An 11-year retrospective review of venlafaxine ingestion in children from the California Poison Control System.

Venlafaxine is commonly used in the United States for approved and non-Food and Drug Administration-approved indications in adults. It is used off-label to treat children for psychiatric diagnoses. The aim of the study was to describe venlafaxine toxicities in children and to identify the venlafaxine dose per weight that correlates with toxicities. An 11-year retrospective study of venlafaxine ingestion in children was performed using the California Poison Control System (CPCS) database. Data was extracted from phone calls received by CPCS clinicians and follow-up phone calls made to assess the patient's progress in a health-care setting. Inclusion criteria were venlafaxine ingestion cases reported to CPCS between January 2001 and December 2011, children aged 20 years and under, venlafaxine as the only ingested substance, managed in a health-care facility, and followed to a known outcome. Two hundred sixty-two cases met the study criteria. Common presentations included gastrointestinal (14.9%), altered mental status (13.7%), and tachycardia (13.4%). The majority of the cases resulted in no effect (51.5%) or minor effect (19.9%). The average estimated dose per weight was 18.3 mg/kg in all patients and 64.5 mg/kg in those experiencing moderate-to-severe adverse effects. Seizures occurred in only 4 of the 262 cases at doses ranging from 1500 to 7500 mg. Although the estimated dose per weight exceeded 10 mg/kg for the majority of the cases, only 12 cases resulted in moderate or severe outcomes. The majority of venlafaxine ingestion cases in children resulted in either no clinical effects or minor clinical effects.

Water intoxication, psychosis, and inappropriate secretion of antidiuretic hormone.

A review of the literature and the three presented cases indicate that multiple factors are often involved in the development of water intoxication in the psychotic. Although the syndrome of inappropriate secretion of antidiuretic hormones (SIADH) is one of these factors, it is usually associated with other causes of the SIADH. Evidence is lacking that the SIADH is an essential feature of a psychotic illness.

Side effects of corticosteroid therapy. Psychiatric aspects.

We reviewed the literature to determine the characteristics of corticosteroid-induced mental disturbances. We conclude that (1) while dosage may be correlated to the risk of developing mental disturbances, neither dosage nor duration of treatment seems to affect the time of onset, duration, severity, or type of mental disturbances; (2) euphoria, depression, and psychotic reactions are the common manifestations of corticosteroid-induced mental disturbances; (3) females seem to be more prone to these disturbances than males; (4) patients with past mental illness are not necessarily predisposed to such disturbances; and (5) corticosteroid-induced mental disturbances are usually reversible on dose reduction or discontinuation of the drug. At present there are no simple models to explain the psychotic reactions, anxiety, or agitation seen in corticosteroid-induced mental disturbances.

Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach.

BACKGROUND: Numerous case reports have linked clozapine to the development of diabetes mellitus and hyperlipidemia in patients with schizophrenia. However, investigators have been unable to clearly demonstrate this association when compared with a control group receiving conventional antipsychotics. METHODS: Medical and pharmacy claims from the Iowa Medicaid program were used to compare incidence rates for diabetes, hyperlipidemia, and hypertension in 552 patients receiving clozapine and 2461 patients receiving conventional antipsychotics (eg, haloperidol, chlorpromazine hydrochloride), with the use of a retrospective cohort design. Logistic regression was used to compare incidence rates adjusting for age, sex, and duration of available follow-up. RESULTS: No significant differences in overall incidence rates for diabetes, hyperlipidemia, or hypertension were observed in patients receiving clozapine vs conventional antipsychotics. However, among younger patients (aged 20-34 years), clozapine administration was associated with a significantly increased relative risk of diabetes (2.5 [95% confidence interval, 1.2-5.4]) and hyperlipidemia (2.4 [95% confidence interval, 1.1-5.2]), but not hypertension (0.9 [95% confidence interval, 0.4-2.0]). CONCLUSIONS: These data suggest that clozapine may not be an independent cause of diabetes or hyperlipidemia, but instead acts as an effect modifier in susceptible populations by increasing weight or affecting insulin secretion and resistance. This finding requires confirmation in other settings and patient populations and with the other atypical antipsychotics (risperidone, olanzapine, and quetiapine fumarate). The potential long-term medical and economic implications of the early induction of diabetes and hyperlipidemia in patients with schizophrenia warrant further study.

Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram.

BACKGROUND: Previous work has suggested factors such as gender, smoking behavior, dose, and age affect the amount of drug a patient requires to achieve a desired plasma concentration of clozapine. Plasma clozapine concentrations ranging from 350 to 504 ng/mL in treatment-refractory schizophrenics and schizoaffective patients produce response rates ranging approximately 55-80%. Without the aid of clozapine plasma concentration monitoring, 3-6 months are recommended for a therapeutic clozapine trial. Data suggest that the lag time to response can be reduced by administering a dose that produces a therapeutic clozapine concentration. METHODS: To generate a clozapine dosing nomogram to predict clozapine steady-state plasma concentrations, a cohort of 71 patients was collected via retrospective chart review and/or patient interview. Clozapine steady-state plasma concentrations and demographic variables were obtained. Multiple-linear regression was utilized to examine the relationship between the plasma clozapine concentration and the independent variables. RESULTS: The dosing model that optimally predicted steady-state clozapine plasma concentrations included the variables dose (mg/day), smoking (yes = 0 and no = 1), gender, and a dose-gender interaction variable. The model explained 47% of the variance in the clozapine concentrations (F = 14.42, p < .001, r2 = .47). Two equations, one for male subjects, i.e., clozapine (ng/mL) = 111 (smoke) + 0.464 (dose) + 145, and one for female subjects, i.e., clozapine (ng/mL) = 111 (smoke) + 1.590 (dose)-149, were derived to predict clozapine steady-state plasma concentrations to serve as a clozapine dosing guide for clinicians. CONCLUSIONS: A clozapine dosing nomogram was constructed as a clinical aid to facilitate clozapine dosing.

Psychosexual effects of three doses of testosterone cycling in normal men.

BACKGROUND: Testosterone is receiving increased attention for contraceptive and therapeutic indications. The potential psychosexual side effects of testosterone therapy and withdrawal are unclear. METHODS: Healthy men between the ages of 21 and 40 years were recruited via advertisement for a randomized, controlled, double-blind study of acute and withdrawal effects of three doses of testosterone. Two weeks of placebo injections were followed by one of three randomized weekly doses of testosterone cypionate (100 mg, 250 mg, or 500 mg) for the next 14 weeks. Twelve weeks of placebo injections followed during the withdrawal phase of the study. Psychosexual effects were monitored throughout the study. RESULTS: All doses of testosterone demonstrated only minimal effects on measures of mood and behavior during acute and withdrawal phases for all study completers. There were no effects on psychosexual function. There was no evidence of a dose-dependent effect on any measure. One noncompleter on 500 mg of testosterone developed a brief syndrome with symptoms similar to an agitated and irritable mania. CONCLUSIONS: Doses of testosterone up to five times physiologic replacement dose appear to have minimal risk of adverse psychosexual effects in the majority of normal men; however, beginning at around 500 mg per week of testosterone cypionate, a minority of normal men may experience significant adverse psychological effects. Because illicit anabolic steroid users may use larger doses of multiple drugs under less restrictive conditions, our study may significantly underestimate the psychological effect of steroid use in the community.

Absorption of oral intramuscular chlordiazepoxide by alcoholics.

The effect of chronic alcoholism on oral and intramuscular plasma levels of chlordiazepoxide (CDX) was assessed. A 50-mg oral dose of CDX resulted in significantly higher plasma levels in the 2 hr following CDX than a 50-mg intramuscular dose administered to acute withdrawing alcoholic subjects. The same CDX dose was administered 7 days later and the same differences were observed between the mean oral and intramuscular plasma levels during the first 2 hr after administration of CDX. Peak concentration occurred significantly sooner after the oral than intramuscular dose of CDX in both the initial dose and the dose given a week later. It was also observed that the areas under the curve for CDX were significantly greater initially than 1 wk later. It is suggested this effect may be at least partially the result of the longer CDX half-lives initially than a week later. The active metabolite, N-desmethylchlordiazepoxide, peaked significantly earlier with the oral dose than with the intramuscular dose after the patient was alcohol free for a week.

