Effects of acute and chronic administration of olanzapine in comparison to clozapine and haloperidol on extracellular recordings of substantia nigra reticulata neurons in the rat brain

Rationale: Previously, we have shown that the atypical antipsychotics clozapine and risperidone, unlike haloperidol, decreased the firing rate of substantia nigra reticulata (SNR) neurons. As the SNR receives substantial input from the striatum, an area where motoric side-effects of antipsychotics are thought to be mediated, the SNR might be an interesting brain structure with regard to motor side-effects. Objective: The newly developed atypical antipsychotic olanzapine was studied for its effects on the firing rate of SNR cells. In addition, to gain insight in the implications of our experimental setup for clinical use, responses upon clozapine, olanzapine and haloperidol were studied after chronic treatment. Methods: In chloralhydrate-anaesthetized male Wistar rats, extracellular recordings were made from SNR neurons upon intravenously (IV) administered cumulative doses of the antipsychotics. Naive rats and rats that were subcutaneously (SC) injected for 21 days with an antipsychotic were used. Results: Olanzapine (50–1600 mg/kg; IV), significantly inhibited the firing rate of the SNR neurons. Upon 21 days of treatment with a daily SC injection of 20 mg/kg clozapine, the challenge on day 22 with cumulative injections of clozapine (200–6400 mg/kg; IV) significantly inhibited the firing rate of the SNR neurons. Olanzapine (50–1600 mg/kg; IV) also significantly inhibited the SNR activity when pretreated with olanzapine in an SC administered dose of 1 mg/kg, but not 5 mg/kg. Haloperidol (12.5–800 μg/kg; IV) did not significantly affect the SNR activity in rats pretreated with SC administered 0.5 mg/kg haloperidol. Conclusions: Upon acute and chronic administration of clozapine and olanzapine versus haloperidol, differential effects on SNR neuronal firing could be obtained. The experimental setup seem to be valid for further studies into the mechanism of action of typical versus (relatively low doses of) atypical antipsychotics. The implications of the inhibitory effect of atypical antipsychotics on the SNR firing rate are presently unknown, but could be associated with the lower propensity to induced motoric side-effects. On the other hand, the SNR activity might also reflect non-motoric activity possibly related to negative symptoms. Received: 11 December 1998/Final version: 20 January 1999     

Characterizing withdrawal in rats following repeated drug administration using an amphetamine-vehicle-haloperidol drug discrimination

Rationale: Previous research using an amphetamine (AM)-haloperidol (HA) drug- drug discrimination task has shown that predominant responding on the HA-appropriate lever occurs 24 h after a single or multiple administrations of 10 mg/kg AM. Conversely, rebound responding on the AM-appropriate lever occurs following single or multiple administrations of 1 mg/kg HA. HA-appropriate responding was also observed 24 h following a single injection of AM using a three-lever, AM-vehicle-HA discrimination task. However, a single administration of HA did not produce robust rebound responding on the AM-appropriate lever. The present studies seek to clarify the discrepancy between responding following HA in the two- and three-choice tasks. Objective: Experiment 1 examined the extent of rebound responding that could be achieved following ten daily administrations of either 10 mg/kg AM or 1 mg/kg HA. Experiment 2 explored potential differences between the two- and three-choice tasks in characterizing the post-HA cue. Methods: Animals were trained to discriminate 0.35 mg/kg AM, vehicle, and 0.033 mg/kg HA. In experiment 1, animals received ten daily injections of 10 mg/kg AM, vehicle, or 1 mg/kg HA, and were tested 24 h after the final injection, and again 8, 15, and 22 days post-treatment. In experiment 2, animals were retrained and then treated daily with either vehicle or 1.0 mg/kg HA for 10 days, and then tested 24 h after the final injection, and again 5 and 11 days post-treatment, with either all three levers or with only the AM- and HA-appropriate levers available. Results: In experiment 1, multiple injections of AM produced robust HA lever responding, which is consistent with results from previous studies that used the two-choice, AM-HA discrimination task. However, multiple injections of HA did not produce predominant responding on the AM-appropriate lever. In experiment 2, animals treated with either vehicle or HA responded predominantly on the vehicle-appropriate lever when tested with all three levers present. When tested with the vehicle lever removed, however, animals treated with vehicle responded predominantly on the HA-appropriate lever, whereas those treated with HA responded predominantly on the AM-appropriate lever. Conclusions: These results suggest that the two-choice and three-choice task used here differ in how the post-HA withdrawal cue is characterized. This finding emphasizes the importance of knowing the relative locations of the agonist-, vehicle-, and antagonist-produced cues on the interoceptive stimulus continuum established by discrimination training. Received: 3 December 1997/Final version: 16 November 1998     

