Double-blind Cross-over Trial Comparing Intranasal Beclomethasone Dipropionate and Placebo in Perennial Rhinitis

Twenty-five patients with perennial rhinitis completed a double-blind cross-over trial of intranasal beclomethasone dipropionate 200 μg daily and placebo. Of these patients 19 preferred the active drug and two preferred placebo. There were significant reductions in symptom scores for nasal obstruction and rhinorrhoea and in the use of decongestant nasal drops when using the active drug. No changes in morning plasma cortisol levels occurred during the three-week treatment period.     

Circadian discrimination of reward: evidence for simultaneous yet separable food- and drug-entrained rhythms in the rat

A unique extra-suprachiasmatic nucleus (SCN) oscillator, operating independently of the light-entrainable oscillator, has been hypothesized to generate feeding and drug-related rhythms. To test the validity of this hypothesis, sham-lesioned (Sham) and SCN-lesioned (SCNx) rats were housed in constant dim-red illumination (LL(red)) and received a daily cocaine injection every 24 h for 7 d (Experiment 1). In a second experiment, rats underwent 3-h daily restricted feeding (RF) followed 12 d later by the addition of daily cocaine injections given every 25 h in combination with RF until the two schedules were in antiphase. In both experiments, body temperature and total activity were monitored continuously. Results from Experiment 1 revealed that cocaine, but not saline, injections produced anticipatory increases in temperature and activity in SCNx and Sham rats. Following withdrawal from cocaine, free-running temperature rhythms persisted for 2-10 d in SCNx rats. In Experiment 2, robust anticipatory increases in temperature and activity were associated with RF and cocaine injections; however, the feeding periodicity (23.9 h) predominated over the cocaine periodicity. During drug withdrawal, the authors observed two free-running rhythms of temperature and activity that persisted for >14 d in both Sham and SCNx rats. The periods of the free-running rhythms were similar to the feeding entrainment (period = 23.7 and 24.0 h, respectively) and drug entrainment (period = 25.7 and 26.1 h, respectively). Also during withdrawal, the normally close correlation between activity and temperature was greatly disrupted in Sham and SCNx rats. Taken together, these results do not support the existence of a single oscillator mediating the rewarding properties of both food and cocaine. Rather, they suggest that these two highly rewarding behaviors can be temporally isolated, especially during drug withdrawal. Under stable dual-entrainment conditions, food reward appears to exhibit a slightly greater circadian influence than drug reward. The ability to generate free-running temperature rhythms of different frequencies following combined food and drug exposures could reflect a state of internal desynchrony that may contribute to the addiction process and drug relapse.     

The lupus syndrome induced by hydralazine: a common complication with low dose treatment.

The true incidence of the lupus syndrome induced by hydralazine was determined in a longitudinal study of 281 patients consecutively starting hydralazine for hypertension over a 51 month period. Data on the duration of treatment and the maximum dose achieved were examined using life table analysis. After three years'' treatment with hydralazine the incidence of the lupus syndrome was 6.7% (95% confidence limits 3.2-10.2%). The incidence was dose dependent, with no cases recorded in patients taking 50 mg daily and incidences of 5.4% with 100 mg daily and of 10.4% with 200 mg daily. The incidence was higher in women (11.6%) than in men (2.8%). In women taking 200 mg daily the three year incidence was 19.4%. Hydralazine is an effective antihypertensive drug that has come to be used in restricted dosage (not more than 200 mg daily) because of its risk of inducing the lupus syndrome. This study shows that the true incidence of the syndrome is still unacceptably high even when the drug is prescribed according to current recommendations.     

