Tobacco and Alcohol Use and Medical Symptoms Among Cocaine Dependent Patients

Despite the widespread use of tobacco and alcohol by illicit drug users, the medical effects of smoking and alcohol use remain understudied among such individuals. We investigated the relationship between smoking and alcohol use, and medical symptoms among 125 cocaine dependent patients. Subjects were assessed for smoking, alcohol use, and medical problems using a standardized self-report instrument (MILCOM). Medical symptoms were compared among nonsmokers, moderate smokers (less than 10 cigarettes per day), and heavy smokers (10 or more cigarettes per day) using partial chi-square statistics. Similar comparisons of medical symptoms were made between alcohol users (more than 2 drinks per day) and nonusers. Contrary to our expectations, there were no significant differences between nonsmokers, moderate smokers, and heavy smokers across most of the 14 major medical systems. However, regardless of the level of cocaine use, nonsmokers reported the fewest symptoms on the general subscale (p < 0.05) while moderate smokers reported the most nose/throat and respiratory symptoms (p < 0.01) among the three groups. As expected, significant relationships were observed between medical symptoms and alcohol use. Alcohol users reported more respiratory (p < 0.05), cardiovascular (p < 0.01), digestive (p < 0.05), head/neck (p < 0.001), eye (p < 0.01), and general (p < 0.05) symptoms than nonusers. While the findings generally support the link between alcohol and medical problems, it seems that the relationship between medical symptoms and smoking among cocaine patients may be more complex than that observed in the general population.     

The metabolic effects of dopamine in man

Summary The metabolic effects of dopamine have been investigated by its infusion in normal man with and without simultaneous somatostatin administration. Dopamine was infused into overnight fasted men at 1.5 µg/kg/min (n=6) and 3.0 µg/kg/min (n=5) for 120 min. Plasma dopamine concentrations at 120 min were 78±9 nmol/l and 117±17 nmol/l respectively, associated with a marginal rise in plasma noradrenaline. Dopamine (1.5 µg/kg/min) induced an early and sustained rise in plasma glucagon (48±9 pg/ml versus 19±6 pg/ml in saline controls at 10 min, p<0.01)and a transient elevation in serum growth hormone which peaked to 17.7 (range 4.5–71.8)mU/l at 60 min (7.2 (range 0.6–37.7) mU/l with saline, p<0.05), but did not alter serum insulin, blood glucose or other metabolite levels. At 3.0 µg/kg/min, dopamine in addition provoked mild and transient elevations in blood glucose and serum insulin. Somatostatin (250 µg/h) suppressed circulating insulin, glucagon, and growth hormone levels and abolished the small hyperglycaemic effect seen with the higher dopamine dose. Somatostatin alone induced a progressive rise in circulating non-esterified fatty acid and 3-hydroxybutyrate levels reflecting insulin deficiency. This rise in NEFA and 3-hydroxybutyrate was increased by dopamine particularly at the higher dosage (plasma NEFA; somatostatin alone, 1.08±0.13 mmol/l; somatostatin plus dopamine 3 µg/kg/min, 1.44±0.17 mmol/l at 120 min, p<0.01: blood 3-hydroxybutyrate; somatostatin alone, 0.32±0.04 mmol/l; somatostatin plus dopamine 3 µg/kg/min, 0.56±0.12 mmol/l at 120 min, p<0.05). Thus: 1) dopamine at pharmacological dosage has minor effects when other endocrine mechanisms are intact, 2) it enhances lipolysis and ketogenesis during somatostatin-induced insulin deficiency, 3) the hyperglycaemic effect of the higher dopamine dose is probably mediated through stimulated glucagon secretion.     

Individualized aminophylline therapy in patients with obstructive airway disease: Oral dosage prediction from an intravenous test dose

