Correlation between dopamine receptor D2 expression and presence of abnormal involuntary movements in Wistar rats with hemiparkinsonism and dyskinesia. / Correlación entre la expresión del receptor dopaminérgico D2 y presencia de movimientos involuntarios anormales (MIA) en un modelo de disquinesia en ratas Wistar hemiparkinsonizadas.

Parkinson's disease (PD) is characterised by motor alterations, which are commonly treated with L-DOPA. However, long-term L-DOPA use may cause dyskinesia. Although the pathogenic mechanism of L-DOPA-induced dyskinesia is unclear, the condition has been associated with alterations in dopamine receptors, among which D2 receptors (D2R) have received little attention. This study aims to: (i)develop and standardise an experimental model of L-DOPA-induced dyskinesia in rats with hemiparkinsonism; and (ii)evaluate the correlation between D2R expression and presence of abnormal involuntary movements (AIM). We allocated 21 male Wistar rats into 3 groups: intact controls, lesioned rats (with neurotoxin 6-OHDA), and dyskinetic rats (injected with L-DOPA for 19 days). Sensorimotor impairment was assessed with behavioural tests. Dyskinetic rats gradually developed AIMs during the treatment period; front leg AIMs were more severe and locomotor AIMs less severe (P<.05). All AIMs were significantly evident from day 5 and persisted until the last day of injection. D2R density was greater in the striatum and the medial anterior brain of the lesioned and dyskinetic rats than in those of controls. Our results suggest an association between D2R expression and locomotor AIMs. We conclude that RD2 is involved in L-DOPA-induced dyskinesia.

Correlación entre la expresión del receptor dopaminérgico D2 y presencia de movimientos involuntarios anormales (MIA) en un modelo de disquinesia en ratas Wistar hemiparkinsonizadas / Correlation between dopamine receptor D2 expression and presence of abnormal involuntary movements in Wistar rats with hemiparkinsonism and dyskinesia

La enfermedad de Parkinson (EP) se caracteriza por una serie de deficiencias motoras que son tratadas comúnmente con L-DOPA; sin embargo, tras un uso crónico se desarrollan disquinesias inducidas por L-DOPA (DIL). Por otra parte, el origen de las DIL no está del todo claro, pero se asocia con alteración en receptores dopaminérgicos, donde los receptores D2 (RD2) han sido poco estudiados. El presente trabajo buscó: 1) desarrollar y estandarizar un modelo experimental de disquinesia con L-DOPA en ratas hemiparkinsonizadas, y 2) evaluar la correlación entre la expresión del RD2 y la manifestación de movimientos involuntarios anormales (MIA). Se utilizaron 21 ratas Wistar macho asignadas a 3 grupos: control intacto, lesionados (con la neurotoxina 6-OHDA) y lesionados disquinéticos (inyectados con L-DOPA durante 19 días). Los reactivos biológicos se sometieron a pruebas comportamentales para evaluar el deterioro sensoriomotor. Los animales del grupo disquinético desarrollaron de forma gradual MIA durante el tratamiento, siendo mayores los MIA de miembro anterior y menores los de tipo locomotor (p < 0,05). Todos los MIA fueron significativamente evidentes a partir del día 5 y se mantuvieron hasta el último día de inyección. Además, se pudo evidenciar incremento en la densidad del RD2 en el estriado y el cerebro anterior medial en los grupos lesionados con respecto al control, así como también una posible asociación entre la expresión del RD2 y MIA de tipo locomotor. Por lo que concluimos que el RD2 está implicado en el fenómeno disquinético generado con la L-DOPA. (AU)

Parkinson's disease (PD) is characterised by motor alterations, which are commonly treated with L-DOPA. However, long-term L-DOPA use may cause dyskinesia. Although the pathogenic mechanism of L-DOPA-induced dyskinesia is unclear, the condition has been associated with alterations in dopamine receptors, among which D2 receptors (D2R) have received little attention. This study aims to: (i) develop and standardise an experimental model of L-DOPA-induced dyskinesia in rats with hemiparkinsonism; and (ii) evaluate the correlation between D2R expression and presence of abnormal involuntary movements (AIM). We allocated 21 male Wistar rats into 3 groups: intact controls, lesioned rats (with neurotoxin 6-OHDA), and dyskinetic rats (injected with L-DOPA for 19 days). Sensorimotor impairment was assessed with behavioural tests. Dyskinetic rats gradually developed AIMs during the treatment period; front leg AIMs were more severe and locomotor AIMs less severe (P < .05). All AIMs were significantly evident from day 5 and persisted until the last day of injection. D2R density was greater in the striatum and the medial anterior brain of the lesioned and dyskinetic rats than in those of controls. Our results suggest an association between D2R expression and locomotor AIMs. We conclude that RD2 is involved in L-DOPA-induced dyskinesia. (AU)

