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The Excretion of Caffeine in the Semen of Men: Pharmacokinetics and Comparison of the Concentrations in Blood and Semen
Abstract
The concentration of caffeine in the blood and semen of men was measured after an oral dose of 200 or 400 mg caffeine. Caffeine was rapidly absorbed (mean tmax = 0.76 +/- 0.12 hour), with an average maximum concentration in the blood of 7.4 micrograms/ml for the 400-mg dose and 3.4 micrograms/ml for the 200-mg dose. The mean clearance of caffeine was 161 and 156 ml/min, while the mean volume of distribution was 50 and 47 liters for the 400- and 200-mg doses, respectively. Distribution of caffeine into the semen was rapid, with a concentration of caffeine in the semen almost identical to that observed concurrently in the blood (blood/semen concentration ratio = 0.97). The mean half-life of caffeine in the blood and semen was 3.7 and 3.6 hours, respectively, indicating that the decline of caffeine in the blood is very similar to that in semen. Thus, caffeine partitions rapidly into and out of the prostatic and seminal vesicular secretions, which contribute to the formation of the ejaculate.
- ... However, a study on rats found that prenatal administration of theophylline (a caffeine metabolite) resulted in failure of development of seminiferous cords and, as a consequence, Leydig cells (Pollard et al., 2001). Caffeine concentrations in blood and semen are almost identical (Beach et al., 1984), and a few studies have assessed the association between current male coffee consumption and semen quality with conflicting results: the results from the cross-sectional studies of Oldereid et al. (1992) and Horak et al. (2003) suggest no association, whereas results from the studies of Adelusi et al. (1998), Marshburn et al. (1989) and Sobreiro et al. (2005 indicate that coffee consumption is associated with increased sperm motility. Vine et al. (1997) found weak evidence for an association between caffeine intake from coffee, tea and soft drinks and sperm nuclear morphometry, and Parazzini et al. (1993) found increasing risk of poor semen quality with increasing coffee consumption. ...A few studies have investigated the association between male caffeine consumption in adult life and semen quality with conflicting results, but so far no studies have explored the effect of prenatal coffee exposure. We studied the association between prenatal coffee and current caffeine exposure and semen quality and levels of reproductive hormones. From a Danish pregnancy cohort established in 1984-1987, 347 sons out of 5109 were selected for a follow-up study conducted 2005-2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones and were related to information on maternal coffee consumption during pregnancy and present caffeine consumption. Data were available for 343 men. There was a tendency toward decreasing crude median semen volume (P = 0.06) and adjusted mean testosterone (P = 0.06) and inhibin B (P = 0.09) concentrations with increasing maternal coffee consumption during pregnancy. Sons of mothers drinking 4-7 cups/day had lower testosterone levels than sons of mothers drinking 0-3 cups/day (P = 0.04). Current male caffeine intake was associated with increasing testosterone levels (P = 0.007). Men with a high caffeine intake had approximately 14% higher concentration of testosterone than those with a low caffeine intake (P = 0.008). The results observed in this study are only tentative, but they do not exclude a small to moderate effect of prenatal coffee exposure on semen volume and levels of reproductive hormones. Present adult caffeine intake did not show any clear associations with semen quality, but high caffeine intake was associated with a higher testosterone concentration.
- Progressive deterioration of male reproductive function is occurring in Western countries. Environmental factors and unhealthy lifestyles have been implicated in the decline of testosterone levels and sperm production observed in the last fifty years. Among unhealthy lifestyles, substance and drug abuse is a recognized cause of possible alterations of steroidogenesis and spermatogenesis. Alcohol, opioids and anabolic-androgenic steroids are capable to reduce testosterone production in male interfering with testicular and/or hypothalamic-pituitary function. Other substances such as nicotine, cannabis, and amphetamines alter spermatogenesis inducing oxidative stress and subsequent apoptosis in testicular tissue. Substance and drug abuse is a potentially reversible cause of hypogonadism, defined as the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa. The identification of the abuse is important because the withdrawal of substance intake can reverse the clinical syndrome. This review summarizes the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production.
