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PubMed1967

Complement as a mediator of inflammation. 3. Purification of the activity with anaphylatoxin properties generated by interaction of the first four components of complement and its identification as a cleavage product of C'3.

Purified preparations of human C'1 esterase, C'4, C'2, C'3, and C'5 were labeled with (125)I. Reaction mixtures were prepared containing a single labeled component and other unlabled components. After incubation at 37 degrees C for 10 min at pH 7.4 in the presence of 5 x 10(-4)M Mg(2+), they were adjusted to pH 3.5 and subjected to sucrose density gradient ultracentrifugation and gel filtration at pH 3.5. In all cases, an activity capable of contracting guinea pig ileum with tachyphylaxis was obtained in low molecular weight fractions. However, these fractions were labeled only when (125)I-C'3 was employed, indicating that biological activity was associated with a cleavage product of C'3. This fragment has been designated F(a)C'3 in a nomenclature consistent with that of immunoglobulin degradation products. The much larger, residual portion of the C'3 molecule has been designated F(b)C'3. The biochemical characteristics of generation of F(a)C'3 were consistent with a mechanism involving action of C'1 esterase on C'4 and C'2, activation of C'2, and cleavage of C'3. F(a)C'3 had a molecular weight by gel filtration techniques of 6800 or less. It was thermostable and susceptible to inactivation by endo- and exopeptidases. The isolated fragment possessed all of the biological properties of unfractionated mixtures of C'1 esterase, C'4, C'2, and C'3. In addition to contraction of guinea pig ileum, these included failure to contract rat uterus, enhancement of vascular permeability in guinea pig skin, degranulation of mast cells in guinea pig mesentery, and release of histamine from rat peritoneal mast cells. F(a)C'3 did not cross-desensitize guinea pig ileum to rat agar anaphylatoxin and vice versa. The existence of different protein fragments with anaphylatoxin properties has been discussed. Distinctive characteristics of F(a)C'3 from classical anaphylatoxin generated by treatment of fresh rat serum with agar have been indicated.

Anaphylaxis↗
PubMed1976

Pancuronium bromide: an indirect sympathomimetic agent.

In the dog, pancuronium 0.2 mg/kg increased left ventricular systolic pressure and systemic arterial pressure, but did not change central venous pressure. Repeated doses produced diminishing responses and eventually no change in arterial pressure. After tachyphylaxis was established, a pressor response to pancuronium could be induced by an i.v. infusion of noradrenaline. Desipramine, a noradrenaline blocking agent, prevented the restoration of the pressor effect of noradrenaline. Guanethidine and reserpine abollished the restoration of the pressor response to pancuronium by noradrenaline. These findings are consistent with the hypothesis that pancuronium acts on the postganglionic nerve endings and causes release of noradrenaline.

Animals↗
PubMed1976

Extradural analgesia in obstetrics: a controlled trial of carbonated lignocaine and bupivacaine hydrochloride with or without adrenaline.

Four local anaesthetic solutions (2% carbonated lignocaine with or without adrenaline and 0.5% bupivacaine HCl with or without adrenaline) were used randomly for 335 continuous lumbar extradural blocks in labour. Carbonated lignocaine caused a more rapid onset of analgesia than bupivacaine HCl. The addition of adrenaline made little difference to the onset times, prolonged markedly the duration of analgesia with carbonated lignocaine and had little effect on the duration of analgesia with bupivacaine HCl. Tachyphylaxis was a feature with carbonated lignocaine and adrenaline, but not with the other solutions. The incidence of unblocked segments was 7-9% in the four groups. The incidence of unilateral analgesia was 6% with plain lignocaine and 13% in the other groups. Complete pain relief occurred more frequently with bupivacaine HCl than with carbonated lignocaine and the use of adrenaline had little effect on the degree of analgesia.

Anesthesia, Epidural↗
PubMed1976

Spontaneous recovery of the thumb twitch from neuromuscular block by suxamethonium in anaesthetized man.