Summary Theophylline disposition after an intravenous test dose of aminophylline was determined in 83 subjects: 7 patients with and 58 without congestive heart failure (CHF), and 18 healthy controls. Based on the pharmacokinetics of theophylline in the individual, the oral dosage of aminophylline was scheduled to attain steady-state trough theophylline concentrations (C_pred) near the therapeutic margin. Significant differences in theophylline clearance with a relatively constant volume of distribution were observed between various groups divided by age, smoking habit and CHF; the significantly different (p<0.001) mean clearance values were: 0.042±0.0161/h/kg (mean ± SD) in patients without CHF (n=58) as opposed to 0.016±0.001 l/h/kg in patients with CHF(n=7), 0.038±0.013 l/h/kg in non-smokers (n=59) versus 0.054±0.015 l/h/kg in smoking subjects (n=17), and 0.030±0.010 l/h/kg in elderly (>60 years) non-smoking patients (n=7) versus 0.057±0.017 l/h/kg in smoking patients (n=5) aged 40 to 59 years. No gender-related difference was detected in theophylline disposition. For all subjects together (n=83), there was no significant correlation between age and clearance (r=-0.111, p>0.1). The multivariate analysis indicated that the overall variability in theophylline clearance was affected first by the smoking habit (t=4.960; p<0.001) and second by CHF (t=-3.052; p<0.001), but not by age (t=1.140) or by sex (t=0.069). 78% of the patients who did not have CHF required a daily dose of aminophylline of 600 to 900 mg, whereas a dose of 300 to 450 mg was the rule in patients with CHF. The measured steady-state minimum concentration (C_meas) ranged from 5.4 to 14.6 µg/ml (9.0±2.2 µg/ml: mean ± SD) which was in good agreement with the C_pred (5.6 to 13.6, 9.0±1.6 µg/ml) in all patients (n=60) who received the oral dose of aminophylline calculated from the test dose. The overall prediction error was -0.08±1.83 µg/ml (–1.42±19.90%); only 3 of 60 measurements were found to be outside±2 SD. It is concluded that using a test dose to individualize aminophylline therapy is likely to remain the most reliable means to assure the maximum therapeutic benefit in patients with airway obstruction.A preliminary account of this study was presented at the Eighth International Congress of Pharmacology, Tokyo, July 19–24, 1981     

Lower serum cytokine levels in smokers than nonsmokers with chronic schizophrenia on long-term treatment with antipsychotics

Objective  Schizophrenia is associated with various abnormalities in the immune system. Suppression of inflammatory cytokines by cigarette smoke is well-established. The purpose of this study was to determine any differences in cytokine profiles in smokers and nonsmokers with schizophrenia and whether there were any relationships among altered cytokine profiles and psychopathological symptoms. Materials and methods  Serum interleukin (IL)-2, IL-6, IL-8, and tumor necrosis factor (TNF)-α levels were measured in 96 male inpatients with DSM-IV schizophrenia: 66 smokers and 30 nonsmokers. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Results  The positive PANSS symptoms were lower in smokers than nonsmokers, while the negative symptoms were lower in those who smoked more cigarettes. Cytokine levels were positively correlated: IL-2 level with IL-6 and IL-6 with both IL-8 and TNF-α. Both IL-2 and IL-6, but not IL-8 or TNF-α, were significantly lower in smokers than nonsmokers (p < 0.002; p < 0.01). Lower IL-2 levels correlated with fewer negative symptoms and with smoking more cigarettes. Conclusions  The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be associated with nicotine-induced suppression of some inflammatory cytokines.     

Pharmacokinetics of N-desmethyldiazepam after a single oral dose of clorazepate: The effect of smoking

Summary The pharmacokinetics of N-desmethyl-diazepam was evaluated after oral administration of clorazepate 20 mg to 12 healthy male volunteers (6 smokers; 6 non-smokers), aged 23–29 years. Plasma levels of desmethyldiazepam were measured by gas liquid chromatography. The half life of elimination (t_1/2) was significantly longer in the non-smoking volunteers than in the smokers: 54.7±17.7 versus 29.8±9.9 h (p<0.05). Peak plasma concentrations (C_max) were higher in non-smokers than in smokers, 413±106 µg/l and 245±50 µg/l, respectively (p<0.05). The sedative effect of clorazepate was less severe in smokers than in non-smokers.     

