2019, Maine Maritime Academy, Stejnar's review: "Order online Detrol cheap no RX - Cheap online Detrol".
On its journey from the mouth (the point of first administration) to the drug’s receptor deep within the organ systems of the body cheap 2 mg detrol otc, the drug molecule undergoes a variety of potential assaults to the integrity of its chemical structure discount detrol 1 mg fast delivery. This attack begins in the mouth where saliva contains digestive enzymes such as ptyalin or salivary α-amylase best buy detrol. The journey from the point of administration to the microenvironment of the receptor is a complex and arduous journey for the drug molecule. Under such acidic conditions, certain functional groups, such as esters, are vulnerable to hydrolysis—an important point of consideration during drug design. From the stomach, the drug molecule sequentially enters the three portions of the small intestine: duodenum, jejunum, and ileum. The drug designer must consider these environments of varying pH combined with digestive enzymes when selecting functional groups to be incorporated into a drug molecule. The pharmaceutical phase also includes the process of drug absorption from the gas- trointestinal tract into the body fluids. In general, little absorption of a drug molecule occurs in the stomach since the surface area is relatively small. Absorption takes place mainly from the intestine where the surface area is greatly expanded by the presence of many villi, the small folds in the intestinal surface. Drug absorption across the gas- trointestinal lining (which may be regarded functionally as a lipid barrier) occurs mainly via passive diffusion. Accordingly, the drug molecule should be largely un-ionized at the intestinal pH to achieve optimal diffusion/absorption properties. The most signif- icant absorption occurs with weakly basic drugs, since they are neutral at the intestinal pH. Weakly acidic drugs, on the other hand, are more poorly absorbed since they tend to be un-ionized in the stomach rather than in the intestine. Consequently, weakly basic drugs have the greatest likelihood of being absorbed via passive diffusion from the gas- trointestinal tract. A final point of consideration (at the pharmaceutical phase) when designing drugs for oral administration concerns product formulation. Rather, it is a complicated mixture of fillers, binders, lubricants, disintegrants, colouring agents, and flavoring agents. Additional excipient additives are required to permit the pill to be compressed into a tablet (binders), to pass through the gastrointestinal tract without sticking (lubricants), and to burst open so that it can be absorbed in the small intestine (disintegrants). Fillers include dextrose, lactose, calcium triphosphate, sodium chloride, and microcrystalline cellulose; binders include acacia, ethyl cellulose, gelatin, starch mucilage, glucose syrup, sodium alginate, and polyvinyl pyrrolidone; lubricants include magnesium stearate, stearic acid, talc, colloidal silica, and polyethylene glycol; disintegrants include starch, alginic acid, and sodium lauryl sulphate. The importance of this design consideration follows a 1968 Australasian outbreak of phenytoin drug toxicity caused by the replacement of an excipient in a marketed formulation of an anti- seizure drug called phenytoin; the new excipient chemically interacted with the phenytoin drug molecule, ultimately producing toxicity. This phase covers the time duration from the point of the drug’s absorption into the body until it reaches the microenvironment of the receptor site. During the pharmacokinetic phase, the drug is transported to its target organ and to every other organ in the body. In fact, once absorbed into the bloodstream, the drug is rapidly transported throughout the body and will have reached every organ in the body within four minutes. Since the drug is widely distributed throughout the body, only a very small fraction of the administered compound ultimately reaches the desired target organ—a significant problem for the drug designer. The magnitude of this problem can be appreciated by the following simple calculation. A typical drug has a molecular weight of approximately 200 and is administered in a dose of approximately 1 mg; thus, 1018 molecules are administered. The human body contains almost 1014 cells, with each cell containing at least 1010 molecules. Therefore, each single administered exogenous drug molecule confronts some 106 endogenous molecules as potential available receptor sites—the proverbial “one chance in a million. While being transported in the blood, the drug molecule may be bound to blood proteins. Highly lipophilic drugs do not dissolve well in the aqueous serum and thus will be highly protein bound for purposes of transport. If a person is taking more than one drug, various drugs may compete with each other for sites on the serum proteins. During this transport process, the drug is exposed to metabolic transformations that may chemically alter the integrity of its chemical structure. In fact, some drug molecules are com- pletely transformed to biologically inactive metabolites during their first pass through the liver; this is the so-called first pass effect. Due to the anatomical arrangement of blood vessels in the abdomen, all orally administered drugs must immediately pass through the liver follow- ing absorption from the small intestine. Accordingly, a drug molecule that is susceptible to a first pass effect should in theory be designed and formulated in a