Rapid pituitary and peripheral tissue responses to intravenous L-triiodothyronine in hypothyroidism.

Acute cardiovascular, renal, pulmonary, metabolic, and pituitary responses to therapy of hypothyroidism with 25 micrograms iv T3 (group I G-I, n = 11) or 50 micrograms iv T3 (group II, G-II, n = 10)/day for 1 week have been studied. Serum T3 levels were acutely normalized in both groups with the mean basal serum T3 levels (X +/- SE) after 7 days, 98 +/- 10 micrograms/dl and 229 +/- 19 ng/dl, respectively. Myocardial performance, noninvasively assessed by the pulse wave arrival time (QKd) and the phonocardiographic systolic time interval ratio was significantly altered after 1 day of therapy (QKd for G-I = -10 +/- 4 msec, P less than 0.05; and for G-II = -18 +/- 14 msec, P less than 0.01). After 7 treatment days, both the mean QKd (203 +/- 7 msec, P less than 0.001) and phonocardiographic systolic time interval ratio (0.41 +/- 0.02, P less than 0.01) were within the normal range in G-II. Abnormal pretreatment renal excretion of an oral water load (G-I, 65 +/- 6%; and G-II, 57 +/- 6%) was also reversed after 1 week (G-I, 84 +/- 5%, P less than 0.05; and G-II, 89 +/- 5%, P less than 0.01). Patients with blunted hypercapnic (n = 6) and hypoxic (n = 4) ventilatory drives were improved in both groups after 6 days. The mean basal metabolic rate, serum cholesterol, and serum creatine phosphokinase were altered by the week of therapy in a dose-response manner, and were in the normal range in G-II. Pituitary TSH secretion was promptly suppressed in both groups. Two hours after the first T3 dose, the mean serum TSH for G-I and G-II decreased to 85% (P less than 0.02) and 70% (P less than 0.001) of their respective pretreatment values. After 7 days of therapy, the mean basal TSH levels had declined to 75% (P less than 0.001) and 5% (P less than 0.001%) of pretreatment, respectively. In comparison with previous observations of responses to 100 micrograms/day iv T4 for 1 week, the 25 micrograms dose T3 was equivalent in terms of changes in basal serum T3 and peripheral (nonpituitary) tissue responses, but less effective than T4 in lowering serum TSH. Based on these parameters, 50 micrograms/day iv T3 was the most effective of the three regimens within this time frame. The implications of these observations in the clinical management of severe complicated myxedema are discussed.

Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone.

Plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined after administration of 20 mg oral controlled-release oxycodone tablets to four subject groups: young (aged 21 to 45 years) men, elderly (aged 65 to 79 years) men, young women, and elderly women. Area under the oxycodone and noroxycodone concentration-time curve (AUC) values were comparable among the four groups. Compared with oxycodone, the oxymorphone AUC values were small, with significant differences between subject groups. AUC values were also calculated for the pharmacodynamic variable "drug effect," scored on a 100 mm visual analog scale. The two groups with the highest oxycodone AUC values (young and elderly women) had the lowest oxymorphone AUC values and the greatest drug effect AUC values. The two groups with the lowest oxycodone AUC values (young and elderly men) had the highest oxymorphone AUC values and the lowest drug effect AUC values. These results support oxycodone, and not oxymorphone, as being primarily responsible for pharmacodynamic and analgesic effects.

Analgesic efficacy and potency of two oral controlled-release morphine preparations.