The neuromuscular blocking effect of repeated bolus administration of suxamethonium 1 mg/kg was observed in 10 healthy surgical patients under enflurane-nitrous oxide-oxygen anaesthesia. Tachyphylaxis and slow recovery of the thumb twitch occurred in close dose-relationships with transition of Phase I block to Phase II, using train-of-four fade as an indicator of the transition. Failure of the thumb twitch to recover to 75% of control, and subsequent step-wise depression from additional doses of suxamethonium had a sudden onset shortly after establishment of marked train-of-four fade.

Adult↗
PubMed2001

Reduction of vasopressor requirement by hydrocortisone administration in a patient with cerebral vasospasm.

A 67-yr-old female received hypertensive, hypervolaemic treatment for cerebral vasospasm after severe subarachnoid haemorrhage. After 3 days of continuous vasopressor infusion and despite adequate hydration and normal cardiac function, the phenylephrine dose had to be increased to obtain the same systolic blood pressure. This tachyphylaxis to phenylephrine infusion was probably caused by down-regulation of alpha adrenoceptors, and was reversed by giving i.v. hydrocortisone.

Adrenergic alpha-Agonists↗
PubMed1991

Anaphylactoid reactions to glycopeptide antibiotics.

Anaphylactoid reactions to vancomycin have been reported consistently since the earliest clinical trials. Signs and symptoms of the reaction, which usually occur during the first dose, can range in severity from mild pruritus and upper body flushing, to dramatic hypotension and cardiovascular arrest. The frequency of the reaction, and its severity, is proportional to the total dose administered and the infusion rate. Recent prospective investigations report that when 1 g of vancomycin is administered over 60 min to normal volunteers and infected patients, between 50-90% of adults will have a reaction, although most are mild and of little clinical consequence. Vancomycin causes a release of histamine into blood, and the severity of the reaction is proportional to the amount of histamine released. Tachyphylaxis rapidly develops in most persons, although decreasing the dose, or increasing the infusion time will also help alleviate the signs and symptoms. Antihistamine H1 blocking agents are also effective in preventing the reaction. Teicoplanin, a new glycopeptide antibiotic, does not appear to cause histamine release or related symptoms, even when administered at a more rapid rate than vancomycin.

Anaphylaxis↗
PubMed1983

Potentiation of succinylcholine phase II block with isoflurane.

To determine the effect of isoflurane upon phase II block 20 patients were given succinylcholine by infusion at a rate which maintained the twitch tension of the adductor pollicis muscle at 10% of control for 2 to 4 h. The patients were assigned randomly to either nitrous-oxide-isoflurane (0.75-1.5% inspired) or nitrous-oxide-fentanyl for maintenance of anesthesia, and neuromuscular activity was monitored using train-of-four stimulation. Tachyphylaxis to succinylcholine was observed in both groups but this was followed, in the isoflurane group but not in the fentanyl group, by a decrease in succinylcholine requirement. This decrease was related to the extent of phase II block present. It is concluded that isoflurane potentiates succinylcholine phase II block although the mechanisms involved are not necessarily the same as in the potentiation of nondepolarizing neuromuscular blocking drugs.

Adult↗
PubMed1984

The neuromuscular response of infants to a continuous infusion of succinylcholine.

The response of the adductor of the thumb to ulnar nerve stimulation (0.1 Hz) was evaluated during continuous infusion of succinylcholine (SCh) in 20 infants anesthetized with halothane (1%) and N2O2/O2. Train-of-four stimulation (2 Hz for 2 s) was used to differentiate between phase I and phase II block. Some infants were very resistant to the neuromuscular effects of SCh. These infants (Group 1) were younger in age, 57 +/- 15 days (mean +/- SE) and required 24.6 +/- 3.3 mg X kg-1h-1 SCh to achieve more than 90% depression of the twitch. Older infants (Group 2), 188 +/- 33 days, required significantly less (P less than 0.001) SCh (8.7 +/- 0.5 mg X kg-1h-1) to achieve the same degree of twitch suppression. Group 1 infants recovered from the effects of SCh very rapidly. After 10 mg/kg SCh, the train-of-four ratio in Group 1 infants recovered to 75% in 4.7 +/- 0.6 min, whereas it took 34 +/- 10 min in Group 2 infants (P less than 0.01). Tachyphylaxis developed in infants after 3.6 +/- 0.3 mg/kg (mean +/- SE) and phase II block after 5.3 +/- 0.7 mg/kg (P less than 0.05) SCh. Combining the data of infants with that of children from a previous study conducted in a similar fashion resulted in significant correlation (P less than 0.001) between the log age and SCh requirement. The rate of administration of a continuous infusion of SCh in infants should be based upon the response of infants and not on a fixed dose (mg X kg-1 X h-1).