manner that mini- mizes small intestine absorption. One method of reducing a first pass effect is to admin- ister the drug sublingually so that it is absorbed under the tongue and has an opportunity of avoiding the initial pass through the liver. Like the liver, the kidney is another organ system that may influence the effectiveness of a drug molecule during the pharmacokinetic phase. Such molecules have short half-lives (the period of time during which one-half of the drug molecules is excreted). A short half-life reduces the effectiveness of a drug molecule because it shortens the time duration available to the drug for distribution and binding to its receptor. In addition, as a general rule, a drug is administered at least once every half-life; a drug with a half-life of 24 hours may be administered once per day whereas a drug with a 12 h half-life must be given at least twice per day. If a drug has a half-life of 20 minutes it would be impractical to administer it three times per hour. The final impediment to drug molecule effectiveness during the pharmacokinetic phase is the existence of barriers. In order to reach its target organ, the drug molecule must traverse a variety of membranes and barriers. This is particularly true if the drug is destined to enter the brain, which is guarded by the blood–brain barrier. This is a lipid barrier composed of endothelial tight junctions and astrocytic processes. This design feature is highly desirable if one wishes to develop drug molecules for non-neurologic indications that will have no neurologic side effects. On the other hand, the existence of the blood–brain barrier must be explicitly consid- ered when designing drugs for neurological indications. Different organ systems inflict varying degrees of assault on the integrity of the drug molecule during its journey to the receptor. Once the drug molecule has entered the region of its receptor, it is in the pharmacodynamic phase. During this phase, the molecule binds to its receptor through the complementarities of their mole- cular geometries. The functional groups of the drug molecule interact with correspond- ing functional groups of the receptor macromolecule via a variety of interactions, including ion–ion, ion–dipole, dipole–dipole, aromatic–aromatic, and hydrogen bond- ing interactions.
This appears to block hydroxy- lation at the 3 position purchase detrol 4 mg free shipping, with N- and O-demethylations forming the primary metabolites (Fig discount 2mg detrol free shipping. Successive hydroxylations of the methyl groups followed by N-hydroxymethy- 14 Moody Fig cheap detrol online. From (401); reproduced from the Jour- nal of Analytical Toxicology by permission of Preston Publications, a division of Preston Industries, Inc. Tofisopam (tofizopam) is an unusual 2,3-diazepine with hydroxymethyl groups at four positions. O-Demethylation at the R1 and R4 positions has been described as the major routes of tofisopam’s metabolism (Fig. Based upon the principles discussed above, however, one can speculate on putative pathways of their metabolism (Table 7). Metabolism of the 4,5-oxazolone ring as postulated for mexazolam by Ishigami et al. Methods Used to Determine Enzyme Involvement in the Metabolic Pathway The methods for determination of the role of a specific enzyme in the pathway of a drug’s metabolism have been developed most thoroughly for the cytochrome P450s 16 Moody Fig. From (401); repro- duced from the Journal of Analytical Toxicology by permission of Preston Publications, a division of Preston Industries, Inc. Studies are done using human liver tissue that is now usually procured from donor tissue that is deemed unsuitable for transplantation. Most often studies uti- lize the microsomal cell fraction prepared from differential centrifugation of homogen- ates of liver tissue (20), but cultured hepatocytes and liver slices are also being used. Each of these methods has certain strengths and weaknesses; the most con- vincing studies use most of them in an integrated approach (Table 8). Metabolic pathways for some other benzodiazepines: (A) bromazepam, (B) cloba- zam, (C) clotiazepam, and (D) loprazolam. From (401); reproduced from the Journal of Analytical Toxicology by permission of Preston Publications, a division of Preston Indus- tries, Inc. Selective inhibitors are often the easiest reagents to obtain and perform studies with. The results from their use, however, must be interpreted with care, as selectivity either is not complete, or is lost as the concentration of the inhibitor is increased. Drug Interactions with Benzodiazepines 19 Table 7 Speculation on Putative Metabolic Pathways for Benzodiazepines that Have Not Had Metabolites Defined 5-Aryl-1,4-Benzodiazepines Cinolazolam conjugation of 3-hydroxyl; N-dealkylation Delorazepam 3-hydroxylation ® conjugation Ethyl Lorazepate 3-ester hydrolysis ® conjugation Fludiazepam 3-hydroxylation ® conjugation; N-dealkylation Pinazepam 3-hydroxylation ® conjugation; N-dealkylation Tetrazepam 3-hydroxylation ® conjugation; N-dealkylation 7-Nitroso-5-Aryl-1,4-Benzodiazepines Nimatazepam amine reduction ® N-acetylation 3-hydroxylation ® conjugation; N-dealkylation 4,5-Oxazolo-Benzodiazepines Cloxazolam cleavage of 4,5-oxazolo-ring; 3-hydroxylation ® conjugation Haloxazolam cleavage of 4,5-oxazolo-ring; 3-hydroxylation ® conjugation Mexazolam cleavage of 4,5-oxazolo-ring; 3-hydroxylation ® conjugation 1,2-Triazo-Benzodiazepine Etizolam a-hydroxylation ® conjugation; 4-hydroxylation Table 8 Tools Used to Determine