolar and alveolar epithelial cells and proliferation of loose fibrovascular connective tissue formed polyps or plugs of variable size and shape. Polyps in the airways primarily consisted of fibroblasts with loose or myxoid stroma and were variably covered with attenuated epithelial cells. Some polyps had prominent vasculature, mixed inflammatory cell infiltration, and/or necrosis. Polyps or plugs variably effaced bronchioles and adjacent alveoli. The changes closely resembled human bronchiolitis obliterans-organizing pneumonia (BOOP). Controlled intra-airway delivery of oleic acid in dogs may be a potential animal model of obstructive pulmonary diseases such as BOOP or bronchiolitis obliterans.

Olanzapine-induced diabetes mellitus.

OBJECTIVE: To report two cases of new-onset diabetes mellitus resulting after the initiation of olanzapine treatment. CASE SUMMARY: A 31-year-old African American man and a 44-year-old white man, both with schizoaffective disorder, developed diabetes mellitus within weeks or months of olanzapine initiation. DISCUSSION: Our reports of new-onset diabetes due to olanzapine are consistent with those in the literature. Although the mechanism is not yet known, it has been hypothesized that perhaps damage to the pancreatic islet cells, weight gain, dysregulation of the sympathetic system, and insulin resistance are contributing factors. CONCLUSIONS: Diabetes mellitus secondary to olanzapine use seems to be a rare occurrence. However, certain risk factors such as obesity, family history, and concomitant medications may predispose an individual to development of diabetes mellitus while taking olanzapine. An increased awareness of this reaction is essential in the treatment of patients at risk. Periodic serum glucose monitoring in these individuals may be warranted.

Clozapine-induced hypersalivation.

OBJECTIVE: To review underlying pathophysiology and possible treatments for clozapine-induced hypersalivation. DATA SOURCES: Primary literature was accessed through MEDLINE (1966-May 1999). Key search terms included clozapine, hypersalivation, sialorrhea, and treatment. DATA SYNTHESIS: Hypersalivation occurs in up to 54% of patients receiving clozapine. An evaluation of studies and case reports focusing on management of clozapine-induced hypersalivation was conducted. CONCLUSIONS: It is unclear whether clozapine increases salivation through its muscarinic M4 receptor activation and/or blockade of alpha2-adrenoceptors, or by causing a distortion in swallowing reflex. Treatment options include chewing gum, reducing the dosage of clozapine, or prescribing pharmacologic agents such as anticholinergics or alpha2-adrenoceptor agonists.

Gabapentin and lamotrigine in bipolar disorder.

The utility of gabapentin and lamotrigine for the treatment of bipolar disorder is reviewed. Bipolar disorder is characterized by extreme mood fluctuations, including mania, hypomania, depression, and mixed episodes. Extrapolation of postulated mechanisms of anticonvulsant activity in bipolar disorder has led to the use of the newer anticonvulsants gabapentin and lamotrigine for therapy. Both agents appear promising on the basis of limited (often anecdotal) evidence. They may prove effective in patients with difficult cases of bipolar disorder, such as patients with rapid cycling, mixed episodes, and illness refractory to other treatments. Lamotrigine may offer a much-needed treatment alternative for bipolar depression and could be found effective for acute mania, but the need for slow dosage adjustment and the risk of rash may limit overall clinical utility. Gabapentin may offer significant advantages for acute mania: The dosage can be adjusted rapidly, adverse effects are generally minimal, the therapeutic index is high, there is no required laboratory monitoring, and there is minimal potential for interactions with other psychotropics. Until the results of randomized controlled trials are known, however, these two agents should be reserved for patients with bipolar disorder unresponsive to traditional therapies and for patients who cannot tolerate traditional agents. Preliminary evidence indicates that gabapentin and lamotrigine may be useful for the treatment of bipolar disorder.

Acute stress causes skin ulceration in striped bass and hybrid bass (Morone).

Exposure of striped bass (Morone saxatilis) and hybrid bass (M. saxatilis female x Morone chrysops male) to an acute (2-hour) confinement stress caused skin ulceration on the fins but not on the body of all confined fish. Striped bass displayed more severe lesions than did hybrid bass. Histologically, lesions had varying degrees of epithelial erosion and ulceration, which was most severe at the distal portion of the fins. Ulceration was associated with dermal and hypodermal edema and necrosis of the remaining stromal tissue and tips of bone in the fin rays. No hemorrhage or thrombosis was present to suggest any obvious vascular derangement. No evidence was found for either trauma or an infectious agent initiating the lesions. Injecting fish with epinephrine caused a similar response, although the degree of ulceration was less severe. These findings may explain why many opportunistic skin pathogens can rapidly develop into serious infections in fish.

