Drug and medical device product failures and the stability of the pharmaceutical supply chain.

OBJECTIVE: Our objective was to review recent drug and medical device recalls, categorize recall types based on the free text descriptions posted within the recall announcements, and conduct exploratory analyses for researchers interested in pharmaceutical supply chain challenges. METHODS: A cross-sectional study of all current recalls, market withdrawals, and safety alerts published by the United States Food and Drug Administration pertaining to drugs was conducted. A manual review of all the recalls was also conducted to extract additional information including company details, recall type (labeling or quality), and location of failure in the pharmaceutical supply chain (manufacturing or distribution). Descriptive statistics and exploratory bivariate analyses were conducted to test any potential differences between drug and device recalls. RESULTS: Most recalls issued between January 2017 and September 2019 were pharmaceutical drug recalls (85.2%), while 34 (14.8%) medical device recalls were issued for the same period. For drug recalls, 85.1% (166/195) were because of quality, while 14.9% (29/195) were because of labeling issues. Of the quality issues for drug recalls, lack of sterility was the most frequent issue (139/166, 83.7%). There was no difference between drug or device recalls based on recall type (P = 0.16), top 20 pharmaceutical company (P = 0.62), or location of the supply chain failure (P = 0.20). CONCLUSIONS: This study provides a process to categorize and evaluate drug and device recalls by recall type and location of the supply chain. By categorizing the free text provided in public recall data it would be easier to monitor trends over time.

Pain and analgesia in domestic animals.

The biggest challenge to the use of analgesic agents in animals is the determination of the efficacy of these agents. In humans, the verbal communication of the alleviation of pain is fundamental to the effective use of analgesics. In animals, the lack of verbal communication not only confounds the diagnosis and characterisation of the experience of pain, but also challenges the evaluation of the analgesic therapy. As animals possess the same neuronal pathways and neurotransmitter receptors as humans, it seems reasonable to expect that their perceptions of painful stimuli will be similar, and this is a basis for the use of laboratory animals for screening of analgesics for human use. However, as the evaluation in the laboratory animal tests is based mainly on behavioural responses, and although some physiological responses do occur, it is often difficult to separate these from stress responses. The use of behavioural responses to evaluate analgesics in a range of species is complicated by the fact that different species show different behaviours to a similar pain stimulus, and different pain stimuli produce different pain responses in the same species. Thus behaviours may be species- and pain-specific and this can complicate analgesic evaluation. As most animals possess similar neuronal mechanisms to humans for pain perception, it is not surprising that the standard human pain control strategies can be applied to animals. For instance, local anaesthetics, opioids, non-steroidal anti-inflammatory drugs (NSAIDs), as well as other analgesics used in humans are all found to be effective for animal use. Differences in metabolism and distribution between various species, as well as financial considerations in larger animals can affect efficacy and thus limit their use. In addition, the use of any drug in a species that may be intended for human consumption will be limited by residue considerations. The treatment of pain in animals presents many challenges, but the increasing public concerns regarding animal welfare will ensure that studies into the nature and control of animal pain will continue to have a high profile.

Antinociceptive, cardiopulmonary, and sedative effects of five intravenous infusion rates of lidocaine in conscious dogs.

OBJECTIVE: To observe antinociceptive, cardiopulmonary and sedative effects of five different 12-hour lidocaine infusions in conscious dogs, and measure plasma lidocaine concentrations. STUDY DESIGN: Two-part randomized, prospective, blinded, cross-over experimental study. ANIMALS: Six neutered male, crossbred dogs approximately 1-2 years of age and weighing 29.1 +/- 4.0 kg. METHODS: Dogs received lidocaine [2 mg kg(-1), intravenous (i.v.)] or equivalent volume of 0.9% saline followed by infusion of either lidocaine at 10 (L10), 25 (L25), 50 (L50), 75 (L75), or 100 (L100) microg kg(-1) minute(-1), or equivalent rate of saline (Control). The study was conducted in two parts comparing L10, L25 and L50 to control, and then L75 and L100 to another control. Heart and respiratory rates, and indirect arterial blood pressure were measured for 12 hours; before (baseline), during and after infusion. Sedation was scored using descriptive categories, and nociceptive threshold determined using electrical cutaneous stimulation. Plasma lidocaine concentrations were measured using ELISA. Nonparametric and parametric tests for repeated measures were used and p < 0.05. RESULTS: Nociceptive thresholds were not different from the saline control treatment at any time. Respiratory rate decreased 2-12 hours in treatments L25, L75 and L100. Blood pressure increased after 4 hours in treatment L100 compared to baseline. Sedation scores increased compared to baseline (L10: 30 minutes-8 hours; L25: 30 minutes-2 hours, 8 hours; L50: 30 minutes, 8 hours, 12 hours; L75: 4-12 hours; L100: 15 minutes, 8-12 hours), and to Control. Treatment L75 had higher plasma lidocaine concentrations than L10; and L100 had higher concentrations than L10 and L25. Occasional vomiting was observed in dogs receiving lidocaine when plasma lidocaine concentrations exceeded 4 microg mL(-1). CONCLUSIONS AND CLINICAL RELEVANCE: High lidocaine infusion rates did not have antinociceptive effects compared with saline and were associated with mild-moderate sedation and some signs of toxicity in awake dogs.