Cimetidine-phenytoin interaction: Effect on serum phenytoin concentration and antipyrine test

Summary In a prospective study in nine patients the effects of phenytoin and of cimetidine (1000mg/day) + phenytoin on the antipyrine test and serum phenytoin concentrations were studied. Serum phenytoin increased from the steady state level of 5.7±1.3 mg/l to 9.1±1.4mg/l after three weeks on cimetidine (p<0.01), and fell to 5.8±1.2 mg/l within two weeks after withdrawal of cimetidine. The protein binding of phenytoin was not changed by cimetidine. After use of phenytoin for 2–4 months, antipyrine clearance increased from 0.67±0.06ml/min/kg to 1.61±0.22 ml/ min/kg, and antipyrine half-live fell from 10.9±1.3h to 4.5±0.6h as compared to the values before phenytoin treatment (p<0.01). After three weeks combined use of cimetidine and phenytoin, antipyrine clearance was decreased to 1.01±0.07 ml/min/kg and antipyrine half-life was prolonged to 6.1±0.5h, (p<0.01) compared to the values on phenytoin alone. The distribution volume of antipyrine was not affected by phenytoin nor by cimetidine + phenytoin. The half-life of cimetidine was 2.8±0.3h in the patients on longterm phenytoin treatment. There was a significant positive correlation (p<0.001) between the increase in serum phenytoin concentration and the prolongation of antipyrine half-life caused by cimetidine. Thus, cimetidine increases serum phenytoin concentration, very probably by inhibiting its metabolism. Care should be taken in the concomitant use of cimetidine and phenytoin, and the dose of phenytoin should be modified according to the clinical symptoms and serum phenytoin concentrations.Part of this work was presented at the Joint Meeting of the Scandinavian and German Pharmacological Societies, September 1980 [14]     

Pharmacokinetics of bacmecillinam and pivmecillinam in volunteers

Summary The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (±SD) peak levels of plasma mecillinam were 1.43±0.34, 2.73±0.43, and 4.62±1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38±0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21±0.19, 3.99±0.63, and 7.74±1.38 mg·h·l^–1 for bacmecillinam and 5.35±0.93 mg·h·l^–1 for pivmecillinam. The elimination half-lives were 0.8–1.1h for bacmecillinam and 0.7h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p<0.001), AUC (p<0.001) and urinary recovery (p<0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p<0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam.     

Paracetamol as a test drug to determine glucuronide formation in man. Effects of inducers and of smoking

Summary A simple, noninvasive procedure was developed to monitor glucuronidation and sulphation in patients using paracetamol as the test drug. Urinary paracetamol and its metabolites were determined by UV absorption and electrochemical detection after separation by HPLC. The metabolite to paracetamol ratio (M/P) was used as an approximation of the partial clearance due to metabolite formation. In 14 healthy volunteers, all nonsmokers without medication, M/P was 18±5 for glucuronides and 12±4 for sulphate esters. The test was validated in patients treated with enzyme inducers. In 10 patients with epilepsy given phenytoin 0.3 g/day, and in 10 patients with tuberculosis treated with rifampicin 0.6 g/day, the M/P value for glucuronidation was significantly increased to 41±11 and 35±7, respectively. In contrast, M/P values for sulphation were not significantly different from untreated controls. In 9 heavy smokers (about 40 cigarettes/day) M/P values for glucuronidation were also significantly increased to 33±11. However, in 4 moderate smokers (about 10 cigarettes/day) no significant increase was found. The results suggest that in man glucuronidation of paracetamol is inducible both by phenobarbital-and 3-methylcholanthrene-type inducers. Monitoring the ratios of various urinary paracetamol conjugates/paracetamol may be useful as a new tool for the evaluation of factors determining glucuronide and sulphate ester formation in man.     

Noninvasive measurement of smoking-associated N-ethyladenine and N-ethylguanine in human salivary DNA by stable isotope dilution nanoflow liquid chromatography–nanospray ionization tandem mass spectrometry

