Antipyrine kinetics in undernourished diabetics

Summary In developing countries diabetics frequently suffer from varying grades of malnutrition. The combined effect of malnutrition and non-insulin dependent diabetes (NIDDM) on the drug metabolising enzyme system has been evaluated using antipyrine as a protodrug. All the patients were under treatment and their plasma glucose values were within normal limits.The AUC of antipyrine was similar in all the groups. Although none of the kinetic parameters was altered in normal diabetics, the clearance of antipyrine was decreased and its half life was prolonged, with an increase in volume of distribution, in undernourished diabetics compared to undernourished controls. The results indicate that diabetes per se may not influence antipyrine kinetics when the blood glucose is well under control, but in the presence of undernutrition, it significantly alters the disposition of the drug.     

Helping undernourished adults in the community

People who are undernourished, whatever the cause, feel unwell, function badly and, compared with others, are more likely to consult their GPs, to need medication and be admitted to hospital. Once in hospital, they have a higher rate of complications, such as infections and pressure sores, and they take longer to recover and to return home. In an article 3 years ago, we discussed the detection and management of undernourished adults in hospital. Here, we consider undernourishment in those living in the community. As in the previous article, we concentrate on general undernourishment (protein and energy deficiency), rather than specific deficiencies of micronutrients (such as vitamins and minerals).     

Vascular reactivity in perinatally undernourished rats

Adult rats submitted to perinatal protein deprivation (from day 14 of fetal life till 50 days of age) followed by a longer phase of nutritional recovery on balanced laboratory chow, showed a significant decrease of the pressor response elicited by noradrenaline and adrenaline, an effect that persisted after ganglionic blockade by hexamethonium. However, the effects of serotonin, acetylcholine, angiotensin II and vasopressin on blood pressure did not differ from those in the controls. Cumulative dose-response curves to noradrenaline and methoxamine on the circular contraction of isolated iliac arteries showed a significant shift to the right, together with a reduction in the maximal contraction. No significant difference in the maximal contraction elicited by Ba2+ was observed in experimental preparations as compared with controls. These results suggest the development of a specific subsensitivity to sympathetic drugs in the vascular bed as a consequence on undernutrition during perinatal life.     

Experimental study on rats to find the usefulness of nutritional supplementation to undernourished offspring of parents undernourished life-long

Undernourished parents getting only about half of normal feed requirement and whose body weights were deficient by 40-65% were mated and out of the resulting litters, the medium size (about 8) ones were culled to 8 per dam whose food supply was restricted to 10 g per day during the suckling (category M2). Another category (M3) was constituted out of large (over 12) litters born to similar undernourished parents and culling the litter size to 15 per dam besides restricting the dam's food to only 10 g per day during first week and to 15 g per day during the second and third weeks of suckling. Another category (M1) was constituted like M3 except that the parents were provided with normal, ad libitum nutrition throughout. Effects of post-weaning continuation of undernutrition or of rehabilitation with ad libitum food were studied in M2 groups of pups till 425 days of age. Further, an additional protein-deficient type of undernutrition (M4) was also superimposed in one group of M2 category of pups between day 41 and 60 of age, and then rehabilitated on to normal diet to find the additional effect of this additional load of the protein-malnutrition. The control groups of normal pups were also reared along with the above groups for comparisons. The normal diet had: 22.8% protein, 10.6% fat, 61% carbohydrate, and vitamins and minerals. By 21 days of age, the deficiencies of the M1, M2 and M3 were about 28%, 64% and 77% respectively in body weights, and about 8%, 21% and 30% respectively in brain weights. Continuing the undernutrition after weaning on half of normal feed, the M2 group of males and females stabilized at about 41% and 62% respectively of normal body weights by about 150 days of age. Rehabilitation of M2 or M4 groups by providing ad libitum feed had never recovered their pre-rehabilitation body weight deficits even after the ad libitum feeding for as long as 425 days of age. On the contrary, the brain weights seemed to have partially recovered from the earlier deficits, but here also the general conclusion of permanency of deficits stood unequivocally. The present study affirms that different degrees of gestational, lactational and post-weaning undernutrition can lead to different degrees of growth deficits and that supplemental feeding regimens introduced afterwards cannot bring out recoveries from such previous deficits which seem to remain permanently.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cognitive impairments in poly-drug ketamine users

Rationale

Cognitive impairment has been found to be reversible in people with substance abuse, particularly those using ketamine. Ketamine users are often poly-substance users. This study compared the cognitive functions of current and former ketamine users who were also abusing other psychoactive substances with those of non-users of illicit drugs as controls.

