Cardiac autonomic responses to transrectal examination and parlor milking of lame and non-lame dairy cows.

We studied the changes in the heart rate variability of lame and non-lame dairy cows in response to transrectal examination and parlor milking. We hypothesized that lame cows experience greater stress, manifested in heart rate variability parameters, which would serve as an argument to promote more caution in the everyday handling of lame animals. In the study, we selected 55 lame (with lesions on at least one hoof, otherwise clinically healthy, with locomotion scores 4 and 5 of 5 point scores) and 55 non-lame (clinically healthy, with locomotion scores 1 and 2 of 5 point scores) cows. The heart rate (HR), root mean square of successive beat-to-beat intervals (RMSSD), the normalized unit of the high-frequency component (HF) of the spectral analysis and Poincaré measures (SD2/SD1) were compared between lame and non-lame cows during five distinct stages of transrectal examination (TRE) and seven stages of parlor milking. HR, RMSSD, and SD2/SD1 showed similar patterns during TRE and milking, while HF remained fairly constant during the studied phases. No distinct RMSSD, HF or SD2/SD1 changes were observed during the phases expected to elicit a stress response. Between-group differences were only observed in terms of HF. Baseline HF was higher in lame cows than in non-lame ones, and such a difference in direction was observed throughout the whole procedure. During milking and TRE, the HR, RMSSD, and SD2/SD1 values showed temporal changes in times of higher physical activity: moving to and waiting in the holding pen and moving into the milking stalls in the parlor for preparation in both lame and non-lame cows. The differences in baseline HF (normalised units) between lame and non-lame cows can not be fully explained based on available information. The lack of a distinct, stress-related change in heart rate variability parameters in both groups can originate in methodological challenges inherent in animal heart rate variability measurements in field conditions.

Single-dose meloxicam treatment improves standing ability of low-vitality dairy calves.

A promising strategy to improve newborn calf survival could be the administration of nonsteroidal antiinflammatory drugs (NSAID) especially in cases of low vitality calves born from difficult calvings. The objective of this clinical trial was to determine the effect of a single-dose meloxicam treatment [target dosage = 0.5 mg/kg ad usum veterinarium (A.U.V.) injection] on parameters of lying behavior of Holstein-Friesian dairy calves (n = 180) born to eutocic (n = 98) compared with dystocic dams (n = 82). Animal-based measures included newborn calf vitality (low, 1-6 scores; normal, 7-12 scores, scored immediately after birth), calf sex and birth weight, parity of the dam, and early maternal behavior (the time spent licking the calf). Parameters of the complex lying behavior were recorded during the first 48 h after delivery and included (1) the time spent standing, (2) lying down frequency, (3) the longest standing bout, (4) the average duration of standing bouts, (5) the first successful standing, and (6) the first attempt to stand. None of the parameters related to lying behavior were influenced by the parity of the dam, calf sex, or birth weight and maternal grooming behavior. The latency and the first attempt to stand were not influenced by the NSAID treatment; however, the time spent standing, the longest standing bout, and the average duration of standing indicated increased standing ability of meloxicam-treated calves with low vitality, but not in normal-vitality calves. The latency to stand and first attempt to stand were both increased by dystocia. Based on the present findings, sensory measurement of parameters of lying behavior during the immediate neonatal period might be useful to evaluate the efficiency of NSAID protocols. A single-dose meloxicam treatment showed considerable promise for improving standing ability of low-vitality calves.

Cardiac vagal tone, plasma cortisol, and dehydroepiandrosterone response to an ACTH challenge in lame and nonlame dairy cows.

We studied the adrenocortical and vagal tone responses to a single ACTH challenge in lame (n = 9) vs nonlame (n = 9) dairy cows. Cows were paired according to parity, days in milk, and milk yield. Plasma cortisol and dehydroepiandrosterone concentrations and cardiac vagal tone response (high-frequency component of heart rate variability) were compared after intravenous ACTH administration. Baseline, minimum or maximum, amplitude of the response and area under the response curve were compared. No difference was detected between groups in the cortisol response. Dehydroepiandrosterone was irresponsive to ACTH treatment, and concentrations did not differ between lame and nonlame cows. Vagal tone decreased in response to the ACTH treatment. High frequency component of heart rate variability was lower in the lame group at all sampling times. Lameness was associated with delayed return to baseline. We concluded that the adrenal response capacity is not influenced by lameness, which supports the concept of lameness being a chronic intermittent rather than a chronically persistent stressor. Dehydroepiandrosterone concentrations were not proven to be useful indicators of hypothalamus-pituitary axis dysfunction in cattle. A decreased vagal contribution to heart rate variability-possibly coupled with increased sympathetic modulation-was observed in lame cows, which suggests that lameness affects the mechanisms underlying the action of ACTH on cardiovascular activity.