Treatment of Congestive Heart Failure with Triamterene

Triamterene, a newer oral diuretic, was administered to nine hospitalized patients with congestive heart failure for an average of 15 days, and to 22 ambulatory patients for a period of three to 11 months. The daily dosage of triamterene ranged from 50 to 250 mg., but usually 100-200 mg. was administered daily in two divided doses, with or without the addition of 50 mg. of hydrochlorothiazide daily.Triamterene is a safe and effective diuretic at doses of 100-200 mg. daily and no drug tolerance develops with long-term therapy. However, when used alone, it is not as effective as hydrochlorothiazide, but in combination with the latter drug the resultant diuresis is unsurpassed by any other oral diuretic therapy that we have used to date.Triamterene itself does not produce kaliuresis and it blocks thiazide-induced kaliuresis. Serum uric acid levels may rise slightly, but no clinical gout was seen in this study.     

Treatment of chronic drug-resistant pulmonary tuberculosis with rifampin and ethambutol

Twenty patients with chronic pulmonary tuberculosis completed eight months of rifampin-ethambutol treatment. Half the patients received daily 600 mg. rifampin and 25 mg./kg. ethambutol for the first two months and subsequently 15 mg./kg. The others received the same dosage of ethambutol and 450 mg. rifampin daily. The average time of sputum conversion was seven weeks and 11 weeks in the two groups respectively. The patients tolerated these drug regimens well.Rifampin blood levels and urinary excretion were studied monthly during the therapy. They indicated that after a short period of treatment the elimination of this drug became faster owing to increased excretion of rifampin, and particularly of its desacetyl metabolite, in the bile. Liver damage resulted in a slower excretion rate. Rifampin should be taken on an empty stomach because simultaneous food intake reduces the peak blood concentration.     

Effect of methallibure on gonad development and carotenoid content of the fins of Sarotherodon mossambicus (Tilapia mossambica)

Juvenile Sarotherodon mossambicus were exposed to a daily dose of 1 or 2 p.p.m. of the antigonadotropic drug methallibure for a period of seven weeks. The control fish all showed well-developed gonads and a considerable concentration of astaxanthin in the dorsal fins. The dominant male showed a much higher astaxanthin value than the other fishes. Methallibure completely prevented gonad development. Nevertheless, some astaxanthin deposition did occur in the drug-treated fish.     

Circadian Discrimination of Reward: Evidence for Simultaneous Yet Separable Food- and Drug-Entrained Rhythms in the Rat

A unique extra-suprachiasmatic nucleus (SCN) oscillator, operating independently of the light-entrainable oscillator, has been hypothesized to generate feeding and drug-related rhythms. To test the validity of this hypothesis, sham-lesioned (Sham) and SCN-lesioned (SCNx) rats were housed in constant dim-red illumination (LL_red) and received a daily cocaine injection every 24?h for 7 d (Experiment 1). In a second experiment, rats underwent 3-h daily restricted feeding (RF) followed 12 d later by the addition of daily cocaine injections given every 25?h in combination with RF until the two schedules were in antiphase. In both experiments, body temperature and total activity were monitored continuously. Results from Experiment 1 revealed that cocaine, but not saline, injections produced anticipatory increases in temperature and activity in SCNx and Sham rats. Following withdrawal from cocaine, free-running temperature rhythms persisted for 2–10 d in SCNx rats. In Experiment 2, robust anticipatory increases in temperature and activity were associated with RF and cocaine injections; however, the feeding periodicity (23.9?h) predominated over the cocaine periodicity. During drug withdrawal, the authors observed two free-running rhythms of temperature and activity that persisted for >14 d in both Sham and SCNx rats. The periods of the free-running rhythms were similar to the feeding entrainment (period?=?23.7 and 24.0?h, respectively) and drug entrainment (period?=?25.7 and 26.1?h, respectively). Also during withdrawal, the normally close correlation between activity and temperature was greatly disrupted in Sham and SCNx rats. Taken together, these results do not support the existence of a single oscillator mediating the rewarding properties of both food and cocaine. Rather, they suggest that these two highly rewarding behaviors can be temporally isolated, especially during drug withdrawal. Under stable dual-entrainment conditions, food reward appears to exhibit a slightly greater circadian influence than drug reward. The ability to generate free-running temperature rhythms of different frequencies following combined food and drug exposures could reflect a state of internal desynchrony that may contribute to the addiction process and drug relapse. (Author correspondence: heiko@vetmed.wsu.edu)     

Methadone maintenance in general practice: patients,workload, and outcomes.

