Clozapine as a drug of dependence

Rationale: In schizophrenics, clozapine has been reported to induce various withdrawal signs and rapid onset relapse to psychosis on cessation of chronic treatment. Objective: The study was designed to develop an animal model of one aspect of clozapine tolerance and withdrawal using core body temperature measures. Methods: Two groups of 15 female Wistar rats were treated chronically (b.i.d.) with clozapine at 6 or 12 mg/kg per injection for 21 days prior to cessation of drug treatment, withdrawal being studied over 4 consecutive days. Body temperatures were assessed daily throughout the study. Results: Acutely, clozapine induced dose-related hypothermia, to which complete tolerance developed in both groups, the development of tolerance being more rapid in the group treated with 6 mg/kg per injection of clozapine. During withdrawal only the group treated chronically with 12 mg/kg per injection of clozapine showed rapid onset significant hyperthermia. This dissipated progressively over days, and was completely absent after 4 days of withdrawal. Conclusions: Clozapine induced a clear somatic withdrawal sign after chronic treatment. It is suggested that, in future research in both humans and animals, it is important to attempt to differentiate between clozapine withdrawal and clozapine withdrawal-induced relapse to psychosis. It is also important to characterise the clozapine withdrawal syndrome fully in animals; to establish the neurochemical mechanisms involved in such withdrawal; and to determine which novel antipsychotics are most efficacious in inducing clozapine-like withdrawal effects, in suppressing clozapine withdrawal, and in preventing relapse to psychosis in patients being transferred from clozapine to novel atypical antipsychotic drugs. Received: 14 May 1998/Final version: 14 September 1998     

Laser Induced Autofluorescence Diagnosis of Bladder Cancer

Purpose

We assessed the ability of laser induced autofluorescence to differentiate malignant from nonmalignant bladder lesions.

Materials and Methods

We studied 53 patients with bladder cancer undergoing mucosal biopsies or transurethral resection of a bladder tumor. A quartz optical fiber was advanced through the working channel of a cystoscope and placed in gentle contact with the bladder. Tissue fluorescence was excited by 337 nm. light pulses (nitrogen laser). One fiber was used for transmission of the excitation and emission (fluorescence) light. An optical multichannel analyzer system was used to record fluorescence spectra of the sites of interest.

Results

We analyzed the fluorescence spectra of 114 bladder areas (1 carcinoma in situ as well as 28 malignant, 35 inflammatory, 7 dysplastic, 1 squamous metaplastic and 42 normal areas). These lesions included 44 difficult to diagnose suspicious tumors (11 malignant and 33 nonmalignant). We developed an algorithm that used the I385:I455 nm. fluorescence ratio to distinguish malignant from nonmalignant lesions, including inflammatory areas. By analyzing the data on all 114 lesions, we noted the sensitivity, specificity, and positive and negative predictive values of this method for differentiating malignant from nonmalignant bladder lesions to be 97, 98, 93 and 99 percent, respectively.

Conclusions

Under excitation with 337 nm. light a clear differentiation between malignant and nonmalignant bladder tissues can be made using the I385:I455 nm. autofluorescence ratio.     

Drug Distribution in Obesity and following Bariatric Surgery: A Literature Review

Background: The pharmacokinetic variables of drug clearance and volume of distribution are usually corrected for body weight or surface area. Only recently have the relationships which exist between body size, physiologic function and pharmacokinetic variables been evaluated in the obese population. These effects are not widely known, and data on this and the effects of bariatric surgical procedures are scantily documented in the surgical literature. Methods: Literature review. Results: Drugs with a low or moderate affinity for adipose tissue have a moderate increase in the volume of distribution (Vd), and this correlates with the increase in lean body mass (LBM). Highly lipophilic drugs, with some exceptions, show the expected increase in Vd and prolongation of elimination half-life, indicating a marked distribution into adipose tissue. Drug absorption, in general, is slowed by delayed gastric emptying and is normal when gastric emptying is normal or increased. Most drug absorption occurs in the small intestine where duration of drug/mucosal contact is the most important factor. Conclusions: Drugs whose distribution is restricted to LBM should utilize a loading dose based on ideal body weight (IBW). For those drugs which distribute freely into adipose tissue, the loading dose should be based on total body weight (TBW). Adjustment of the maintenance dose depends on clearance rates. In a few cases dosage adjustment depends on pharmacodynamic data, since drug clearance does not conform to these recommendations, for reasons which remain to be defined. Following bariatric surgery, in the absence of delayed gastric emptying or uncontrolled diarrhea, drug absorption rates are usually comparable to the non-operated patient.     

