Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels.

Preemptive management of post-incisional pain remains challenging. Here, we examined the role of preemptive use of neuroactive steroids with activity on low-voltage activated T-type Ca2+ channels (T-channels) and γ-aminobutyric acid A (GABAA) receptors in the development and maintenance of post-incisional pain. We use neuroactive steroids with distinct effects on GABAA receptors and/or T-channels: Alphaxalone (combined GABAergic agent and T-channel inhibitor), ECN (T-channel inhibitor), CDNC24 (GABAergic agent), and compared them with an established analgesic, morphine (an opioid agonist without known effect on either T-channels or GABAA receptors). Adult female rats sustained the skin and muscle incision on the plantar surface of the right paw. We injected the agents of choice intrathecally either before or after the development of post-incisional pain. The pain development was monitored by studying mechanical hypersensitivity. Alphaxalone and ECN, but not morphine, are effective in alleviating mechanical hyperalgesia when administered preemptively whereas morphine provides dose-dependent pain relief only when administered once the pain had developed. CDNC24 on the other hand did not offer any analgesic benefit. Neuroactive steroids that inhibit T-currents-Alphaxalone and ECN-unlike morphine, are effective preemptive analgesics that may offer a promising therapeutic approach to the treatment of post-incisional pain, especially mechanical hypersensitivity.

Comparison of the effects of buprenorphine and methadone in combination with medetomidine followed by intramuscular alfaxalone for anaesthesia of cats undergoing ovariohysterectomy.

OBJECTIVES: The aim of this study was to compare the quality of anaesthesia and analgesia between methadone and buprenorphine in combination with medetomidine after induction with intramuscular (IM) alfaxalone in cats undergoing ovariohysterectomy. METHODS: Fifty-one female cats (American Society of Anesthesiologists status I-II), with a median age of 12 months (range 2-60 months), weighing a mean ± SD of 2.5 ± 0.5 kg, were recruited to the study. Cats were randomly allocated to receive medetomidine (600 µg/m2) and buprenorphine (180 µg/m2) (group MB) or medetomidine (500 µg/m2) and methadone (5 mg/m2) (group MM) IM. Anaesthesia was induced 15 mins later using alfaxalone (3 mg/kg) IM. Anaesthesia was maintained with isoflurane in oxygen. All cats received meloxicam preoperatively. Quality of premedication and induction and intraoperative physiological parameters were recorded. Atipamezole (50% of medetomidine dose) was administered at the end of surgery. Cats were assessed postoperatively by the same blinded observer using a simple descriptive scale, numeric rating scale, dynamic interactive visual analogue scale (DIVAS) and UNESP-Botucatu multidimensional composite pain scales, at 10, 20 and 30 mins post-extubation. Parametric and non-parametric data were compared using Student's t-test or Mann-Whitney U-tests, respectively. RESULTS: Forty-one cats completed the study. No significant differences were detected between groups before or during anaesthesia. No cats required rescue analgesia. DIVAS scores at 10 mins were significantly less in the MM group compared with the MB. No differences between groups at any other time points were detected using the four metrology instruments. CONCLUSIONS AND RELEVANCE: Both protocols provided good anaesthesia conditions for ovariohysterectomy in the cat.

Anaphylaxis associated with intravenous administration of alphaxalone in a dog.

CASE REPORT: We describe the clinical signs and management of a case of anaphylaxis in a dog after intravenous administration of alphaxalone (Alfaxan®, Jurox, NSW, Aust), which has not been previously published. A female spayed cattle dog undergoing routine imaging for forelimb lameness was induced with Alfaxan after receiving sedation with acepromazine and methadone 70 min prior. Immediately after intravenous administration of Alfaxan, the dog exhibited vomiting and diarrhoea associated with acute hypotension. Gallbladder wall oedema was visualised consistent with anaphylaxis. The dog responded to rapid volume expansion. Adrenaline was not required. The dog made a full recovery within 6 h of the reaction and was re-anaesthetised 3 days later without incident, using propofol as the induction agent. CONCLUSION: To our knowledge, this is the first published case of anaphylaxis associated with intravenous Alfaxan in the dog. The APVMA reporting of reactions in small animals from 2003 to 2013 of Alfaxan is consistent with this case report's finding involving the respiratory, circulatory and gastrointestinal systems.

A review of the pharmacology and clinical application of alfaxalone in cats.