OBJECTIVE--To assess recruitment to and work-load associated with methadone maintenance clinics in general practice; to investigate the characteristics of patients and outcomes associated with treatment. DESIGN--Study of case notes. SETTING--Methadone maintenance clinics run jointly by general practitioners and drug counsellors in two practices in Glasgow. PARTICIPANTS--46 injecting drug users receiving methadone maintenance during an 18 month period, 31 of whom were recruited to clinic based methadone maintenance treatment and 15 of whom were already receiving methadone maintenance treatment from the general practitioners. Mean (SD) age of patients entering treatment was 29.6 (5.5) years; 29 were male. They had been injecting opiates for a mean 9.9 (5.1) years, and most had a concurrent history of benzodiazepine misuse. Average reported daily intake of heroin was approximately 0.75 g. Participants in treatment had high levels of preexisting morbidity, and most stated that they committed crime daily. RESULTS--2232 patient weeks of treatment were studied. Mean duration of treatment during the study period was 50.7 (21.1) weeks and retention in treatment at 26 weeks was 83%. No evidence of illicit opiate use was obtained at an average of 78% of patients'' consultations where methadone had been prescribed in the previous week; for opiate injection the corresponding figure was 86%. CONCLUSIONS--Providing methadone maintenance in general practice is feasible. Although costs are considerable, the reduction in drug use, especially of intravenous opiates, is encouraging. Attending clinics also allows this population, in which morbidity is considerable, to receive other health care.     

Effects of alcohol on natural resistance to Ancylostoma caninum in mice.

Experiments were performed to study the effect of alcohol on natural immunity of Swiss albino mice during Ancylostoma caninum infection. Natural resistance is lowered in alcoholic mice; 40% alcohol by mouth produced significant effect after 20 daily injections. The effect of the drug on natural immunity depended upon the concentration and the period of consumption. Animals retained maximum number of larvae during alcohol treatment.     

Diazepam: A Preliminary Study of its Effects on Patients with Athetoid Cerebral Palsy

Diazepam was administered to seven severely affected athetoid children for a period of two to three months to determine whether beneficial effects could be demonstrated from its use. All patients were started on a daily dose of 2.5 mg. and the dose was increased as tolerated. The patients were assessed by a neurologist, an occupational therapist, a physiotherapist and a speech therapist before and after the trial.The dose of diazepam cannot be determined in advance. The optimum dose must be established by trial in each individual patient. No beneficial effects were noted in four of these children. One of those who showed improvement became significantly worse when the drug was withdrawn and it was necessary to reinstitute the drug. The response in any individual patient is unpredictable. The most significant side effect was drowsiness.     

Changes in platelet function and gastrointestinal bleeding following repeated administration of acetylsalicylic acid in the rat and the dog.

Two dogs were prepared with Pavlov pouches of the fundic area of the stomach using standard techniques. During treatment periods of 14 days, 200 mg acetylsalicylic acid (ASA) was introduced into the pouch twice daily by insufflation. One hour after each drug administration the pouch was washed with saline and the fluid assayed for blood. Bleeding from the pouch increased to a maximum on the 3rd or 4th day of the treatment period and subsequently declined such that by the 8th day blood loss was minimal and approximated that found during control periods. Platelet aggregation (in vitro) responses to adenosine diphosphate were significantly (p less than 0.01) inhibited on day 3 when aggregation curve heights were reduced by 66.2 +/- 13.11% (mean +/- SEM) from control values. On day 7 and during the ensuing 7-day period when ASA was given twice daily, the heights of aggregation responses were reduced by only 20-30% from controls. These responses were significantly (p less than 0.001) greater than those found on day 3. Similar changes in platelet reactivity were found in plasma from rats given ASA twice daily for 7 days. Aggregation responses to collagen were depressed by 95.5 +/- 4.49% on day 1 following two doses of ASA. As the treatment period continued, the aggregation responses increased in magnitude until the 7th day they were similar in height to those from control animals. The mechanism involved in this adaptation to ASA treatment seen with these platelets is not known.     