Evidence showed that ethylating agents are contained in cigarette smoke, which damage DNA producing ethylated DNA adducts, including N³-ethyladenine (3-EtAde) and N⁷-ethylguanine (7-EtGua). These two ethylpurines can be depurinated spontaneously and be repaired by enzymes and they have been detected in human urine. In this study, a highly specific and sensitive assay based on stable isotope dilution nanoflow liquid chromatography nanospray ionization tandem mass spectrometry (nanoLC–NSI/MS/MS) was used to measure 3-EtAde and 7-EtGua in human salivary DNA. These ethylpurines were released from DNA by neutral thermal hydrolysis and then enriched by a solid-phase extraction column before nanoLC–NSI/MS/MS analysis. The detection limits (S/N ≥ 3) of 3-EtA and 7-EtG were 15 fg (92 amol) and 10 fg (56 amol), respectively, injected on-column. The lower quantification limits of 3-EtAde and 7-EtGua were both 100 fg, i.e. 620 and 560 amol, respectively, corresponding to 9.4 and 8.6 adducts in 10⁹ normal nucleotides, respectively, starting with as little as 20 μg of DNA isolated from an average of 3 mL of saliva. The mean (±SD) levels of 3-EtAde in 15 smokers and 15 nonsmokers were 12.6 ± 7.0 and 9.7 ± 5.3 in 10⁸ normal nucleotides, respectively, while those of 7-EtGua were 14.1 ± 8.2 and 3.8 ± 2.8 in 10⁸ normal nucleotides in smokers and nonsmokers, respectively. Levels of 7-EtGua, but not 3-EtAde, were statistically significantly higher in smokers than in nonsmokers (p < 0.0001). Furthermore, salivary 7-EtGua levels are significantly correlated with the number of cigarettes smoked per day as well as with the smoking index. This highly specific and sensitive stable isotope dilution nanoLC–NSI/MS/MS assay might be feasible in measuring 7-EtGua in human salivary DNA as a noninvasive biomarker for DNA damage induced by cigarette smoking.     

Prizidilol (SK & F 92657), a new vasodilator with beta-blocking properties in the treatment of essential hypertension

Summary The antihypertensive effect of a new vasodilator with betablocking properties (SK & F 92657) was investigated in 10 patients with mild to moderate essential hypertension. After a mean treatment period of 26,5 weeks (6,5–49 weeks) blood pressure was significantly reduced, from 168±22/106±6 mmHg to 144±19/94±12 mmHg (p<0.05 and 0.025). The mean dose was 410 mg (100–700 mg). Heart rate decreased slightly from 77±12 to 70±8 beats/min. Plasma renin activity and plasma aldosterone showed only minor changes. Nausea, heavy dreams, facial and hand flushing and mild depression were reported as side effects. In most patients the symptoms disappeared without reduction in the dose. In one patient anaemia developed after 7 weeks and treatment with prizidilol was stopped. A slight but statistically significant decrease in haemoglobin concentration of 1.1±0.6 g/dl was observed in 5 of the 10 patients (p<0.02). Thus, a mean dose of prizidilol of 410±242 mg/day had a mean blood pressure lowering effect of 24/12 mmHg. In 7 of the 10 patients (70%) diastolic blood pressure could be reduced to 95 mmHg or less. However, the observed haematological side-effects should be carefully monitored in further studies and may limit the clinical use of prizidilol.     

Metabolic parameters after changing from hydrochlorothiazide to verapamil treatment in hypertension

Summary The effect of verapamil on different metabolic parameters has been studied after changing the treatment of hypertension from hydrochlorothiazide to verapamil monotherapy. Verapamil 80 to 160 mg b.i.d. was continued for 6 months. The antihypertensive efficacy of verapamil was comparable to that of hydrochlorothiazide. Plasma total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and free fatty acids did not change significantly after the change in treatment; serum total cholesterol, LDL-cholesterol and HDL-cholesterol were 7.28±1.80 (m±SD), 5.11±1.59 and 1.65±0.39 mmol/l at the end of the hydrochlorothiazide period and 7.10±1.92, 5.09±1.70 and 1.56±0.35 mmol/l at the end of the verapamil period, respectively. The only statistically significant differences were the increases in total and LDL-cholesterol after three months on verapamil as compared to the basal values before diuretic therapy. Marked changes were not observed in fasting blood glucose, insulin or C-peptide values. Serum uric acid concentration decreased significantly (p<0.001) from 326±66 to 252±53 mmol/l, and serum potassium level increased significantly (p<0.01) from 3.5±0.4 to 3.9±0.3 mmol/l, on verapamil as compared to the diuretic period. Serum calcium decreased from 2.45±0.10 to 2.37±0.08 mmol/l (p<0.01) and calcium excretion increased significantly (p<0.01) to 5.43±2.55 mmol/24 h during verapamil administration from the level of 3.56±2.78 mmol/24 h whilst on the diuretic.     