Haloperidol plasma levels and dose optimization.

OBJECTIVE: This study was designed to test the practical utility of haloperidol plasma level determinations in the management of schizophrenic patients who show poor initial responses to haloperidol. METHOD: Inpatients with acute exacerbations of DSM-III schizophrenia (N = 66) were randomly assigned to receive fixed haloperidol doses intended to achieve plasma levels of 8-18 ng/ml or of 25-35 ng/ml. Patients whose scores on the Brief Psychiatric Rating Scale (BPRS) failed to improve by at least 30% at the end of 3 weeks were then subject to dose reassignment. RESULTS: Among the patients who completed the first phase of the protocol, 30 had steady-state haloperidol plasma levels of less than 18 ng/ml, and 22 had levels that exceeded 25 ng/ml; 14 had intermediate plasma levels of 18-25 ng/ml. A survival analysis of time to 30% improvement significantly favored the two lower plasma level groups, although side effect ratings did not differ. Of the 30 patients whose BPRS scores failed to improve by 30% after 3 weeks, 11 and five were randomly assigned to receive lower and higher doses, respectively. Those whose dose was lowered experienced significantly more improvement in the subsequent weeks than did those whose dose was increased. CONCLUSIONS: Haloperidol plasma levels that substantially exceed 18 ng/ml may be countertherapeutic. In particular, increases in dose beyond this level are not efficacious for patients who have not responded to lower doses.

Profound hypoglycemia with the addition of a tricyclic antidepressant to maintenance sulfonylurea therapy.

Cases of profound hypoglycemia after the initiation of tricyclic antidepressant therapy in two patients taking sulfonylureas are described. To the authors' knowledge, this is the first report of a potential drug interaction between tricyclic antidepressants and sulfonylureas.

Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients.

OBJECTIVE: Clozapine, an atypical antipsychotic, has been estimated to be effective in 30% of treatment-refractory schizophrenic patients. The authors hypothesized that if a dose-response relationship was obvious for this drug, the response rate could be significantly amplified. METHOD: Following an 8-24-day dose titration phase, 29 inpatients with treatment-resistant schizophrenia diagnosed according to DSM-III-R were given a clozapine dose of approximately 400 mg/day for 4 weeks; blood samples were obtained weekly during this period. RESULTS: A receiver operator curve demonstrated that the threshold clozapine plasma concentration for therapeutic response was 350 ng/ml. Sixty-four percent of the patients with clozapine plasma concentrations greater than 350 ng/ml responded, whereas only 22% of the patients with concentrations less than 350 ng/ml responded. CONCLUSIONS: Use of clozapine blood levels as a predictor for treatment response in treatment-refractory schizophrenic patients appears worthwhile, since the measurement's sensitivity for response was 64% and the specificity for nonresponse was 78%.

1,4- and 2,6-disubstituted amidoanthracene-9,10-dione derivatives as inhibitors of human telomerase.

A number of 1,4- and 2,6-difunctionalized amidoanthracene-9, 10-diones have been prepared. We have examined their in vitro cytotoxicity in several tumor cell lines and their ability to inhibit the telomere-addition function of the human telomerase enzyme together with their inhibition of the Taq polymerase enzyme. Compounds with -(CH2)2- side chains terminating in basic groups such as piperidine show inhibition of telomerase at telIC50 levels of 4-11 microM. These are thus among the most potent nonnucleoside telomerase inhibitors reported to date. Cytotoxicity levels in human tumor cell lines were at comparable levels for several compounds. Implications for amidoanthracene-9,10-dione telomerase inhibitors as potential anticancer agents are discussed.

2,7-Disubstituted amidofluorenone derivatives as inhibitors of human telomerase.

