Steady-state pharmacokinetics of zonisamide, an antiepileptic agent for treatment of refractory complex partial seizures.

A 56-day pharmacokinetic study of zonisamide was conducted in 24 healthy volunteers. Steady state was achieved in 29 days including two dose escalations, and in an average of 15 days from the last dose adjustment. Twice-daily administration of 200 mg every 12 hours produced a 14% serum level fluctuation at steady state. After once-daily administration of 400 mg, a 27% serum level fluctuation was observed. The terminal-phase half-life after the last dose was 63 to 69 hours, which is consistent with the half-life of 52 to 60 hours found in single-dose studies. This result demonstrates that zonisamide is not an autoinducer. Serum oral clearance of 0.60 to 0.71 L/hr (0.121-0.132 mL/min/kg) was similar to that observed in other multiple-dose studies.

Toxicity of cordycepin in combination with the adenosine deaminase inhibitor 2'-deoxycoformycin in beagle dogs.

For 3 consecutive days, the nucleoside cordycepin (3'-deoxyadenosine) was administered as 1-hr iv infusions (0, 1, 4, 8, 10, or 20 mg/kg/day) to dogs. These doses were given 1 hr after a bolus iv injection (0.25 mg/kg/day) of 2'-deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase. The hypothesis was that dCF would affect the toxicity of cordycepin. Plasma adenosine deaminase activity was strongly inhibited during the dose period and for 5 days following the final dose of dCF. Dogs given cordycepin alone showed no drug-related toxicities. In dogs given only dCF, drug-related toxicity to lymphoid tissue (lymphopenia and thymus lymphoid depletion), thrombocytopenia, and decreases in food consumption were observed. Cordycepin in combination with dCF produced symptoms associated with severe gastrointestinal toxicity (decreased body weights, emesis, diarrhea, decreased food consumption, and necrosis of the gastrointestinal tract) and bone marrow toxicity (lymphopenia, thrombocytopenia, and depletion of hematopoietic cells). The gastrointestinal tract and bone marrow were sites associated with dose-limiting toxicities. In surviving dogs, most of the effects were reversible by Day 30. The maximum tolerated dose of cordycepin administered in combination with dCF was 8 mg/kg/day (160 mg/m2/day) given daily for 3 days.

Chronic toxicity studies of 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione, a potential chemopreventive agent.

The synthetic compound Oltipraz, 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione, is related to the 1,2-dithiolthiones naturally found in cruciferous vegetables, the consumption of which has been epidemiologically associated with reduced frequency of colorectal cancers. Oltipraz has shown chemopreventive efficacy in numerous laboratory epithelial cancer models and is a potential chemopreventive, antimutagenic compound that specifically induces Phase II enzymes. Thirteen-week and 1-year toxicity studies in rats and dogs were performed to characterize the toxicities of the compound at high dosages and to support potential further development as a chemopreventive agent in clinical trials. Administration to rats by gavage for 13 weeks at dosages of 5 and 50 mg/kg/day and for 52 weeks at dosages of 10, 30, and 60 mg/kg/day produced effects on the liver and on clinical chemistry and hematology parameters. Absolute and relative liver weight increases correlated with diffuse hypertrophy in the mid- and high-dose males and centrilobular hypertrophy in the high-dose females. Granularity of hepatocyte cytoplasm was also observed. These anatomical findings were associated with dose-associated slight increases in albumin, total protein, and cholesterol in the males and a moderate increase in cholesterol only in the females. In addition, slight decreases in erythrocyte count, hemoglobin, and hematocrit and reticulocyte elevations occurred. The no effect dose was considered 10 mg/kg/day. Administration by capsule to dogs at dosages of 10 and 100 mg/kg/day for 13 weeks and of 5, 15, and 60 mg/kg/day for 52 weeks also produced effects on the same endpoints noted in the rodent studies. In the 13-week study, precipitate was observed in the bile canaliculi, and gonadal atrophy and increased pituitary weights occurred in the males. Cholesterol and alkaline phosphatase activity were slightly elevated in both studies. Decreased hematology parameters in the 13-week study also occurred. The no effect dose was considered to be 5 mg/kg/day. Oltipraz is being carefully evaluated in clinical trials as a potential antimutagenic compound.