- Caffeine is a widely recognized psychostimulant compound with a long history of consumption by humans. While it has received a significant amount of attention there is still much to be learned with respect to its toxicology in humans, especially in cases of overdose. A review of the history of consumption and the clinical toxicology of caffeine including clinical features, pharmacokinetics, toxicokinetics, a thorough examination of mechanism of action and management/treatment strategies are undertaken. While higher (i.e., several grams) quantities of caffeine are known to cause toxicity and potentially lethality, cases of mainly younger individuals who have experienced severe side effects and death despite consuming doses not otherwise known to cause such harm is troubling and deserves further study. An attempted case reconstruction is performed in an effort to shed light on this issue with a focus on the pharmacokinetics and pharmacodynamics of caffeine.
- Der Diskurs, ob Koffein gesundheitsfördernd oder gesundheitsschädlich sei, zieht sich schon über Jahrhunderte. Während in den letzten Jahren Meldungen über wissenschaftliche Studien, die positive Auswirkungen des Koffeinkonsums herausgefunden haben wollen, in den Medien stets präsent sind, tauchen jene, die über negative Auswirkungen berichten, kaum auf. Obwohl diese Studien selbstverständlich den gleichen wissenschaftlichen Interpretationsschwierigkeiten unterliegen, sollten sie genauso ernst genommen werden wie jene über die gesundheitsfördernde Wirkung. – Denn Koffein kann uns von der Zeugung bis ins Erwachsenenalter unter bestimmten Umständen auch schaden.
- Semen analysis results from over 750 fathers in the USA demonstrated marked differences in the quality of semen from men at different locations and of different ethnic groups. Another paper failed to demonstrate any effects of moderate alcohol consumption during the week before provision of an ejaculate on semen quality and few on serum hormones, of over 8300 men in Europe and the USA. While these observations are interesting, the reasons for regional and ethnic differences in semen quality of fathers are unclear. Although, there was no attempt to confirm the participant-provided level of alcohol consumption, an increase in serum testosterone in the men at the higher end of alcohol intake is compatible with an alcohol effect on liver metabolism, although whether alcohol intake was the cause of higher testosterone, or men with higher androgen levels consume more alcohol, is not known.
- The kinetics of caffeine elimination were investigated in 10 normal male subjects and in 11 recovering alcoholics before and during disulfiram dosing. In normal subjects the total body clearance of caffeine declined 30% (142 to 99 ml/min) at the maintenance dose of disulfiram, 250 mg/day, and 29% (161 to 114 ml/min) at the loading dose of 500 mg/day. In recovering alcoholics, the total body clearance decreased from 333 to 253 ml/min, a 24% change. The mean caffeine t½increased 39% and 34% in normal subjects after 250 and 500 mg disulfiram, respectively, and 29% in recovering alcoholics. The inhibition of caffeine elimination was moderate in most subjects. However, the clearance of caffeine decreased by 50% after disulfiram in three of the 11 recovering alcoholics. These patients may have an increased risk of cardiovascular and cerebral excitation associated with higher concentrations of caffeine, which could complicate withdrawal from alcohol.
- A gas chromatographic procedure is reported for the determination of caffeine in plasma, saliva, and xanthine beverages. Using a 75 cm column packed with OV-17, nitrogen-sensitive detection, and 1 ml samples, a suitable limit of analysis (coefficient of variation (CV)=10.2%) of 50 ng/ml was obtained in plasma. Within-day CVs at caffeine concentrations of 0.1−0.5−2.0−7.5−15.0 μg/ml in plasma were 7.7−5.6−4.8−3.8−3.4%, respectively. The limit of detection, defined as the injected quantity of caffeine giving rise to a signal to noise ratio of 2, is 40 pg, corresponding to a plasma concentration of 1 ng/ml. The procedure involves addition of the internal standard 7-pentyl theophylline and alkaline extraction of the sample with dichloromethane. The method described rivals any gaschromatographic assay published so far in rapidness and accuracy. Plasma and saliva caffeine concentrations were determined in a healthy male volunteer after swallowing 400 ml of coffee. The calculated pharmacokinetic parameters, assuming complete absorption of caffeine from the G.I. tract, agree well with previously published values.