Methods

One hundred ketamine poly-drug users and 100 controls were recruited. Drug users were divided into current (n = 32) and ex-users (n = 64) according to the duration of abstinence from ketamine (> 30 days). The Beck Depression Inventory (BDI), the Hospital Anxiety Depression Scale (HADSA) and the Severity of Dependence Scale (SDS) were used to evaluate depression and anxiety symptoms and the severity of drug use, respectively. The cognitive test battery comprised verbal memory (Wechsler Memory Scale III: Logic Memory and Word List), visual memory (Rey–Osterrieth Complex Figure, ROCF), executive function (Stroop, Wisconsin Card Sorting Test, and Modified Verbal Fluency Test), working memory (Digit Span Backward), and general intelligence (Information, Arithmetic and Digit-Symbol Coding) tests.

Results

Current users had higher BDI and HADSA scores than ex-users (p < 0.001 for BDI and p = 0.022 for HADSA) and controls (p < 0.001 for BDI and p = 0.002 for HADSA). Ex-users had higher BDI (p = 0.006) but equal HADSA scores (p = 1.000) compared to controls. Both current and ex-users had lower scores on Logical Memory delayed recall (p = 0.038 for current users and p = 0.032 for ex-users) and ROCF delayed recall (p = 0.033 for current users and p = 0.014 for ex-users) than controls. Current users also performed worse on ROCF recognition than controls (p = 0.002). No difference was found between the cognitive functions of current and ex-users.

Conclusions

Ketamine poly-drug users displayed predominantly verbal and visual memory impairments, which persisted in ex-users. The interactive effect of ketamine and poly-drug use on memory needs further investigation.     

Spirometric data in South Indian subjects 60-80 years of age

Forced expiratory and inspiratory vital capacities and the timed expiratory and inspiratory volumes and forced expiratory and inspiratory flow rates were determined in 50 old men and women between 60-80 years of age. Some of the ratios between expiratory and inspiratory volumes and flow-rates that have been found to be useful for detecting some forms of ventilatory defects are also given.     

Reactivity to amphetamine in perinatally undernourished rats: behavioral and neurochemical correlates

Adult rats deprived at perinatal age and then rehabilitated on balanced chow were treated with a multiple amphetamine (AMPH) schedule (2 mg/kg/48 hr) and submitted, on days of injections, to an open-field test. Throughout 11 sessions, deprived rats showed a progressive increase of locomotor activity as compared with controls. Stereotyped activity evaluated during the AMPH treatment did not differ between control and deprived animals. No differences were detected in basal values of the dopaminergic function measured in naive control and deprived animals. By the end of the multiple AMPH treatment, a reduction of striatal DA and DOPAC levels together with a lower apparent DA turnover rate was detected in deprived animals. Besides, DA receptor binding was significantly increased in striatum from deprived rats as compared with controls. These results demonstrate that a repeated AMPH treatment, that was unable to alter the normal behavior of control rats, produced in early undernourished animals a progressive sensitization to AMPH effects, in addition to significant changes in the striatal dopaminergic function.     

Nimodipine prevents scopolamine-induced impairments in object recognition

The effects of acute administration of the dihydropyridine calcium channel antagonist, nimodipine, were studied on the actions of scopolamine in the object recognition test. Scopolamine at 0.125 mg/kg decreased the difference in the time spent exploring novel and familiar objects when given either 15 min before, or immediately after, exposure to objects. Administration of nimodipine at 10 mg/kg, or 1 mg/kg, at the same time as the scopolamine completely prevented the deleterious effects on memory in this task. This effect was seen when nimodipine and/or scopolamine were given prior to the object exposure and also when the drugs were given after the experience of seeing the objects. Nimodipine had no effects on performance when given in the absence of scopolamine. This lack of change in total time spent exploring the objects indicated that the effects of scopolamine and nimodipine were not due to changes in motor coordination or alertness. The results are discussed in the light of the role of cholinergic transmission in memory and the known actions of dihydropyridines on brain function.     

BHC induced testicular impairments in rats.

Benzene hexachloride (BHC) was fed to mature male rats weighing 160 g at dosages of 3 and 6 mg/kg body weight over a period of 180 days. Significant decrease in testicular weight and degeneration of seminiferous tubules with deformed spermatogenic cells were noted at a dose of 6 mg/kg BHC. Marked increase in BHC residue in testis revealed that the drug was able to cross blood-testis barrier.     