Effect of artificial shade on saliva cortisol concentrations of heat-stressed dairy calves.

Responses to heat stress have not been evaluated in dairy cattle by noninvasive techniques such as analysis of saliva cortisol concentrations. The aim of the present study was the assessment of saliva cortisol levels in Holstein bull calves with (n = 8) or without supplemental shade (n = 8) in response to acute heat stress. Measurements were carried out during a 5-d period [temperature, average/max (°C); day 1 (control, all calves shaded): 22.9/29.4, day 2 (heat stress day): 28.3/38.8, day 3: 26.2/33.5, day 4: 23.7/28.7, and day 5: 21.2/24.7]. The level of thermal stress was characterized with a temperature-humidity index (THI). Saliva cortisol levels did not differ between groups during the control day. On the heat stress day, saliva cortisol levels increased from 8:00 to 12:00 by 51% and 342% in shaded and nonshaded calves, respectively, and nonshaded calves showed higher cortisol concentrations at 12:00, 16:00, and 24:00. Saliva cortisol levels peaked at 12:00 on day 3 in both groups. On days 4 and 5, saliva cortisol did not show significant daytime elevations in either group; however, group differences remained significant until 20:00 on day 4. Based on our results, measurement of saliva cortisol concentrations is a promising approach to detect acute heat stress in dairy calves, which could be reduced by artificial shading.

Association between human and animal thermal comfort indices and physiological heat stress indicators in dairy calves.

Warm summer episodes have a significant effect on the overall health and well-being of young cattle; however, it is not known which temperature measure should be used for estimating heat stress in dairy calves. In this study, generalized linear mixed-effects models were used to estimate the relationships between thermal comfort indices and animal-based heat stress indicators in sixteen Holstein bull calves that were housed in individual calf hutches. Data were collected under continental weather characteristics over a 5-day period: day 1 (lower-temperature day), days 2 and 3 (heat stress days), and a 2-day post-stress period. Relative humidity, ambient temperature, the heat index, the humidex and five different temperature-humidity indices (THI) were used as thermal indices. Physiological variables monitored included respiratory rate, rectal temperature, ear skin temperature and heart rate. The heat index and the humidex measuring human thermal comfort were more closely associated with physiological measures than were the ambient temperature or the THIs (in case of heat index: R2 = 0.87 for respiratory rate, R2 = 0.63 for rectal temperature, R2 = 0.70 for ear skin temperature, and R2 = 0.78 for heart rate, respectively; in case of humidex: R2 = 0.85 for respiratory rate, R2 = 0.60 for rectal temperature, R2 = 0.68 for ear skin temperature, and R2 = 0.75 for heart rate, respectively). Based on our results, parameters of human outdoor comfort seem better to estimate heat stress in dairy calves in a continental region than those of THIs or ambient temperature.

Seasonal and maternal effects on acid-base, l-lactate, electrolyte, and hematological status of 205 dairy calves born to eutocic dams.

In this study, we used linear mixed models to determine the effects of season, time of sampling relative to birth (factors), duration of the delivery process, duration of maternal grooming, calf body weight (BW) at birth, and time of day (covariates) on values of venous blood gas, acid-base and electrolyte parameters, and l-lactate concentrations in dairy calves born to eutocic dams in summer (SUM, n = 101) and winter (WIN, n = 104). Neonatal vitality was assessed at 0, 1, and 24 h after delivery in a linear scoring system using muscle tone, erection of the head, muscle reflexes, heart rate, and sucking drive as criteria. Simultaneously with vitality scoring, venous blood samples were collected by jugular venipuncture. Blood was tested for pH, partial pressure of CO2 (pCO2; mmHg) and oxygen (pO2; mmHg), l-lactate (mmol/L), hemoglobin (Hb; g/L), ionized calcium (Ca2+; mmol/L), sodium (Na+; mmol/L), potassium (K+; mmol/L) and chloride (Cl-; mmol/L). Bicarbonate (HCO3-; mmol/L), base excess (BE; mmol/L), total carbon dioxide (TCO2; mmol/L), and anion gap (mmol/L) were calculated. Electrolyte parameters were affected by none of the factors or covariates. Time of day at birth did not affect any of the parameters of interest. Vitality score tended to increase over time and it showed higher values in WIN calves than in SUM calves. Concentrations of HCO3-, BE, and l-lactate indicated a higher degree of metabolic acidosis in SUM calves; however, pH was not affected by season. Concentrations of Hb were higher in SUM calves than in WIN calves; however, covariates did not affect Hb concentrations. Blood pH, concentrations of pO2, HCO3-, and BE decreased, whereas l-lactate concentrations and values of pCO2, TCO2, and anion gap increased with longer duration of delivery. A shift in acid-base balance was also linked to BW of the calf at birth, with lower values of blood pH, HCO3-, and BE in calves with higher BW compared with those with lower BW at birth, whereas TCO2 and l-lactate concentrations increased with higher calf BW at birth. Values of pO2 increased and pCO2 decreased with longer duration of maternal grooming. Blood pH, HCO3-, and BE increased, whereas l-lactate concentrations and anion gap decreased with longer duration of licking the calf. Our results indicate that prolonged delivery can impair acid-base status and can cause slight lactic acidosis, even in calves born from spontaneous or eutocic calvings, and that high BW at birth predisposes calves to acidosis. The positive effect of maternal grooming on neonatal acid-base status should be considered in parturition management. Season, duration of the delivery process, calf BW at birth, and duration of maternal grooming are recommended for consideration in future studies on blood gas and acid-base parameters in dairy calves in the immediate neonatal period.

