Prescription to over-the-counter switch: a regulatory perspective.

This paper discusses the origins of the over-the-counter (OTC) drug category and presents information about the process of switching a drug from prescription (Rx) to OTC status. It also reviews past and current drug laws in terms of how they relate to OTC drugs.

Effects of aspirin and ibuprofen on the pharmacokinetics and pharmacodynamics of glyburide in healthy subjects.

OBJECTIVE: To determine the effects of aspirin and ibuprofen on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers. DESIGN: Single-center, randomized, two-way, crossover design following an initial baseline evaluation phase. SETTING: Outpatient, university-based ambulatory care facility. PATIENTS: Sixteen healthy nonsmoking men aged 20-34 years. INTERVENTION: Three phases consisting of six treatments. Phase 1 began with treatment A, a baseline oral glucose tolerance test (GTT), followed by treatment B, glyburide 5 mg plus a GTT. The other two phases were administered in a crossover design. Phase 2 consisted of the administration of aspirin 975 mg qid for 4 days. On day 3 a GTT was administered (treatment C) and on day 4 glyburide 5 mg plus a GTT was administered (treatment E). Phase 3 consisted of the administration of ibuprofen 600 mg qid for 4 days with a GTT on day 3 (treatment D) and glyburide 5 mg plus a GTT on day 4 (treatment F). MAIN OUTCOME MEASURES: Serum glyburide concentrations after each treatment, as well as glucose and insulin, ibuprofen, and salicylate serum concentrations and glyburide free fractions. RESULTS: Aspirin administration resulted in an 85% increase in mean total glyburide oral clearance and a 29% increase in glyburide free fraction. Ibuprofen administration resulted in a slight increase in mean glyburide free fraction, but no significant changes in glyburide pharmacokinetic parameters were observed. Insulin concentrations were increased during the glyburide plus aspirin treatment. Conflicting results were observed in the glucose parameters. CONCLUSIONS: The potential for this glyburide-aspirin interaction resulting in a transient hypoglycemia should be considered in diabetic patients receiving glyburide therapy.

Nighttime dosing of triazolam in patients with liver disease and normal subjects: kinetics and daytime effects.

This study was designed to determine whether the severity of liver dysfunction in cirrhosis affects the kinetics and next-day effects of triazolam after bedtime administration of a single oral dose. Eight patients with biopsy-proven cirrhosis and seven normal subjects matched for age, weight, and sex participated as paid volunteers. The first night was the control night, when no nighttime sedative was administered. The next day, psychomotor testing was performed at 8:30 AM, 2 PM, and 5 PM. Triazolam 0.25 mg was administered at 10:30 PM that evening. Psychomotor testing was repeated on the posttriazolam day in the same manner as on the control day. Blood samples were obtained from a venous catheter at 11 predetermined times in the 14 hours after triazolam administration. Memory testing was also performed. Apparent oral clearance of triazolam was directly related to albumin concentration and indocyanine-green elimination rate constant, and inversely related to partial thromboplastin time expressed as seconds over control. Clearance was 6.69 +/- 2.52 mL/min/kg in the normal subjects and 4.99 +/- 3.14 in the subjects with cirrhosis. There were no significant differences in Cmax between normal subjects (1.43 +/- 0.44 ng/mL) and subjects with cirrhosis (1.62 +/- 0.31 ng/mL) or in tmax (2.0 +/- 1.0 vs 2.5 +/- 1.9 hr) between normal and cirrhosis subjects, respectively. Posttriazolam, cirrhotic subjects took significantly longer to sort cards at 8:30 AM than on the control day. There was a significant correlation between extent of impairment on 8:30 AM card sorting by suit and AUC0-8 (r = 0.687; P = 0.0046).(ABSTRACT TRUNCATED AT 250 WORDS)

The paradoxical effect of cimetidine and ranitidine on glibenclamide pharmacokinetics and pharmacodynamics.