Bronchodilator Effect of Oral Salbutamol in Asthmatics Treated with Corticosteroids

In a double-blind trial the effect on ventilatory function of oral salbutamol (in two different doses) and a placebo were studied in 12 patients with chronic asthma receiving regular maintenance treatment with prednisolone. Salbutamol in a dose of 4 mg four times daily, given for a period of four weeks, produced a sustained and statistically significant increase in peak expiratory flow rate over the pretreatment recordings. This effect was not observed with a lower dose of salbutamol (2 mg four times daily) or with a placebo. Salbutamol in the higher dose would seem to be an effective and safe oral bronchodilator that can be recommended for the treatment of mild or moderate asthma. The duration of treatment in this study was, however, limited to four weeks, and it is not known whether effective bronchodilatation would be maintained if the drug were given for longer periods.     

Treatment of Parkinsonism with Laevo-Dopa

Thirty-two patients with Parkinsonism were treated with L-dopa. Nine were markedly and 14 moderately improved. Twenty patients tolerated the drug well, derived definite improvement, and were treated for an average period of six months. Improvement was sustained during this period even though the average daily dosage of L-dopa was reduced. Dose-dependent side-effects occurred in 25 patients. It is suggested that dosage schedules should be flexible and tailored to the needs of each individual patient, and that treatment should be continued for six months before presuming it to be ineffective.It is concluded that L-dopa often ameliorates Parkinsonism for long periods, but its effect on the natural history of the disease is undertermined.     

What happens to opiate addicts immediately after treatment: a prospective follow up study.

In the first British study to investigate systematically what happens to opiate addicts after treatment 50 opiate addicts admitted for inpatient treatment of their drug dependence were followed up for six months after discharge. All had been withdrawn from opiates before follow up. Six months later 26 were not using opiates: 12 had not used opiates at any time since discharge. When subjects in hospital or in prison were excluded from the analysis 21 (47%) of the subjects living in the community were not taking opiates. Many subjects used opiates within days of leaving the inpatient unit, but this first lapse did not necessarily lead to a full relapse into addictive use. During the six months after discharge several subjects used opiates on a less than daily basis. During each two month period throughout the six months of follow up the proportion of subjects who were occasional users fell, the proportion of abstinent subjects grew, and the proportion of daily users (assumed to be readdicted) remained constant. Although many of the addicts relapsed soon after treatment, it was encouraging that almost half were opiate free after six months. These results have important implications for the treatment of drug addicts.     

Comprehensive Approach to Functional State Evaluation in Humans: Report I. Methodology of Diagnosis of the Functional State

By means of a complex of cost-effective, rapid, and, whenever possible, computerized screening procedures, a systematic two-week study period of the functional states of subjects in a small group of healthy adults was performed. The daily variations of 125 parameters and periodic changes in 51 parameters of somatic and mental health were investigated at increasing doses of an adaptive drug. In the initial state of the subjects, various deviations of the somatic parameters from the normal level were found, presumably of a nutritional origin. The adaptive drug was found to normalize the changed parameters of somatic health within a week due to a strain in the regulatory systems and a decline in the functional reserves of adaptation. At the end of the examination, excessive doses of the adaptive drug returned the majority of the somatic parameters to the initial levels. At the same time, the work capacity of the subjects decreased and the strain on the autonomic nervous system and the level of stress increased. Discomfort and fatigue developed, which restricted the abilities of the examined subjects to choose behavioral tactics.     