Rumination time and reticuloruminal temperature as possible predictors of dystocia in dairy cows.

The objectives of this study were to explore changes of rumination time and reticuloruminal pH and temperature of dairy cows and heifers (means ± standard deviation; age = 5.8 ± 1.9; parity = 2.7 ± 1.4; body condition score = 3.2 ± 0.2) with eutocic (EUT, n = 10) and dystocic calving (DYS, n = 8). The recording period lasted from 3 d before calving until 7 d in milk. For the comparison of rumination time and reticuloruminal characteristics between groups, time to return to baseline (the time interval required to return to baseline from the delivery of the calf) and area under the curve (AUC; both for prepartum and postpartum periods) were calculated for each parameter. Rumination time decreased from baseline 28 h before calving both for EUT and DYS cows; after 20 h before calving, it decreased to 32.4 ± 2.3 and 13.2 ± 2.0 min/4 h between 8 and 4 h before delivery in EUT and DYS cows, respectively, and then it decreased below 10 and 5 min during the last 4 h before calving. Until 12 h after delivery, rumination time reached 42.6 ± 2.7 and 51.0 ± 3.1 min/4 h in DYS and EUT dams, respectively; however, AUC and time to return to baseline suggested lower rumination activity in DYS cows than in EUT dams for the 168-h postpartum observational period. Reticuloruminal pH decreased from baseline 56 h before calving both for EUT and DYS cows, but did not differ between groups before delivery. Reticuloruminal pH showed a decreasing tendency and clear diurnal variation after calving for both EUT and DYS cows, with slightly higher AUC values in DYS cows. In DYS cows, reticuloruminal temperature decreased from baseline 32 h before calving by 0.23 ± 0.02°C, whereas in EUT cows such a decrease was found only 20 h before delivery (0.48 ± 0.05°C). The AUC of reticuloruminal temperature calculated for the prepartum period was greater in EUT cows than in DYS cows. During the first 4 h after calving, reticuloruminal temperature decreased from 39.68 ± 0.09 to 38.96 ± 0.10°C and from 39.80 ± 0.06 to 38.81 ± 0.08°C in EUT and DYS cows, respectively, and reached baseline levels after 35.4 ± 3.4 and 37.8 ± 4.2 h after calving in EUT and DYS cows, respectively. Based on our results, continuous monitoring of changes in rumination time and reticuloruminal temperature seems to be promising in the early detection of cows with a higher risk of dystocia. Depressed rumination activity of DYS cows after calving highlights the importance of the postpartum monitoring of cows experiencing difficulties at calving. The effect of dystocia on postpartum reticuloruminal pH was not pronounced.

Hypothalamic-pituitary-adrenal and cardiac autonomic responses to transrectal examination differ with behavioral reactivity in dairy cows.