Alfaxalone-2-hydroxpropyl-ß-cyclodextrin (alfaxalone-HPCD) was first marketed for veterinary use in Australia in 2001 and has since progressively became available throughout the world, including the USA, where in 2012 Food and Drug Administration (FDA) registration was granted. Despite the growing body of published works and increasing global availability of alfaxalone-HPCD, the accumulating evidence for its use in cats has not been thoroughly reviewed. The purpose of this review is: (1) to detail the pharmacokinetic properties of alfaxalone-HPCD in cats; (2) to assess the pharmacodynamic properties of alfaxalone-HPCD, including its cardiovascular, respiratory, central nervous system, neuromuscular, hepatic, renal, haematological, blood-biochemical, analgesic and endocrine effects; and (3) to consider the clinical application of alfaxalone-HPCD for sedation, induction and maintenance of anaesthesia in cats. Based on the published literature, alfaxalone-HPCD provides a good alternative to the existing intravenous anaesthetic options for healthy cats.

Multicentre, randomised clinical trial evaluating the efficacy and safety of alfaxalone administered to bitches for induction of anaesthesia prior to caesarean section.

OBJECTIVE: To determine the clinical safety and efficacy of alfaxalone in bitches undergoing caesarean section (CS) and their puppies when it is administered for induction of anaesthesia followed by maintenance with isoflurane and oxygen and in conjunction with perioperative pharmaceuticals. DESIGN: A multicentre, randomised, positive-controlled clinical study. METHODS: A total of 74 bitches were enrolled in the study with 48/74 (65%) and 26/74 (35%) receiving alfaxalone and propofol, respectively, for induction of anaesthesia. Bitches were examined prior to induction and monitored during induction, surgery and recovery. Assessments were made for quality of induction, maintenance and recovery from anaesthesia. Assessments were made on pup viability for suction, dorsal flexion, withdrawal and anogenital reflexes. RESULTS: Of the 48 bitches receiving alfaxalone, 47 (98%) and 39 (81%) scored a top score of excellent for induction and anaesthesia effectiveness, respectively. For the same parameters with propofol in 26 bitches, 23 (88%) and 17 (65%) scored excellent. Average scores for recovery were not different between the two treatment groups with alfaxalone 46/48 (96%) and 25/26 (96%) of propofol induced bitches scoring a good or excellent rating. Bitches tolerated a number of concurrent medications throughout the peri-operative period. No bitch fatalities were observed in this study. There were no statistically significant differences between treatment groups for the puppy variables. Live puppies born by CS to bitches having been administered alfaxalone or propofol had similar survival rates 24 h after birth (i.e. 205/213 (96%) and 124/131 (95%), respectively). CONCLUSION: This study confirms the safety and efficacy of alfaxalone for the purpose of anaesthetic induction for CS in the bitch. In addition, alfaxalone had a negligible effect on the neonate with >95% of puppies alive 24 h after the bitch had recovered from anaesthesia with alfaxalone induction.

Alfaxalone as an induction agent for anaesthesia in terrapins and tortoises.

The aim of this study was to evaluate short-term intravenous anaesthesia with alfaxalone in chelonians. In the first part of the study, alfaxalone at a dose rate of 5 mg/kg was administered intravenously to 10 adult female red-eared terrapins (Trachemys scripta elegans) following 24 hours of fasting. The induction time, tracheal tube insertion time, surgical plane of anaesthesia interval, and full recovery time were recorded. The head, neck and leg withdrawal reflex was lost within 21.09±8.07 seconds. The mean tracheal tube insertion time, the time of surgical plane of anaesthesia and full recovery time were 27.50±12.96 seconds, 26.40±4.72 minutes and 33.70±4.76 minutes, respectively. In the second part of the study, 50 chelonians (20 red-eared terrapins, 10 Hermann's tortoises, eight spur-thighed tortoises, six marginated tortoises and six Russian tortoises) were treated intravenously with 5 mg/kg alfaxalone after administration of 1 mg/kg meloxicam and 2 mg/kg butorphanol intramuscularly. The head, neck and leg withdrawal reflex was lost within 21.52±6.57 seconds, the endotracheal tube could be inserted within 25.76±8.24 seconds, and the time to deep pain sensation loss was 29.46±9.67 seconds. Intravenous use of alfaxalone proved to be a suitable method of induction for inhalation anaesthesia in terrapins and tortoises.

Apgar score after induction of anesthesia for canine cesarean section with alfaxalone versus propofol.