Consumption of drugs for sea lice infestations in Norwegian fish farms: methods for assessment of treatment patterns and treatment rate

Sea lice are a major problem in Norwegian fish farms; however, data on drug treatment patterns or treatment rates of sea lice infestations are not available. Such data are important for analysing resistance patterns against drugs used for such infestations. The main objective of the present study was to develop a method to estimate the treatment patterns and treatment rates for drugs used in the treatment against sea lice (Lepeophtheirus salmonis and Caligus elongatus) in farm salmonids by means of national sales statistics. Annual sales figures, as weight of active substances, were obtained from the drug wholesalers and the feed mills. The weight of active drug substances is not useful as a unit of measurement of drug use in an epidemiological context because it does not correct for dosage differences and number of repeat treatments. To correct for these factors, we introduced approved daily dose (ADD(farm fish)) and treatment course-doses(farm fish) kg(-1) live-weight fish. To express the drug treatment patterns, the biomass (in weight) of farm salmonids treated with 1 course of a drug were estimated. When measured as kg active substance, the quantities of drugs for the treatment of sea lice infestations declined by 98% during the study period (1989 to 2002) but this figure increased 5-fold when it was corrected for differences in dosage. To correct for amounts of farm salmonids liable to require treatment we estimated the annual treatment rate, defined as the number of treatments for sea lice infestations per biomass slaughtered Atlantic salmon Salmo salar and rainbow trout Oncorhynchus mykiss. The annual treatment rate increased gradually during the study period; however, it varied considerably (range 0.45 to 1.34, mean 0.90). Before 1995, organophosphates were the most frequently used drugs against sea lice; since then pyrethroids have become the dominating drug group.     

Changes in thyroid function caused by continuous treatment with thiouracil in rats

Serum concentration evolution of thyroxine and triiodothyronine, and thyrotropin (TSH), have been studied in rats while they were given 6-propylthiouracil (PTU) as antithyroid drug, and during the recovery period after suppression of treatment. In the same way thyroid hypertrophy and plasmatic levels of thyrotropin were correlated. Animals received orally a daily dose of 1 mg/100 g body weight during thirty-five days and had a two week recovery period. Thyroid hormone concentrations in plasma were determined by immunoenzymatic assay ELISA with peroxidase as labelled enzyme. From the results obtained, it can be stated that chronic administration of PTU implies a continuous decrease in thyroid hormone concentrations in plasma, reaching nearly zero values, while after treatment, levels recover their normal values in a week's time. A parallelism exists between thyroid hypertrophy and pituitary TSH hypersecretion, due to a decrease in thyroid hormone levels.     

The Effect of Phenothiazines on the Electrocardiogram

Thioridazine, chlorpromazine and trifluoperazine were administered to six psychiatric patients. Each was used in four dosage levels (thioridazine and chlorpromazine: 200, 400, 800 and 1200 mg. daily; trifluoperazine: 8, 16, 32, 64 mg. daily); and each increase in dosage was effected after four days of drug administration.Before the trial, twice during each drug period and before commencement of the next dose regimen, an electrocardiogram (ECG) was recorded. The findings indicated that thioridazine modifies the terminal portion (S-T segment, T and U waves) of the human ECG. A similar change occurred in three of six subjects while taking chlorpromazine and in one of six while taking trifluoperazine. Thioridazine induced changes in all six subjects studied, viz., blunting and notching of T waves with or without prolongation of QT interval. In some the notching produced a doublehump appearance in which a T wave of reduced voltage formed the proximal hump and a positive U wave of increased voltage formed the distal hump.Thioridazine-induced alterations in the ECG have been described as resembling those caused by quinidine; they also resemble changes associated with hypokalemia.     

Lack of Potentiation by Chlordiazepoxide (Librium) of Depression or Excitation due to Alcohol

A double-blind study was completed comparing the interaction of chlordiazepoxide (Librium), 10 mg. given three times for one day, and 6 oz. of Canadian rye whiskey given over a three-hour period in the evening of the same day. The comparison drug was a placebo. Four evening experiments were conducted using the same six normal subjects and two observers. At the end of the evening, the observers were unable to detect which subjects had had placebo or chlordiazepoxide. It was concluded that chlordiazepoxide, given in this recommended daily dose, did not potentiate what was considered a social quantity of alcohol.