The Patient Factor

Long-term results of bariatric surgery are reviewed. The weight criteria for patient acceptance for bariatric surgery and their variation are presented graphically and discussed. Factors affecting patient selection in an attempt to improve outcome results in the small group of patients who currently achieve less weight loss than anticipated are defined. An attempt is made to define pre-operative criteria for selection of pure restrictive versus combined restrictive and malabsorptive procedures. Aspects of motivation, co-morbidity, age and pre-operative weight are discussed and the position statement of the ASBS in regard to laparoscopic bariatric surgery is defined.     

Receipt of specialty eye care by children.

BACKGROUND: No nationally representative data are available regarding use of eye care services by children. OBJECTIVES: To determine the proportion of children who receive specialty eye care and to evaluate the association of such care with age and other factors associated with health care utilization. METHODS: We used the 2000 National Health Interview Survey to estimate the proportion of nonblind children who received eye care in the preceding 12 months. The association between eye care and the factors of interest among children aged 6-17 years was measured through adjusted bivariate comparisons and logistic regression modeling. RESULTS: Eye care was received in the preceding 12 months by an estimated 7.3% (95% confidence interval [CI] 6.0-8.6) of the 22.8 million children aged 0-5 years and 24.8% (95% CI 23.5-26.2) of the 48.5 million children aged 6-17 years. Among children aged 6-17 years, girls had 29% greater odds than boys to have received eye care (P=.001). Among children <200% of the federal poverty level, those with public health insurance had greater odds of receiving eye care than did uninsured children or those with private health insurance (P<.001). Among children >200% of the federal poverty level, uninsured children had lower odds than did children with public or private health insurance (P<.004) to receive eye care. Well-child care was associated with increased eye care utilization among children aged 12-14 years (P<.001). CONCLUSIONS: Receipt of specialty eye care is common and increases with age. However, there are marked variations among school-aged children. Future studies should address the causes and effects of these findings.     

Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor.

PURPOSE: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. RESULTS: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. CONCLUSION: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.     

A Cost-Effective and Rational Surgical Approach to Patients With Snoring,Upper Airway Resistance Syndrome,or Obstructive Sleep Apnea Syndrome

The past decade has seen several innovations in the surgical techniques available for treatment of patients with sleep-disordered breathing. Outpatient techniques such as laser-assisted uvulopalatoplasty (LAUP) and more aggressive procedures designed to address hypopharyngeal and base of tongue obstruction (genioglossus advancement and hyoid myotomy) have been developed and proven successful. We describe the efficacy of LAUP for snoring (72.7%), upper airway resistance syndrome (81.8%), and mild (mean[±SD] respiratory disturbance index [RDI] = 12 ± 8.1) obstructive sleep apnea (41.7%) in 56 patients who underwent 132 LAUP procedures in a 26-month period. Thirty-two patients with more significant obstructive sleep apnea (mean RDI = 41.8 ± 23.1) underwent multilevel pharyngeal surgery consisting of genioglossus advancement and hyoid myotomy combined with uvulopalatopharyngoplasty. The surgical success rate in this group of patients was 85.7% when commonly accepted criteria were applied. We recommend a stratified surgical approach to patients with sleep-disordered breathing. Progressively worse airway obstruction marked by multilevel pharyngeal collapse and more severe sleep-disordered breathing is treated with incrementally more aggressive surgery addressing multiple areas of the upper airway.