Behavior, hypothalamic-pituitary-adrenal axis, and cardiac autonomic nervous system (ANS) activity were evaluated in response to transrectal examination in nonlactating Holstein-Friesian cows with different behavioral reactivity. According to behavioral reactions shown to the procedure of fixing the heart rate (HR) monitors, the 20 cows with the highest and the 20 cows with the lowest behavioral reactivity were involved in the study (high responder, n=20; and low responder, n=20, respectively). Activity of the ANS was assessed by HR and HR variability parameters. Blood and saliva were collected at 5 min before (baseline) and 0, 5 10, 15, 20, 30, 40, 60, and 120 min after the examination to determine cortisol concentrations. The examination lasted for 5 min. Cardiac parameters included HR, the root mean square of successive differences between the consecutive interbeat intervals, the high frequency (HF) component of heart rate variability, and the ratio between the low frequency (LF) and HF parameter (LF/HF). Following the examination, peak plasma and saliva cortisol levels and the amplitude of the plasma and saliva cortisol response were higher in high responder cows than in low responders. Areas under the plasma and saliva cortisol response curves were greater in high responder cows. Plasma and salivary cortisol levels correlated significantly at baseline (r=0.91), right after examination (r=0.98), and at peak levels (r=0.96). Area under the HR response curve was higher in low responder cows; however, maximum HR and the amplitude of the HR response showed no differences between groups. Minimum values of both parameters calculated for the examination were higher in high responders. Following the examination, response parameters of root mean square of successive differences and HF did not differ between groups. The maximum and the amplitude of LF/HF response and area under the LF/HF response curve were lower in low responder cows, suggesting a lower sympathetic activation of the ANS. Although changes in behaviors indicated that the procedure was painful for the animals, no differences were observed either in vocalization or in attendant behavior between groups during the examination. Our results demonstrate that behaviorally more reactive animals exhibit increased plasma and salivary cortisol concentrations and higher cardiac autonomic responsiveness to transrectal examination than less reactive cows. Salivary cortisol may substitute for plasma cortisol when assessing response of cattle to stress.

Heart rate and heart rate variability in multiparous dairy cows with unassisted calvings in the periparturient period.

Behavioural changes before calving can be monitored on farms; however, predicting the onset of calving is sometimes difficult based only on clinical signs. Heart rate (HR) and heart rate variability (HRV) as non-invasive measures of autonomic nervous system (ANS) activity were investigated in Holstein-Friesian cows (N=20) with unassisted calvings in the periparturient period to predict the onset of calving and assess the stress associated with calving. R-R-intervals were analysed in 5-min time windows during the following three main periods of measurement: 1) between 0 and 96 h before the onset of calving restlessness (prepartum period); 2) during four stages of calving: (I) early first stage; between the onset of calving restlessness and the first abdominal contractions; (II) late first stage (between the first abdominal contractions and the appearance of the amniotic sac); (III) early second stage (between the appearance of the amniotic sac and the appearance of the foetal hooves); (IV) late second stage (between the appearance of the foetal hooves and delivery of the calf), and 3) over 48 h following calving (postpartum period). Data collected between 72 and 96 h before calving restlessness was used as baseline. Besides HR, Poincaré measures [standard deviation 1 (SD1) and 2 (SD2) and SD2/SD1 ratio], the root mean square of successive differences (RMSSD) in R-R intervals, the high-frequency (HF) component of HRV and the ratio between the low-frequency (LF) and the HF components (LF/HF ratio) were calculated. Heart rate increased only following the onset of the behavioural signs, peaked before delivery of the calf, then decreased immediately after calving. Parasympathetic indices of HRV (RMSSD, HFnorm and SD1) decreased, whereas sympathovagal indices (LF/HF ratio and SD2/SD1 ratio) increased significantly from baseline between 12 and 24 before the onset of calving restlessness. The same pattern was observed between 0 and 1h before calving restlessness. Following the onset of behavioural signs, parasympathetic activity increased gradually with a parallel shift in sympathovagal balance towards parasympathetic tone, which was possibly a consequence of oxytocin release, which induces an increase in vagus nerve activity. Parasympathetic activity decreased rapidly between 0 and 0.5h following calving and was lower than measured during all other stages of the study, while sympathetic activity peaked during this stage and was higher than measured during any other stages. Between 0 and 4h after calving vagal tone was lower than baseline, whereas sympathovagal balance was higher, reflecting a prolonged physiological challenge caused by calving. Vagal activity decreased, whereas sympathovagal balance shifted towards sympathetic tone with increased live body weight of the calf during the late second stage of calving, suggesting higher levels of stress associated with the higher body weight of calves. All HRV indices, measured either at the late second stage of calving and between 12 and 24h after calving, were affected by the duration of calving. Our results indicate that ANS activity measured by HRV indices is a more immediate indicator of the onset of calving than behaviour or HR, as it changed earlier than when restlessness or elevation in HR could be observed. However, because of the possible effects of other physiological mechanisms (e.g. oxytocin release) on ANS activity it seems to be difficult to measure stress associated with calving by means of HRV between the onset of calving restlessness and delivery. Further research is needed to enable more precise interpretation of the prepartum changes in HR and HRV in dairy cattle.

Cardiac responses to palpation per rectum in lactating and nonlactating dairy cows.