- The study was undertaken to determine the distribution of aspirin and its metabolites in the semen of humans after an oral dose of aspirin. Each of seven healthy male volunteers was given a single oral dose of 975 mg of aspirin on an empty stomach together with 200 mL of water. Timed samples of blood and semen were obtained from each subject, and the concentrations of aspirin, salicylic acid, and salicyluric acid determined by a specific high-performance liquid chromatographic assay. The mean peak concentration of aspirin was 6.5 micrograms/mL in plasma (range, 4.9-8.9 micrograms/mL), reached in 26 minutes (range, 13-33 minutes). The half-life of aspirin was 31 minutes. The concentration ratio of aspirin (semen/plasma) was 0.12 (except for one subject in whom it was 0.025). The mean peak concentration of salicylate in plasma was 49 micrograms/mL (range, 42-62 micrograms/mL), reached in 2.5 hours (range, 2.0-2.8 hours). Salicylate distributed rapidly into semen and maintained a concentration ratio (semen/plasma) of 0.15. Salicyluric acid (the glycine conjugate of salicylic acid) was found in the semen. Its high concentration in some subjects' semen (four times the concurrent plasma concentration) was attributed to contamination of semen sample with residual urine, containing salicylurate, in the urethra of those who urinated after the dose of aspirin. Possible side effects of aspirin and salicylate in semen include adverse effects on fertility, male-medicated teratogenesis, dominant lethal mutations, and hypersensitivity reactions in the recipients.
- The acute effect of a single oral dose of methoxsalen on the pharmacokinetics of caffeine was investigated in five nonsmoking volunteers with psoriasis. Caffeine, 200 mg orally, was administered to each subject at baseline before treatment with methoxsalen. One week later each subject was given a single oral dose of 1.2 mg/kg methoxsalen 1 hour before administrations of another oral dose of 200 mg caffeine. The clearance of caffeine declined markedly from 110 +/- 17 ml/min (mean +/- SE) in the control study to 34 +/- 5 ml/min after methoxsalen. During the period of maximum inhibition the mean elimination half-life of caffeine increased from 5.6 hours at baseline to 57 hours after administration of methoxsalen. The peak concentration of caffeine and the time to reach the peak concentration of caffeine were not affected by pretreatment with methoxsalen. Thus, methoxsalen, administered acutely, is a potent inhibitor of caffeine metabolism in humans with psoriasis. Results of this investigation suggest that the elimination of concurrently administered drugs may be inhibited in patients receiving methoxsalen. In comparison with other drugs, methoxsalen is the most potent inhibitor of drug metabolism in humans. Other work has shown that inhibition of drug metabolism by methoxsalen is associated with both extensive covalent binding of metabolite(s) of methoxsalen to liver microsomal protein in vitro and in vivo and inactivation of cytochrome P-450.
- The effect of finger tremor of the administration of 150 mg of caffeine three times daily for two days was measured using an accelerometer in 7 healthy subjects taking their normal diet (excluding caffeine-containing beverages). The effect on finger tremor of a short period of fasting with and without the 450 mg daily dose of caffeine was also studied in the same 7 subjects. Fasting increased finger tremor significantly when caffeine was administered. In doses comparable to the likely adult daily intake in this country, caffeine did not increase finger tremor whilst subjects were taking their normal diet.
- A single dose of 80 mg racemic propranolol hydrochloride was administered by mouth to six healthy male volunteers. The mean concentration achieved in seminal plasma at 2 h after dosing was almost identical to that in blood serum. The concentrations of propranolol in seminal plasma and saliva were much less than those known to reduce sperm motility by 50% in vitro. The concentrations in saliva did not reflect those in blood serum. Propranolol in the dose administered in this study is unlikely to affect fertility by its presence in saliva or semen.