国产生长激素治疗生长激素缺乏症的疗效观察

了解国产人生长激素（ｈＧＨ）的治疗效果。方法：对１５例未经生长激素治疗的生长激素缺乏症（ＧＨＤ）病人（均经精氨酸和可乐宁两项生长激素激发试验明确诊断,生长激素峰值均小于 １０ μｇ／Ｌ）应用国产分泌型基因重组人生长激素（ｒｈＧＨ）进行治疗,剂量为０．１ｕ／（ｋｇ·ｄ）睡前脐周皮下注射,治疗时间６个月。结果：１５例ＧＨＤ病人６个月身高平均增长（６．３４±０．９４）ｃｍ,生长速度由治疗前的（３．３３±０．４９）ｃｍ／年增加到治疗后的（１２．６８±１．８６）ｃｍ／年。结论：国产人生长激素治疗效果达到国外同类产品水平,而价格仅为进口产品的１／６左右。可安全有效地用于治疗ＧＨＤ身材矮小病人。     

Acyclovir treatment of relapsing-remitting multiple sclerosis

Acyclovir treatment was used in a randomized, double-blind, placebo-controlled clinical trial with parallel groups to test the hypothesis that herpes virus infections are involved in the pathogenesis of multiple sclerosis (MS). Sixty patients with the relapsing-remitting form of MS were randomized to either oral treatment with 800 mg acyclovir or placebo tablets three times daily for 2 years. The clinical effect was investigated by an extensive test battery consisting of neurological examinations, neuro-ophthalmological and neuropsychological tests, and evoked potentials. Results were based on intent-to-treat data and the primary outcome measure was the exacerbation rate. In the acyclovir group (n = 30), 62 exacerbations were recorded during the treatment period, yielding an annual exacerbation rate of 1.03. The placebo group (n = 30) had 94 exacerbations and an annual exacerbation rate of 1.57. Thus, 34% fewer exacerbations were encountered during acyclovir treatment. This difference in exacerbation rate between the treatment groups was not significant (P = 0.083). However, this trend to a lower disease activity in acyclovir-treated patients was supported in subsequent data analysis. If the patients were grouped according to exacerbation frequencies, i.e. into low (0–2), medium (3–5) and high (6–8) rate groups, the difference between acyclovir and placebo treatment was significant (P = 0.017). Moreover, in a subgroup of the population with a duration of the disease of at least 2 years providing an exacerbation rate base-line before entry, individual differences in exacerbation rates were compared between the 2-year pre-study period and the study period in acyclovir-treated (n = 19) and placebo (n = 20) patients and acyclovir-treated patients showed a significant reduction of exacerbations (P = 0.024). Otherwise, neurological parameters were essentially unaffected by acyclovir treatment and there were no convincing signs of reduced neurological deterioration in the acyclovir group. This study indicates that acyclovir treatment might inhibit the triggering of MS exacerbations and thus suggests that acyclovir-susceptible viruses might be involved in the pathogenesis of MS. This possibility warrants further investigation.     

How long is too long? Determining the early management ofmeningococcal disease in Birmingham

Objective:

To determine the length of time cases of meningococcal disease wait before receiving parenteral antibiotic therapy in hospital.

Method:

The hospital case notes of residents of Birmingham who were admitted to local hospitals in 1993 anddischarged with a diagnosis of meningitis or meningococcal disease were reviewed. This information was combined with that held by the West Midlands Ambulance Service.

Results:

Forty out of the 82 patients (49%) who met the case definition had meningococcal infection. Twentyone patients (26%) were admitted by ambulance, 11 of whom had meningococcal infection. The mean time from a request for an ambulance to the patient reaching hospital was 52 min for those with meningococcal infection compared to 55 min for those without. Nineteen patients (47.5%) with meningococcal infection waited more than one hour after admission for antibiotic treatment. Seven had an initial diagnosis of meningitis or meningococcal infection. Ten out of 27 patients with a meningococcal rash (37%), 13 out of 22 patients aged under five years (59%) and 13 out of 24 patients with microbiologically confirmed meningococcal infection (54%) waited more than one hour for treatment. Seven patients with meningococcal infection received benzyl penicillin before admission. Six received hospital antibiotic treatment within the hour.

Conclusion:

The assumption that patients suspected of having meningitis or meningococcal disease are treated promptly once in hospital is not always correct. The results of this study reinforce the need for all doctors to give benzyl penicillin promptly to patients they suspect have meningococcal disease.     

Friday,December 8, 1995 8Th Annual San Antonio flow cytometry forum

Summary Pseudomonas exotoxin has been genetically modified so that it targets cancer cells. This was accomplished by deleting its cell binding domain and replacing it with Fv fragments of antibodies that react with breast, colon, and other cancers. Several recombinant immunotoxins are now in clinical trials.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.     

