Rimantadine pharmacokinetics in healthy subjects and patients with end-stage renal failure.

The single-dose (two 100 mg doses) pharmacokinetics of rimantadine hydrochloride were compared in eight patients with end-stage renal disease who were on hemodialysis and seven age-matched healthy subjects. Plasma and urine rimantadine concentrations were determined by a GC/MS method. The plasma half-life (43.6 vs 27.5 hours) and AUC (9.9 +/- 2.1 vs 6.0 +/- 1.6 micrograms.hr/ml) were significantly (p less than 0.05) increased in the patient population. No significant differences were noted in the maximum rimantadine concentration, time of maximum concentration, or apparent volume of distribution. Urinary excretion of unchanged rimantadine accounted for 16% of the dose in the healthy subjects. Hemodialysis did not appreciably remove rimantadine. These findings suggest that rimantadine dosage may need to be reduced in patients with end-stage renal disease but supplemental doses on dialysis days are not required.

Disopyramide hemodialysis and kinetics in patients requiring long-term hemodialysis.

Disopyramide hemodialysis and kinetics after 200 mg orally in six patients receiving long-term hemodialysis were examined. Mean volume of distribution (area) was 66.5 +/- 13 l. Mean times of the peak serum concentration and mean peak serum concentration were 2.3 +/- 0.9 hr and 3.1 +/- 0.9 microgram/ml. Mean absorption half-life (t 1/2) was 21.6 +/- 12.5 min. Mean disopyramide elimination t 1/2 during dialysis was 16.8 +/- 11.9 hr, not significantly different from mean elimination t 1/2 without dialysis of 16.1 +/- 5.2 hr. End-dialysis bath concentrations of disopyramide showed that not more than 2.4% of the dose was dialyzed during a 2-hr dialysis period. Our data indicate that at therapeutic concentrations disopyramide was not appreciably dialyzed.

The clinical spectrum of ascites associated with maintenance dialysis.

Among 197 patients being treated with maintenance dialysis, six were found to have ascites. Unlike previous reported series, the cause of ascites and the clinical course were variable. Two patients responded to definitive therapy directed against the specific cause. No consistent association was found with the etiology of renal disease or therapy of uremia including the duration of hemodialysis or prior peritoneal dialysis. Nonspecific therapy attempting to alleviate ascites was unsatisfactory. Severe hypertension was not characteristic and bilateral nephrectomy did not influence the course. An extensive diagnostic evaluation is recommended along with skepticism before declaring that idiopathic, refractory ascites exists signaling progressive deterioration.

Enhanced control by radiotherapy of cervical lymph node metastases arising from nasopharyngeal carcinoma compared with nodal metastases from other head and neck squamous cell carcinomas.

PURPOSE: To test the hypothesis that metastatic cervical lymph nodes arising from nasopharyngeal carcinoma (NPC) are more readily controlled with radiotherapy than comparable nodes from squamous cell carcinomas of other head and neck sites (SCC). METHODS AND MATERIALS: One hundred four NPC patients with metastatic cervical nodes (mean size of the largest node equals 4.1 cm) were randomly selected from radiation treatment files for two time periods, 1969-1976 and 1983-1988, when radiation alone was the first line treatment. Candidate controls were selected randomly from radiation treatment files of node positive squamous cell carcinomas arising from the oropharynx, hypopharynx, oral cavity or larynx who were also treated by radical radiation therapy as sole initial treatment in the 1970s and 1980s. Each NPC case was matched with a control using the size of the largest involved node as the matching criterion. The median follow-up of all 208 patients was 3 years (4.2 years in NPC cases and 1.4 years in the matched controls). For those who were alive at last follow-up, the median follow-up for both arms was 7.7 years (6.7 years in NPC cases and 10.2 years in the matched controls). Nodal control was evaluated by clinical neck examination in both arms. Nodal recurrence was defined as relapse or persistence of metastatic nodal disease from day 1 of radiotherapy treatment. RESULTS: Despite a similar mean delivered dose to involved neck nodes (52.9 Gy for the NPC group and 53.9 Gy for the matched controls), the SCC group had significantly worse nodal control with radiation when compared to the NPC group (p < 0.0001, relative risk 3.0, 95% [1.8, 5.1]). The 3-year nodal recurrence-free rate among NPC cases was 71 +/- 5%, compared to 43 +/- 5% among matched controls. CONCLUSION: The result of this study supports the hypothesis that metastatic cervical nodes from NPC are more readily controlled by irradiation than cervical nodes of similar size arising from other head and neck squamous cell carcinomas. Further study is required to explore the reasons for this apparent radiosensitivity.