Safety of flurbiprofen in the treatment of ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis. A summary of liver and kidney assay data.

The safety of flurbiprofen (Ansaid, Upjohn) was assessed after pooling data on kidney and liver function collected from nine separate phase III clinical trials involving 1,677 patients (941 receiving flurbiprofen and 736 receiving comparison drugs) with ankylosing spondylitis, osteoarthritis, or rheumatoid arthritis. Multiple categories were created to discern the effects of treatment, disease, age (under 60 and 60 years or older), and duration of exposure to flurbiprofen. No clinically significant trends in kidney or liver function were detected in any category following the administration of flurbiprofen.

Treatment of acute shoulder syndrome with flurbiprofen.

A multi-dose, double-blind, randomized, placebo-controlled, multicenter study was conducted to evaluate 68 patients with acute bursitis or tendinitis following treatment with flurbiprofen (Ansaid, Upjohn) or placebo. Flurbiprofen was administered in a total daily dosage of 200 to 300 mg four times daily. Based on efficacy rating scales, flurbiprofen-treated patients had the greatest proportion of improvement at almost all time periods. They also showed statistically significant improvement compared with placebo-treated patients, according to investigators' overall assessments at all time periods. Most patients showed improvement within three to four days of treatment. Flurbiprofen was both well tolerated and effective for the relief of pain caused by bursitis or tendinitis of the shoulder.

Flurbiprofen in the treatment of ankylosing spondylitis. A comparison with phenylbutazone.

Flurbiprofen (Ansaid, Upjohn), a potent new analgesic and anti-inflammatory agent, was compared with phenylbutazone in 90 patients with ankylosing spondylitis. In this double-blind, randomized, 26-week study, a total daily dose of 200 mg of flurbiprofen, administered three times daily, was as effective as 300 mg of phenylbutazone in controlling the pain and other symptoms of ankylosing spondylitis. In some patients, symptoms were adequately controlled by 150 mg of flurbiprofen per day, administered twice daily. There were no statistically significant differences between flurbiprofen and phenylbutazone in the investigators' and patients' assessments of improvement at all key follow-up periods. In addition, there were no consistently significant differences between drugs in the efficacy pain scales and quantitative measurements studied. Flurbiprofen was well tolerated in doses of up to 300 mg per day, and no clinically significant laboratory abnormalities were detected. Flurbiprofen appears to be an excellent alternative to phenylbutazone in the management of patients with ankylosing spondylitis.

Flurbiprofen in the treatment of ankylosing spondylitis. A comparison with indomethacin.

In this randomized, double-blind study, 57 patients with ankylosing spondylitis were evaluated after 26 weeks of treatment with either flurbiprofen (Ansaid, Upjohn) or indomethacin. Flurbiprofen administered four times a day in a total daily dose of 200 mg was effective in controlling the pain and associated symptoms of ankylosing spondylitis. Pain was adequately controlled in some patients following a total daily dose of 100 mg of flurbiprofen administered twice a day. Flurbiprofen was as effective as indomethacin in most key efficacy measurements analyzed. The drug was well tolerated in doses of up to 300 mg per day, and no clinically significant laboratory abnormalities were detected. Flurbiprofen is an excellent treatment for the control of pain and inflammation in patients with ankylosing spondylitis.

Flurbiprofen in the treatment of rheumatoid arthritis. A comparison with aspirin.