The effects of alfaxalone and propofol on neonatal vitality were studied in 22 bitches and 81 puppies after their use as anesthetic induction agents for emergency cesarean section. After assessment that surgery was indicated, bitches were randomly allocated to receive alfaxalone 1 to 2 mg/kg body weight or propofol 2 to 6 mg/kg body weight for anesthetic induction. Both drugs were administered intravenously to effect to allow endotracheal intubation, and anesthesia was maintained with isoflurane in oxygen. Neonatal vitality was assessed using a modified Apgar score that took into account heart rate, respiratory effort, reflex irritability, motility, and mucous membrane color (maximum score = 10); scores were assigned at 5, 15, and 60 minutes after delivery. Neither the number of puppies delivered nor the proportion of surviving puppies up to 3 months after delivery differed between groups. Anesthetic induction drug and time of scoring were associated with the Apgar score, but delivery time was not. Apgar scores in the alfaxalone group were greater than those in the propofol group at 5, 15, and 60 minutes after delivery; the overall estimated score difference between the groups was 3.3 (confidence interval 95%: 1.6-4.9; P < 0.001). In conclusion, both alfaxalone and propofol can be safely used for induction of anesthesia in bitches undergoing emergency cesarean section. Although puppy survival was similar after the use of these drugs, alfaxalone was associated with better neonatal vitality during the first 60 minutes after delivery.

Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model.

Molecular and electrophysiological studies have provided evidence for a general downregulation of the GABAergic system in the Fmr1 knockout mouse. GABA(A) receptors are the main inhibitory receptors in the brain and the GABA(A) receptor was proposed as a novel target for treatment of the fragile X syndrome, the most frequent form of intellectual disability. This study examined the functionality of the GABA(A) receptor in rotarod and elevated plus maze tests with fragile X mice treated with GABA(A) receptor agonists, the benzodiazepine diazepam and the neuroactive steroid alphaxalone. In addition, the effect of GABA(A) receptor activation on the audiogenic seizure activity was determined. We proved that the GABA(A) receptor is still sensitive to GABAergic drugs as the sedative effect of diazepam resulted in a decreased latency time on the rotarod and alphaxalone had a clear anxiolytic effect in the elevated plus maze, decreasing the frequency of entries, the total time spent and the path length in the closed arms. We also observed that treatment with ganaxolone could rescue audiogenic seizures in Fmr1 knockout mice. These findings support the hypothesis that the GABA(A) receptor is a potential therapeutic target for fragile X syndrome.

5alpha-reduced neuroactive steroids alleviate thermal and mechanical hyperalgesia in rats with neuropathic pain.

5alpha-reduced neuroactive steroids with selective modulatory action in vitro on T or combined modulatory action on T and GABA(A) currents present in peripheral sensory neurons have been shown to induce potent peripheral analgesia in vivo in intact animals. Although the role of T and GABA(A) currents in pathophysiology of neuropathic pain (NPP) is not established, it appears that blockade of T currents and/or potentiation of GABA(A) currents could be beneficial in the management of NPP. To study the potential usefulness of 5alpha-reduced neuroactive steroids in alleviating NPP, we selected two newly synthesized steroids-ECN and CDNC24-with a selective blocking effect on T currents and a selective potentiating effect on GABA(A) currents, respectively, and commercial analogs-alphaxalone and 3alpha5alphaP-with the effects on both ion channels. We used a sciatic nerve ligation model to induce thermal and mechanical hyperalgesia in adult rats and tested peripheral thermal and mechanical nociception following local injection of neuroactive steroids into the peripheral receptive fields of a ligated hind paw. We found that 5alpha-reduced neuroactive steroids alleviate thermal and mechanical hyperalgesia in NPP rats. ECN and CDNC24 were more selective in alleviating thermal nociception in NPP than in sham animals when compared to 3alpha5alphaP and alphaxalone although the anti-nociceptive effect induced by 3alpha5alphaP and alphaxalone was more profound. CDNC24 was most selective since it had very minimal anti-nociceptive effect in sham animals but a very profound anti-nociceptive effect in NPP animals suggesting that, under pathological conditions, peripheral GABA(A) receptors might be an attractive therapeutic target.

Antinociceptive properties of neurosteroids IV: pilot study demonstrating the analgesic effects of alphadolone administered orally to humans.

Fourteen patients scheduled for orthopaedic knee reconstruction surgery were enrolled in a prospective, double-blind, randomized study in which they received alphadolone (25-500 mg, n = 9) or placebo (lactose, n = 5) given orally 1 h after operation. All the subjects received a standardized general anaesthetic and the same type of surgery followed by physiotherapy using a continuous passive movement machine. Morphine was administered intravenously after operation by patient-controlled analgesia. Verbal rating and visual analogue scores assessed pain experiences for 6 h. Orally administered alphadolone up to 500 mg caused no increase in sedation, respiratory depression, nausea or vomiting. The experiences of these side-effects were all rated as none, mild or moderate. Orally administered alphadolone caused statistically significant reductions in morphine use and simultaneous highly significant reductions in pain scores. We conclude that alphadolone is a useful analgesic in humans when given by the oral route.

