Steady-state pharmacokinetics of controlled release and immediate release formulations of remoxipride in patients with chronic schizophrenia.

Twenty-four stable, chronic schizophrenic inpatients were entered in a double-blind crossover study designed to compare single dose and steady state pharmacokinetic profiles of an immediate release formulation (IR) 200 mg BID and a controlled release formulation (CR) of remoxipride 400 mg once daily. The rate of absorption of remoxipride CR was significantly lower than the IR formulation and tmax was prolonged from 1.3 to 7.9 h after a single dose and from 2.2 to 6.0 h after repeated dosing. Although the single dose of remoxipride CR was twice as large as the single dose of the IR, the Cmax was similar for both formulations after a single dose. However, the Cmax at steady state was slightly lower for CR. There was significantly less fluctuation in plasma concentrations at steady state with the CR formulation, although the average plasma concentration of remoxipride IR and CR was similar. The mean relative bioavailability with regard to the amount of remoxipride absorbed after remoxipride CR 400 mg once daily compared to IR 200 mg BID was 97%. It was concluded that the CR formulation is suitable for a once-daily administration from a pharmacokinetic point of view.

Factors affecting rehospitalisation rates of chronic schizophrenic patients living in the community.

Eighty-eight [corrected] patients selected from a depot neuroleptic clinic in the hospital outpatients department were assessed clinically on various demographic and clinical variables with a view to determining the factors that may contribute to high rates of rehospitalisation amongst schizophrenics in remission. It was found that rehospitalisation rates during the preceding 5 years correlated with an early age of onset of illness, severity of positive and affective symptoms, current neuroleptic dose and total AIMS score, all reflecting the severity of underlying psychotic disorder and the neuroleptic treatment required to treat the psychosis. Poor compliance with neuroleptic prophylaxis was not found to be of importance in contributing to high relapse rates in this sample. It was concluded that patients who repeatedly relapse may do so because of the clinical characteristics of their illness.

Effects of the 5HT antagonist cyproheptadine on neuropsychological function in chronic schizophrenia.

This study tests the hypothesis that the ability of atypical neuroleptics to improve negative symptoms is due to 5HT-receptor antagonism and enhanced frontal lobe function. We investigated the effects of cyproheptadine (a 5HT2 antagonist) on neuropsychological tests of frontal lobe functions in chronic schizophrenic patients. Eighteen stable schizophrenic patients on depot neuroleptic medication participated in a 4-week double blind crossover study. Outcome measures were clinical symptoms rating scales, neuropsychological tests (verbal fluency, Stroop colour word task, trail making) and antisaccade eye movements. During the cyproheptadine phase statistically significant improvement was seen on Stroop colour word task, verbal fluency and Trail B tests. The ability to suppress reflexive eye movement to a target light in an anti saccade task was also significantly enhanced. The patients had low clinical ratings of negative symptoms and they were unaffected by cyproheptadine. The results indicate that 5HT2C receptors selectively modulate speed and motor control mechanisms related to frontal lobe functions but this was not associated with changes in symptoms.

Fluspirilene in the treatment of non-hospitalized schizophrenic patients.

A study was carried out to assess the efficacy of fluspirilene, a long-acting psychotropic agent, in the treatment of 29 non-hospitalized schizophrenic patients. Patients received an initial weekly injection of 6 mg to 10 mg fluspirlene, depending on the severity of the illness, and this was increased by 2 mg weekly as necessary to achieve control without side-effects. The mean weekly dose after stabilization was 9.2 +/- 3.4 mg (range 6 mg to 20 mg). Global assessment of patients' response to treatment showed a significant improvement in schizophrenic symptoms within 4 weeks in 20 of the 29 patients, and in 24 of 29 by the end of the 12-week trial period. Four patients were unable to be controlled in the community and were admitted to hospital. Side-effects were minimal and led to withdrawal of treatment in only 1 patient. It is suggested that fluspirilene is a useful drug in the treatment of schizophrenics without having to admit them to hospital initially.

UV irradiation of nucleic acids: characterization of photoproducts of thymidylyl-(3'-->5')-2'-deoxy-5-fluorouridine.

The acetone-sensitized irradiation using UV-B (ultraviolet light, 280-320 nm; sunlamps) of thymidylyl(3'-->5')deoxyfluorouridine monophosphate produces two main photoproducts. The distribution of these photoproducts is dependent on the pH of the irradiation solution. At pH 6, the cis-syn cyclobutane-type photodimer is the major product, whereas at high pH (8-10) a photoadduct is the major product. These photoproducts have been identified and structurally characterized by H-1 and C-13 NMR spectroscopy. The photoadduct arises from defluorination of the 5-fluorouracil moiety. The structure of the photoadduct maintains the sugar-phosphate backbone of the starting material (d-TpF), and contains a saturated thymine moiety with an added Thy(C6-hydroxyl) and a Thy(C5)-(C5)Ura covalent bond.