Telomerase is a major new target for the rational design of novel anticancer agents. We have previously identified anthraquinone-based molecules capable of inhibiting telomerase by stabilizing G-quadruplex structures formed by the folding of telomeric DNA. In the present study we describe the synthesis and biological evaluation of a series of analogous fluorenone-based compounds with the specific aims of, first, determining if the anthraquinone chromophore is a prerequisite for activity and, second, whether the conventional cytotoxicity inherent to anthraquinone-based molecules may be reduced by rational design. This fluorenone series of compounds exhibits a broad range of telomerase inhibitory activity, with the most potent inhibitors displaying levels of activity (8-12 microM) comparable with other classes of G-quadruplex-interactive agents. Comparisons with analogous anthraquinone-based compounds reveal a general reduction in the level of cellular cytotoxicity. Molecular modeling techniques have been used to compare the interaction of fluorenone- and analogous anthraquinone-based inhibitors with a human G-quadruplex structure and to rationalize their observed biological activities.

Human telomerase inhibition by regioisomeric disubstituted amidoanthracene-9,10-diones.

Telomerase is an attractive target for the design of new anticancer drugs. We have previously described a series of 1,4- and 2, 6-difunctionalized amidoanthracene-9,10-diones that inhibit human telomerase via stabilization of telomeric G-quadruplex structures. The present study details the preparation of three further, distinct series of regioisomeric difunctionalized amidoanthracene-9,10-diones substituted at the 1,5-, 1,8-, and 2,7-positions, respectively. Their in vitro cytotoxicity and Taq DNA polymerase and human telomerase inhibition properties are reported and compared with those of their 1,4- and 2,6-isomers. Potent telomerase inhibition (telIC50 values 1.3-17.3 microM) is exhibited within each isomeric series. In addition, biophysical and molecular modeling studies have been conducted to examine binding to the target G-quadruplex structure formed by the folding of telomeric DNA. These studies indicate that the isomeric diamidoanthracene-9,10-diones bind to the human telomeric G-quadruplex structure with a stoichiometry of 1:1. Plausible G-quadruplex-ligand complexes have been identified for each isomeric family, with three distinct modes of intercalative binding being proposed. The exact mode of intercalative binding is dictated by the positional placement of substituent side chains. Furthermore, in contrast to previous studies directed toward triplex DNA, it is evident that stringent control over positional attachment of substituents is not a necessity for effective telomerase inhibition.

Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients.

This study investigated the effect of grapefruit juice on cyclosporine A (CsA) bioavailability in 10 renal transplant patients. Under CsA steady state conditions, patients were randomly administered their usual dose of CsA with either 8 ounces of grapefruit juice or 8 ounces of water. Using a crossover design, a 12-hr pharmacokinetic study was then conducted. Grapefruit juice increased the area under the concentration versus time curve (4218+/-1497 ng x hr/ml [grapefruit juice] vs. 3415+/-1288 ng x hr/ml [water], P=0.029) and 12-hr trough (244+/-214 ng x ml [grapefruit juice] vs. 132+/-56 ng x ml [water], P=0.09), but it did not change peak concentration (734+/-290 ng x ml [grapefruit juice] vs. 708+/-305 ng x ml [water], P=0.76). In addition, grapefruit juice delayed the time to peak concentration compared with water (5.4+/-3.0 hr [grapefruit juice] vs. 2.8+/-0.8 hr [water], P=0.025). These data suggest that concurrent administration of grapefruit juice with CsA will delay the absorption of CsA and increase the drug exposure of CsA without changing peak concentration.

The relationship between antidepressant response and tricyclic antidepressant plasma concentrations. A retrospective analysis of the literature using logistic regression analysis.

The relationship between the antidepressant effect of the tricyclic antidepressants and their plasma concentrations was reviewed. Logistic regression was utilised as an analytical tool to facilitate the evaluation. The currently available literature allowed the construction of 4 tricyclic data sets of sufficient size to warrant statistical analysis. Inspection of the distribution of the data and the logistic regression analyses resulted in several conclusions regarding the existence of 'therapeutic windows' for these drugs. Firstly, no relationship between amitriptyline plasma concentrations and therapeutic response was apparent. Secondly, curvilinear relationships were apparent for 2 of the other tricyclic antidepressants studied. The currently recommended therapeutic range of 60 to 150 micrograms/L for nortriptyline was found to be the range most likely to produce a positive antidepressant effect. Desipramine concentrations between 108 and 158 micrograms/L were most commonly associated with beneficial therapeutic responses. Finally, a linear relationship was noted for imipramine in which an imipramine therapeutic plasma concentration threshold of 244 micrograms/L and above was most commonly associated with a beneficial response to the drug.