- Over the past 50 years, a decline in the quality of semen has been observed, possibly resulting in a reduction in male fertility. Among the factors affecting semen quality, exposure to drugs is of particular importance. It is known that drugs can be transported to the seminal plasma, which is made up of secretions from the various accessory genital glands. There is evidence that many drugs enter the male genitourinary tract by an ion-trapping process. Lipid solubility and the degree of ionisation of the drug, which depend on the pH of plasma and seminal fluid, are important factors in this process. To date, few studies have been conducted on this topic. Pharmacokinetic evaluation of the fluids of the male accessory gland have been performed in the case of chloroquine and caffeine only, while the effects of mesalazine (5-aminosalicylic acid), sulfasalazine, salicylate, propranolol, diltiazem, flunarizine, verapamil, caffeine and nicotine on sperm physiology and morphology have been examined. Although data from the literature are scarce and incomplete, it is evident that many drugs can be excreted into semen. These drugs may interfere with the most common semen characteristics, potentially resulting in a male-mediated teratogenic effect, or local and systemic responses in female recipients. Therefore, it may be advisable to include, in the processes of drug development, pharmacokinetic evaluation of a drug in the semen and analysis of standard microscopic parameters of the semen. This is particularly important for drugs known to concentrate in the semen.
- Determination of the concentration of drugs and metabolites in biological fluids or matrices other than blood or urine (most commonly used in laboratory testing) may be of interest in certain areas of drug concentration monitoring. Saliva is the only fluid which can be used successfully as a substitute for blood in therapeutic drug monitoring, while an individual’s past history of medication, compliance and drug abuse, can be obtained from drug analysis of the hair or nails. Drug concentrations in the bile and faeces can account for excretion of drugs and metabolites other than by the renal route. Furthermore, it is important that certain matrices (tears, nails, cerebrospinal fluid, bronchial secretions, peritoneal fluid and interstitial fluid) are analysed, as these may reveal the presence of a drug at the site of action; others (fetal blood, amniotic fluid and breast milk) are useful for determining fetal and perinatal exposure to drugs. Finally, drug monitoring in fluids such as cervical mucus and seminal fluid can be associated with morpho-physiological modifications and genotoxic effects. Drug concentration measurement in nonconventional matrices and fluids, although sometimes expensive and difficult to carry out, should therefore be considered for inclusion in studies of the pharmacokinetics and pharmacodynamics of new drugs.
- The seminal excretion, plasma elimination, tissue distribution and metabolism of naltrexone in the rabbit
- Taylor SM
- Rodgers RM
- Lynn RK
- Gerber N.
- Food and Drug Administration News Release No. P80-36
- Goyen JE
- Excretion of primidone and its active metabolites in the semen of rabbit and man
- Kaufman SN
- Lynn RK
- Gerber N.
- The excretion of carbamazepine in the semen of the rabbit and man: comparison of the concentration in semen and plasma
- Rimerman RA
- Taylor SM
- Lynn RK
- Rodgers RM
- Gerber N.
- Coffee and birth defects
- Jacobson MF
- Goldman AS
- Syme RH
- Excretion of methadone in semen from methadone addicts; comparison with blood levels
- Gerber N
- Lynn RK
- Disposition of caffeine in the rabbit
- Beach CA
- Sterman BM
- Bianchine JR
- Gerber N.
- Male sexual dysfunction during treatment with cimetidine
- Preden NR
- Cargill JM
- Browning MC
- Saunders JB
- Wormsley KG
- Dipropylacetic acid (VPA, valproic acid) has been quantified in plasma and semen from rabbits and man using a new gas-liquid chromatographic assay. The drug assay is rapid, sensitive and free from interference by VPA metabolites. The β phase half-life of VPA in rabbits after an i.v. dose (50 mg/kg) was 56 ± 6 min. The concentration of VPA in rabbit plasma was 17 to 30 times the concentration in rabbit semen. In man, 500 mg doses of the free acid, p.o., resulted in VPA concentrations in plasma that were 11 to 17 times the concurrent levels in semen. VPA, in concentrations up to 10⁻³ M, did not influence the motility of rabbit spermatozoa in vitro.