MS Contin tablets and Oramorph SR tablets are two forms of oral controlled-release morphine sulfate available for the alleviation of pain. Our objective was to compare their analgesic effects in a relative potency assay. In this study, 151 patients undergoing caesarean section or abdominal hysterectomy and reporting moderate or severe postoperative pain received a 30 or 90 mg dose of either drug in a balanced, randomized, double-blind, parallel-group, single-dose experimental design. Patients provided self-ratings of analgesia. Relative potency for pain relief were calculated from log dose-effect curves. For total pain relief (rated by visual analog scales) over 12 hours, the log dose relative potency estimate for MS Contin tablets/Oramorph SR tablets was 1.9 (95% confidence limits, 0.89 to 11.1); for peak pain relief (visual analog scales) the relative potency estimate was 1.7 (95% confidence limits, 0.65 to 48.3). Overall, the 90 mg dose of MS Contin was more effective than 30 or 90 mg doses of Oramorph SR and the 30 mg dose of MS Contin at hours 6 to 12. Adverse experiences (mainly drowsiness) were mostly mild to moderate, with no significant differences in their overall incidence or severity between equivalent doses. MS Contin tablets provided greater peak, total, and duration of analgesia, without higher incidence of adverse experiences.

The impact of grief on ventilatory control.

The authors studied ventilatory control in four parents grieving over the death of an infant. Abnormalities in respiratory control were common and resembled those previously reported in depressed patients. The results raise questions about the relationship between affective state and ventilatory control.

Pulmonary dysfunction in cocaine smokers.

The authors report another complication of freebase cocaine smoking. They found a significant reduction in the carbon monoxide diffusing capacity in the lungs of two patients. This suggests that inhalation of the freebase of cocaine may damage the pulmonary gas exchange surface.

Prediction and reversal of blunted ventilatory responsiveness in patients with hypothyroidism.

To define the prevalence of impaired ventilatory responses in hypothyroidism, clinical and chemical parameters predicting their presence, and the potential for their acute reversal, ventilatory responses to hypercapnia and hypoxia were studied in 38 hypothyroid patients before treatment, and after short-term (seven days) and long-term (12 to 24 weeks) thyroid hormone therapy. Before treatment, hypercapnic ventilatory responses were blunted in 10 of 29 patients (34 percent), whereas hypoxic ventilatory responses were abnormal in eight of 30 patients (27 percent). Hypothyroid women and patients with marked pretreatment elevation of the serum thyrotropin concentration (greater than 90 mU/liter) were significantly more likely to have impaired ventilatory responses. In patients with an abnormal pretreatment response, parenteral thyroid hormone therapy (25 to 50 micrograms of L-triiodothyronine or 100 micrograms of L-thyroxine per day for seven days) significantly enhanced hypercapnic (0.75 +/- 0.06 to 1.19 +/- 0.16 liters/minute/mm Hg, p less than 0.05) and hypoxic (93 +/- 12 to 176 +/- 31 liters.mm Hg/minute, p less than 0.05) ventilatory responsiveness acutely. In seven of nine patients with abnormal pretreatment hypercapnic responses, and six of eight patients with abnormal hypoxic responses, normal ventilatory responsiveness was restored after one week of therapy. It is concluded that: (1) a subset of hypothyroid patients have blunted ventilatory responses to hypercapnia and/or hypoxia; (2) hypothyroid women and patients with a serum thyrotropin greater than 90 mU/liter more often manifest this abnormality; and (3) thyroid hormone therapy for one week reverses impaired ventilatory responses in hypothyroidism.

Early peripheral responses to intravenous L-thyroxine in primary hypothyroidism.

The metabolic, cardiovascular, renal, and pulmonary responses of 10 hypothyroid patients were studied during the first week of therapy with intravenous levothyroxine (L-thyroxine), 100 micrograms per day. Mean serum thyroxine, triiodothyronine, and reverse triiodothyronine concentrations were normalized within four days. Significant decreases in serum thyrotropin, creatine phosphokinase, and cholesterol levels, and an increase in the basal metabolic rate, were observed. An early cardiovascular response was demonstrated by serial measurement of the mean pre-ejection period (138 to 134 msec, p less than 0.05), its ratio to left ventricular ejection time (0.49 to 0.46, p less than 0.02), and pulse-wave arrival time (236 to 224 msec, p less than 0.05). The mean renal excretion of a water load (four hours) increased (54 to 77 percent, p less than 0.02) by the fourth day. The blunted ventilatory responses to hypercapnea seen in two patients were improved. We conclude that a physiologic replacement dose of intravenous L-thyroxine for one week produces significant responses in organ systems responsible for the common clinical complications of myxedema.