Humans↗
PubMed1994

Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome. Effects on pulmonary hemodynamics and oxygenation.

BACKGROUND: Nitric oxide (NO) inhalation selectively decreases pulmonary artery hypertension and improves arterial oxygenation in patients with the adult respiratory distress syndrome (ARDS). In this study of patients with severe ARDS, we sought to determine the effect of inhaled NO dose and time on pulmonary artery pressure and oxygen exchange and to determine which patients with ARDS are most likely to show this response. METHODS: Thirteen patients with severe ARDS (hospital mortality 67%) inhaled 0-40 parts per million (ppm) NO. Seven of these patients continued to breathe 2-20 ppm NO for 2-27 days. RESULTS: Inhaling 5-40 ppm NO decreased mean pulmonary artery pressure in a dose-related fashion (from 34 +/- 7 to 30 +/- 7 mmHg at 20 ppm NO). Systemic arterial pressure did not change. The ratio of arterial oxygen tension to inspired oxygen fraction increased (from 126 +/- 36 to 149 +/- 38 mmHg) and the venous admixture decreased (from 31.2 +/- 5.5 to 28.2 +/- 5.2%) without a clear dose-response effect. During prolonged NO inhalation, 2-20 ppm NO effectively reduced mean pulmonary artery pressure (38 +/- 7 vs. 31 +/- 6 mmHg) and increased arterial oxygen tension (79 +/- 10 vs. 114 +/- 27 mmHg) without evidence of tachyphylaxis. The decrease of pulmonary vascular resistance during NO inhalation correlated with the level of pulmonary vascular resistance without NO (r = -0.72). The reduction of venous admixture correlated with the level of venous admixture without NO (r = -0.78). CONCLUSIONS: Long-term NO inhalation at low concentrations selectively decreases mean pulmonary artery pressure and improves arterial oxygen tension in patients with ARDS. The selective pulmonary vasodilation effect is most pronounced in ARDS patients with the greatest degree of pulmonary vasoconstriction.

Administration, Inhalation↗
PubMed1994

Plasticity in spinal opioid control of lower urinary tract function in paraplegic cats.

Spinal cord injury disrupts micturition reflexes, which produces morbidity. The contribution of endogenous opioid systems to urinary retention were assessed in chronic spinal cats by administering the opioid receptor antagonist, naloxone (5-500 micrograms kg-1, i.p.), to unanesthetized paraplegic cats while monitoring lower urinary tract function and observing hind limb reflexes. While naloxone had no overt effect in acute spinal cats, in chronic spinal cats naloxone induced the release of large volumes of urine and produced marked hind limb hyper-reflexia. Prominent tachyphylaxis and tolerance to the effects of naloxone were evident. Immunohistochemical studies indicated a marked increase in leucine enkephalin and dynorphin in sacral spinal neurons. Together, these data indicate hyperactivity of the endogenous spinal opioid system following recovery from spinal cord injury and, furthermore, suggest that the spinal neural circuitry may become 'dependent' upon elevated levels of endogenous opioid peptides.

Animals↗
PubMed2004

Erythromycin in the short- and long-term control of dyspepsia symptoms in patients with gastroparesis.