Anger,Smoking Behavior,and the Mediator Effects of Gender: An Investigation of Heavy and Moderate Smokers

Background: The existing literature suggests the presence of a possible relationship between high anger levels and smoking behavior; however, there are no available data highlighting possible differences between moderate and heavy smokers and the putative effect of gender on smoking behavior. Objectives: The aims of the current study were to assess the relationship among anger, depression, and anxiety and smoking patterns taking into account the possible mediator role of gender. Methods: 150 smokers and 50 nonsmokers volunteers were recruited from the staff of the University of Messina, Italy. The final sample consisted of 90 smokers, divided in 50 heavy smokers (HS: more than 40 cigarettes per day), 40 moderate smokers (MS: 10–30 cigarettes per day), and 42 nonsmokers (NS). All subjects were assessed by State-Trait Anger Expression Inventory-2, Self-Rating Depression Scale, and Self-Rating Anxiety Scale. Results: On anger, depression, and anxiety measures the HS group scored higher than MS and NS groups. HS showed higher than expected levels of trait-anger, a greater tendency to control anger reactions and to access to anger-management techniques. A moderate consumption of cigarettes (10–30 cigarettes per day) was not associated with negative emotions, as MS only showed higher than expected levels of state-anger. Cigarettes consumption was related to gender-specific anger features. Conclusions/Importance: Our study highlighted the importance of anger in smoking behavior and its related gender differences. Recognizing the link among anger, gender differences and smoking behavior could improve the knowledge for future-focused interventions on smoking cessation.     

Influence of mild thyroid dysfunction on antipyrine clearance and metabolite formation in man

Summary The salivary kinetics and rates of metabolite formation of antipyrine were studied in 6 hyperthyroid and 6 hypothyroid out-patients on 2 occasions, on admission and when T3 and T4 levels had returned to normal after treatment with carbimazole (hyperthyroidism) or l-thyroxine (hyperthyroidism). In hyperthyroidism the half-life of antipyrine was significantly shorter (p<0.05) than after recovery (9.3±1.0 versus 10.6±0.9 h). Hypothyroid patients showed a significantly longer elimination half-life before treatment than after recovery (12.7±2.6 versus 10.3±2.6 h). Antipyrine clearance in hyperthyroid patients was decreased after treatment from 2.7±0.3 to 2.4±0.3 l/h, and it was increased in hypothyroid patients from 2.1±0.4 to 2.5±0.5 l/h (p<0.05). The changes in clearances for the production of the antipyrine metabolites 4-hydroxyantipyrine (OHA), norantipyrine (NORA) and 3-hydroxy-methylantipyrine (HMA) were of the same order of magnitude as total antipyrine clearance, and no selectivity towards any of the metabolic pathways of antipyrine was apparent. Mild thyroid dysfunction seems to affect oxidative drug metabolizing enzyme activity in a non-selective manner and only to a small extent (10–30%). It is suggested that adjustment of the therapeutic regimens of various drugs in mild thyroid disease will only rarely by required on the basis of pharmacokinetic considerations.     

Longitudinal distribution of ozone absorption in the lung: Comparison of cigarette smokers and nonsmokers

In nonsmokers, ozone (O₃) is removed primarily by the epithelial lining fluid (ELF) of the conducting airways. We hypothesized that cigarette smokers, whose ELF antioxidant capacity may be limited by smoking, would remove less O₃ from their conducting airways than nonsmokers. We recruited 29 nonsmokers (17M, 12F) and 30 smokers (19M, 11F, 4 ± 4 pack-years) with similar anthropometric characteristics and measured the longitudinal distribution of O₃ using the bolus inhalation method. We also assessed the physiological effect of this transient exposure regimen using forced spirometry and capnography. Contrary to our hypothesis, the penetration volume at which 50% of a bolus was absorbed was not different between smokers and nonsmokers (97.1 ± 5.4 mL versus 97.9 ± 5.8 mL, p  = 0.92). However, smokers did experience an increase in the slope of the alveolar plateau of the capnogram (S_N) (8.1 ± 3.2%, p  = 0.02) and a small decrease in FEV₁ (− 1.3 ± 0.6%, p  = 0.03), whereas nonsmokers did not (ΔFEV₁ − 0.1 ± 0.5% and ΔS_N − 0.2 ± 2.5%, p  > 0.10). Thus, smokers are more sensitive to inhaled O₃ boluses than nonsmokers, despite a similar internal dose distribution.     