Differential toxicity of camptothecin, topotecan and 9-aminocamptothecin to human, canine, and murine myeloid progenitors (CFU-GM) in vitro.

PURPOSE: 20(S)-Camptothecin (CAM), topotecan (TPT, active ingredient in Hycamtin) and 9-amino-20(S)-camptothecin (9AC) are topoisomerase I inhibitors that cause similar dose-limiting toxicities to rapidly renewing tissues, such as hematopoietic tissues, in humans, mice, and dogs. However, dose-limiting toxicity occurs at tenfold lower doses in humans than in mice. The purpose of the current study was to determine whether hematopoietic progenitors of the myeloid lineage from humans, mice, and dogs exhibit the differential sensitivity to these compounds that is evident in vivo. METHODS: Drug-induced inhibition of in vitro colony formation by a myeloid progenitor in human, murine, and canine marrow colony-forming unit-granulocyte/macrophage (CFU-GM) provided the basis for interspecies comparisons at concentrations which inhibited colony formation by 50% (IC50) and 90% (IC90). RESULTS: Murine IC90 values were 2.6-, 2.3-, 10-, 21-, 5.9-, and 11-fold higher than human values for CAM lactone (NSC-94600) and sodium salt (NSC-100880), TPT (NSC-609699), and racemic (NSC-629971), semisynthetic and synthetic preparations (NSC-603071) of 9AC, respectively. In contrast, canine IC90 values were the same as, or lower than, the human IC90 values for all six compounds. CONCLUSIONS: The greater susceptibility of humans and dogs to the myelotoxicity of camptothecins, compared to mice, was evident in vitro at the cellular level. Differential sensitivity between murine and human myeloid progenitors explains why the curative doses of TPT and 9AC in mice with human tumor xenografts are not achievable in patients. Realizing the curative potential of these compounds in humans will require the development of therapies to increase drug tolerance of human CFU-GM at least to a level equal to that of murine CFU-GM. Because these interspecies differences are complicated by species-specific effects of plasma proteins on drug stability, not all in vitro assay conditions will yield results which can contribute to the development of such therapies.

Acute and chronic administration of ibogaine to the rat results in astrogliosis that is not confined to the cerebellar vermis.

Acute administration of high doses of ibogaine (IBG) to the male rat results in degeneration of Purkinje cells and reactive gliosis in the cerebellar vermis. We examined whether acute and chronic administration of IBG to male and female rats results in gliosis as determined by quantification of the astroglial intermediate filament protein, glial fibrillary acidic protein (GFAP). After acute administration of IBG, rats of both sexes showed dose-related increases in GFAP that were not confined to the cerebellar vermis. After chronic administration of IBG, female, but not male rats, showed large (as much as 200% of control), dose-related increases in GFAP in hippocampus, olfactory bulbs, brain stem and striatum, but not cerebellum. In hippocampus, the cytoskeletal proteins, neurofilament 68 (NF-68) and beta-tubulin were increased in females treated chronically with IBG, findings consistent with a damage-induced sprouting response. Together, the data indicate that IBG damages areas of the brain outside the cerebellum and that the sites damaged are dependent on sex and dosage regimen.

The nurse practitioner: management of minor trauma.

OBJECTIVE: to identify patient groups within Accident and Emergency (A & E) practice where the nurse practitioner, following agreed protocols and treatment regimes, might make a contribution to patient care; and to describe a possible process of preparation required to introduce nurse practitioners into an A & E department. DESIGN: A 14-day study (6-12 January and 24-30 July 1994) in which the case notes of all patients attending the A & E department were analysed. SETTING: The A & E department of Aberdeen Royal Infirmary, UK. PARTICIPANTS: A census of the case notes of 1785 patients. MAIN OUTCOME MEASURES: Demographic and clinical characteristics of new patients, diagnosis, investigations, treatment ordered, numbers of return visits, source of referrals and disposal destinations. RESULTS: On analyses of the workload profile it became apparent that a small number of injury categories, investigations and treatments, accounted for a significant percentage of patient throughput and that 75% of cases attended between 09:00 and 21:00 h. Many cases were of a minor nature, discharged home after minimal treatment and no follow-up. It was thought possible that the assessment and treatment of a significant percentage of patients (30%) could be carried out by suitably trained and experienced nurses working to an agreed protocol. CONCLUSIONS: The paper discusses the concept of the nurse practitioner and seeks to demonstrate a possible role for such a clinical worker using previously agreed protocols devised from a clinical database of patient requirements. Their employment could possibly bring a considerable routine saving in waiting time for patients with minor injuries.