Labeling of monoclonal antibodies with samarium-153 for combined radioimmunoscintigraphy and radioimmunotherapy.

The labeling of a monoclonal antibody K-1-21 with 153Sm has been investigated using the bifunctional chelate cyclic diethylenetriaminepentaacetic acid (DTPA) anhydride. Labeling efficiencies greater than 60% were obtained using high specific activity [153Sm]chloride and a cDTPAa:MAb conjugation ratio of 20:1. The resultant labeled antibody had a s.a. greater than 150 MBq.mg-1 and a % retained immunoreactivity greater than 90%. Imaging and biodistribution studies in a rat model demonstrated that specific uptake of 153Sm-K-1-21 into s.c. implants of the target antigen could be clearly detected in scintigrams at 6 days p.i. The specific uptake (1.90 +/- 0.45% ID/g, 19.95 +/- 2.20 Implant:Blood ratio) compared favorably to 131I- and 111In-labeled K-1-21 (2.52 +/- 0.20 and 3.33 +/- 0.20% ID/g, 7.69 +/- 0.45 and 10.10 +/- 0.60 I:B, respectively). Labeling of MAbs with 153Sm for combined scintigraphy/therapy is feasible at clinically appropriate specific activities using cDTPAa, with the resultant conjugates retaining immunoreactivity and in vivo antigen localization.

Chimpanzees (Pan troglodytes) are predominantly right-handed: replication in three populations of apes.

Population-level right-handedness has historically been considered a hallmark of human evolution. Even though recent studies in chimpanzees (Pan troglodytes) have demonstrated population-level right-handedness for certain behaviors, some have questioned the validity and consistency of these findings by arguing that reported laterality effects are specific to certain colonies of apes and to those chimpanzees reared by humans. The authors report evidence of population-level right-handedness in 3 separate colonies of chimpanzees. Moreover, handedness in the 3 colonies was unrelated to the proportion of subjects that were raised by humans. This is the strongest evidence to date that population-level handedness is evident in chimpanzees and is not an artifact of human rearing.

An evaluation of the pharmacokinetics, pharmacodynamics, and dialyzability of verapamil in chronic hemodialysis patients.

The pharmacokinetics and pharmacodynamics of verapamil were investigated in six chronic hemodialysis patients. A single oral 120-mg dose was administered both on a non-hemodialysis day and a hemodialysis day separated by greater than or equal to 7 days. Blood pressure and PR interval were measured simultaneously with each blood sample. Plasma verapamil and norverapamil concentrations were analyzed by high pressure liquid chromatography. The mean Cmax, tmax, AUC, apparent plasma clearance, and terminal t 1/2 were 190 +/- 108 ng/mL, 0.6 +/- 0.2 hour, 676 +/- 443 ng.hr/mL, 3926 +/- 1933 mL/min, and 11.4 +/- 4.0 hr, respectively, on the nonhemodialysis day. The dialysis clearance of verapamil and norverapamil was negligible. The t 1/2 during hemodialysis was 3.6 +/- 1.1 hr, compared with 3.4 +/- 0.7 hr during the same period of time postdose on the nonhemodialysis day (NS, P greater than .05). Systolic and diastolic blood pressure decreased for up to 4 hours postdose, whereas the PR interval tended to increase. Conclusions include: (1) the single oral-dose pharmacokinetics and pharmacodynamics of verapamil in chronic hemodialysis patients are similar to published data in normal subjects and cardiac patients and (2) verapamil and norverapamil are not significantly removed by hemodialysis, so that supplemental doses are not necessary.