Cigarette smoking by women: interactions with alcohol use

Cigarette smoking increased during alcohol self-administration in comparison to an alcohol-free baseline in 24 women given access to alcohol for 21 days. Heavy smokers (25 or more cigarettes per day) increased smoking significantly during drinking (P<0.05). Analysis of tobacco smoking by level of alcohol consumption showed that both heavy and moderate alcohol users increased smoking significantly during alcohol availability (P<0.05, 0.01). The heavy and moderate smokers smoked significantly more between noon and midnight (P<0.001) than at other times when alcohol was available. The rate of cigarette smoking (defined by inter-cigarette intervals) was faster during alcohol self-administration than during the alcohol-free baseline. Heavy smokers smoked most cigarettes at intervals of 11–20 min during heavy or moderate drinking. During the pre-alcohol baseline, these women smoked most cigarettes at intervals of 21–30 or 31–40 min. Most women (70–74%) also increased tobacco smoking at the premenstruum. Both heavy and occasional smokers increased smoking at the premenstruum significantly more than the moderate smokers (P<0.05). All women reported increased psychological discomfort at the premenstruum on the Premenstrual Assessment Form (PAF) but reports of physical discomfort were more marked in women who smoked less at the premenstruum. These data extend previous findings in men that alcohol consumption is associated with increased cigarette smoking to female social drinkers.     

Hypotensive effects of diltiazem to normals and essential hypertensives

Summary The hypotensive effect of acute and long-term, intravenous and oral administration of the calcium antagonist, diltiazem, was investigated in 8 normotensive volunteers and 55 patients with essential hypertension. Diltiazem i.v. infusion of 45 mg/h (0.5 mg/min, then 1.0 mg/min, each for 30 min rapidly decreased both blood pressure (BP) from 164±22/98±8 to 144±15/86±9 mmHg (mean±SD) and total peripheral resistance from 32.6±8.4 to 25.3±5.4 mmHg/l/min (p<0.001), and increased stroke volume from 58.2±9.5 to 64.2±8.6 ml/beat (p<0.05). It altered neither heart rate nor cardiac output in the hypertensives (n=10). Oral diltiazem 60 mg rapidly decreased BP from 155±10/103±6 to 142±12/90±8 mmHg after 3 hours (p<0.01/p<0.001) in hypertensives (n=8), but not in normotensives (n=8). Diltiazem 90 mg p.o. decreased BP from 157±15/102±9 to 129±13/83±8 mmHg (p<0.01) in hypertensives (n=15), and reduced the heart rate from 71±8 to 65±8 beats/min (p<0.01). The drug did not change plasma renin activity either in normotensives or hypertensives. The fall in diastolic BP was correlated with the plasma diltiazem concentration (r=0.910, n=6, p<0.05). Long-term treatment with diltiazem 30mg t.d.s. decreased BP from 163±12/104±8 to 145±9/88±9 mmHg (p<0.001, n=13), and 60mg t.d.s. decreased BP from 169±15/102±6 to 148±13/87±8 mmHg (p<0.001, n=8), and significantly reduced the heart rate (p<0.01) in hypertensives. Thus, the hypotensive action of diltiazem, which is due to arterial dilatation, is effective, either on intravenous or oral administration, during acute and long-term treatment of essential hypertension.     

The effects of long term administration of dopamine on renal function in hypertensive patients

Summary The effect of an intravenous infusion of dopamine (0.5 to 1.25 µg/kg/min) for periods of between 36 and 105h has been studied in eight patients with hypertension and varying degrees of renal impairment. There was a significant rise in the glomerular filtration rate (GFR) from 31.2±20.2 to 42.8±26.8 ml/min (p<.05) after four hours of the infusion but after 48 h of infusion the mean GFR was no different from the control value. The paraaminohippuric acid (PAH) clearance also rose from 129.8±115.4 ml/min to 173.1±164.3 ml/min (p<0.05) after four hours of infusion, but like the GFR it was no different from control after 48 h of the infusion. The daily urine volumes increased significantly during the dopamine infusion from 2176.0±49.2 ml/day to 3809.0±118.8 ml/day (p<0.002) but had returned to control values after 48 h of continuing dopamine infusion. Following the end of the infusion there was a significant reduction in the urine volume to 1213.0±195.0 ml/day (p<0.001). There was a rise in sodium excretion during the dopamine infusion from 94.8±50.7 meq/day to 264.7±172.8 meq/day (p<0.01) with a fall after the end of the infusion to 33.2±27.5 meq/day (p<0.05). There was no change in the blood urea during the dopamine infusion but after stopping the infusion the blood urea rose from 83.5±39.4 mg% to 95.1±39.0 mg% (p<0.02). We conclude that intravenous infusion of dopamine to patients with hypertension and renal impairment may produce initial clinical improvement but is of little therapeutic benefit when given for prolonged periods.     