Lack of neuronal adaptive changes following chronic treatments in perinatally undernourished rats

Reactivity of presynaptic dopaminergic and alpha 2-adrenoceptors following repeated stress or desipramine treatment was investigated by means of apomorphine (APO)- or clonidine (CLO)-induced hypoactivity, respectively, in adult rats undernourished at perinatal age. Under basal conditions, a comparable hypoactive response was observed in control and experimental animals following either APO or CLO administration. Chronic DMI or repeated immobilization sessions attenuated the hypoactivity elicited by APO or CLO in control animals; however, this effect was not observed in experimental rats. These findings demonstrate that deprived animals show impairment to produce neuronal adaptive changes in response to appropriate stimuli, which may account for the behavioral alterations attributed to early undernutrition.     

Selective impairments in the stress response in schizophrenic patients

Objective: In the vulnerability-stress concept of schizophrenia, schizophrenic patients are thought to display increased sensitivity to stress. Little is known about the biological mechanisms that are involved in stress processing in schizophrenic patients. In this study, hypothalamic-pituitary-adrenal (HPA) function in schizophrenic patients was studied for its essential role in stress processing and adaptation to the environment. Methods: Eighteen schizophrenic patients were compared to 21 healthy controls in their salivary cortisol response to a physical (bicycle ergometry) and a psychosocial (public speaking) stressor. Coping questionnaires were included as a measure of stress processing at the psychological level. Basal HPA function was assessed by measuring cortisol day profiles and feedback activity by using dexamethasone and hydrocortisone. Results: Schizophrenic patients showed blunted cortisol responses to the psychosocial stressor, but not to the physical stressor, in spite of similar increases in heart rate. The cortisol response to the psychosocial stressor tended to be negatively correlated to the use of passive and avoidant coping strategies. Basal HPA function appeared intact in the schizophrenic patients. Conclusions: The findings show a selective impairment in the response to psychosocial stress in schizophrenic patients. This suggests the involvement of brain systems that play a role in the activation of the HPA system to psychosocial stress, like arginin-vasopressin (AVP), and cognitive processes, like coping. Received: 21 October 1999 / Final version: 12 January 2000     

Effect of cadmium on lipid peroxidation and antioxidant enzymes in undernourished weanling rat brain

The effect of early postnatal cadmium exposure on lipid peroxidation and antioxidant enzymes in undernourished weanling rat brain has been studied. The results suggest that undernutrition makes the weanling rat brain more susceptible to the neurotoxic effects of cadmium. Cadmium at a low dose of 1 mg/kg body weight did not produce any changes in lipid peroxidation and antioxidant enzymes in normal weanling rat brain, but caused a significant increase in lipid peroxidation and markedly decreased the activities of antioxidant enzymes like glutathione peroxidase, superoxide dismutase and catalase when subjected to undernutrition.     

Acute opiate withdrawal in rats undernourished during infancy: impact of the undernutrition method

Acute morphine withdrawal was assessed in adult rats following early postnatal undernutrition produced by two different methods (Large Litter procedure-20 pups/litter and Modified Slob procedure-rats cross-fostered on days 2, 4, and 6 to nonlactating dams for 24-hour periods). Response rates were first stabilized on a FR16 operant schedule. A single dose of morphine (20 mg/kg) was then administered, followed 4 h later by a single injection of naloxone (2.5 mg/kg). Males reared in large litters showed little behavioral disruption after morphine, suggesting either insensitivity to the opiate or the rapid development of tolerance. After naloxone. Modified Slob males displayed milder withdrawal than those in the well-nourished control or large litter groups. Thus the method of undernutrition influenced morphine's action and expression of withdrawal. A clear sex difference was also evident, females appearing to be generally less sensitive to the opiate- and naloxone-induced withdrawal than males. Body temperature underwent a characteristic elevation following morphine and a depression following naloxone across all groups, but undernutrition did not affect these responses. Hence, behavior proved to be the more sensitive measure for revealing differences in opiate dependence and withdrawal following early life undernutrition, under the test conditions employed.     