Disposition of intravenous amiodarone in subjects with normal and impaired renal function.

In a study designed to determine the influence of renal dysfunction on the disposition of amiodarone and its metabolite, desethylamiodarone (DEA), 30 subjects received a single 5 mg/kg intravenous dose of amiodarone over 15 minutes. Of the 30, 11 had normal renal function (group I; mean +/- SD glomerular filtration rate [GFR] = 118 +/- 20 mL/min/1.73 m2), 9 had renal impairment (group II; GFR = 23 +/- 10 mL/min/1.73 m2), and 10 were long-term hemodialysis patients (group III; 4 of these patients were studied during dialysis). Total and free concentrations of amiodarone and DEA were measured by high-performance liquid chromatography. There were no significant differences between the three groups in mean systemic clearance, steady state volume of distribution, or mean residence time of amiodarone. However, the area under the concentration-time curve (AUC) for amiodarone was significantly higher in group I than in group II, and this finding was related to total body weight. Free fraction was similar in groups I and III. The disposition of amiodarone and its metabolite DEA was similar in patients with normal renal function, moderate renal dysfunction, and end-stage renal disease. Thus, dosage adjustment in patients with renal impairment is not necessary based on this pharmacokinetic analysis.

Lactation length in three species of Galago.

Milk expression was used to determine lactation length in three species of Galago at the Duke University Primate Center. Lactation length in G. senegalensis moholi was significantly shorter than the lactation length of either G. garnettii or G. crassicaudatus, but lactation length did not differ between G. garnettii or G. crassicaudatus. Litter size had no significant effect on lactation length. The lactation lengths determined in this study are substantially longer than those reported by investigators who used observational techniques. These discrepancies may be partially explained by failure to observe nursing during the diurnal inactive period.

Lactation and care for unrelated infants in forest-living ringtailed Lemurs.

An adult female ringtailed lemur (Lemur catta) known not to have been pregnant showed spontaneous lactation in response to twin infants born to an unrelated female. The females had met only 7 months earlier, when they and two other unrelated adult females were released from separate locations in a forest enclosure to form a new social group. Three months after release, an adult male from an adjacent enclosure gained access to the new group for 1 day, the day of one female's estrus. No males had access to the females throughout the remainder of the breeding season. Within 2 weeks of the birth of the twins, one of the other adult females began carrying the infants frequently, typically one at a time. All three females were checked for lactation when the infants were two months old. Both their mother and the unrelated adult who had been carrying the infants were producing milk. The third adult female, who never carried either infant, had no milk. The third adult female, who never carried either infant, had no milk. This female, however, like the two maternal females, frequently attacked unfamiliar immigrating adult males when the males approached the infants. Potential implications of these observations concerning the social organization of ringtailed lemurs are discussed.

Reproduction in the slender loris (Loris tardigradus malabaricus).

A breeding colony of slender lorises (Loris tardigradus malabaricus) was studied to obtain data for comparison with other prosimian species, to contribute reproductive information for improving management of captive lorises, and to resolve some uncertainties in the literature regarding reproduction in the slender loris. At the Duke University Primate Center, a female slender loris reached sexual maturity at approximately ten months of age and conceived at one year of age. The length of the estrous cycle was 29-40 days, with copulation occurring over two consecutive days during estrus. Gestation length was 166-169 days. Litter size for each six births was one. Conception did not occur during an immediate post-partum estrus, but four months after birth, resulting in a 9 1/2-month interbirth interval. There was no evidence of reproductive seasonality. Lactation lasted between five and seven months. Reproductive rates of slender lorises are among the lowest of primates less than 500 g. Differences in reproductive parameters may exist between different subspecies of slender lorises.

Isolation of females prior to parturition reduces neonatal mortality in Galago.

Eighteen years of birth records for three species of Galago at the Duke University Primate Center were examined to determine the effects of isolation of pregnant females on neonatal mortality rates. Isolation significantly decreased neonatal mortality rates in all three species over neonatal mortality rates in infants born to unisolated females. The frequency of cannibalism of infants did not differ between isolated and unisolated females. Secondary sex ratio differed significantly from 1:1 for all three species, but higher mortality in males in the first 10 days of life resulted in sex ratios that did not differ from 1:1 in G. garnettii and G. crassicaudatus.