Marijuana smoking as cause of reduction in single-breath carbon monoxide diffusing capacity.

To investigate the effects of chronic marijuana smoking on lung function, pulmonary function tests including single-breath carbon monoxide diffusing capacities were performed in 15 healthy women who smoked 1.7 +/- 1.4 (mean +/- SD) marijuana cigarettes per day for 235 +/- 135 days per year for a mean of 10.5 +/- 3.7 years. Control groups included 27 nonsmoking and 26 tobacco-smoking women. Results revealed that marijuana smoking with or without tobacco is associated with a reduction in the single-breath carbon monoxide diffusing capacity to 74 +/- 20 percent of predicted, which was significantly different from that in the nonsmoking control subjects (92 +/- 11 percent; p less than 0.05). The subset of subjects who smoked marijuana and tobacco had a further reduction of the single-breath carbon monoxide diffusing capacity to 65 +/- 17 percent, which was significantly different from that in both nonsmoking and smoking control subjects (80 +/- 7 percent). These results suggest that heavy marijuana smoking when added to tobacco smoking may damage the gas exchange surface of the lung.

Steady-state pharmacokinetics of controlled release oral morphine sulphate in healthy subjects.

The pharmacokinetics of oral morphine sulphate as controlled release tablets ('MS-Contin') and solution were compared at steady-state. Plasma morphine concentrations were determined over 24 hours following the last dose of each drug when given in a randomised, crossover fashion to healthy subjects. Radioimmunoassay was used, which was sensitive yet provided good specificity relative to high-performance liquid chromatography. Controlled release tablets had 86% the bioavailability of the solution. Although each dose of controlled release tablets was double that of the solution, their peak plasma concentrations were the same. Time to maximum concentration was 3 times longer for controlled release tablets with an absorption half-life twice that of the solution. Elimination of both drugs was similar and biphasic with the minor terminal portion at 10 times the half-life of the major early process. These data explain the analgesic duration of 12 hours observed in clinical studies and the lack of accumulation with morphine compared with methadone.

Pulmonary function in normal subjects and patients with sarcoidosis after bronchoalveolar lavage.

To determine if fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage impairs pulmonary function in normal subjects or those with sarcoidosis, we measured flow-volume loops, thoracic gas volume, and single breath carbon monoxide diffusing capacity before, one half hour and 24 hours after lavage. We studied 12 normal subjects; six underwent a large volume lavage (approximately 500 ml saline instilled), and six underwent a small volume lavage (approximately 175 ml). Five subjects with sarcoidosis also had a small volume lavage. Six control subjects underwent FOB without lavage. The FOB alone produced no significant changes in pulmonary function one half hour after the procedure. Small volume lavage in normal subjects produced no change except for a 16.3 +/- 5.1 percent (mean- +/- SEM) decline in peak expiratory flow rate (p less than .05) one half hour postlavage which returned to normal by 24 hours. This contrasts with sarcoidosis subjects in whom forced expiratory volume in one second, peak expiratory flow rate, and vital capacity declined by 20 +/- 4.8 percent, 26.7 +/- 7.3 percent, and 15.2 +/- 4.1 percent, respectively, (all p less than 0.05) one half hour postlavage. No change occurred in total lung capacity or diffusing capacity. Only with large volume lavage did decrements in lung function occur in normal patients that were comparable to those seen in the sarcoidosis subjects. Our findings suggest that bronchoalveolar lavage in normal patients can be associated with a significant and volume-related decline in pulmonary function and that in subjects with sarcoidosis, the deterioration is more pronounced.

Chronotherapy of reversible airways disease with once-daily evening doses of a controlled-release theophylline preparation.