This large-scale, double-blind study compared 200 mg per day of flurbiprofen (Ansaid, Upjohn) with 4,000 mg per day of aspirin in 822 patients with definite or classical rheumatoid arthritis who were evaluated for up to 52 weeks. Overall response to therapy was similar in both groups. By the end of the study, however, significantly more patients remained in the flurbiprofen (54 percent) than in the aspirin group (40 percent). Significant differences were also found in the incidence and severity of adverse reactions: 36 percent of flurbiprofen-treated and 63 percent of aspirin-treated patients reported side effects. Severe adverse reactions occurred in 6.7 percent of the flurbiprofen-treated patients compared with 16.5 percent of the aspirin-treated patients. Withdrawals that were due at least in part to adverse reactions were more than twice as frequent in the aspirin group (21.4 percent) than in the flurbiprofen group (10.2 percent). Laboratory data collected throughout the study showed no clinically significant abnormalities in either group. This study suggests that flurbiprofen effectively controls the pain and other symptoms of rheumatoid arthritis, and is superior in safety to aspirin in the treatment of patients with acute and chronic disease.

Treatment of osteoarthritis of the knee. A comparison of flurbiprofen and aspirin.

The analgesic efficacy of flurbiprofen (Ansaid, Upjohn) and aspirin were compared in a 12-week, double-blind, randomized, parallel, multicenter study of 147 patients with osteoarthritis of the knee. Flurbiprofen (73 patients) was administered two, three, or four times a day in total daily doses of 100, 150, or 200 mg; aspirin (74 patients) was also given two, three, or four times a day in total daily doses of 2,000, 3,000, or 4,000 mg. Flurbiprofen was found effective in controlling pain and other symptoms of osteoarthritis. In general, the flurbiprofen group showed greater improvement in efficacy variables than did the aspirin group. Statistically significant improvements were noted in the flurbiprofen-treated patients for disability at week 12, and in the clinicians' assessment of response to therapy and disability at the final evaluation. Many flurbiprofen-treated patients (46 percent) completing the trial followed a relatively low dosage regimen of 50 mg twice daily for more than half the study. Flurbiprofen was well tolerated, and no significant laboratory abnormalities were detected.

Flurbiprofen in the treatment of acute gout. A comparison with indomethacin.

The relative efficacy and safety of flurbiprofen (Ansaid, Upjohn) and indomethacin were compared in 29 patients with monoarticular gouty arthritis of less than 48 hours' duration. A loading dose of 400 mg of flurbiprofen or 200 mg of indomethacin was administered for 24 hours, followed by 200 mg of flurbiprofen per day or 100 mg of indomethacin per day for a maximum of five days. Based on global assessment of improvement, at least 50 percent of patients in both treatment groups showed improvement within 24 hours. There were statistically significant improvements in pain, swelling, erythema, and skin temperature in both groups of patients within 48 hours of treatment. By 72 hours, the proportion of patients with improvement in the flurbiprofen group was equal to or greater than the proportion in the indomethacin group for all clinical efficacy parameters. At the end of treatment, eight of 15 patients in the indomethacin group and five of 14 patients in the flurbiprofen group were asymptomatic. There were no statistically significant differences between indomethacin and flurbiprofen in the percentage of asymptomatic patients at the end of treatment. Side effects were mild in both groups. No clinically significant between-treatment differences were noted in vital signs or in the results of laboratory assays.

Clinical safety of flurbiprofen.

Data from 58 premarketing studies of the nonsteroidal antiinflammatory drug flurbiprofen were pooled for analyses of adverse drug reactions (ADRs). These studies included 5602 patients treated with flurbiprofen (N = 4123), aspirin (N = 1033), or placebo (N = 446) for varying durations. Diagnoses included rheumatoid arthritis, osteoarthritis, and other painful musculoskeletal conditions. In these studies serious upper gastrointestinal ADRs occurred in flurbiprofen-treated patients at less than one half the rate seen in aspirin-treated patients. The incidence of serious urinary tract ADRs was lower with flurbiprofen than with aspirin. The flurbiprofen group had no serious clinical ADRs related to the hemic/lymphatic system. The most common laboratory abnormality was a decrease in hematocrit, which occurred less often than in the aspirin group. We also evaluated serious flurbiprofen-related ADRs in 4370 patients in a variety of other studies and reviewed published reports of flurbiprofen clinical trials and case reports. These reviews showed no additional, unanticipated patterns of intolerance. These clinical safety data indicate that in the doses studied, flurbiprofen is a well tolerated agent for patients requiring nonsteroidal antiinflammatory drug therapy.