Description of ultrasonic vocalizations of the mouse lemur (Microcebus murinus) and the fat-tailed dwarf lemur (Cheirogaleus medius).

Ultrasonic (>20 kHz) vocalizations were recorded from two species of prosimian primates, Microcebus murinus and Cheirogaleus medius. Three types of ultrasonic calls were emitted by isolated or paired M. murinus: 1) "chirps," short-duration (30 msec) calls with a sharp onset at 40 kHz followed by rapid and steep declines in frequency and intensity; 2) "twitters," characterized by a brief pulse at 25 kHz prior to the onset of repeating, frequency-modulated units; and 3) "long whistles," monotone signals with a frequency of 20 kHz. Partially ultrasonic "whines" were recorded from C. medius during interactions between mothers and infants. These calls began with a short, high-intensity component at 25 kHz and then dropped gradually in frequency before leveling off at 15 kHz. Study of the acoustic behavior and the structure of vocalizations in these species may lead to a better understanding of animal communication at high frequencies.

Reproduction in the slow loris (Nycticebus coucang).

The reproductive biology of the slow loris (Nycticebus coucang) is poorly documented because of infrequent captive breeding success and the absence of field studies of this species. Reproductive data were collected from a breeding colony of slow lorises held at the Duke University Primate Center for the past 10 years. Nineteen infants were born, with a sex ratio of 1:1 and a neonatal mortality rate of 15.8%. In all cases, litter size was one. Females born in the colony copulated for the first time between 18 and 24 months of age. A male that reached sexual maturity in the colony sired his first offspring at the age of 17 months. Estrous cycles ranged in duration from 29-45 days, with copulations usually occurring for 1 day of estrus. Gestation length averaged 192.2 days. Although a postpartum estrus was observed in three cases of infant death, no conceptions resulted. Lactation lasted approximately 6 months. A clear birth peak was observed, with 12 out of 19 births occurring in March, April, and May. The comparatively low basal metabolic rate of this species may account for the unusually low reproductive rate of the slow loris in comparison with other prosimian primates.

Reproduction in Coquerel's dwarf lemur (Mirza coquereli).

Most nocturnal Malagasy primates, as well as many diurnal species, are highly endangered in their natural habitat. Captive breeding programs have been established for many species, but detailed information on reproduction is only available for three nocturnal taxa: the mouse lemur (Microcebus murinus), the dwarf lemur (Cheirogaleus medius), and the greater dwarf lemur (Cheirogaleus major). In this study, we present data for another nocturnal Malagasy primate, Coquerel's dwarf lemur (Mirza coquereli), which has been propagated since 1982 at the Duke University Primate Center. Unlike all other Malagasy primates bred in captivity, M. coquereli cycles throughout the year, and is clearly less seasonal in its birth distribution than is C. medius or M. murinus. Estrous intervals ranged between 19 and 30.5 days. Estrus lasted no longer than 1 day. After an average gestation length of 89.2 days, litters of one or two were born. Females cycled for the first time between 8 and 15 months of age, and gave birth for the first time between 12.8 and 33.5 months of age. The earliest mating of a male leading to conception was observed at the age of 17 months. For males and females, an increase in daylength appears to trigger pubertal development. Males had seasonal changes in testicular volume which were not explained by covariation with body weight. Maximum testis size occurred in spring, when breeding activity was highest. The occurrence of year-round reproduction in M. coquereli, and the absence of seasonal fattening and/or hibernation, along with their specialized winter diet, may be correlated. © 1995 Wiley-Liss, Inc.

Gestation length in Tarsius bancanus.

A gestation length of 178 days was determined for Tarsius bancanus based on a vaginal smear containing whole sperm. This value replaces the only previously reported information on gestation length in tarsiers, a rough estimate of approximately 6 months for T. syrichta.