Deflazacort na terapêutica da doença reumatóide / Deflazacort in the treatment of rheumatoid arthritis

Em um ensaio aberto contolado foram estudados 30 pacientes portadores de doença reumatóide do adulto, seropositivos e em manutençäo terapêutica com prednisonam que foi substituída por deflazacort (na relaçäo 5 mg para 6 mg respectivamente). O deflazacort, assim como a aprednisona, também era administrado numa dose única pela manhä. Concluiu-se que o deflazacort é um novo glicocorticóide dotado de eficácia na terapêutica da doença reumatóide e, por apresentar açöes indesejáveis menos severas sobre o metabolismo ósseo e dos carboidratos, representa um avanço antiinflamatório hormonal, por períodos prolongados nesta enfermidade

In vivo interactions between the benzodiazepine antagonist Ro 15-1788 and the steroid anaesthetic althesin in rats.

Althesin and delta 16-alphaxalone have been used alone and in combination with the benzodiazepine antagonist Ro 15-1788 to investigate any protective effect these drugs might have against bicuculline-induced convulsions in rats. We found that Althesin provided good protection against bicuculline-induced convulsions which was enhanced when Ro 15-1788 was also present. delta 16-Alphaxalone lacks the anaesthetic properties of Althesin, but did have some activity in preventing bicuculline-induced convulsions, although it was less effective than Althesin. Its action was not enhanced by treatment with Ro 15-1788. Although we have no definitive explanation of these results, it is possible that when Ro 15-1788 is used clinically, it may interact with other drugs not related chemically to the benzodiazepines.

Specific effects of drugs at pressure: animal investigations.

The interactions of anaesthetics and other drugs with high pressure suggest that protection against the high pressure neurological syndrome (h.p.n.s.) can no longer be considered in terms of generalized non-specific mechanisms. The evidence from our work shows that anaesthetics may either protect, have no effect, or potentiate h.p.n.s. Structural analogues of the steroid anaesthetic Althesin have a protective effect against high pressure tremors in spite of the fact that they have no anaesthetic effects. Low doses of flurazepam are effective against tremor but can be antagonized by Ro 15-1788, which implies in this case a role for the benzodiazepine receptor complex. Pressure interactions with other drugs have included the classic anticonvulsants--which, in general, were relatively ineffective--and various agents perturbing the balance of specific neurotransmitter systems. Representative examples from different studies include 6-hydroxydopamine, muscimol, and sodium valproate. Finally, the potent protection against h.p.n.s. by 2-amino-phosphonoheptanoic acid, an antagonist with preferential action against excitation produced by aspartate and N-methyl-D-aspartate, provides the first evidence that enhanced excitatory amino acid neurotransmission may have an important role in the h.p.n.s.

[The use of alfatesine in the treatment of epilepsy (author's transl)]. / Effets de l'alfatésine sur l'état de mal épileptique. Rapport préliminaire.

7 patients (aged 15 months-72 years) were treated by intravenous infusion of alfatesine in varying dose depending on age and body weight. Treatment was effective in 6 of the 7 patients, 4 of whom had previously derived no benefit from standard treatment with benzodiazepines. Intravenous injection in 2 cases only increased the interval between seizures from 3-12 minutes to 25-40 minutes. No major side-effects were observed.

[Choice of anesthesia technic for suspension larygoscopy]. / Choix d'une technique d'anesthésie destinée à la laryngoscopie en suspension

Anesthesia, during suspension laryngoscopy should permit the ENT surgeon to work in a field without the hindrance of an intra-tracheal tube, and with a calm larynx. After rapid review of anesthesias of brief duration, which are eliminated, several techniques of anesthesia of variable duration are discussed. Neuroleptanalgesia is nevertheless exclused owing to the environmental conditions necessary for its use. Gamma OH was reserved for patients in poor general health, and gave satisfaction. Alfatisine was used here and procured anesthesia of good quality, with minimal respiratory depression, provided a precise protocol is respected, but one cannot hope for success of suspension laryngoscopy without local anesthesia in addition.

[Bronchoscopies under Alfatesine]. / Bronchoscopies sous alfatésine

Alfatesine in perfusion, associated with laryngo-tracheal local anesthesia, was used to carry out 131 bronchoscopies. The comfort of the patient and of the bronchoscopist were then assessed. A few cardio-vascular side-effects, e.g. severe hypotension in two cases, hypertensive effects and tachycardia during introduction of the bornchoscope, were noted.