Atypical antipsychotics in the managed care era.

Over the past decade, a new class of atypical antipsychotic drugs has been developed for the treatment of schizophrenia and related conditions. This new generation of antipsychotic agents represents the first significant breakthrough in the treatment of schizophrenia since the advent of chlorpromazine in the early 1950s. Although the designation "atypical" is currently the most widely used term for referring to these drugs, they are not likely to be viewed as atypical in the future--given their rapidly increasing use as first-line agents. Increased acceptance of these drugs early in the course of schizophrenia holds the promise of real long-term benefits in outcome. Although the acquisition cost of these drugs is significantly higher than that of older agents, pharmacoeconomic analysis suggests the possibility of substantial reductions in the overall financial burden posed by schizophrenic illness. This review summarizes the role of atypical antipsychotics in the treatment of schizophrenia, their merits compared to conventional medications, and their cost effectiveness.

Diagnostic criteria for degenerative, inflammatory, proliferative nonneoplastic and neoplastic liver lesions in medaka (Oryzias latipes): consensus of a National Toxicology Program Pathology Working Group.

Diagnostic criteria are presented for degenerative, inflammatory, nonneoplastic proliferative, and neoplastic lesions in the liver of medaka (Oryzias latipes), a small fish species frequently used in carcinogenesis studies. The criteria are the consensus of a Pathology Working Group (PWG) convened by the National Toxicology Program. The material examined by the PWG was from Medaka exposed to N-nitrosodiethylamine for 28 days, removed to clean water, and sacrificed 4, 6, or 9 mo after initiation of exposure. Degenerative lesions included hepatocellular intracytoplasmic vacuolation, hepatocellular necrosis, spongiosis hepatis, hepatic cysts, and hepatocellular hyalinization. Inflammatory lesions consisted of granulomas, chronic inflammation, macrophage aggregates, and focal lymphocytic infiltration. Nonneoplastic proliferative lesions comprised foci of cellular alteration (basophilic focus, eosinophilic focus, vacuolated focus, and clear cell focus) and bile duct hyperplasia. Neoplastic lesions included hepatocellular adenoma, hepatocellular carcinoma, cholangioma, and cholangiocarcinoma. Two lesions composed mainly of spindle cells were noted, hemangiopericytoma and spindle cell proliferation. Rather than being an exhaustive treatment of medaka liver lesions, this report draws from the published literature on carcinogen-induced liver lesions in medaka and other fish species and attempts to consolidate lesion criteria into a simplified scheme that might be useful to pathologists and other researchers using medaka lesions for risk assessment or regulatory purposes.

In vitro and in vivo characterization of avian reoviruses. I. Pathogenicity and antigenic relatedness of several avian reovirus isolates.

Pathogenicity, pathogenesis, and antigenic relatedness of four avian reovirus isolates obtained from commercially reared broilers were investigated. Chickens of various ages were inoculated both orally and intratracheally with reovirus. Based on disease signs, mortality, weight depression, tissue lesions, invasiveness, and viral persistence in chickens inoculated at 1 day of age, the isolates were classified as being of low, intermediate, or high pathogenicity. The low-pathogenicity isolate (2177) did not cause mortality, weight depression, or clinical disease. The isolate of intermediate pathogenicity (2035) produced low mortality rates (8%), some weight reduction by 7 weeks postinoculation, and microscopic lesions in the intestine and gastrocnemius tendons. The pathogenic isolates, 2408 and 1733, caused severe clinical disease characterized by stunting, feathering abnormalities, mortality as high as 84%, and microscopic lesions in the liver, intestine, pancreas, and/or gastrocnemius tendon. Highly pathogenic isolates also persisted longer in tissues of infected birds and elicited a more prompt and prolonged antibody response. Birds inoculated at 1 day or 1 week of age were more susceptible to reovirus-induced disease than birds inoculated at 2 weeks, suggesting an age-associated resistance. All isolates produced mortality with equal frequency in embryos. The isolates characterized were found to be antigenically similar based on cross-neutralization and cross-protection studies.