1. Asthma and COPD worsen at night and in the early morning, due to various circadian influences. 2. Uninterrupted sleep, stable lung function over 24 h, and reduced and stable airways responsiveness are primary therapeutic goals in asthma and COPD. 3. Once-daily evening theophylline chronotherapy meets these goals, providing rising blood levels at night and in the early morning, when most needed. 4. This regimen is now indicated for morning and evening dosing for reversible airway obstruction, in the United States and Canada, and marks the first available treatment for these diseases to include dosing time in the therapeutic strategy. It reflects increasing recognition by the medical community of the need to consider the individual patient's timing of symptoms in relation to the kinetics of the drug. 5. Theophylline chronotherapy is as well tolerated as more frequently administered methylxanthine preparations despite the relatively large single doses required by the prolonged dosing interval. The convenience of once-daily administration favors drug-taking compliance. 6. Theophylline chronotherapy does not provide constant blood levels over the 24-h day. Indeed, by improving lung function by means of a larger peak-to-trough difference than associated with twice-daily theophylline, once-daily chronotherapy has altered our thinking about theophylline pharmacodynamics.

A bioequivalence study of oral controlled-release morphine using naltrexone blockade.

Twenty-three normal volunteers who received morphine sulphate (MS Contin) with naltrexone completed this randomized, analytically blinded, two-way crossover comparison of the bioavailability of one 200-mg oral controlled-release morphine sulfate tablet with two 100-mg MSC tablets. Morphine effects were blocked by three 100-mg doses of naltrexone. The first dose of naltrexone was given 24 hours before MSC dosing, followed by a second dose at the time of MSC dosing and a third dose 24 hours after MSC administration. Compared with two 100-mg MSC tablets, the 200-mg tablet was 96% bioavailable (90% confidence interval, 88.14-105.74%). The 90% confidence intervals for mean Cmax and AUC0-24 for one 200-mg MSC tablet were within +/- 20% of the Cmax and AUC0-24 of two 100-mg tablets, indicating the two dosage forms are bioequivalent. Single 200-mg doses of MSC given with the naltrexone blockade were generally well tolerated, and adverse effects were similar to those reported for naltrexone alone and for lower doses of morphine without naltrexone. Naltrexone proved safe and effective in blocking the effects of controlled-release morphine, permitting bioequivalence studies of a high dose of morphine in normal volunteers.

Analgesic efficacy of controlled-release oxycodone in postoperative pain.

The efficacy and safety of graded doses (10, 20, and 30 mg) of controlled-release (CR) oxycodone was compared with that of immediate-release (IR) oxycodone (15 mg), immediate-release oxycodone 10 mg in combination with acetaminophen 650 mg (APAP), and placebo in a single-dose, double-blind, randomized, parallel-group study. The participants, 182 inpatients experiencing moderate to severe pain after abdominal or gynecologic surgery, provided hourly ratings of pain intensity and relief for 12 hours after administration. All active treatments were significantly superior to placebo for many hourly measurements and for the sum of pain intensity differences (SPID) and total pain relief (TOTPAR). A dose response was found among the three levels of CR oxycodone for pain relief and peak pain intensity difference (PID), with the 20- and 30-mg doses being significantly better than the 10-mg dose. For all active treatments, peak PID and peak pain relief occurred approximately 2 to 4 hours after administration. The median time to onset of relief was 32 minutes for oxycodone plus APAP, 41 minutes for IR oxycodone, and 46 minutes for CR oxycodone 30 mg. Duration of pain relief showed that the 10-, 20-, and 30-mg doses of CR oxycodone had durations of action of 10 to 12 hours compared with IR oxycodone and oxycodone plus APAP (both approximately 7 hours). Typical adverse events, particularly somnolence, occurred in all active treatment groups. Treatment with CR oxycodone was safe and effective in this study, and its characteristics will be beneficial in the treatment of pain.

Decreased single breath carbon monoxide diffusing capacity in cocaine freebase smokers.

The authors performed pulmonary function tests on 10 chronic cocaine freebase smokers. Testing occurred at least 2 weeks after stopping cocaine use. Mean single breath carbon monoxide diffusing capacity (DLCOSB) was significantly reduced (P less than 0.05) in the cocaine smokers when compared with a control group of non-smokers and non-drug users. All other parameters of lung function were normal. Since most of the cocaine smokers also smoked tobacco, the observed abnormality may have been due to an additive effect of the 2 substances. The authors conclude that smoking cocaine may damage the gas exchange surface of the lung.