Effects of cannabinoid drugs on the reinforcing properties of food in gestationally undernourished rats

Involvement of the endocannabinoids in hyperphagia has been demonstrated, however, behavioral characterization of its role in food reinforcement is limited. The present study investigated whether 2-arachidonoyl glycerol, an endocannabinoid ligand, and rimonabant, a CB1 antagonist, change the reinforcing properties of food in gestationally undernourished rats (a putative model of obesity) vs controls. Albino dams were food deprived by 0 to 45% of their free-feeding weights up to day 18 of their gestational period. Their offspring were allowed to free-feed until postnatal day 75. Then, behavior of the offspring was placed under progressive ratio schedules of sucrose reinforcement. After baseline data were established, intraperitoneal injections of 2-AG (0.03-3.75 mg/kg), and rimonabant (SR141716, 0.3-3.0 mg/kg) were administered and compared across group. Results show gestationally undernourished (GU) rats as adults weighed less than controls at the time of testing and female offspring allowed to free-feed for over 35 weeks exhibited lower body weights than controls. Under baseline, GU rats had lower breakpoints than controls. 2-AG and rimonabant significantly increased and decreased, respectively, breakpoint and responses made per session, suggesting involvement of the cannabinoid system in food reinforcement. When comparing peak doses of 2-AG on breakpoint, gestationally undernourished rats exhibited lower peak doses than controls. These data suggest that under the gestation deprivation method employed, GU rats were thinner and had lower food reinforcer efficacy than controls, and may have heightened sensitivity to 2-AG.     

Chronic drug use and cognitive impairments

Reports regarding the effects of chronic drug use on human cognition and comparisons of different drug user groups have been inconsistent. Methodological flaws may account for some inconsistencies. To determine the effects of chronic drug use on cognition, drug users (n=192) were tested 17.1+/-0.3 days (mean+/-S.E.) and 99.4+/-1.7 days on average after their last use of drugs before beginning treatment. Drug users were categorized as stimulant, alcohol, or polydrug users. Their performance on tests of academic achievement, verbal memory, and abstraction was compared to performance of community-dwelling controls (n=137). The groups were matched on selected demographic and psychiatric characteristics. Historical records of achievement test scores were used to attempt to control for premorbid intellectual ability. Drug users showed impairments on each of the achievement tests (P<.001), as well as poorer total recall (P<.01) and abstraction ability (P<.05). Stimulant users performed worse on several tests relative to the other drug use groups. Only one of six tests demonstrated improvements following about 3 months of abstinence. Thus, chronic drug use is associated with cognitive impairments that do not improve substantially even after several months of abstinence.     

Modality-specific impairments in response habituation following postnatal binge ethanol

The rate of habituation of the heart rate orienting response (OR) to both olfactory and auditory cues was examined in subjects neonatally exposed to ethanol. Subjects were administered 5.25 g/kg/day ethanol in a binge-like manner on either postnatal days (PDs) 4-9 or 10-15. Controls were given sham intubations. Ethanol exposure had no effect on the form or magnitude of the heart rate OR; all subjects exhibited a monophasic bradycardia to the olfactory and auditory cues. However, ethanol treatment severely affected the rate of response habituation to an olfactory cue, regardless of the timing of that exposure. Ethanol treatment on either PDs 4-9 or 10-15 resulted in a failure of animals to show complete heart rate response habituation. For the auditory cue, rate of response habituation was unaffected by ethanol treatment. These results indicate that response habituation deficits in a postnatal model of human fetal-alcohol exposure are modality specific. The response habituation paradigm may be useful for studying mechanisms of short-term recognition memory deficits following early alcohol exposure, although modality of the test stimulus needs to be taken into account. The results suggest that central nervous system structures affected by ethanol may be specific to those involved in olfactory processing, such as the olfactory bulb or hippocampus.     

Behavioral impairments related to lead-induced developmental neurotoxicity in chicks

Lead intoxication affects the central nervous system and produces structural disorders and behavioral deficits in several animal species. Although lead neurotoxicity is a well-reported phenomenon, studies on the developmental neurotoxicity induced by this metal in avian are scarce. The aim of this study was to evaluate how a single dose of 28 mug lead acetate administered into the yolk sac on the fifth incubation day of Gallus domesticus can affect the behavior and the brain tissue in the first postnatal week. Several behavioral tests, mainly those related to the motor and exploratory functions were evaluated at fifth and sixth postnatal days (PN). The lead deposition into mesencephalon and cerebellum was investigated by autometallography (AMG) method. Congenital anomalies, as failure on closure of body's ventral midline and leg dysfunction, were observed in treated chicks. During the first postnatal week, inactivity and anomalous movements were significantly high in lead treated chicks in comparison to control animals. Lead impregnation was observed in both mesencephalon and cerebellum and the cerebellar molecular layer presented higher lead deposition in comparison to granular layer and Purkinje cells. Our results indicate that the in ovo exposure to lead induces important deficits on motor behavior of chicks during the first postnatal week and such phenomena are related to lead deposition in the cerebellar tissue during embryonic development. The proposed exposure schedule represents an interesting experimental approach for studding behavioral and cellular mechanisms related to lead-induced developmental neurotoxicity.