Research based training for the nurse practitioner.

Exploration for oil and gas began in the North Sea in the mid 1960s. Since that time offshore medics have had the authority to diagnose and treat patients within a set of guidelines. As such they are one of the earliest groups of British nurse practitioners. Training for offshore medics in the UK sector of the North Sea is regulated by the Health and Safety Commission. In order to promote training based on research, a study was conducted to examine the pattern of referrals to the Accident and Emergency department of Aberdeen Royal Infirmary from offshore. This was done for a 9 year period. The purpose was to establish a reliable database of the most frequently occurring injury types and affected body parts, and to use this information to modify existing training courses for offshore medics. The total number of injury referrals during the study was 6270. The most common injury type was fracture/suspected fracture (mean = 50% +/- 3.2%) and the most common body part affected was the hand (mean = 37% +/- 3.7%). This paper indicates the changes which were made to an offshore medic training programme as a result of the research. It is suggested that unless such research is undertaken it is not possible to claim that the training of nurse practitioners, in this case offshore medics, is research based and therefore relevant to the needs of the community being served.

Zidovudine bioavailability and linear pharmacokinetics in female B6C3F1 mice.

The bioavailability and pharmacokinetics of zidovudine (3'-azido-3'-deoxythymidine) (AZT) were determined in female B6C3F1 mice after administration of 15, 30, and 60 mg/kg doses via oral gavage or intravenous injection. Three animals in each administration group were sacrificed, and blood samples were collected at each of the following times: 0, 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, and 120 min after drug administration. Plasma zidovudine concentrations were determined by HPLC. After oral administration, mean maximum plasma concentrations (Cmax) of 9.1, 18.9, and 40.3 mg/liter were observed at 18.3, 21.7, and 15.0 min (tmax) for the 15, 30, and 60 mg/kg doses, respectively. Following intravenous administration, mean Cmax values of 15.9, 41.8, and 76.0 mg/liter were observed for the 15, 30, and 60 mg/kg doses, respectively. Nonlinear least squares regression of all data sets, using a 1/y weight, indicated that zidovudine disposition was best described by a one-compartment open model with first-order absorption, where appropriate, and first-order elimination. The mean elimination half-life values ranged from 17.3 to 19.9 min for the three intravenous doses and from 16.5 to 21.9 min for the three oral doses. The mean values for the apparent volume of distribution (Vd) ranged from 0.8 to 1.0 liter/kg following oral and intravenous administration. There were no significant differences in Vd between the oral and intravenous groups. The mean total body clearance values ranged from 28.9 to 34.3 ml/min/kg following intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of lansoprazole, a new H+,K(+)-ATPase inhibitor, on gastric pH and serum gastrin.

This study examined the effects of dose and time of administration of lansoprazole on gastric pH and serum gastrin in healthy male volunteers. Three groups of six subjects received 10, 20 or 60 mg doses of lansoprazole or placebo. Doses were administered at 22.00 hours daily for 7 days. An additional 18 subjects received once daily 30 mg oral doses of lansoprazole or placebo; these subjects were dosed at either 08.00 hours or 22.00 hours in a randomized, crossover fashion with a 2-week washout period. Gastric pH was monitored for 24 h following the first and final dose, and 1 week following the completion of dosing. Lansoprazole, at all doses except 20 mg/day, significantly increased the median 24-hour gastric pH following 7 days of dosing (P less than 0.05). In addition, morning dosing in the 30-mg crossover group led to a higher 24-h median pH than evening dosing (P = 0.003). There was no difference in night-time median pH between morning and evening dosing. Morning dosing also led to a significant increase in gastric pH on study Day 1 (P less than 0.05). Plasma concentrations of lansoprazole were highly variable between subjects, but there was a significant correlation between AUC and the median 24-h gastric pH. Plasma concentrations and AUCs were higher on Day 7 than on Day 1 for subjects receiving 10 or 20 mg, but not for those receiving 30 or 60 mg doses. Lansoprazole bioavailability demonstrated a circadian effect manifested by higher plasma concentrations following morning dosing. Serum gastrin concentrations were elevated in all active medication groups.