Relationship between extrapyramidal symptoms and serum anticholinergic levels in treated chronic schizophrenics.

Serum anticholinergic levels were measured by radioreceptor assay (RRA) in schizophrenic patients treated for drug-induced Parkinsonism; 68 patients stabilized on a single neuroleptic and an anticholinergic antiparkinsonian agent (benzhexol, benztropine or procyclidine) were assessed using the extrapyramidal side effects (EPS) scale prior to each blood sampling. Serum anticholinergic levels showed a significant inverse correlation with EPS but did not appear to be dose-related in any of the three anticholinergic drug groups. Percentage binding to proteins was significantly less with benztropine than either benzhexol or procyclidine. Serum-free anticholinergic levels correlated significantly with total serum levels in the benzhexol and procyclidine groups but not in the benztropine group. At serum levels above 4.5 pmol/ml atropine equivalents, EPS was significantly less than at levels below that. We discuss the implications of this finding and suggest practical clinical applications of measurement of serum anticholinergic levels. Serum neuroleptic and serum prolactin levels did not correlate with either dose or serum level of anticholinergics.

Determination of chlorpromazine in serum by radioreceptor assay and HPLC.

A radioreceptor assay for chlorpromazine in serum, which is based on binding to dopamine receptors, is described. This method has been postulated to measure all active metabolites as well as the parent drug. We have compared this method with an HPLC method for chlorpromazine. Dopamine-blocking activity, measured in serum samples from schizophrenic patients receiving chlorpromazine, was 1.85-9.1 times higher than serum chlorpromazine level measured by HPLC. The correlation between the two methods was 0.75. Dopamine-blocking activity was related more closely to dose of drug and to serum prolactin level than was serum chlorpromazine level measured by HPLC.

Metabolic activation of sulfur mustard leads to oxygen free radical formation.

We recently published electron paramagnetic resonance (EPR) spin trapping results that demonstrated the enzymatic reduction of sulfur mustard sulfonium ions to carbon-based free radicals using an in vitro system containing sulfur mustard, cytochrome P450 reductase, NADPH, and the spin trap α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) in buffer (A.A. Brimfield et al., 2009, Toxicol. Appl. Pharmacol. 234:128-134). Carbon-based radicals have been shown to reduce molecular oxygen to form superoxide and, subsequently, peroxyl and hydroxyl radicals. In some cases, such as with the herbicide paraquat, a cyclic redox system results, leading to magnified oxygen free radical concentration and sustained tissue damage. Low mustard carbon radical concentrations recorded by EPR in our in vitro system, despite a robust (4.0mM) sulfur mustard starting concentration, led us to believe a similar oxygen reduction and redox cycling process might be involved with sulfur mustard. A comparison of the rate of mustard radical-POBN adduct formation in our in vitro system by EPR at atmospheric and reduced oxygen levels indicated a sixfold increase in 4-POBN adduct formation (0.5 to 3.0 µM) at the reduced oxygen concentration. That result suggested competition between oxygen and POBN for the available carbon-based mustard radicals. In parallel experiments we found that the oxygen radical-specific spin trap 5-tert-butoxycarbonyl-5-methylpyrroline-N-oxide (BMPO) detected peroxyl and hydroxyl radicals directly when it was used in place of POBN in the in vitro system. Presumably these radicals originated from O(2) reduced by carbon-based mustard radicals. We also showed that reactive oxygen species (ROS)-BMPO EPR signals were reduced or eliminated when mustard carbon radical production was impeded by systematically removing system components, indicating that carbon radicals were a necessary precursor to ROS production. ROS EPR signals were completely eliminated when superoxide dismutase and catalase were included in the complete in vitro enzymatic system, providing additional proof of oxygen radical participation. The redox cycling hypothesis was supported by density functional theory calculations and frontier molecular orbital analysis.

Therapeutic effects of gelatin matrix-embedded IL-12 gene-modified macrophages in a mouse model of residual prostate cancer.

We evaluated the potential use of intraoperative gelatin matrix hemostatic sealant (GMHS; FloSeal; Baxter Healthcare) embedded with macrophages (Mphi) transduced with murine interleukin (IL)-12 recombinant adenoviral vector (G/Mphi/AdmIL-12) for prevention of recurrence of prostate cancer following radical prostatectomy. Application of G/Mphi/AdmIL-12 resulted in significant suppression of tumor growth and spontaneous lung metastases, a statistically significant survival advantage of the G/Mphi/AdmIL-12-treated animals, more efficient trafficking of Mphi to lymph nodes draining from the prostate and generation of systemic natural killer cell activity and tumor-specific cytolytic T lymphocyte responses compared to the controls in a preclinical mouse model of residual prostate cancer. Our data recommend this treatment as a novel adjuvant for prevention of local recurrence of prostate cancer following radical prostatectomy.