The potential interactions between H2-receptor antagonists, cimetidine and ranitidine, and glibenclamide were studied in 15 non-smoking male volunteers. The study consisted of six treatment phases. Treatment A (3 h oral glucose tolerance test) consisted of 75 g dextrose in 300 ml carbonated water. Treatment B consisted of one 5 mg tablet of glibenclamide in addition to a glucose tolerance test. Treatment C, cimetidine 300 mg orally four times daily for 4 days and Treatment D, ranitidine 150 mg orally twice daily for 4 days were administered in a randomized, crossover fashion. On day 3 of Treatments C and D, subjects received an oral glucose tolerance test. On day 4 of Treatments C and D, subjects received 5 mg of glibenclamide in addition to cimetidine (Treatment E) or ranitidine (Treatment F) and an oral glucose tolerance test. Compared with the control treatment, cimetidine increased the glibenclamide AUC (973 vs 710 ng ml-1 h), but during ranitidine dosing glibenclamide AUC (726 ng ml-1 h) was not significantly different from the control. Apparent oral glibenclamide clearance decreased from 8.25 l h-1 under the control treatment to 6.0 l h-1 following cimetidine but was unchanged during ranitidine (7.97 l h-1). Plasma glucose concentrations were unexpectedly higher when glibenclamide was administered with cimetidine or ranitidine (glucose AUC 237 mg dl-1 h, 228 mg dl-1 h) when compared with glibenclamide administered alone (195 mg dl-1 h, P less than 0.0001). Plasma insulin concentrations were significantly elevated when H2-receptor antagonists and glibenclamide were administered concurrently.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical pharmacist in drug research and development. An academic-industrial center.

The center for Pharmacodynamic Research represents a novel approach to academic-industrial research agreements that may be a useful model for others to pursue. It is designed to take advantage of the strengths of the company and the university in order to enhance the research conducted and to provide benefits to both. At the same time, it takes into account the responsibility of the university to provide graduate education and the need of industry for scientists in the future. The center was only recently established, however, and must be considered work in progress. Although it has been successful to this point, its value will only be established by longevity and productivity. We have every confidence that it will prove to be a valuable experiment.

Disposition of moracizine (ethmozine) in healthy subjects after oral administration of radiolabelled drug.

Moracizine (ethmozine) is a phenothiazine derivative with demonstrated antiarrhythmic activity. To characterize the pharmacokinetics and material balance relationships in humans, we have given 14C-moracizine X HCl as a single oral dose of 500 mg (50 microCi) to six healthy men. Plasma, urine, and faecal samples were collected for 7 days after administration and the concentrations of total radioactivity and intact moracizine were determined by liquid scintillation counting and HPLC, respectively. Urine and faecal recovery accounted for 95% of the administered radioactivity. Most of this radioactivity was found in the faeces (59%). Only 0.05% of the dose was recovered from urine as intact moracizine. The Cmax and AUC for moracizine equivalents of total radioactivity were 4- and 18-fold higher, respectively, than the corresponding values for intact moracizine. Additionally, both the disappearance of total radioactivity from plasma and its excretion rate into urine were slower in comparison to intact drug. Terminal t1/2 values calculated from plasma concentration-time data were 85.2 and 3.5 h for total radioactivity and intact moracizine, respectively. However, based on urinary excretion rates, the t1/2 for total radioactivity was shorter (29.3 h) while the t1/2 for intact drug was comparable (2.7 h) to the results obtained from the plasma data. The oral plasma clearance of moracizine was relatively large (2.2 l X min-1), suggesting first-pass metabolism. The estimated oral systemic availability of moracizine was 34%.

Metoclopramide as an antiemetic agent in pediatric oncology patients.

Metoclopramide (MCP) was used as an antiemetic agent in 11 pediatric oncology patients during 22 courses of cancer therapy including cisplatin, doxorubicin, and other agents. Initial MCP regimens used 2 mg/kg/dose iv prior to and at 1.5, 3.5, 5.5, and 8.5 hours post-chemotherapy. Subsequent dose reduction to 1 mg/kg and addition of diphenhydramine to all regimens has been made to decrease adverse drug effects. Seven of 11 children reported subjective benefit, defined by comparison with previous antiemetic response, comfort, and willingness to continue MCP therapy. MCP effectively reduced the volume of emesis per 24-hour period as compared with volume of emesis recorded following other antiemetics, an observation that should be confirmed in controlled studies of efficacy. Acute dystonic reactions developed in five children, occurring most frequently in those who received 2 mg/kg/dose regimens or consecutive day dosing. These reactions were rapidly reversible with diphenhydramine, but limited patient acceptance of further MCP use.

Attitudes of patients with hypertension or arthritis toward the frequency of medication administration.

The attitudes of patients with a nonpainful chronic illness (hypertension) and the attitudes of patients with a painful chronic illness (arthritis) toward the frequency of medication administration were compared. Hospitalized patients with rheumatoid arthritis (n = 83) and hypertension (n = 117) were interviewed by study monitors. Multiple-daily dosing was preferred by 70% of the arthritis patients and 61% of the hypertension patients for pain medications. The majority of patients in both groups preferred single-daily dosing for nonpainful conditions. The majority of patients in both groups believed that there was no difference between the dosing regimens in terms of the number of side effects. Thirty-five percent of the patients with arthritis and 19% of the patients with hypertension stated that they would consider increasing or decreasing the number of daily doses of their medication. A single daily dose might not be the optimal dosing regimen for all medications for all patients. Clinicians should consider the nature of the patient's illness and its potential influence on compliance when selecting a dosing regimen.