- A population of CD-1 mice has been bred for four generations with continuous ingestion of caffeine. Three caffeine levels (and a control) were used with intakes averaging 4–5, 12–18 and 25–39 mg/kg/day (25–39 mg/kg/day is equivalent to 19–30 cups of coffee in man). At each level 20 pairs of animals were bred in each generation, the F1 matings being divided between brother-sister matings and out-crosses. F2's and F3's were out-crossed. There were no consistent, dose-related effects of caffeine on fertility, age at sexual maturity, mean litter size, weight of offspring at weaning, sex ratio or fetal abnormalities. A few pairs at the highest caffeine level failed to produce litters, but only in the F1 brother-sister and in the F3 matings. Litters in the caffeine-treated series showed a somewhat higher incidence of underweight animals in the F2 and the F3 generations, but not in a dose-related way. A difference in sex ratios (males slightly predominating) in the caffeine-treated groups compared to the control groups is related to an apparent deficit of male births in the control groups rather than to an effect of caffeine. In this study 3824 caffeine-exposed offspring (352 litters) were examined at birth for birth defects and 1365 of these (147 litters) were reexamined at weaning age. The only defect observed was in one litter (of F2 offspring from out-cross parents receiving the middle dose of caffeine) with a digital abnormality. This low frequency of abnormal offspring is consistent with control group experience. Further litters from the same parental pair continued on caffeine showed no abnormalities. These studies in the mouse, thus support the safety of caffeine in relatively high doses during reproduction.
- The concentration of phenytoin (diphenylhydantoin, DPH) was measured in plasma and semen of rabbits and man. In the rabbit, a single iv injection of DPH (4.64 mg) resulted in a concentration-time curve for DPH in semen parallel to the concentration-time curve for DPH in plasma (t1/2beta = 171 +/- 29 min). A semen/plasma drug concentration ratio of 0.20 was maintained for at least 8 hr, demonstrating that DPH concentrations in semen are directly proportional to DPH concentrations in plasma. In epileptic subjects maintained on oral DPH the mean drug concentration in semen was 2.31 microgram/ml while that in plasma was 13.8 microgram/ml. The mean semen-plasma DPH concentration ratio in man was 0.17; this closely approximates the observed ratio in rabbits.
- Preservation of human semen in liquid nitrogen causes a significant impairment of sperm motility. Ejaculated human spermatozoa show an increased motility in the presence of caffeine, a phosphodiesterase inhibitor, and pancreatic kallikrein (EC 3.4.21.8), a kinin-producing proteinase. Hence, the effect of both substances on post-thaw motility, fructose consumption, and cervical mucus penetration of cryo-preserved human spermatozoa was investigated. The results indicate that both substances stimulate the motility of freshly ejaculated spermatozoa and also improve the motility pattern of cryo-preserved human spermatozoa, thus offering a possible means of improving the quality of freeze-preserved human semen.
- Principal investigations on the genetic effects of caffeine alone and in combination with known mutagens, as well as effects on repair systems that may contribute to overall mutagenicity, are reviewed. Major emphasis is placed on studies in higher eukaryotes dealing with the ability of caffeine to induce point mutations and chromosome breaks in plants, Drosophila, rodents, and humans. Although caffeine appears not to induce point mutations in all plant systems studied, consistent positive results have been obtained on induced chromosome breakage, and a synergistic effect on breakage induced by known chemical mutagens was demonstrated. Data in Drosophila from tests assaying for induced recessive lethals and nondisjunction have produced conflicting results, but consistent low level effects of caffeine on chromosome loss (presumably breakage) in both male and female germ cells appears well documented. In rodent cell cultures, there appears to be no evidence that caffeine induces point mutations; on the other hand, caffeine induces chromosome breakage, and potentiates breakage induced by a variety of chemical mutagens. Post-UV-irradiation exposure to caffeine has been reported, in rodent cell cultures, to reduce the UV-induced frequency of mutations. However, further experimental work indicates that caffeine induces a dose-dependent delay in the expression of UV-induced mutations rather than bona fide antimutagenic effects. Results from dominant lethal tests in rodents suggest: (a) no demonstrable effect of caffeine in F1 hybrid strains; (b) a low level effect at certain doses in some inbred strains, and (c) no consistent effect in combination with known mutagens. Results were negative from a specific locus test using one dose of caffeine. On the other hand, in vivo cytogenetic studies provide evidence of a synergistic effect in caffeine-oxygen and caffeine-cyclophosphamide combinations in the only studies of this kind reported. In humans, one