Pharmacokinetics of 2',3'-dideoxyadenosine in dogs.

The pharmacokinetics of 2',3'-dideoxyadenosine (ddAdo) and 2'-3'-dideoxyinosine (ddIno) were determined after intravenous bolus administration and long-term intravenous infusion of ddAdo in dogs. ddAdo was rapidly deaminated to ddIno and ddAdo plasma concentrations were only a fraction of ddIno concentrations. The total body clearance of ddAdo exceeded the literature value for the cardiac output of the dog, indicating an extremely rapid metabolism, and the existence of extrahepatic metabolism. Urinary excretion of unchanged ddAdo was a minor route of elimination (approximately 1%). The pharmacokinetics of ddIno was determined assuming complete conversions of ddAdo to ddIno. ddIno elimination was dose-dependent with total body clearance ranging from 4 to 55 ml/min/kg in individual animals. The plasma half-life was approximately 30 min after most routes of administration, but increased to approximately 60 min in two animals receiving a large intravenous dose of 500 mg/kg. ddIno penetrated into the cerebrospinal fluid to a limited extent, reaching concentrations of 3-11% of those in plasma. Urinary excretion of unchanged ddIno accounted for approximately 20% of the administered dose of ddAdo, while uric acid and hypoxanthine were minor urinary metabolites. Concentrations exceeding the in vitro minimal viral inhibitory concentration (2.4 micrograms/mL) could be safely maintained in plasma for a 10-day period. Infusions which gave cerebrospinal fluid concentrations of 12 to 17 micrograms/mL resulted in dose limiting myelosuppression and intestinal toxicity, after less than 10 days of infusion. Orally administered ddAdo was absorbed as ddIno, with bioavailabilities ranging from 28 to 93% in experiments where no emesis occurred. These studies indicate the rapid in vivo conversion of ddAdo to ddIno, and support the selection of ddIno over ddAdo for further drug development.

The effect of the monoamine oxidase inhibitor isocarboxazid on the canine metabolism of the cell-differentiating agent hexamethylene bisacetamide.

The acute toxicities of the cellular differentiating agent hexamethylene bisacetamide (HMBA) in humans and animals include CNS toxicity (agitation, somnolence, seizures, hallucinations) and an anion-gap metabolic acidosis. N-Acetyl-1,6-diaminohexane (NADAH), the first metabolite of HMBA, is as active as the parent compound in causing differentiation of leukemic cells in vitro, whereas 6-acetamidohexanoic acid (6AcHA), which is formed by the oxidation of NADAH in the presence of monoamine oxidase (MAO) and aldehyde dehydrogenase, is inactive. To test whether the inhibition of MAO blocks the production of an inactive and possibly toxic HMBA metabolite (6AcHA) or increases the amount of active compounds (HMBA + NADAH) in vivo, we investigated the effect of the MAO inhibitor isocarboxazid on the metabolism and toxicity of HMBA in beagle dogs. Two groups of dogs, composed of one male and one female dog per group, were used in the study. One group received isocarboxazid (3.3 mg/kg p.o. q8h x 9) beginning at 24 h before the initiation of a 48-h i.v. infusion of HMBA (40 mg kg-1 h-1), whereas the other received placebo in an identical fashion prior to the start of an identical HMBA infusion. The mean plasma steady-state concentration (css) of HMBA was 0.91 mM in dogs given HMBA and isocarboxazid as opposed to 0.78 mM in those given HMBA and placebo. As measured spectrophotometrically, plasma MAO activity was inhibited by 86% +/- 3% in dogs receiving isocarboxazid. Gas chromatography/mass spectrometry detected 6AcHA in the plasma of animals that were given placebo but not in the plasma of dogs that received isocarboxazid. Gas chromatographic analysis of urine samples revealed that the total amount of 6AcHA and of NADAH excreted in urine was 8 times less and 3 times greater, respectively, in isocarboxazid-treated dogs than in animals that received HMBA and placebo. One dog was excitable after the initial two doses of isocarboxazid and developed seizures at the end of the HMBA infusion. Another dog was agitated during treatment with HMBA and isocarboxazid. No CNS toxicity occurred in animals that were treated with HMBA and placebo. We conclude that isocarboxazid inhibits the production of 6AcHA in vivo, thus supporting the involvement of MAO in HMBA metabolism. Because the combination of HMBA and isocarboxazid produces CNS toxicity, 6AcHA is probably not the neurotoxic agent in dogs.