Efficacy of changing testosterone gel preparations (Androgel or Testim) among suboptimally responsive hypogonadal men.

The study objective was to evaluate the efficacy of changing testosterone gel preparations among suboptimally responsive hypogonadal men. The records of all hypogonadal men on gel (Testim or Androgel) testosterone replacement therapy (TRT) were reviewed to identify men who underwent a brand substitution in gel TRT due to initial suboptimal response. Total and free serum testosterone levels and the presence of hypogonadal symptoms (ADAM) were compared pre- and post-gel substitution. Of the 370 hypogonadal men on testosterone gel replacement therapy, 75 (20%) underwent a brand substitution. Prior to substitution, among patients initially treated with Androgel, the mean total and free testosterone levels were 311 ng dl(-1) and 10.4 pg ml(-1), respectively. Total testosterone levels were below 300 ng dl(-1) in 58% of these patients. Following a change to Testim, mean total and free testosterone levels increased to 484 ng dl(-1) (P<0.001) and 14.6 pg ml(-1) (P=0.01), respectively. Total testosterone levels remained below 300 ng dl(-1) in only 17% of these patients. Among patients initially treated with Testim, the mean total and free testosterone levels were 544 ng dl(-1) and 18.0 pg ml(-1), respectively. Total testosterone levels were below 300 ng dl(-1) in 15% of men. Following testosterone gel change to Androgel, mean total and free testosterone levels were 522 ng dl(-1) (P=0.7) and 16.1 pg ml(-1) (P=0.6), respectively. Total testosterone levels remained below 300 ng dl(-1) in 27% of these patients. Hypogonadal symptoms improved in a significant proportion of men who underwent a brand substitution following an initial suboptimal biochemical or symptomatic response. A change in testosterone gel preparation among initially unresponsive hypogonadal men is justified prior to abandoning or considering more invasive TRT. Changing from Androgel to Testim offers hypogonadal men the potential for improved clinical and biochemical responsiveness. Changing from Testim to Androgel is indicated to eliminate or minimize unwanted side effects.

Serum creatine phosphokinase in acute psychosis.

Fifty-four patients suffering from a variety of psychotic states were graded by their degree of psychomotor activity. Serum creatine phosphokinase (cpk) levels were found to be related to the degree of psychomotor activity, irrespective of the diagnostic category. Retarded and withdrawn patients had normal serum CPK, but on their return to normal psychomotor activity the CPK levels tended to rise transiently. It appears that unphysiological motor activity has a more direct relationship to the rise of serum CPK than motor activity per se.

AIDS panic: effects of mass media publicity.

Twenty-four patients with AIDS panic, who presented to the psychiatric services between 1983 and 1986, were assessed on various clinical rating scales. The severity of clinical symptoms was estimated by adding together the total scores on Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety. The level of mass media publicity about AIDS was calculated by counting the number of major reports about the disease in national and local newspapers and on television. The findings suggested that, contrary to expectations, the referral rates of AIDS panic cases were highest in the earlier months when the level of media activity was low and decreased during the months following intense publicity about AIDS. Patients who presented in the later stages also showed fewer anxiety symptoms.

Alcohol abuse in chronic schizophrenics: implications for management in the community.

This study was designed to investigate the effects of regular alcohol consumption on chronic schizophrenic patients maintained on fluphenazine decanoate in the community. A group of patients who consumed more than 20 units of alcohol per week was compared with those who did not drink or did so only occasionally. It was found that patients in the alcohol group had a higher frequency of previous relapses, a greater severity of positive symptoms and a lower incidence of extrapyramidal side effects except tardive dyskinesia for which there was no difference. Serum fluphenazine levels were lower in this group (NS). It was concluded that patients who regularly consume alcohol tend to be clinically unstable, perhaps because of poor therapeutic control.

Membrane-induced helical conformation of an active candidacidal fragment of salivary histatins.