BACKGROUND: Few prokinetic drugs are available to treat gastroparesis. Data are limited on short-term and long-term efficacy of erythromycin as a prokinetic drug. GOALS: Assess efficacy of low-dose erythromycin suspension to treat gastroparesis. STUDY: Patients with dyspepsia and gastroparesis by gastric emptying study were treated with low-bulk diet and low-dose (50-100 mg 3 times a day and at bedtime) oral erythromycin suspension. Data were collected by retrospective chart review and telephone questionnaire for short- and long-term follow-up, respectively. RESULTS: Of 25 patients, 18 had short-term follow-up, 18 had longterm follow-up, and 14 had both. On short-term follow-up, 15 patients (83%) experienced some or dramatic improvement, while 3 (17%) experienced worsening or no change in symptoms (P = 0.005). Mean duration of long-term use was 11 +/- 7 months. On long-term followup, 12 (67%) patients noticed some or dramatic improvement, while 6 (33%) experienced worsening or no change in symptoms (P = 0.16). Correlation (0.7) between short- and long-term response was significant (P < 0.005). Of the 3 patients with poor short-term response, none did well long term. Of the 11 patients with some or dramatic response in short-term, 7 continued to have some response long term. There was no relation between gastric emptying time and response to erythromycin suspension. CONCLUSIONS: Treatment of gastroparesis with low-dose erythromycin and low-bulk diet results in a dramatic short-term improvement in the majority of patients. Short-term response predicts long-term response. This response may not be as great, possibly due to tachyphylaxis.

Adult↗
PubMed1991

Dynamics of the secretory response evoked by endothelin-1 in adrenal chromaffin cells.

Recently, we have observed that endothelin-1 (ET-1) evokes the release of catecholamines (CA) from adrenal chromaffin cells. We have investigated this secretagogue action of ET-1 on cultured adrenal chromaffin cells using a real-time monitoring system. Pulsatile exposure to ET-1 evoked transient secretory responses in a dose-dependent manner, whereas repetitive stimulation produced a rapid tachyphylaxis. This secretagogue activity was dependent on extracellular Ca2+ and was blocked by 85% by 10(-5) M nifedipine. The onset of the secretory response to ET-1 was very slow, and the duration of the response was much longer than that seen with acetylcholine (ACh). These novel dynamics may well be related to the mechanism of action of ET-1 in these cells. In addition, ET-1 produced a synergistic increase in ACh-evoked release, suggesting that ET-1 may physiologically modulate ACh-evoked CA release in adrenal chromaffin cells by a mechanism involving dihydropyridine-sensitive Ca2+ channels.

Adrenal Glands↗
PubMed1993

Adenosine-5'-uronamides rapidly desensitize the adenosine A2 receptor in coronary artery.

This study examined the structure-activity-relationship (SAR) of adenosine analogs and their ability to induce tachyphylaxis in vascular smooth muscle. Adenosine-5'-uronamides,5'-N-ethylcarboxamidoadenosine (NECA), 5'-N-cyclopropylcarboxamidoadenosine (CPCA), and 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680), evidenced rapid desensitization of the A2 vasorelaxant response in porcine coronary artery in vitro whereas adenosine, 2-chloroadenosine (CAD), or 2-[(2-cyclohexylethyl)-amino]adenosine (CGS 22492) failed to do so. Tissues with prior exposure to NECA exhibited mitigated relaxation responses to adenosine, CAD, and NECA but not to isoproterenol, forskolin, pinacidil, or sodium nitroprusside (SNP). The data suggest that adenosine-5'-uronamides homologously desensitize the A2 receptor in porcine coronary artery smooth muscle.

2-Chloroadenosine↗
PubMed1985

Characteristics of prostaglandin induced cough in man.

Inhaled PGF2 alpha and PGE2 were evaluated for relative tussive activity to non-prostanoid tussive agents. In addition a comparison was sought between the present observations and those in the cat, the only laboratory animal which consistently coughs to prostanoids. Five healthy volunteers were repeatedly challenged at 90 min intervals with aerosols of PGE2 (100-500 micrograms ml-1) and tussive activity was monitored. In a second separate study again monitoring tussive activity 10 healthy volunteers inhaled aerosols of either PGF2 alpha (0.1-100 micrograms ml-1), PGE2 (0.1-100 micrograms ml-1), acetylcholine (0.1-50 mg ml-1) or citric acid (5-20% w/v) in a randomised procedure. Objective measurement of tussive activity was achieved using a throat microphone linked via a discriminator to a pen recorder. All four compounds produced two distinct phases of tussive activity, an early phase during challenge and a late phase 1-15 min post-challenge. Repeated challenges with PGE2, produced significant (P less than 0.01) tachyphylaxis to the late phase responses only. Both PGF2 alpha and PGE2 were approximately 1000 and 10,000 times more potent than acetylcholine and citric acid respectively for both phases of tussive activity. Tussive activity was accompanied with retrosternal soreness and tightness of the chest for PGE2, increased sputum for PGF2 alpha, and sore throats with citric acid. Although a correlation exists for man and cat with regards to the tussive potency and the early and late phases of PGF2 alpha activity no such correlation seems to exist for PGE2. The high tussive potency of the prostaglandins in man suggest that their local release in various respiratory pathophysiological conditions may be responsible for the accompanying coughs/irritancy.