Pharmacological and toxicological evaluation of orally administered pyridostigmine in dogs.

Pyridostigmine bromide, a reversible cholinesterase inhibitor, was administered orally (capsule gavage) to beagle dogs (10-15 months of age) of both sexes once daily at 5, 10, or 20 mg/kg for 14 days; every 8 hr at 2 or 5 mg/kg for 28 days; or every 8 hr at 0.05, 0.5, or 2 mg/kg for 3 months as part of its preclinical safety assessment. A small portion of the dogs receiving pyridostigmine for 3 months were allowed an untreated recovery period of an additional 3 months. Daily doses of 10 or 20 mg/kg were lethal to some of the dogs when given for up to 14 days and caused severe intestinal distress, including diarrhea, emesis, and reddened feces in all animals. The cause of death was intestinal intussusception. Signs of systemic toxicity apparent at these doses included hypersalivation and tremors. Similar but less severe effects were produced by 5 mg/kg per day; plasma cholinesterase activities were inhibited by all three doses in a dose-related manner. Signs of toxicity in the 28-day and 3-month studies were generally limited to the gastrointestinal tract and included diarrhea or soft stools and reddened or mucoid-containing stools; these signs appeared to reverse upon discontinuation of the drug. A single dog at 2 mg/kg every 8 hr developed an apparent intussusception. There were no pathological changes in clinical chemistry, hematology, or urinalysis parameters associated with doses of 0.05, 0.5, or 2 mg/kg every 8 hr for up to 3 months, nor were any drug-related lesions observed upon gross necropsy and microscopic evaluation of the major tissues and organs. Red blood cell (RBC) acetylcholinesterase (AChE) activities in the 3-month study were inhibited by approximately 10, 50, and 70% in the 0.05, 0.5, and 2 mg/kg every 8-hr dose groups, respectively, and these degrees of inhibition were maintained throughout the period of treatment. These data suggest that prolonged oral administration of pyridostigmine at doses sufficient to cause profound and sustained inhibition of RBC AChE activity (i.e., as high as 70%) cause mainly local, gastrointestinal distress related to altered intestinal motility. At the extreme, this can be manifested as a life-threatening intestinal intussusception. Systemic anticholinesterase effects (other than enzyme inhibition) were observed only at doses of 2 mg/kg and greater, while local (gastrointestinal) effects and inhibition of RBC AChE were observed at doses as low as 0.05 mg/kg.

Pharmacokinetics of buthionine sulfoximine (NSC 326231) and its effect on melphalan-induced toxicity in mice.