Interest in the monitoring of heart rate variability (HRV) has increased recently, as it gives more detailed and immediate information about the level of stress than traditional behavioral or hypothalamus-pituitary-adrenal measures. In this study, we evaluated heart rate (HR) and parasympathetic HRV parameters to monitor cardiac stress responses to palpation per rectum (PPR) in lactating (LACT; n = 11) and nonlactating (NLACT; n = 12) dairy cows. Heart rate and HRV were recorded from 40 min before PPR until 120 min after it was completed. Heart rate, the root mean square of successive differences (RMSSD), and the high-frequency component (HF) of HRV were analyzed by examining 5-min time windows. To compare cardiac responses to PPR between groups, changes in HR and HRV parameters were calculated as area under the curve (AUC) for LACT and NLACT cows. An immediate increase in HR was detected during PPR in both LACT (+21.4 ± 2.4 beats/min) and NLACT cows (+20.6 ± 2.3 beats/min); however, no differences were found between groups on the basis of parameters of AUC. The increase in HR in both groups along with a parallel decrease in RMSSD (LACT cows: -5.2 ± 0.4 ms; NLACT cows: -5.1 ± 0.4 ms) and HF [LACT cows: -10.1 ± 0.8 nu (where nu = normalized units); NLACT cows: -16.9 ± 1.2 nu] during PPR indicate an increase in the sympathetic, and a decrease in the parasympathetic tone of the autonomic nervous system. The increase in RMSSD (LACT cows: +7.3 ± 0.7 ms; NL cows: +17.8 ± 2.2 ms) and in HF (LACT cows: +24.3 ± 2.6 nu; NLACT cows: +32.7 ± 3.5 nu) immediately after PPR indicated a rapid increase in parasympathetic activity, which decreased under the baseline values 10 min following PPR. The amplitude and the maximum RMSSD and HF values were greater in NLACT cows than in LACT animals, suggesting a higher short-term cardiac responsiveness of NLACT cows. However, the magnitude and the duration of the stress response were greater in LACT cows, as indicated by the analysis of AUC parameters (area under the HRV response curve and time to return to baseline). Cow response to the PPR was more prominent in parasympathetic HRV measures than in HR. Based on our results, the effect of PPR on the cows' cardiac stress responses may have an impact on animal welfare on dairy farms, and investigating the effect of lactation on the cardiac stress reactions could prove useful in modeling bovine stress sensitivity. Further research is needed to find out whether the differences due to lactation are physiological or management related.

Prevention of latex sensitization in guinea pigs by a bacterial and viral filter used in anaesthesia.

BACKGROUND: Preventing anaphylactic reactions as a result of natural rubber latex (NRL) proteins is an important concern in anaesthesia. The clinical relevance of a bacterial/viral filter (Pall BB25) in preventing sensitization to NRL by inhalation was tested in guinea pigs. METHODS: Guinea pigs (n=8-10 in each group) were exposed to aerosolized NRL-contaminated cornstarch powder or to NRL in saline for 1 h every day for 2 weeks. The experiments were repeated with a Pall BB25 filter placed over the aerosol system. Control groups were exposed to non-contaminated cornstarch or to saline alone. Three weeks after the last exposure, specific bronchial challenge was performed and thromboxane (Tx) B2 levels in bronchoalveolar lavage fluid were measured. RESULTS: After bronchial challenge, the animals exposed to NRL or NRL-contaminated cornstarch with the BB25 filter in place showed a level of bronchoconstriction (i.e. the variation of pulmonary insufflation pressure) not different from controls. Conversely, those exposed to NRL or NRL-contaminated cornstarch without the filter showed a higher level of bronchoconstriction (respectively, P<0.02 and P<0.001) than control. Elevated TxB2 levels were found in the lungs of the guinea pigs, which inhaled NRL or NRL-contaminated cornstarch in the absence of a filter. Animals treated with the filter showed comparable TxB2 levels with those of control. CONCLUSION: The Pall BB25 filter efficiently protected the guinea pigs from sensitization to NRL. This filter can be used as a complementary measure for avoidance of NRL contact during surgical procedures particularly if the mechanical ventilator apparatus contain NRL devices.

Inhaled cornstarch glove powder increases latex-induced airway hyper-sensitivity in guinea-pigs.