Two prospective dosing methods for nortriptyline.

This study compared two prospective pharmacokinetic dosing methods to predict steady-state concentrations of nortriptyline. One method required multiple determinations of the nortriptyline plasma concentration to estimate the drug's steady-state concentration. The second method required a single nortriptyline concentration drawn at a fixed time, preferably 36 hours, following a nortriptyline test dose. The 36-hour nortriptyline plasma concentrations (NTP 36h) were substituted into the straight-line equation of Cssav = 17.2 + 3.74 (NTP 36h), where Cssav is the average steady-state concentration for a 100 mg/day dose of nortriptyline. No differences were noted between the observed steady-state nortriptyline concentration of 121 +/- 19 ng/ml, the 36-hour single-point prediction mean concentration of 121 +/- 21 ng/ml, or the multiple-point prediction mean concentration of 122 +/- 19 ng/ml. Because of the similar findings between the two methods, the clinical advantages and disadvantages of each kinetic approach are discussed to put these prospective dosing protocols into their proper perspective.

Telomerase inhibitors for the treatment of cancer: the current perspective.

Telomerase is a holoenzyme responsible for the maintenance of telomeres, the protein-nucleic acid complexes at the ends of eukaryotic chromosomes that serve to maintain chromosomal stability and integrity. Telomerase activity is essential for the sustained proliferation of most immortal cells, including cancer cells. Since the discovery that telomerase activity is detected in 85-90% of all human tumours and tumour-derived cell lines but not in most normal somatic cells, telomerase has become the focus of much attention as a novel and potentially highly-specific target for the development of new anticancer chemotherapeutics. Herein we review the current perspective for the development of telomerase inhibitors as cancer chemotherapeutics. These include antisense strategies, reverse transcriptase inhibitors and compounds capable of interacting with high-order telomeric DNA tetraplex ("G-quadruplex") structures, so as to prevent enzyme access to the necessary linear telomere substrate. Critical appraisal of each individual approach is provided together with highlighted areas of likely future development.

Benzodiazepine withdrawal: a review of the evidence.

In a recent series of controlled studies, investigators looked at what happened when benzodiazepines were discontinued. Despite methodological problems, these studies showed that rebound anxiety occurred in a substantial minority of patients after several weeks of drug use. Also, a withdrawal syndrome developed in nearly half of patients who used benzodiazepines for more than a year. In these studies, risk factors included dose, duration of use, elimination rate of the drug, and abruptness of discontinuation. Patients who are physically dependent on benzodiazepines may need help in stopping these agents. Physicians should advise gradual discontinuation and, along with emotional support, should consider the use of alternative medications for the control of symptoms.

Recent psychostimulant use in hospitalized schizophrenics.

The incidence of CNS stimulant use among 300 patients admitted to an acute care psychiatric facility was estimated to be 31% overall; 11% of patients admitted to use within 6 months of the index hospitalization. A number of previously described relationships between stimulant use and schizophrenia were confirmed. Relapsing schizophrenics utilized stimulants prior to hospitalization more often than nonschizophrenic patients; outpatient antipsychotic prophylaxis did not prevent these relapses. It is concluded that stimulants partially contribute to relapse in schizophrenics.

Plasma clozapine concentrations as a predictor of clinical response: a follow-up study.

We investigated the relationship between plasma clozapine concentrations and clinical response in treatment-refractory schizophrenic patients. In a previous study, we found that plasma drug concentrations above 350 ng/mL maximized clinical response in a group of 29 patients. This study represents a follow-up of these original 29 patients over approximately 2 1/2 years of clozapine treatment. We found that during the initial 6-week trial of clozapine, 38% (N = 11) of the patients were considered to be responders. With continued treatment, we found that 58% (14 of 24) were classified as responders. Consistent with our previous study, we observed that plasma concentrations were helpful in predicting response. Five of 7 patients who had unsatisfactory response became responders when their plasma clozapine concentrations increased to above 350 ng/mL. We conclude that the assessment of plasma clozapine concentrations as a guide to dose adjustment may be useful in maximizing response.