Acetylcholine↗
PubMed1976

Acute tolerance to effects of topical glucocorticosteroids.

Tachyphylaxis (acute tolerance) to two important actions of topical glucocorticosteroids is demonstrated. In humans, topically active glucocorticoids applied to the skin cause vasoconstriction initially but this response fades with successive applications. In hairless mouse epidermis, inhibition of DNA synthesis and mitosis is caused by one application of a glucocorticoid but with repeated administration of the drug this effect is lost. The degree of inhibition of cell division appears to be similar 30 and 54 h after one application of steroid to that following three or five applications during such a time period. These findings suggest that an optimum therapeutic approach to the use of these agents exists.

Animals↗
PubMed1992

Inhibition profiles of sodium cromoglycate and nedocromil sodium on mediator release from mast cells of human skin, lung, tonsil, adenoid and intestine.

We have studied an aspect of the functional heterogeneity of human mast cells, namely responsiveness to the inhibitory effects of sodium cromoglycate and nedocromil sodium. The effects of these drugs were examined on the release of histamine and PGD2 from mast cells of human skin, lung, tonsils, adenoids and intestine. A high concentration, 1000 microM, of sodium cromoglycate was required to significantly inhibit histamine release from lung and tonsillar mast cells. Nedocromil sodium, 1000 microM, was more effective than sodium cromoglycate against histamine release from lung, tonsillar and adenoidal cells. Both compounds showed tachyphylaxis in lung and tonsillar mast cells but not in adenoidal and intestinal mast cells. In contrast, in intestinal mast cells, the effect of nedocromil sodium was weaker and more variable than sodium cromoglycate. Skin mast cells differed from mast cells of the other anatomical sites in being unresponsive to sodium cromoglycate and nedocromil sodium. Our results confirm that high concentrations of sodium cromoglycate and nedocromil sodium are required to achieve even modest inhibition of mediator release from human mast cells under in vitro conditions. Notwithstanding this, the results also indicate that differences exist among skin, lung, tonsillar, adenoidal and intestinal mast cells with respect to their sensitivity to sodium cromoglycate and nedocromil sodium, thus extending our knowledge of functional heterogeneity within the human mast cell populations.

Adenoids↗
PubMed1995

The pathophysiology and treatment of rhinitis medicamentosa.

To evaluate the treatment of rhinitis medicamentosa, 10 consecutive patients discontinued their use of topical vasoconstrictors and were treated with budesonide nasal spray, 400 micrograms, daily for 6 weeks. The thickness of the nasal mucosa, the decongestive effect of oxymetazoline and the histamine sensitivity were measured with rhinostereometry. All patients were able to stop using the vasoconstrictors and objective variables showed that they needed treatment for at least 6 weeks. The results strongly support the theory that the rebound swelling is due to interstitial oedema rather than to vasodilatation. The presence of tachyphylaxis reflected by a reduction in both the decongestive effect of oxymetazoline and a reduction of drug duration was seen.

Administration, Topical↗
PubMed1976

Thoracic epidural analgesia III--prolongation in the early postoperative period by intermittent injections of etidocaine with adrenaline.

In 38 patients who had undergone elective upper abdominal surgery, postoperative analgesia was obtained by thoracic epidual analgesia, prolonged by intermittent injections of 3.0, 4.0 and 5.0 ml, respectively, of 1.0% etidocaine with adrenaline 1:200,000. The spread of analgesia after repeated doses is given, as are also the incidences of incomplete analgesia and urinary retention. Signs of tachyphylaxis were noticed. Decreases in the systolic blood pressure were evident, especially after the first injections in the three groups investigated. The falls in blood pressure in the 5 ml group were so pronounced that this part of the study had to be terminated. Accumulation of etidocaine in plasma was noticed in all groups. The clinical implications of the method are discussed.

Acetanilides↗