BACKGROUND: Breathing is one of the most important modes of sensitization to natural rubber latex (NRL) for health-care workers, a group most at risk. Cornstarch powder (CSp) from medical powdered NRL gloves is known to be an allergen carrier, and sensitization to NRL can occur by inhaling airborne particles from such gloves. OBJECTIVE: The aim of this study was to demonstrate, using an experimental model, which CSp may act as an adjuvant in NRL-induced airway hyper-responsiveness. METHODS: Guinea-pigs were exposed to aerosolized NRL-contaminated CSp or to NRL in saline solution for 1 h every day for 2 weeks. The control groups were exposed either to CSp or to saline alone. An additional group of guinea-pigs was exposed to aerosolized ovalbumin (OVA) in saline. Three weeks after the last exposure, specific bronchial challenges were performed. In addition, Specific IgG and IgG1 in sera and thromboxane (Tx) B(2) levels in bronchoalveolar lavage fluid (BALF) were measured. RESULTS: The NRL challenge caused significant bronchospasm in the animals that had been exposed to NRL compared with those in the control groups (P<0.02). Guinea-pigs exposed to OVA also demonstrated a significant bronchospasm after OVA challenge (P<0.001). The guinea-pigs that had inhaled NRL-contaminated CSp had a significantly higher bronchoconstriction level than those that had inhaled NRL alone (P<0.02). Specific IgG and IgG1 were undetectable in sera from all groups, whereas significant amounts of TxB(2) (P<0.001) were found in the lungs of the guinea-pigs exposed to NRL or OVA. CONCLUSION: Inhaling CSp increases the airway response to NRL. The fact that specific IgG and IgG1 were not detected might be the result of an immune response limited to the airways. This finding is supported by a significant increase of TxB(2) level in the BALF of sensitized guinea-pigs.

Immunoadjuvant properties of glove cornstarch powder in latex-induced hypersensitivity.

BACKGROUND: Cornstarch powder present in medical gloves plays an important role in latex-induced hypersensitivity as allergen carrier either, by the inhalation route, by skin contact or by direct contact with mucous membranes. OBJECTIVE: Our objective was to test the hypothesis that cornstarch could act as an immunoadjuvant in immediate type-I latex-induced hypersensitivity. METHODS: Guinea-pigs were sensitized by intraperitoneal route with two different antigens (latex proteins and ovalbumin) with or without cornstarch powder. Airway responsiveness after specific bronchial provocation was evaluated and specific IgG and IgG1 levels were determined by enzyme-linked immunosorbent assay (ELISA). Controls were treated with cornstarch powder or saline alone. RESULTS: Animals sensitized with latex proteins (n = 7 in each group) showed significant bronchoconstriction (P < 0.03) and higher anti-latex antibody levels than the controls (P < 0.005). Guinea-pigs sensitized with latex-contaminated cornstarch had higher levels of specific antibodies than those sensitized with latex alone (P < 0.05). Animals sensitized to latex mixed with cornstarch showed higher bronchospasm than those treated with latex alone (P < 0.003). Animals sensitized to ovalbumin mixed with cornstarch also showed higher antibody and bronchoconstriction levels (P < 0.05) than those immunized with ovalbumin alone but antibody titres were significantly lower than those of the animals treated with ovalbumin and Freund's complete adjuvant (P < 0.01; n = 5 in each group). CONCLUSION: Our findings show that cornstarch powder increases antigen-induced bronchoconstriction and antibody production. This role of immunoadjuvant is not antigen-specific. The cornstarch powder used as donning agent in latex gloves is an allergen carrier and it can enhance latex-induced hypersensitivity.

[Potential importance of antileukotrienes in the treatment of asthma and other inflammatory diseases: apropos of a new pharmacological class]. / Intérêt potentiel des antileucotriènes dans le traitement de l'asthme et autres pathologies inflammatoires: à propos d'une nouvelle classe pharmacologique.

OBJECTIVES: Among the mediators involved in the asthma bronchoconstriction and inflammation mechanisms, there is now substantial evidence that the sulfidopeptide leukotrienes (LTs) are important. Antagonists of their receptors and inhibitors of their synthesis have been developed. IMPORTANT POINTS: Antagonists of LTs, as well as inhibitors of their synthesis, reduce the LTs actions: bronchoconstriction, bronchial hyperresponsiveness, hypersecretion and inflammation. They produce an acute bronchodilating effect in mild asthma, reduce the hyperresponsiveness responses due to allergens, aspirin and cold and dry air, and also cutaneous and gastrointestinal reactions. Oral administrations tested during 4 or 6 weeks diminish the use of the beta-agonists, decrease the asthma symptom scores and other inflammatory signs. PERSPECTIVES AND PROJECTS: More studies for longer periods, double blind trials and comparisons with classical treatments will be necessary to define the real place of LTs antagonists in the treatment of asthma. So their efficacy has to be confirmed as well as their good tolerance profile (particularly for hepatic functions). CONCLUSION: Antagonists of receptors and synthesis inhibitors of LTs have known a recent and important development. They constitute a new therapeutic class: further studies are needed to better define the place of these new drugs in the treatment of asthma and other inflammatory diseases.

Induction of hypertension and cardiac hypertrophy in guinea pig by DOCA salt.