The conformational preference of the candidacidal C-terminal 16 residue fragment (9-24; G-Y-K-R-K-F-H-E-K-H-H-S-H-R-G-Y) of salivary histatin 5 was examined in water, methanol, and dimethyl sulfoxide solutions using 500 MHz two-dimensional-NMR. Fourier transform infrared and CD spectroscopy were used to delineate its membrane-bound conformation in lipid vesicles. The peptide backbone and side-chain proton resonance assignments were accomplished by two-dimensional total correlated and nuclear Overhauser effect (NOE) spectra. The coupling constant (JNH-C alpha H) values determined from the double quantum-filtered correlated spectra, temperature coefficients of NH chemical shifts (d delta/dT), 1H/2H exchange rates on amide resonances, and the set of NOE connectivities were used to delineate backbone conformational features. The high JNH-C alpha H values (> or = 7.4 Hz), absence of any characteristic NH-NH (i, i + 1) or C alpha H-C beta H (i, i + 3) NOE connectivities, high d delta/dT values (> or = 0.004), and the fast 1H/2H amide exchange suggest that the histatin peptide favors unfolded random conformations in aqueous solution at pH 3.8. In contrast, the JNH-C alpha H values (< or = 6.5 Hz), slow 1H/2H exchange, low d delta/dT values (< or = 0.003) observed for amide resonances of residues 5-16, and the characteristic NH-NH (i, i + 1), C alpha H-C beta H (i, i + 3) NOE connectivities, provide evidence for the presence of largely alpha-helical conformations in dimethyl sulfoxide, which mimics the polar aprotic membrane environment. In methanolic solutions, 3(10)-helical conformations could exist as a minor population together with the major alpha-helical conformations. Fourier transform infrared spectroscopy and CD data indicate that lipid environments such as dimyristoylphosphatidylcholine vesicles could induce the peptide to fold into predominantly alpha-helical conformation. The results suggest that in dimethyl sulfoxide and dimyristoylphosphatidylcholine vesicles the candidacidal domain of salivary histatin 5 prefers a largely helical conformation, which could facilitate its interaction with the membrane of Candida albicans. The mechanism of antimicrobial action of this class of polypeptides appears to involve primarily electrostatic and hydrogen-bonding interaction of cationic and polar residues with the head groups of the plasma membranes of target cells.

A controlled trial of oxypertine in tardive dyskinesia.

A study was undertaken to investigate the effects of oxypertine in treating tardive dyskinesia. The design was double-blind, placebo-controlled, between-patient, in 28 patients from whom previous medication was withdrawn, with 14 patients in each group. Treatment was for 4 weeks. Although more oxypertine patients improved than placebo, i.e. 71.4 vs. 50%, the results did not reach statistically significant difference. A further study is planned to increase the overall number of patients in the study, and to lengthen treatment periods.

Radio receptor assay of serum neuroleptic levels in psychiatric patients.

The radioreceptor assay for the measurement of neuroleptic drugs in serum has been used to study the relationship between dose and serum level in schizophrenic patients receiving these drugs. The assay was found to be reproducible and capable of detecting neuroleptics in the sera of patients receiving a range of both oral and depot drugs, with the exception of trifluoperazine spansules. Linear correlations were obtained between daily dose and serum level for each drug both in individual patients on different doses and between patients on a stable dose. Extrapyramidal side effects were related to the serum neuroleptic level within, but not between, patients. The assay may be of use in clinical practice, including the assessment of compliance or poor response to neuroleptics.

Rationalizing neuroleptic polypharmacy in chronic schizophrenics: effects of changing to a single depot preparation.

This study investigated the effects of transferring patients on combined depot and oral neuroleptics to a single depot preparation; a secondary objective was to assess the effects of transferring patients from one depot neuroleptic to another. It was found that, whereas transferring from one depot preparation (flupenthixol) to another (fluphenazine) had no clear disadvantage for the patients, changing over from a combined oral and depot (fluphenazine) regimen to equivalent doses of depot alone resulted in an unacceptably high rate of relapse. The reasons for this may relate to either the unique pharmacokinetics of these drugs or subtle qualitative differences between them. It is suggested that caution is necessary whenever attempts are made to rationalize polypharmacy in schizophrenic patients.

Differences between chronic schizophrenic patients in the hospital and in the community.

Clinical differences between stable, chronic schizophrenic patients with long stays in the hospital and schizophrenic patients living in the community were investigated. Patients were matched for age, gender, and diagnosis. Hospitalized patients had more severe thought disorder and negative symptoms, and those in the community had a significantly higher incidence of depression and anxiety. The community-based patients were also receiving higher doses of neuroleptic drugs and had a higher incidence and severity of extra-pyramidal side effects. Results suggest that living in the community, despite its obvious benefits, may have its price in terms of the distressing effects of affective symptoms and neuroleptic side effects.

Dexamethasone suppression test in dementia and depression. Clinical and biological correlates.

To determine the usefulness of the DST in differentiating depression from dementia, the test was administered to three diagnostic groups of psychogeriatric patients: depression; dementia; and dementia with depression. Clinical assessments were supplemented by ratings on the HRSD and SCAG, as well as by EEG and CT. All three groups showed a high incidence of abnormal DST results unrelated to presence or severity of affective symptoms, but showing a better association with SCAG and its 'organic' subsets. The mechanism(s) underlying these abnormal results may reflect organic brain disease. The usefulness of the DST in differentiating depression from dementia in the elderly was not confirmed.