Paul Goldenheim

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 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.

T-lymphocyte subsets in peripheral blood and lung lavage in idiopathic pulmonary fibrosis and sarcoidosis: Analysis by monoclonal antibodies and flow cytometry

Abstract Thymus-dependent (T) lymphocytes may contribute to the pathogenesis of human interstitial lung disease. In order to determine whether alterations of immunoregulatory T cells occur in patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis, we characterized T lymphocytes in peripheral blood (n = 8 and 11, respectively) and lung lavage (n = 4 and 6, respectively) in untreated patients with these diseases. In IPF, we found a decreased percentage, but normal total count of circulating OKT3+ (mature) and OKT4+ (inducer/helper) cells compared to normal controls. We observed a normal percentage and total count of circulating OKT8+ (cytotoxic/suppressor) cells. The ratio of OKT4+ to OKT8+ ( 4 8 ) lymphocytes, reflecting the balance of immunoregulatory cells, was normal in peripheral blood. Comparing peripheral blood to lung lavage, we noted a lower proportion of OKT4+ cells and a higher proportion of OKT8+ cells in lung lavage. The 4 8 ratio in lung lavage tended to be low compared to blood. In contrast, we found in sarcoidosis patients a decrease in both percentage and total circulating OKT3+, OKT4+, and OKT8+ cells as compared to normal. In lung lavage, there was an increase in OKT3+ cells, due to an increase in the OKT4+ subset. The percentage of OKT8+ cells in lung lavage was low. Compared to blood the 4 8 ratio was high in lung lavage. Thus, a number of alterations in circulating and lavage T cells were found both in patients with IPF and sarcoidosis. These results suggest that immunoregulatory abnormalities contribute to pathogenesis of these disorders.

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.

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 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.

Steady-State Pharmacokinetics of Controlled Release Oral Morphine Sulphate in Healthy Subjects

SummaryThe 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.

Controlled-release morphine bioavailability (MS Contin tablets) in the presence and absence of food.

The bioavailability of a single, orally administered, 30-mg controlled-release morphine tablet (MS Contin Tablet; The Purdue Frederick Company, Norwalk, Conn.) was compared after fasting or a high fat meal in this single dose, randomized, crossover study involving 24 healthy male subjects. There was no significant (p greater than 0.05) difference in the mean extent of morphine absorption over 24 hours in the presence or absence of food (area under the plasma concentration vs. time curve [AUC(0,24)], fed = 107% of fasted). Time to maximal concentration (Tmax) was similar (p greater than 0.05) in the two treatment groups; the mean Tmax for fed volunteers was 2.5 hours versus 2.4 hours for fasted volunteers. The two regimens did not differ significantly (p greater than 0.05) with regard to maximal morphine concentration (Cmax); mean Cmax for fed subjects was 8.22 ng/ml whereas mean Cmax for fasted subjects was 8.53 ng/ It was concluded that consumption of a high fat meal did not affect either the rate or extent of morphine absorption, or any of the other pharmacokinetic parameters tested, following administration of MSC.

The United States experience with oral controlled-release morphine (MS contin tablets).parts i and ii. review of nine dose titration studies and clinical pharmacology of 15-mg, 30-mg, 60-mg, and 100-mg tablet strengths in normal subjects

The results of nine US multicenter, sequential crossover, dose titration studies of controlled‐release oral morphine (MS Contin 30 mg tablets [MSC], Purdue Frederick, Norwalk, CT) are reviewed in Part I. The studies demonstrated the prolonged analgesic efficacy of the preparation in the treatment of patients with moderate to severe cancer‐related pain. Approximately 93% of the patients achieved satisfactory to excellent analgesia on a 12‐hour regimen when appropriate dose titration was allowed. The remaining patients were successfully maintained on an 8‐hour regimen. The preparation was well‐tolerated and comparable in safety to immediate‐release oral morphine. In global evaluations, MSC was judged to be significantly (P < 0.05) more effective, and with significantly (P < 0.05) fewer side effects than both the prestudy opioid analgesics and 4‐hour immediate‐release oral morphine. Patients had a broad range of morphine requirements (mean daily MSC dose, 240 mg; range, 60 mg/day to 1800 mg/day); therefore various MSC tablet strengths were developed. Part II presents three studies in which the MSC formulations (15‐mg, 60‐mg, and 100‐mg tablets) were compared to the 30‐mg tablet within three randomized, single‐dose, two‐way crossover, analytically blinded bioavailability protocols, to determine bioequivalence and dose proportionality. The maximum morphine concentration, time of maximum morphine concentration, and area under the plasma morphine versus 12‐hour and 24‐hour time curve (AUC 0,12; AUC 0,24) were determined in each study. There were no significant differences between the values associated with MSC 1 × 30 mg tablet and 2 × 15 mg tablets (study 1), MSC 2 × 30 mg tablets and 1 × 60 mg tablet (study 2), and MSC 3 × 30 mg tablets and 1 × 100 mg tablet (study 3, values adjusted to dose of 90 mg), except for one marginally significant difference in study 3 (AUC 0,24; P = 0.04) which was not clinically or biopharmaceutically significant. The results showed that MSC 15‐mg, 30‐mg, 60‐mg, and 100‐mg dosage strengths are bioequivalent and dose proportional, and, therefore, therapeutically interchangeable. It was concluded that with routine assessment of the patient and adherence to the principles of analgesic dosing, MSC can be successfully used to control cancer‐related pain. Furthermore, the availability of various MSC tablet strengths can be expected to facilitate the analgesic management of a patient population with widely differing opioid requirements.

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.