experiment testing a single dose of caffeine in vivo provided no evidence of an effect of break induction, and a 50% but non-significant increase in the frequency of gaps. Repeatable results have been observed demonstrating the ability of caffeine to induce chromosome breaks in in vitro human cell culture at doses higher than would be obtained from ingestion of caffeine-containing beverages (in HeLa cells, normal lymphocytes, and embryonic fibroblasts). However, only one publication deals with the effects of caffeine in human cell culture at doses approximating normal consumption and in the view of the present authors, with equivocal results. Meaningful assessment of the contribution that caffeine alone, or in combination with known mutagens, may make to the mutational load in man is therefore difficult since (a) negative in vivo data in humans is derived from one publication using one dose of caffeine and (b) experiments are yet to be carried out on a sufficiently large scale and with appropriate number of replicas to explore the possibility of a low level effect in normal human cell lines of (1) caffeine alone and (2) caffeine in combination with known mutagens. Experiments along these lines are especially desirable since, in view of its pervasive usage pattern, even if a weak positive genetic effect is found, the number of caffeine-induced (or promoted) mutations in somatic and germinal cells of the U.S. population ingesting caffeine could be considerable.
- Most of the population of the world is exposed to caffeine to a greater or lesser extent since it occurs in a number of plants used in the preparation of widely consumed drinks, and has in addition a limited therapeutic use. Chromosomal abnormalities are induced by caffeine in both plant cells and in mammalian cells in culture and it also has some anti-mitotic activity. DNA-repair processes sensitive to caffeine have been demonstrated in a number of cell systems and it has been shown to affect a wide range of other cellular processes. Caffeine has potent mutagenic effects in Escherichia coli and other micro-organisms both when acting alone and in combination with other mutagens. However its mutagenic activity in Drosophila has been disputed and the available evidence suggests that it is neither mutagenic in mammals nor synergistic with other mutagens although at very high doses it appears to have some teratogenic activity in mammals.
- Large groups of male Swiss mice received per os on average 100 mg caffeine per kg body weight per day for 1 or 8 weeks. The dominant lethal test was designed to achieve maximum sensitivity in order to detect any possible mutagenic effect. No mutagenic induction of dominant lethals, pre-implantation egg loss or depression of the fertility of females, caused by caffeine at the dose levels administered were observed. The half life of caffeine, which was between 2.5 and 3 h, was similar in plasma and testicular tissue. It was concluded that caffeine did not accumulate in the testicular tissue of mice. The maximum concentration of caffeine found was below 10 microgram/g testicular tissue, which is about a 100 times lower than concentrations that cause chromosome aberrations in cultured mammalian cells.
- The effect of ethanol feeding on testicular function and structure in adult male rats was studied in alcohol-fed animals, isocalorically fed controls, and weight-starved controls. Testicular weight was reduced by more than 50% in alcohol-fed animals compared to the control groups. Marked disruption of the histological appearance of the testes was observed in the alcohol-fed animals when compared to the controls. Specifically, there was prominent reduction in the mean seminiferous tubule diameter (P<0.01) and number of contained germ cells (P<0.01). Plasma levels of testosterone (P<0.01) were reduced in the alcohol-fed animals when compared to either of the two control groups. In contrast, plasma estradiol levels were reduced in the alcohol-fed and weight-starved animals when compared to those of the isocaloric controls (P<0.05). Plasma FSH levels in the alcohol-fed animals were twice those of the controls (P<0.01), while not difference in plasma LH levels was observed among the various groups. Acute alcohol infusion in castrate rats produced a significant reduction (P<0.05) in plasma LH and reduced the responses of both FSH and LH to LRF stimulation (P<0.05). LRF stimulation of castrate alcohol-fed rats was followed by an even greater reduction in the LH response (P<0.01). These results establish that: 1) ingestion of a diet containing 5% ethanol can produce gonadal atrophy and reduce plasma testosterone and estradiol levels in adult male rats; 2) such gonadal injury occurs despite the absence of important biochemical or structural liver disease and can not be ascribed to caloric deprivation associated with chronic ethanol ingestion; 3) ethanol infusion of castrate rats acutely reduces basal LH secretion and blunts the response of such rats to LRF; and 4) LRF responses of castrate rats chronically fed alcohol are markedly reduced when compared to those of either castrate isocaloric or weight-starved controls.