Kinetics of phenobarbital in normal subjects and epileptic patients

Summary The kinetics of phenobarbital (PB) were evaluated in six normal subjects and six epileptic patients treated with phenytoin or carbamazepine. Each normal subject received three single doses of PB: PB-sodium 130 mg i.v. (IV), PB sodium 130 mg i.m. (IM), and PB acid 100 mg orally (PO), in random order at least one month apart. After IV PB distributive half-lives varied from 0.13 to 0.70 h, disposition half-lives were 75 to 126 h, steady state volume of distribution (V_ss) was 0.54±0.03 l/kg, and clearance (CL) was 3.8±0.77 ml/h/kg. Absolute bioavailability of IM PB was 101±13%, of PO PB (corrected for dose) 100±11%. Peak serum PB concentrations were achieved from 2 to 8 h after IM administration, and from 0.5 to 4 h after PO administration. Epileptic patients exhibited similar PB kinetics: disposition half-lives were 77 to 128 h, V_ss 0.61±0.05 l/kg, and Cl 3.9±0.76 ml/h/kg. Phenobarbital appears to represent an exception among antiepileptic drugs, in that pharmacokinetic data obtained in normals can reasonably be extrapolated to the epileptic population.     

Correlation between self-reported smoking status and serum cotinine during pregnancy

Maternal smoking is associated with adverse perinatal outcomes. Because of concerns of underreporting, investigators routinely perform biochemical testing to confirm smoking status, such as serum cotinine, a major metabolite of nicotine, adding an increased cost to examine compliance. The objectives of this study were to determine the sensitivity and specificity of self-reported smoking with serum cotinine as the gold standard and to determine the correlation between self-reported smoking in cigarettes per day and serum cotinine levels. In this cross-sectional study, we surveyed women during the first trimester of pregnancy on their tobacco exposure. A total of 40 women reported that they were smokers, and 40 were nonsmokers, 1 of whom had quit 5 days prior. The mean (+/-S.D.) serum cotinine value among smokers was 155 (+/-122) ng/l, vs. 1 (+/-6) ng/l in nonsmokers, p<0.001. The sensitivity of self-reported smoking status was 97.6%, and the specificity was 100%. Comparing the reported number of cigarettes smoked and the serum cotinine level, the Spearman correlation coefficient was 0.92 (p=0.015) overall and 0.67 (p=0.088) for the subgroup of smokers. This study demonstrates that self-reported smoking exposure during pregnancy is highly accurate. The high correlation coefficient suggests that this is a robust surrogate for cotinine levels.     

Monocyte and neutrophil direct counts correlate with C-reactive protein plasma concentration in patients with acute pancreatitis

Acute pancreatitis (AP) is associated with the intensive inflammatory response in white blood cells (WBC) and C-reactive protein (CRP). This paper presents the relationship between the CRP plasma concentration and the direct counts of peripheral WBC in AP during the initial five days. The study consisted of 56 patients with AP, 36 patients with mild form of AP and 20 patients with severe form of AP. ABX VegaRetic hematological analyzer was used to perform the count of blood cells, and the immunonephelometric method was performed to measure the CRP concentration levels. AP patients presented with WBC count values in the range of 3.2 − 22.4 × 10³/μl and CRP concentration levels in the range 3.3 − 599.8 mg/l. The WBC count correlates with CRP levels during the entire observation period. The relationship of CRP and WBC is expressed in the following regression equation: WBC (10³/μl) = 3.66 + 1.40 × log_eCRP (mg/l). The highest median neutrophil count (8.15 × 10³/μl) was observed on the first day. The count decreased to 5.27 × 10³/μl on the fifth day. The most substantial finding in this study involved the values found for the monocytes and CRP (r= 0.53; p<0.001). Day two and day three were the highest (r=0.59, p<0.001). On day two, the regression equation for this relationship is: Monocytes (10³/μl) = −0.34 + 0.21 × log_eCRP(mg/l). The correlation between direct monocyte count and plasma CRP concentration in AP reflect a CRP-dependent stimulation of IL-6 release from activated blood monocytes.