Pharmacodynamic evaluation of the benzodiazepine-oral contraceptive interaction.

The sedative, psychomotor, and memory effects of single oral doses of alprazolam (ALP), lorazepam (LOR), temazepam (TMP), and triazolam (TRZ) were evaluated in women taking oral contraceptives (OCs) and a comparable group of control women. Nine women taking OCs and 11 control women took doses of 1 mg ALP and 2 mg LOR and 10 OC users and 10 control women took 30 mg TMP and 0.5 mg TRZ on two occasions separated by 28 days. Minimal psychomotor impairment was noted after TMP. ALP, LOR, and TRZ produced greater performance impairment in the OC users. Correcting the maximum observed performance decrement for plasma concentration did not account for the differences between OC users and controls. After TMP, there was less sedation during the first 2 hours in OC users, who also had higher plasma TMP clearance. There were no differences in sedation between OC users and controls after ALP, LOR, and TRZ; however, there was less than 50% power to detect a 30% difference. Amnestic effects in OC users and controls did not differ after any of the four drugs. The observed patterns of anterograde amnesia were different, with the earliest and most pronounced recognition failure after TRZ (50% at 1.5 hours), while the LOR effect increased to a maximum (30%) 4 hours after dosing. Our data suggest that differences in benzodiazepine pharmacokinetics between OC users and control women do not account for observed differences in psychomotor impairment. Women taking OCs are more sensitive to the psychomotor effects of single oral doses of benzodiazepines.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of end stage renal disease and aluminium hydroxide on triazolam pharmacokinetics.

Triazolam 0.5 mg was administered to 11 dialysis patients and 11 age, weight and sex matched controls. Peak plasma concentrations (Cmax) were higher in control subjects, but there were no other differences between the groups. When dialysis patients took triazolam with 3600 mg aluminum hydroxide suspension, Cmax and AUC were increased into the range observed in control subjects. It appears that triazolam can be used at normal doses in patients with renal dysfunction, without regard to interaction with aluminum hydroxide gel, or to alterations in elimination.

Effects of end-stage renal disease and aluminum hydroxide on temazepam kinetics.

The kinetics of temazepam, 30 mg, were evaluated in 11 patients with end-stage renal disease. Age ranged from 18 to 65 years. On two occasions separated by 1 week, single oral 30 mg doses of temazepam were given once with water (TM) and once with 3600 mg aluminum hydroxide gel (TM + AHG). There were no significant differences in the maximum plasma concentration, the time to reach maximum concentration, or elimination rates between TM and TM + AHG dosing. In approximately half the subjects there were secondary temazepam peak concentrations. In the remaining subjects, temazepam elimination was biphasic, with the terminal t1/2 ranging from 11 to 77 hours. There was a lag time before absorption in all subjects. The percent free temazepam in plasma from dialysis subjects ranged from 4.4% to 8.8% (mean = 5.9%). Compared with literature reports of subjects with normal renal function, the maximum plasma concentration was lower and the percent free temazepam was higher in dialysis subjects. When sedation score was plotted against plasma temazepam concentration, there was clockwise hysteresis consistent with tolerance or adaptation to effects of the drug. Thus aluminum hydroxide gel does not affect temazepam absorption. The clinical significance of the low plasma concentrations and high free temazepam fraction in dialysis subjects is uncertain.

The excretion of rosaramicin in breast milk.

The excretion of rosaramicin, a macrolide antibiotic, was studied in the breast milk of ten lactating women. Breast milk and serum samples were collected for 48 hours after a single 250-mg oral dose of rosaramicin. Mean serum half-life, apparent volume of distribution, and oral clearance were 4.4 hours, 3.41 L/kg, and 6.34 mL/min/kg, respectively. Mean milk/serum ratio was 0.12 and the total amount of drug recovered over the first ten hours was 6.25 micrograms, approximately 0.0025% of the dose. A positive correlation between breast milk volume and breast milk clearance was found, suggesting that the amount of drug received by a nursing infant will depend on the volume of milk produced by the mother. Drug-induced toxicity from the parent drug is unlikely to occur in nursing infants since the amount of rosaramicin that a nursing infant could ingest is small.

Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics.

The effects of low-dose estrogen oral contraceptives (OC) on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprazolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR) were studied in two parallel crossover studies of 20 women each. Women taking OC steroids containing low doses of estrogen and women matched for age, weight, and cigarette smoking received single oral doses of TRZ (0.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Kinetics were determined as plasma concentrations during 48 hr after dosing. OCs inhibited the metabolism of ALP: The AUC increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. In contrast, OCs decreased the AUC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. Low-dose estrogen OCs may therefore inhibit the metabolism of some oxidized benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines.