The effect of long term and high dose interferon treatment in Chronic hepatitis C

The results of 43 interferon treatments of 35 patients (23 male, 12 female) are reported. The duration of the treatment was 6–18 months, the dose of interferon was 3x3-5 MU weekly. Complete response (HCV RNA became negative) was found in 11, relapse was observed in 3 patients. Partial response (transaminase levels became normal, or less than twice normal value, but patients remained HCV RNA positive) occurred in 23 cases, relapse was obeserved in 16. The therapy had no effect in 9 cases. The higher dose and longer term interferon therapy resulted in a higher rate of response to the treatment and a reduction in the number of relapses. This work was supported by the Hungarian Ministry of Welfare (No. T-10 064/93).     

Low-dose (5 mg/kg) desferrioxamine treatment in acutely aluminium-intoxicated haemodialysis patients using two drug administration schedules

BACKGROUND: According to the recommendations proposed at The Consensus Conferenceon Diagnosis and Treatment of Aluminium Overload in End-StageRenal Failure Patients, Paris, 1992 low-dose desferrioxamine(DFO) treatment was applied for the first time in 41 acutelyaluminium-intoxicated patients. METHODS AND RESULTS: DFO-related neurological/ophthalmological side-effects wereobserved in nine of 11 patients with a post-DFO serum aluminiumlevel >300 µg/litre and in two patients of 30 belowthis level after a single administration of a 5-mg/kg dose ofthe chelator in the conventional way (i.e. the last hour ofa dialysis session). They were no longer observed after introducingan alternative DFO administration schedule (i.e. administrationof the chelator 5 h prior to the start of a haemodialysis session;group I: n=14). A significant decrease in the serum aluminiumlevels as well as in the post-DFO serum aluminium increment(sAl) was observed during the first 6 months' course of low-doseDFO treatment in group I as well as group II (which consistedof patients receiving DFO in the conventional way; n=27). Low-doseDFO treatment was accompanied by a significant increase in themean ±SD serum iPTH levels (group I: 174±245 upto 286±285 ng/litre; group II: 206±272 up to 409±424ng/litre; P<0.005) and the mean corpuscular volume (groupI: 80±6.4 up to 85±3.7 fL, P<0.005; group II:76±5.0 up to 87±4.3 fL, P<0.0001). Serum ferritinlevels significantly decreased in both groups. No further side-effectswere observed during the DFO course. Patients in which DFO treatmentcould be stopped (i.e. subjects in which both serum aluminiumand sAl were below 50 µg/litre at two successive occasions)before the end of the 6-months' treatment course had a significantlygreate residual diuresis (700±682 ml/min vs 84±109ml/24 h). Also, residual diuresis was found to protect againstaluminium intoxication as reflected by the values noted in groupI versus those in group II. CONCLUSIONS: The 5-mg/kg DFO treatment provides a safe and adequate therapyfor aluminium overload. In severely aluminium-intoxicated patientspresenting post-DFO serum aluminium levels above 300 µg/litreDFO should be given once weekly 5 h prior to high-extractiondialysis ensuring (i) maximal chelation of aluminium (ii) limitedexposure to circulating aluminoxamine levels, and (iii) adequateremoval of the latter compound. Finally, the necessity for abetter communication between the local water distribution companiesand the dialysis centres is a major lesson that can be drawnfrom this dramatic intoxication.     

The case for liver transplantation in end-stage alcoholic liver disease

Liver transplantation is now a routine procedure and is seen as a valid treatment option for end-stage liver disease. Alcoholism has been regarded as a relative or absolute contraindication to liver transplantation in many transplant units. Recent data document a success rate for transplantation in alcoholic patients that equals that in other patient groups. Issues relating to the ethical and scientific arguments surrounding this complex area of treatment are discussed. It is concluded that individual patients should be assessed in their own right for this treatment option. It is argued that patient groups should not be denied access to specific life-saving treatments.     

Response sensitization and depression following long-term amphetamine treatment in a self-stimulation paradigm

The effects of long-term amphetamine treatment were evaluated on responding supported by self-stimulation of the substantia nigra. Rats repeatedly treated with d-amphetamine, and tested with a low dose of the drug that ordinarily has no behavioral effect, showed higher response rates than animals repeatedly treated with saline and tested with the same dose of amphetamine. In contrast, a depression in responding was observed among animals that received long-term amphetamine administration and were tested with saline. The effects of long-term amphetamine treatment on self-stimulation could not be explained by the intrusion of drug-induced competitive behaviors such as locomotor activity and stereotypy. The results were attributed to changes in dopamine neurotransmission following prolonged exposure to amphetamine and were also discussed in terms of an animal model for amphetamine psychosis and postamphetamine depression in man.