Intravenous doses of buthionine sulfoximine (BSO, NSC 326231), an inhibitor of glutathione synthesis, were eliminated rapidly from mouse plasma in a biexponential manner. The initial phase of the plasma concentration versus time curve had a half-life of 4.9 min and accounted for 94% of the total area under the curve. The half-life of the terminal phase of the curve was 36.7 min and the area accounted for only 6% of the total area under the curve. Plasma clearance of BSO was 28.1 ml/min/kg and the steady state volume of distribution was 280 ml/kg. The oral bioavailability of BSO, based on plasma BSO levels, was extremely low. However, comparable glutathione depletion was apparent after i.v. and p.o. doses of BSO, suggesting a rapid tissue uptake and/or metabolism of BSO. Therefore, due to the rapid elimination of BSO from mouse plasma, plasma drug levels do not directly correlate with BSO-induced tissue glutathione depletion. Administration of multiple i.v. doses of BSO to male and female mice resulted in a marked 88% depletion of liver glutathione at doses of 400-1600 mg/kg/dose. Toxicity of i.v. administered BSO was limited to a transient depression of peripheral WBC levels in female mice given six doses of 1600 mg/kg. Multiple i.v. doses of BSO of up to 800 mg/kg/dose (every 4 h for a total of six doses) did not alter the toxicity of i.v. administered melphalan. However, multiple doses of 1600 mg/kg/dose of BSO did potentiate histopathological evidence of melphalan-induced bone marrow toxicity in 30% of the mice and, additionally, the combination of BSO and melphalan produced renal tubular necrosis in 80% of the male mice. The potentiation of melphalan induced toxicity did not appear to be related to GSH depletion, since: quantitatively similar amount of GSH depletion occurred at lower dose of BSO without any increase in melphalan toxicity.

Effects of leuprolide in the treatment of central precocious puberty.

Leuprolide acetate (D-Leu6 des-Gly-NH2(10), Pro-ethylamide9), a synthetic non-apeptide analog of naturally occurring gonadotropin releasing hormone, was used to treat 62 children with central precocious puberty. Sex steroid levels (testosterone in boys and estradiol in girls) were suppressed during treatment lasting from 3.5 to 24.9 months. Basal follicle-stimulating hormone values and both luteinizing hormone and follicle-stimulating hormone peak responses to stimulation by luteinizing hormone releasing hormone were also suppressed, although basal luteinizing hormone values did not differ. Linear growth rate and the rate of bone age advancement decreased during leuprolide therapy. Side effects were minimal. The long-term safety of this treatment has not yet been established; however, leuprolide appears to be an effective long-term therapy for central precocious puberty.

Comparison of in vivo and in vitro percutaneous absorption of T-2 toxin in guinea pigs.

The fate and distribution of T-2 were examined in 6 guinea pigs. T-2 (1.2 micrograms/cm2), in methanol or DMSO, was painted onto the shaved backs of guinea pigs, a screen barrier was applied, urine and feces were collected daily and the guinea pigs were killed after 48 hr. Disks of skin (lateral to the in vivo site of application) were excised from the guinea pigs and used for in vitro penetration studies with static diffusion cells. Skin excised from 6 additional guinea pigs was used for penetration studies with flow-through diffusion cells. For in vitro studies, T-2 dissolved in methanol or DMSO was applied to the epidermal surfaces and the appearance of penetrant in receptor fluid bathing the dermal surfaces was monitored for 48 hr. Metabolism of T-2 was measured by using thin layer radiochromatography to identify metabolites. In the in vivo study, mean cutaneous absorption (n = 3) after 48 hr (expressed as per cent dose) was 22.5 and 51.9 for the methanol and DMSO groups, respectively. In vitro cutaneous penetration for static diffusion cells was 3.9 and 38.4 for the methanol and DMSO groups. For flow-through diffusion cells, mean penetration (n = 9) was 14.6 and 42.6 for the methanol and DMSO groups. Urinary metabolites of T-2 were T-2 triol, 3' OH-HT-2, T-2 tetraol, the glucuronide conjugate of HT-2 and several more polar metabolites. The main metabolite of T-2 in the receptor fluid bathing the dermal surfaces of excised skin was HT-2.

Treatment of the irritable bowel syndrome with Bentyl (dicyclomine hydrochloride).

The effectiveness of Bentyl (dicyclomine hydrochloride) 40 mg 4 times daily was evaluated in an ambulatory population with recent irritable bowel syndrome (IBS). During the 2-week double-blind study, the effects of dicyclomine hydrochloride compared to placebo were assesed by: 1) physicians' global evaluation of treatment, 2) patients' self-evaluation of treatment, and 3) patients' evaluation of duration of abdominal pain. It was concluded that over a 2-week period dicyclomine hydrochloride 40 mg 4 times a day is superior to placebo in improving the overall condition of the patient, decreasing abdominal pain, decreasing abdominal tenderness, and improving bowel habits. The majority of adverse effects reported were related to the anti-cholinergic activity of the drug.