PIP: Because benzodiazepines and oral contraceptives (OCs) are among the most widely prescribed drugs and have a potential for interaction, 2 parallel crossover studies were conducted to determine the effects of OCs on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprozolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR). 20 healthy women taking OCs containing does of under 35 mcg of ethinyl estradiol for 3 months or more and 20 women matched for age, weight, and cigarette smoking received single oral doses of TRZ (.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Treatments were seperated by 28 days to control for effects of menstural cycle on drug metabolism. Kinetics were determined as plasma concentrations during 48 hours after dosing. The data indicated that OCs differentially affect the elimination of the benzodiazepines studied. OCs inhibited the metabolism of ALP: the area under the curve (AUC) increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. OCs decreased the AUC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. It was concluded that low-dose estrogen OCs may inhibit the metabolism of some conjugated benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines, but the clinical implications are unclear. The relationship between plasma concentration and effect has not been determined for most benzodiazepines, but the results suggest that the time required to achieve steady-state concentrations would be longer and that there would be higher steady state concentrations of ALP in OC users. Because both TMZ and LOR are eliminated more rapidly by OC users, women taking OCs should achieve steady-state concentrations more rapidly than nonusers. Because TMZ clearance is increased by OCs, mean plasma concentration may be decreased. The usual 30 mg dose of TMZ may therefore be less effective as a hypnotic in OC users.

Incidence of next-day anterograde amnesia caused by flurazepam hydrochloride and triazolam.

The incidence of next-day anterograde amnesia was evaluated in hospitalized patients who received flurazepam hydrochloride or triazolam. A blinded observer assessed memory and daytime drowsiness in 154 patients after the bedtime ingestion of flurazepam hydrochloride (n = 54), triazolam (n = 49), or no hypnotic drug (n = 51). The hypnotic agents were administered before midnight. At approximately 0800 the next morning, the patients were shown a picture of an object on colored construction paper and asked to remember it as well as the color of the background. Both the observer and patient assessed drowsiness using the Stanford Sleepiness Scale. The observer also made a note of the items on the patient's breakfast tray. Patients were then revisited at 1100 and asked to recall the object in the picture, the color of the background, and at least three items from their breakfast tray. Ten of the 54 patients in the flurazepam group failed to recall all three items compared with only two in the triazolam group and two in the control group. The 14 patients who experienced memory impairment were significantly more drowsy at 0800 than those who were able to recall the items. Next-day anterograde amnesia occurred more frequently in patients who received flurazepam hydrochloride than in those who received triazolam or no hypnotic drug. This effect may be related to the next-day drowsiness caused by flurazepam and its slowly eliminated active metabolite.

Triazolam protein binding and correlation with alpha-1 acid glycoprotein concentration.

On two occasions separated by a minimum of 1 wk, plasma was obtained from 12 patients (aged 18 to 73 yr) on dialysis after an overnight fast. Samples were assayed for albumin and alpha 1-acid glycoprotein (AGP) concentrations. 14C-Triazolam was added to each sample to a final concentration of 5 ng/ml. Protein binding was determined by equilibrium dialysis. Unbound triazolam ranged from 6.4% to 15.4% (mean = 10.0%). AGP concentrations ranged from 71.8 to 205.1 mg% (mean = 123.4 mg%). Triazolam binding ratio (bound/unbound concentration) correlated with AGP concentration (r2 = 0.69) but not with albumin concentration, age, or sex. This correlation was verified by adding AGP in varying amounts to control plasma.

Comparison of the bioavailability of oral, rectal and intramuscular promethazine.

The bioavailabilities of generic and reference promethazine 50 mg rectal suppositories were compared with that of 50 mg reference oral solution (24 subjects), and all three treatments were compared with a 50 mg reference i.m. injection (six subjects). Plasma samples were assayed by an HPLC method with triflupromazine as the internal standard. Both suppositories produced lower peak plasma concentrations (Cmax) and longer times to peak concentration (Tmax) than did the oral solution. There were no significant differences in the mean area under the plasma concentration-time curves (AUC) from 0 to 24 h among the three treatments. The Cmax of the i.m. injection was significantly higher than the other three treatments, while the Tmax of the injection was significantly shorter than the reference suppository only. The mean AUC of the injection was significantly greater than the AUCs of the other three treatments. Rectal suppositories of promethazine are more slowly absorbed than oral solutions or i.m. injections; rectal suppositories and oral solutions are less bioavailable than i.m. injections. Diminished systemic bioavailability may result from extensive first-pass hepatic metabolism that occurs after both oral and rectal dosing. There is a high degree of intersubject variation in the bioavailability of promethazine rectal suppositories and oral solutions.