Reproductive cycles in Tarsius bancanus.

The reproductive condition of three pairs of Bornean tarsiers (Tarsius bancanus) was documented for 16 months. Each pair was housed separately under a constant photoperiod (L:D = 11.5:12.5) similar to that in their native habitat. Reproductive cycles of females were monitored visually for 6 months and were then monitored with vaginal smears and measurements of external genitalia for an additional 10 months. Progressive proliferation and cornification of vaginal epithelial cells during proestrus and estrus was accompanied by an enlargement of the external genitalia. Cycle lengths averaged 24.0 ± 3.2 days. The external genitalia were swollen each cycle for a period of 6-9 days. Copulations occurred on the 1st day of estrus, which lasted 1-3 days. No menstruation was observed. There was no evidence of seasonality of estrous cycles with this photoperiod. Testicular measurements of males showed no overt seasonal changes. There was variation in testicular size, and one male copulated at a range of testicular sizes. The data indicate that T. bancanus has estrous cycles similar to those of prosimian primates and some New World monkeys and that these cycles occur throughout the year under constant photoperiodic conditions.

Application of fecal steroid techniques to the reproductive endocrinology of female verreaux's Sifaka (Propithecus verreauxi).

Solid phase extraction, high performance liquid chromatography, and radioimmunoassay were used to test the validity of fecal steroid analysis for assessing ovarian function in sifaka (Propithecus verreauxi). Daily fecal samples were collected over a 4 month period from two cycling female sifaka, and single samples were collected from females during normal gestation and males while housed at the Duke University Primate Center. Tests of radioimmunoassay validity indicated that solid phase extraction and microradioimmunoassay techniques were reliable and accurate methods for quantifying ovarian steroids in sifaka feces. The progesterone (P4 ) antibody specifically quantitated only P4 , while several estrogen metabolites made small contributions to immunoreactive measures of estradiol (E2 ). A 1:10 dilution reduced these contributions to 3-15% of the estimated E2 concentration. Although the spectral data suggested that E2 was not the major metabolite present, it accounted for the majority of the immunoreactivity at normal assay dilutions. Fecal profiles of immunoreactive E2 and P4 in the conceptive female resembled serum profiles of other strepsirhines. E2 and P4 were elevated at the end of the conceptive cycle and were more markedly increased in late pregnancy in the two pregnant females. Mating behavior and indices of sexual interest were observed in conjunction with E2 peaks, although not all peaks were accompanied by observations of sexual behavior. © 1995 Wiley-Liss, Inc.

The effects of bull urine on puberty and calving date in crossbred beef heifers.

The effects of bull urine on the percentage of heifers reaching puberty and on subsequent calving dates were examined with 52 crossbred beef heifers. Heifers were palpated for ovarian condition and classified as prepubertal or pubertal before (Palpation I) and after (Palpation II) eight weekly oronasal treatments with bull urine or water. A larger percentage of urine-treated than water-treated heifers reached puberty during the experimental period (67 vs 32%; P less than .05), supporting the hypothesis that bull urine contains a priming pheromone. Body weight of urine-treated heifers that did not reach puberty by Palpation II was lower than that of water-treated heifers that did not reach puberty (P less than .05), indicating that an association exists between body weight and the response to pheromonal cues in bull urine. There were no treatment differences in pregnancy rate after a 90-d breeding period, and no differences in pregnancy rate between heifers that had reached puberty before the breeding season started and heifers that had not reached puberty. Urine-treated heifers reaching puberty during the experiment calved earlier (P less than .05) in the calving season than did water-treated heifers of the same category. The distribution of these calvings was also different (P less than .01), resulting in a shorter calving season for urine-treated heifers. More heifers that had reached puberty by Palpation II calved in the first 20 d of the calving season that did heifers that had not reached puberty by Palpation II, regardless of treatment group (P = .02). There was a tendency for urine-treated heifers to calve earlier than water-treated heifers, with the exception of urine-treated heifers that had not reached puberty by Palpation II. These data support the hypothesis that there is a priming pheromone in bull urine that can hasten the onset of puberty in beef heifers.