The bioavailability of morphine in controlled-release 30-mg tablets per rectum compared with immediate-release 30-mg rectal suppositories and controlled-release 30-mg oral tablets.

The bioavailability of controlled-release morphine 30-mg tablets (MSC) administered orally or rectally and immediate-release morphine (RMS) 30-mg suppositories per rectum, was compared in this 14-subject, randomized, single-dose, analytically blinded, crossover study. Rectal MSC plasma morphine area under the curve from 0-24 hours (AUC0-24) was 50.8% of RMS and was similar for MSC administered by either route (rectal MSC = 90% oral MSC). Rectal MSC had a significantly delayed time to peak plasma level (5.4 vs 1.07 and 2.5 hrs for rectal MSC vs RMS and oral MSC, respectively) and a significantly attenuated time to maximum concentration (6.1 vs 25.4 and 9.7 ng/ml, respectively). Proctoscopy 24 hours after insertion revealed seven instances of mild, transient mucosal erythema or edema with rectal MSC and 12 with RMS. The number of nonlocal adverse effects was 14 with rectal MSC, 19 with RMS, and 18 with oral MSC. Further studies must determine the therapeutic consequences of pharmacokinetic differences and establish guidelines for rectal MSC use. The product is currently not recommended by the manufacturer for rectal administration.

Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control?

Two separate trials compared controlled-release (CR) oral oxycodone (administered every 12 hours) with immediate-release (IR) oxycodone (4 times a day) to determine whether patients with chronic pain could be titrated to stable pain control as readily with the CR as with the IR formulation. In one study, 48 patients with cancer pain were randomized to open-label titration with either CR or IR oxycodone (maximum dose, 400 mg/day) for a period of up to 21 days. In a study of similar design, 57 patients with low back pain were titrated with either CR or IR oxycodone (maximum dose, 80 mg/day) for a period of up to 10 days. The majority of patients in both studies were converted to oxycodone from other opioid analgesics. Results of both studies showed no difference between CR and IR oxycodone with respect to both the percentage of patients achieving stable pain control, the time to achieve stable pain control, and the degree of pain control achieved. Among cancer patients, 85% achieved stable analgesia, 92% with the CR formulation and 79% with the IR formulation. Among noncancer patients, 91% achieved stable pain control, 87% with the CR formulation and 96% with the IR formulation. The most commonly reported adverse effects in both studies were similar for the two formulations and were those anticipated with opioids: nausea, vomiting, constipation, somnolence, dizziness, and pruritus. Nausea and vomiting were the most frequently cited reasons for treatment discontinuations. These studies suggest that dose titration can be accomplished as readily with oral CR oxycodone as with IR oxycodone in patients with chronic, moderate to severe pain.

Treatment of asthma by a controlled-release theophylline tablet formulation: a review of the North American experience with nocturnal dosing.

As many as 80 percent of asthmatics experience nighttime or early-morning episodes, which are difficult to treat and potentially fatal. The greater-than-normal amplitude of circadian airflow variation in many asthmatics contributes heavily to the genesis of the early 'morning dip'. Beta-agonists and corticosteroids are of limited usefulness in nocturnal asthma, and slow-release theophylline drugs, while potentially effective, vary in 24-hr blood profile and hence their influence on nocturnal episodes. Traditional 12-hr 'symmetric' theophylline regimens, instead of meeting increased nocturnal demands, may actually produce lower night- than daytime blood levels. On the other hand, appropriately timed administration of a once-daily theophylline drug might provide maximum blood levels when needed and help stabilize 24-hr airflow. Accumulated data, summarized in this review, demonstrate the chronotherapeutic potential of single-daily evening doses of a controlled-release theophylline preparation (Uniphyl 400-mg tablets) in nocturnal and early morning asthma. Nighttime blood concentrations with this regimen were higher than were those with Theo-Dur tablets, B.I.D., in the same total daily doses, or with once-daily morning Uniphyl administration. In fed and fasted subjects, evening administration of Uniphyl 400-mg tablets was well tolerated and did not lead to 'dose dumping.' Clinically, this treatment demonstrated advantages over B.I.D. theophylline, over single-daily morning regimens, and over prior theophylline therapy. Advantages of the evening regimen included better early-morning airflow (without significant decline later in the day), more effective symptom control, better patient acceptance, fewer night awakenings, and the obvious convenience of once-daily dosing. In addition, lung function showed greater stability, throughout the day, with once-daily evening therapy than with traditional 12 hr dosing. Uniphyl 400-mg tablets may be administered once daily to provide maximum blood levels at the time of peak bronchoconstriction, whether at night or during the day.