Impairment of place navigation of rats in the Morris water maze by intermittent light is inversely related to the duration of the flash.

The relative contribution of allocentric and egocentric orientation to place navigation was studied in Long-Evans rats trained in the Morris water maze in permanent light, permanent darkness or flickering light (1 Hz, flash durations 25, 100, 300, 500 and 800 ms). After 3 days of training (nine blocks of four trials), escape latencies were 38 and 7 s in the dark- and light-trained groups, respectively, and corresponded to the light-dark ratio in the flicker-trained groups. Shorter-than-predicted latencies in the 25- and 100-ms groups reflected visual persistence of approximately 200 ms. The difference between flickering light (100 ms) and permanent light performance during acquisition of place navigation to a new target was significantly smaller in rats previously trained in light than in naive animals. It is concluded that longer flash duration gives the animals more opportunities to locate relevant landmarks and to estimate their distance.

Use of intramuscular prostaglandin for failure of mid-trimester abortion by another method.

Eight investigators, using a common protocol, studied the use of intramuscular (15S)-15-methyl prostaglandin F2 alpha to abort midtrimester pregnancies which had failed treatment by other methods in 398 cases. Results of treatment of 3 subgroups, defined by reason for primary treatment failure, are presented. The combined efficacy rate was 96.2% with 79.6% of the abortions being complete. The mean time from starting intramuscular therapy to successful abortion was 7.35 hours. The incidence of gastrointestinal side-effects was lower than that previously reported for systemically administered prostaglandins. Serious complications were not appreciably different from those reported for commonly used methods of second trimester abortion except for a slightly higher incidence of excessive bleeding requiring blood replacement. Advantages of this method over currently used methods of treating failures of primary attempts to induce midtrimester abortion by pharmacologic means are discussed.

PIP: Intramuscular injections of 250-500 mg. of prostaglandin F2 alpha were administered to 398 women to induce midtrimester abortion after other methods had failed. There was an overall efficiency rate of 96.2% with 79.6% complete abortions in a mean time of 7.35 hours. Adverse reactions were primarily vomting, diarrhea, nausea, and temperature elevation. The incidence of such side effects was high, but severity was mild and well tolerated. Incidence of serious complications was not higher than that associated with other abortion methods, except for the incidence of excessive hemorrhage and blood replacement. In general, results of this study were similar to those reported in previous publications.

Pre-operative electrocardiograph examination.

The leading cause of death following surgery is a cardiac event, and an electrocardiogram is the most common pre-operative test to investigate coronary artery disease. Fifty adults, who required an electrocardiogram, undergoing general surgical procedures, were recruited into this pilot study, which investigated the examination rate of electrocardiographs by doctors pre-operatively. Each tracing was folded in one corner and a paperclip prevented full pre-operative viewing without its removal. Results suggest that 30% of ECGs were not opened and the records of 58% patients overall had no mention of the ECG having been performed. Further analysis showed no correlation with the examination rate of the electrocardiograph with patient age or fitness. If this reflects normal clinical practice, it is sub-optimal use of resources and warrants further audit.

Indirect enzyme-linked immunosorbent assay for zygomycosis.

A 2-h indirect enzyme-linked immunosorbent assay (ELISA) using homogenate antigens of Rhizopus arrhizus and Rhizomucor pusillus was developed and compared with the existing immunodiffusion (ID) test for zygomycosis, using homogenate antigens of R. arrhizus. Utilizing 1:400 as a minimally positive ELISA titer, 33 of 43 proven cases of zygomycosis were diagnosed. The sensitivity of the ELISA was 81%. The ID test, in contrast, detected only 21 cases and demonstrated a sensitivity of 66%. The specificity of the ELISA was 94%, whereas that of the ID test was 91%. Nonspecific ELISA reactivity was particularly evident with sera from patients with aspergillosis and candidiasis. With the antigens now available, the ELISA was unable to generically or specifically identify the etiologic agents.

New immunoenzymatic assay for human thyrotropin compared with two radioimmunoassays.