- Azoospermia was diagnosed in six factory workers who had been chronically exposed to 1,2-dibromo-3-chloropropane. Infertility was the presenting symptom in two patients and a decrease in libido or impotence characterized the others. Hormone studies revealed elevated plasma follicle-stimulating hormone levels and normal plasma luteinizing hormone and testosterone concentrations. Testicular biopsy showed selective atrophy of the germinal epithelium, intact Sertoli cells, and a normal appearance of a relatively increased number of Leydig cells.
- Fifteen male rats were treated with methadone-HCl (Meth) at 10 mg/kg sc per day for 12 days and an equal number received injections of sterile distilled water. Each male was caged with four untreated females each night. A necropsy was performed on male rats following the period of mating and the litter sizes, birth and weaning weights, and survival to 21 days (neonatal mortality) of their progeny were evaluated. METH-treated males had a reduction in body and seminal vesicle weights and in mating frequency, confirming prior studies. Progeny of METH-treated males (507 pups) were of lower average birth weight than the 276 controls. In addition, it was found that prior copulation had a differential effect, resulting in slightly heavier control pups but significantly decreased birth weights in the METH group. Neonatal mortality of the METH progeny was significantly increased, with 18.2% dead by 21 days compared to 9.5% of the controls (p < 0.01). The present data indicated that mortality was related in a complex fashion to number of drug exposures and previous sexual experience of the sire and that male offspring were particularly affected. Ponderal growth of survivors from litters with high neonatal death rates was inhibited, with females being significantly lighter at 75 and 132 days of age. Open-field defecation scores were significantly different at 2 but not at 4 months of age, but no differences in acquisition of a conditioned avoidance response were noted. No differences in litter size, neonatal mortality, or birth or weaning weights as a result of METH administration were found in the F2 generation. These results, together with previous data from our laboratory, establish that there are lethal, sublethal, and possibly delayed effects on the progeny of male rats treated with methadone.
- A population group consisting of 800 households of women who recently had been pregnant was surveyed to determine the level of consumption of a variety of beverages. Three fourths of the subjects were Mormon. Of a subgroup of 16 women identified as having an estimated daily intake of caffeine of 600 mg or greater, 13 had experienced a reproductive loss in the form of spontaneous abortion (eight) or stillbirth (five), two had given birth to premature infants, and only one had had an uncomplicated delivery. An inordinately high rate or reproductive loss also was noted in 13 households where the man's estimated daily intake of caffeine was greater than 600 mg. A cause-and-effect relationship cannot be determined by this type of retrospective study, but physicians should keep in mind the possibility that an excessive intake of caffeine may be a factor in otherwise unexplainable spontaneous abortion or perinatal mortality.
- METHADONE ((+/-)-4, 4-diphenyl-6-dimethylamino-3-heptanone hydrochloride) is a potent (addictive) analgesic with pharmacological effects which are qualitatively similar to those of morphine, although it is far more effective than morphine when given orally. Its ability to diminish the severity of the abstinence syndrome resulting from heroin withdrawal led to the introduction of methadone in the chemotherapy of narcotic addiction1-3. Little is known, however, about its long term toxicity effects. We report that treatment of male rats with either (+/-)-methadone HCl (METH) or morphine sulphate (MS), given orally, for 24 h before mating to untreated females increases the neonatal (21-d) mortality of their offspring.