Relative bioavailability of controlled-release oral morphine sulfate during naltrexone blockade.

The effect of naltrexone hydrochloride on the bioavailability of 60 mg controlled-release oral morphine sulfate in normal volunteers was determined using a randomized, 2-way crossover, analytically blinded study design. Although naltrexone did not qualitatively alter the concentration-time curve for controlled-release morphine, the area under the plasma morphine concentration-time curve from 0-24 h (AUC0-24) was significantly greater (p < 0.01) for morphine given with naltrexone (265 ng x h/ml) than for morphine given alone (215 ng x h/ml). Compared to morphine given alone, the apparent absorption half-life of morphine was decreased from 0.94-0.58 h (p = 0.01) and Cmax was increased from 28.17 ng/ml to 32.26 ng/ml (p = 0.04) during naltrexone blockade, whereas the Tmax and apparent elimination half-life of morphine were not significantly affected. The minimal differences in morphine bioavailability indicate naltrexone may be useful in comparative bioavailability studies of high-dose opioids in opioid-naive normal volunteers.

The effect of povidone-iodine solutions used as surgical preparations on the bacterial flora of the skin.

One hundred fifty hospitalized patients undergoing elective surgery were enrolled in an open study designed to assess the bactericidal and clinical efficacy of a preoperative skin preparation procedure--application of 7.5% povidone-iodine surgical scrub followed by 10% povidone-iodine antiseptic solution. Of 99 patients with bacterial colonization of the skin prior to surgery, 84 patients (85%) had no detectable levels of bacteria at completion of surgery; bacterial flora persisted after surgery in the remaining 15 patients (15%). The difference between pre- and post-surgical bacterial colonization was statistically significant (p = 0.004). Clinically, none of the 146 patients evaluable for analysis of efficacy developed infections at the incision or suture site and there were no incidents of skin irritation at the surgical site during the postoperative observation period. Thus, preoperative cleansing with povidone-iodine surgical scrub followed by povidone-iodine antiseptic solution is an effective, non-irritating bactericidal regimen for use at surgical incision sites.

Analgesic efficacy and safety of two oral controlled-release morphine preparations in orthopedic postoperative pain.

This single-dose, double-blind, randomized, parallel-group study compared the analgesic efficacy and safety of MS Contin (MSC) and Oramorph SR (OSR), two controlled-release preparations of oral morphine sulfate, in patients following orthopedic surgery. One hundred patients received MSC 30 mg, MSC 60 mg, or OSR 60 mg (two 30-mg tablets) when postoperative pain became moderate or severe. Patients self-rated pain intensity and relief on categorical (CAT) and visual analogue scales (VAS) hourly for up to 12 hours. MSC 60 mg produced the greatest peak analgesic effect and was more efficacious than OSR 60 mg through the sixth hour, with statistical significance achieved at 1, 2, and 3 hours postdosage. Compared with OSR 60 mg, both MSC dosages provided significantly more rapid times to peak effect by CAT and VAS ratings. The OSR group experienced almost twice as many adverse events as did the two MSC groups and also reported somnolence and dizziness more frequently. MSC 60 mg provided more rapid and greater peak analgesia with fewer adverse effects than did OSR 60 mg.