We have evaluated a new immunoenzymatic assay for human thyrotropin involving three monoclonal antibodies (Abbott HTSH EIA) and compared the results with those of two conventional nonequilibrium double-antibody radioimmunoassay (RIA) methods: Clinical Assays' RIA and a research RIA (J Clin Endocrinol Metab 1975; 41:676). Mean values for thyrotropin in 100 euthyroid serum samples were similar in the Abbott and Clinical Assays methods, but both sets were significantly higher than those by the research RIA. By all methods, values for hypothyroid patients were clearly higher than values for euthyroid subjects. Results for hyperthyroid and euthyroid subjects were resolved slightly better with the research RIA than with the Abbott kit. The new Abbott assay was far more sensitive than either the Clinical Assays RIA or our research RIA. The correlation of results of the Abbott assay with those of the Clinical Assays and the research RIA exceeded 90% for samples from hypothyroid patients. The Abbott assay replaces radioisotope counting with spectrophotometric detection.

Retrieval of overtrained place navigation during occlusion of one eye and ipsi- or contralateral blockade of relevant brain centers in rats.

Place navigation engrams acquired with intact brain can be retrieved with either eye and are stored in both hemispheres. The retrieval circuitry was examined by testing an overtrained rat under lidocaine inactivation of the hippocampus, visual cortex, and superior colliculus. Thirty-three hooded rats with implanted cannulae aimed at the above structures were trained to find a target in the southwest quadrant of the pool. Retrieval was tested during occlusion of one eye alone or combined with ipsi- or contralateral blockade (1 microliter 4% lidocaine) of hippocampus, hippocampus and visual cortex, or hippocampus, visual cortex, and superior colliculus. The intact brain escape latencies (9.8 s) were only slightly prolonged by occlusion of one eye (to 12.6 s). Blockade of centers ipsi- or contralateral to the occluded eye increased escape latencies to 12.7 or 15.2 s for hippocampus, to 16.8 or 16.9 s for hippocampus and visual cortex, and to 23.6 or 17.4 s for hippocampus, visual cortex, and superior colliculus, respectively. Significant asymmetry appearing in the last case indicates that the superior colliculus plays an important role in mediation of the crossed visual input supporting place navigation. Residual goal-finding capability in rats with blockade of centers ipsilateral to the occluded eye is probably due to uncrossed visual projections to the intact hemisphere.

Platelets and cancer.

The presence of platelets in association with cancer deposits has been recognised for over 100 years; however, the recognition of a two-way interaction has been more recent. The link between cancer spread and platelet stimulation is pivotal to understanding of the hypercoagulable state found in most cancer patients. The assistance of platelets in cancer spread may provide opportunities to interrupt this relation, thus inhibiting metastasis.

Study of behavior of rats with gluten-induced enteropathy.

Association of different psychological and neurological disturbances with gluten intake in coeliac patients was repeatedly described. In the present study gluten-induced enteropathy was elicited in rats by prolonged intragastric administration of gliadin from birth to 10 weeks. Various neurological (contact and visual placing reactions, equilibrium on horizontal bar) and behavioral tests (open field and Morris water maze task) were used to assess the possible deficits. No substantial differences were found in the behavior of rats fed with gliadin compared with those fed with bovine serum albumin (control group). The only difference found between control and experimental rats was that gliadin-fed rats showed slightly higher emotionality in the open field test. It is concluded that prolonged application of gliadin to young rats at enteropathy-inducing dosages does not modify their behavior.

Hypothalamic secretion of thyrotropin releasing hormone declines in aging rats.

Young and aged male rats were used in experiments to investigate a possible decline in hypothalamic secretion of thyrotropin releasing hormone (TRH) to the anterior pituitary of aging mammals. We observed a 66% decrease in basal TRH release by incubated rat hypothalami with aging. Thyroid hormone-responsive hepatic alpha-glycerophosphate dehydrogenase (GPD) and malic enzyme (ME) levels in aged rats did not differ from 5-month-old controls in spite of a significant fall in serum thyroxine (T4) levels with aging. Other results suggest that these particular indicators of thyroidal status should not change in the aging rat because serum T3 is maintained in the normal range. Serum thyrotropin (TSH) levels, which normally rise when serum T4 levels decline, did not change with aging. These data suggest that gradual loss of the essential TRH stimulation of TSH release with aging may be compensated for by a decline in T4 inhibition of TSH release at the pituitary.