- Caffeine administered to male mice acutely or for 8 wk prior to mating produced no mutagenic effect in the dominant lethal assay, as measured directly by increased early foetal deaths or indirectly by increased pre-implantation losses. Furthermore, neither acute nor 8-wk administration of caffeine synergized the effects of the known mutagens, methyl methanesulphonate, TEPA or X-rays.RésuméAdministrée à dose aiguë ou pendant 8 semaines à des souris mles, avant l'accouplement, la caféine n'a pas déterminé d'effet mutagène au cours de l'essai, essentiellement létal comme le prouvent directement les morts prématurées de foetus et indirectement l'augmentation des pertes de pré-implantations. De plus, ni la dose aiguë ni l'administration pendant 8 semaines n'ont eu d'interaction avec les effets de mutagènes connus, en l'occurrence le méthane-sulfonate de méthyle, le TEPA et les rayons X.ZusammenfassungMännlichen Mäusen akut oder auf die Dauer von 8 Wochen vor der Paarungszeit verabreichtes Koffein hatte keine mutagene Wirkung bei dem vorherrschend letal verlaufenen Versuch, die direkt durch die Feststellung vermehrten frühzeitigen Absterbens des Fetus oder indirekt durch Feststellung vermehrter Verluste befruchteter Eizellen vor der Implantation erfasst wurde. Ausserdem synergisierte weder die akute noch die 8wöchige Verabreichung von Koffein die Wirkungen der bekannten Mutagene Methylmethansulfonat, TEPA oder Röntgenstrahlen.
- Previous studies have shown that high dietary theobromine levels fed to rats results in testicular atrophy with changes in testicular cytology. An experiment was performed to determine whether these changes in rat testes are reversible. Proven breeder male rats were fed Purina lab chow containing 0, 0.2, 0.6, or 0.8% theobromine for 49 days. At that time, unilateral orchiectomy was performed on all rats. Testicular weights in the rats fed 0.6 and 0.8% theobromine-containing diets were significantly less than those from control rats and from rats fed 0.2% dietary theobromine (p < 0.01). The seminiferous tubules from rats fed the 0.6 or 0.8% theobromine diets showed extensive severe cellular degeneration and necrosis and contained many multinucleated cells. The interstitial tissue was edematous and there was evidence of apparent proliferation of arterioles. The rats were allowed to recover and were fed the diet without theobromine for an additional 49 days. Testicular weights of the rats given 0.6 and 0.8% dietary theobromine in the first 49-day period remained significantly below those of control rats and of rats fed 0.2% dietary theobromine (p < 0.01). Histologically, 70 to 90% of the seminiferous tubules from the rats given the two highest dietary levels of theobromine appeared almost deplete of well-formed spermatozoa. These results indicate that the theobromine-induced testicular injury appears to be irreversible over time in the affected seminiferous tubules.
- A blend of roasted and ground coffees was brewed and an instant coffee was prepared daily and given to rats in place of their drinking water, at either full-strength (100%) or as 50 or 25% dilutions. A control group was given water. The administration of the coffee solutions began shortly after weaning and continued for about 30 weeks, through two pregnancies. During pregnancy and lactation the caffeine intakes were approximately 80, 40, or 20 mg/kg/day, being slightly higher in the groups given brewed coffee and slightly lower in the groups give instant coffee. The parent rats given either brewed or instant coffee grew as well as or better than controls and ate more feed, although feed efficiencies were not different. The rats given full-strength coffees drank significantly less than controls, but the ones given 50 or 25% solutions drank more. Both male and female rats given 100% brewed or instant coffee to replace their drinking water had enlarged kidneys at 13 and 30 weeks, while only the females given 50% solutions of either coffee had enlarged kidneys. The females given full-strength coffees had enlarged livers at both times, while the females given 50% brewed coffee had enlarged livers only at 30 weeks. No effects on the organ weights were seen in the groups given 25% coffee solutions. No effects were seen on reproduction or lactation, except that the pups in the groups given 100% brewed or instant coffee to replace their drinking water weighed significantly less than the controls at weaning. Neither embryotoxicity nor frank teratogenicity was seen as a result of coffee ingestion. However, the fetuses in the groups given 100 or 50% solutions of the brewed coffee and 100% instant coffee in place of drinking water had a significantly higher incidence of unossified sternebrae, indicating a delay in calcification.