Experimental hypertension can be induced in rats by uninephrectomy, administration of deoxycorticosterone acetate (DOCA) and sodium chloride. We developed this model in the guinea pig, because it presents an isoenzymic myosin pattern and calcium-induced calcium release similar to those of humans. Unilateral nephrectomy was performed in 33 guinea pigs, after which they were given DOCA (300 mg/kg pellets, s.c.; n = 11, or 10 mg, i.m.; n = 12, 5 days a week for 5 weeks). One week after surgery, drinking water was supplemented with NaCl 9 g/l and KCl 2 g/l for 5 weeks. Control guinea pigs (n = 10) were nephrectomized but not treated. Five weeks after surgery, hemodynamic measurements were recorded and the animals sacrificed to assess the degree of left ventricular hypertrophy. Left ventricular hypertrophy was considered significant if the ratio of left ventricular weight/body weight was > 2.3 and if the thickness of the left ventricle free wall was > 3.5 mm. Results showed that the systolic, diastolic and mean blood pressures of the treated groups were 36% higher than in the control group. Cardiac hypertrophy occurred within 5 weeks, and resulted in an increase in left ventricle weight and in left ventricular hypertrophy. The possibility of using the DOCA salt model of experimental hypertension in the guinea pig could help to elucidate the mechanisms responsible for hypertension and induced left ventricular hypertrophy, and thus improve prevention and treatment.

Pharmacokinetics of acipimox and of its N-deoxy metabolite following single and repeated oral administration to healthy volunteers.

The aim of the present study was to evaluate the plasma pharmacokinetics of acipimox and of its N-deoxy metabolite (5-methylpyrazine-2-carboxylic acid, MPCA) following single and repeated administration of 250 mg acipimox (thrice daily, for 6 days) to ten healthy volunteers. Mean maximum concentration, the corresponding time, area under the curve extrapolated to infinity and elimination half-life values of acipimox after single administration were equal to 5.74 micrograms/ml (range 2.56-8.38 micrograms/ml), 1.7 h (1-3 h), 16.99 micrograms/ml.h (11.28-22.17 micrograms/ml.h) and 1.15 h (0.79-1.48 h), respectively. Mean area under the curve over one dosing interval (8 h) and elimination half-life values of acipimox after repeated dosing were not significantly different from the corresponding values after the single dose. No significant accumulation was observed following the repeated treatment, since the mean accumulation ratio was 1.08 (range 0.74-1.52). The mean maximum concentration and corresponding time values in the 7 out of 10 subjects with detectable metabolite levels after the single dose were 0.19 microgram/ml (0.10-0.34 microgram/ml) and 6.7 h (3-12 h), respectively, whilst after the repeated treatment, detectable concentrations of the metabolite were observed in all subjects, the mean maximum concentration value being equal to 0.48 micrograms/ml (0.11-1.19 microgram/ml). The average ratio of the parent/metabolite area under the curve values (8 h) after repeated dosing was equal to 14 (range 2-56). Inter-subject variability in the extent of metabolite formation was very high.

Effect of temafloxacin on the pharmacokinetics of theophylline.

A number of fluoroquinolones have been shown to interact adversely with theophylline. We studied the influence of coadministration of temafloxacin, a new fluoroquinolone antimicrobial agent, on steady-state theophylline pharmacokinetics. Twelve healthy subjects (8 males, 4 females; average age and weight 34 years and 62 kg, respectively) were given oral controlled-release theophylline in an individualized dosage to achieve a target plasma level of 10 mg/L. Once steady state was achieved, temafloxacin 600 mg given orally twice daily was concomitantly administered for 4-5 days. Serial blood samples were collected before and during simultaneous temafloxacin administration and plasma assayed for theophylline using a high-performance liquid chromatography technique. Theophylline pharmacokinetic parameters were determined noncompartmentally, and results of single and combined administration were compared. Theophylline plasma concentrations did not differ significantly with temafloxacin coadministration, and similar area-under-the-curve (AUC) values were observed. Theophylline oral clearance increased from 2.67 +/- 1.01 L/hour to 2.69 +/- 0.93 L/hour, when given alone and with temafloxacin, respectively (p = 0.92). Only 2 of 12 subjects showed an appreciable decrease in clearance when theophylline and temafloxacin were administered together, while 2 subjects demonstrated increases greater than 15% and 8 showed no change. We conclude that temafloxacin does not interact significantly with theophylline and that these agents can be safely administered together.

[The H1 and H2 histamine receptors]. / Les récepteurs H1 et H2 de l'histamine.