Effects of meperidine or saline on thermal, mechanical and electrical nociceptive thresholds in cats.

OBJECTIVE: To measure cutaneous electrical nociceptive thresholds in relation to known thermal and mechanical stimulation for nociceptive threshold detection in cats. STUDY DESIGN: Prospective, blinded, randomized cross-over study with 1-week washout interval. ANIMALS: Eight adult cats [bodyweight 5.1 +/- 1.8 kg (mean + SD)]. METHODS: Mechanical nociceptive thresholds were tested using a step-wise manual inflation of a modified blood pressure bladder attached to the cat's thoracic limb. Thermal nociceptive thresholds were measured by increasing the temperature of a probe placed on the thorax. The electrical nociceptive threshold was tested using an escalating current from a constant current generator passed between electrodes placed on the thoracic region. A positive response (threshold) was recorded when cats displayed any or all of the following behaviors: leg shake, head turn, avoidance, or vocalization. Four baseline readings were performed before intramuscular injection of meperidine (5 mg kg(-1)) or an equal volume of saline. Threshold recordings with each modality were made at 15, 30, 45, 60, 90, and 120 minutes post-injection. Data were analyzed using ANOVA and paired t-tests (significance at p < 0.05). RESULTS: There were no significant changes in thermal, mechanical, or electrical thresholds after saline. Thermal thresholds increased at 15-60 minutes (p < 0.01) and mechanical threshold increased at 30 and 45 minutes after meperidine (p < 0.05). Maximum thermal threshold was +4.1 +/- 0.3 degrees C above baseline at 15 minutes while maximum mechanical threshold was 296 +/- 265 mmHg above baseline at 30 minutes after meperidine. Electrical thresholds following meperidine were not significantly different than baseline (p > 0.05). Thermal and electrical thresholds after meperidine were significantly higher than saline at 30 and 45 minutes (p < 0.05), and at 120 minutes (p < 0.05), respectively. Mechanical thresholds were significantly higher than saline treatment at 30 minutes (p

Pharmacokinetics of intravenous tramadol in dogs.

The purpose of this study was to determine the pharmacokinetics of tramadol and the active metabolite mono-O-desmethyltramadol (M1) in 6 healthy male mixed breed dogs following intravenous injection of tramadol at 3 different dose levels. Verification of the metabolism to the active metabolite M1, to which most of the analgesic activity of this agent is attributed to, was a primary goal. Quantification of the parent compound and the M1 metabolite was performed using gas chromatography. Pharmacodynamic evaluations were performed at the time of patient sampling and included assessment of sedation, and evaluation for depression of heart and respiratory rates. This study confirmed that while these dogs were able to produce the active M1 metabolite following intravenous administration of tramadol, the M1 concentrations were lower than previously reported in research beagles. Adverse effects were minimal, with mild dose-related sedation in all dogs and nausea in 1 dog. Analgesia was not documented with the method of assessment used in this study. Tramadol may be useful in canine patients, but additional studies in the canine population are required to more accurately determine the effective clinical use of the drug in dogs and quantification of M1 concentrations in a wider population of patients.

Receptor changes in the spinal cord of sheep associated with exposure to chronic pain.

There is evidence that post-injury hypersensitivity is partly due to changes in the central nervous system. Sheep with foot rot were used to investigate the effect of chronic pain on some receptors thought to be involved in spinal nociceptive processing systems (alpha 2 adrenoceptor and mu and delta opioid receptors). Saturation binding studies showed a variable distribution of [3H] clonidine (alpha 2 adrenoceptor agonist) in the spinal cord of normal sheep. The number of receptors (Bmax) present in areas thought to be involved in nociceptive processing, laminae I and II and lamina X, increased to 131% and 169% of control sheep values respectively in animals exposed to chronic pain. The affinity of the receptors (KD), however, remained unchanged at approximately 2 nM. There was less [3H]DAGO (mu opioid agonist) and [3H]DPDPE (delta opioid agonist) binding in the sheep spinal cord. Both opioid receptor types being mainly located in the superficial dorsal horn. The [3H]DPDPE binding was unchanged in the sheep with foot rot, whilst the number (Bmax), but not the affinity, of the [3H]DAGO binding sites increased in laminae I and II in lame animals to 130% of the control sheep values. Hence, in animals in chronic pain, the number of alpha 2 adrenoceptors and mu opioid receptors increased mainly in areas of the sheep spinal cord associated with nociception.

The effect of chronic clinical pain on thermal and mechanical thresholds in sheep.

Threshold responses were measured to a thermal skin test and a mechanical pressure test in two groups of conscious unrestrained sheep. The first group of sheep were healthy adult females and formed a control sample, the second group were also adult females, but were all suffering from a condition known as footrot. Footrot is a chronic infective lesion affecting usually one foot which appears to cause severe pain in its worst manifestation. These sheep were assessed for the severity of the lesion and degree of lameness and were divided into high and low severity subgroups. Footrot did not alter the threshold to the thermal test but the mechanical pressure threshold was significantly reduced in both footrot sub-groups compared to controls. A local anaesthetic block of the affected foot restored values to close to the control level. After treatment of the affected foot, the mechanical threshold in the low severity sub-group was returned to normal, but in the high severity sub-group it was still significantly reduced compared to the control animals. However, when retested 3 months later these values had returned to the normal control levels.