Histamine is a major mediator of the allergic reactions. Histamine have different actions: contraction of smooth muscles, vascular action, increase in gastric and adrenal medulla secretion. Effects on central or peripheral nervous system are discussed. The specific H1 or H2 activity explains the different configurations of histamine. The specificity of H1 receptors agonists is now well known: H1 activities have a positive charge on the side chain with an imidazole ring able to rotate around the axis of side chain. The contraction of smooth muscles is due to the action of H1 receptors agonists. Many doubts remain about the exact structures of the H2 receptors, and their agonists. Trough the H2 receptors occur dilatation of small arteries and capillaries, as well as an increase in gastric secretion. Subdivisions of H2 receptors have been, suggested. Recently H3 receptors have been described in the brain and in some peripheral tissues. Interrelations between H1 and H2 histamine receptors have been described as well as a feedback of synthesis and of histamine release.

Beta-2 adrenergic responses to tulobuterol in airway smooth muscle, vascular smooth muscle and adrenergic nerves.

Experiments were designed to determine the mechanism of action of the bronchodilator drug tulobuterol. Tissues were suspended in organ chambers for isometric tension recording. Tulobuterol caused concentration-dependent relaxations of guinea pig tracheae, canine saphenous veins and canine bronchi; the compound relaxed canine coronary arteries only at high concentrations and did not affect spontaneously beating guinea pig atria. A metabolite of tulobuterol, 4-hydroxytulobuterol, was more potent in relaxing guinea pig tracheae than tulobuterol, salbutamol and isoproterenol. Other metabolites (3-hydroxy-, 5-hydroxy- and 4,5-dihydroxytulobuterol) were less efficacious than 4-hydroxytulobuterol. Both tulobuterol and 4-hydroxytulobuterol acted as partial agonists. The effects of tulobuterol in the saphenous vein (but not in the coronary artery) were antagonized by the selective beta-2 adrenergic blocker ICI 118,551 but were not affected by the selective beta-1 adrenergic inhibitor metoprolol. In bronchi, removal of the epithelium reduced the relaxations caused by tulobuterol. The drug did not inhibit responses of canine bronchi to electrical stimulation of the cholinergic nerves more than those to exogenous acetylcholine. Tulobuterol caused a moderate augmentation of the evoked release of [3H]norepinephrine in canine saphenous veins previously incubated with the labeled transmitter. Thus, tulobuterol is a selective beta-2 adrenergic agonist with minimal nonselective inhibitory effect on airway and vascular smooth muscle. It also facilitates adrenergic neurotransmission, which may help to explain its bronchodilator effect in the intact organism. Tulobuterol does not activate beta-1 adrenoceptors and has no direct positive chronotropic effect. A metabolite of tulobuterol, 4-hydroxytulobuterol, is more active than the parent compound.

Comparison of once-daily evening versus morning sustained-release theophylline dosing for nocturnal asthma.

Eight diurnally active (approximately 0730-1100 hr) adults (41-61 yr) suffering from nocturnal asthma volunteered for a double-blind, cross-over randomized study of a once-daily dosing (600-900 mg/24 hr) of Armophylline (Rorer s.a., France), a sustained-release theophylline given either at 0800 hr or 2000 hr for 8-day durations. Study variables monitored daily were: (a) self-measured peak expiratory flow (PEF), heart rate, oral temperature and self-rated fatigue checked every 2 hr during the waking span as well as upon spontaneous nocturnal awakenings and (b) duration and subjective characteristics of sleep rated every morning. In addition, serum theophylline concentration (STC) plus the variables in (a) were sampled every 2 hr during the 24 hr of the eighth day of each timed treatment span. Rx at 0800 hr was associated with a nocturnal dip in PEF of 20 +/- 2.8% (X +/- S.E.M.) from the level achieved at the time of the diurnal crest; Rx at 2000 hr moderated the nocturnal fall; it was only 10 +/- 2.1% and within the physiologic limits of non-asthmatic persons. The STC peak height (Cmax) was greater (P less than 0.05) and time-to-peak (Tmax) shorter (P less than 0.005) with Rx at 0800 hr than at 2000 hr. With Rx at 2000 hr an STC plateau of approximately 12 hr resulted. A statistically significant correlation (r = 0.86; P less than 0.01) between PEF and the corresponding-in-time STC was observed with Rx at 2000 hr but not with Rx at 0800 hr. A small, but statistically significant, higher heart rate resulted from 2000 hr dosings in five out of eight subjects relative to the 0800 hr dosing. There were no differences in the sleep characteristics nor in oral temperature between dosing times. Once-daily (600-900 mg) SRT dosing at 2000 hr controlled the nocturnal dip of bronchial patency with no major side-effects in diurnally active adult patients with nocturnal allergic asthma.