Involvement of Specific Enzymes in Xenobitotic Metabolism 1. Selective inhibitors •Relatively easy to get and most are relatively inexpensive • Selectivity is concentration dependent •U sing titration can help determine % involvement in a pathway •M echanism-based and metabolite intermediate complex inhibitors require 10–15 min preincubation before addition of test substrate 2. Selective antibodies •Either expensive or require collaboration with laboratory that produces them • Selectivity often limited to family of enzyme •U sing titration can help determine % involvement in a pathway 3. Selective antibodies are powerful tools, but their selectivity must be carefully determined. The most common limitation is their inability to distinguish P450s of the same family (e. A common feature of selective inhibitors and selective antibodies is that they can be used to titrate the activity in liver tissue preparations and provide an estimate of the percent involvement. Selective antibodies can also be used to quantitate the amount of a particular P450 or P450 family in liver tissue. A common feature of liver tissue preparations is that there is usually large inter- individual variation between preparations. This arises in part from true individual dif- ferences and from differences in tissue preparation. The metabolic pathway in question is measured in the different preparations and plotted as a scatter gram against the marker activities or contents. High and low correlation coefficients provide supportive evi- dence of the enzymes’ positive or negative involvement, respectively. As with any cor- relation experiments the distribution of activities should be carefully examined to assure no heterogenous scatter is creating a biased result (24). By themselves, they can only determine the ability of the enzyme to perform the reaction. Involvement of Specific P450s in the Metabolism of Benzodiazepines The metabolism of a number of benzodiazepines has been studied using the meth- ods described above. P450 3A4 is the most abundant P450 in most livers, while 3A5 is detected in only approximately 20% of livers (51). In a few of the studies cited above, 3A4 and 3A5 mediated activities have been compared. Equivalent activities were found for diazepam 3-hydroxylation and N-demethylation (27,29), and for midazolam 4-hydroxylation (33,35). Drug Interactions with Benzodiazepines 23 was more active than 3A5 for nordiazepam 3-hydroxylation and temazepam N-dealkyla- tion (27,28). As some differences have been observed in the response of 3A4 and 3A5 to inhibitors (22), the differential metabolism of benzodiazepines by these two members of the 3A family may play a factor in suscep- tibility to certain drug interactions. P450 2C19 appears to play a role in the N-demethylation of diazepam, temazepam, adinazolam, N-desmethyladinazolam, and flurazepam. For diazepam, this involvement has been confirmed from studies comparing extensive and poor 2C19 metabolisors (52). For 3 poor metabolizers, compared to 13 extensive metabolizers, the clearance of diaz- epam was reduced by 50%, and the elimination half-life was increased twofold (52). With nordiazepam also, the clearance was reduced by 50%, and the elimination half-life was increased twofold (52). This suggests that 2C19 can also be involved in some 3-hydroxylation reactions, which was not readily apparent from the results of the in vitro studies (27). Whether this role of 2B6 will have clinical significance has yet to be determined. If high 2B6 content is coupled with low 3A4 and 3A5 content, then the likelihood of 2B6’s contribution to the metabolism of some ben- zodiazepines may be increased. In summary, P450 3A4 (and 3A5) are extensively involved in many pathways of oxidative metabolism of benzodiazepines. P450 2C19 is involved in many of the N- demethylation reactions, and may play a role in some other oxidative pathways. Though a number of metabolic pathways of benzodiazepines have been studied, many have not. Little is known of the role of specific uridine diphosphate glucuronosyl transferases or sulfotransferases in conjugation of benzodiazepines or of the enzymes involved in reduction and subsequent acetylation of the nitroso-benzodiazepines. General Considerations Both pharmacodynamic and pharmacokinetic mechanisms have been observed for drug interactions concerning benzodiazepines. Most pharmacokinetic drug interac- tions involve either the inhibition or induction of specific P450s involved in the metab- 24 Moody olism of benzodiazepines. They are the most common and the better documented of drug interactions with benzodiazepines. Most, however, result in either an increased (inhib- itors) or decreased (inducers) activity of the benzodiazepine. When therapeutic doses are used these interactions may have clinical and forensic, if carried into driving or other machine-operating environments, but rarely lethal consequences.
Monitoring Measure Frequency Rationale Serum K Daily for first 48 hours discount 2 mg detrol visa, * If #K occurs discount 1mg detrol, correct potassium levels order detrol 4mg with mastercard, consider then consider 2--3 times withdrawing cyanocobalamin and monitor weekly during acute cardiac function. Reticulocyte and * Generation of new reticulocytes and erythrocyte count erythrocytes supports a diagnosis and treatment of vitamin B12 deficiency anaemia. Additional information Commonandserious Hypersensitivity reactions (rash, pruritus, rarely anaphylaxis); pyrexia; chills; hot undesirable effects flushes; dizziness; malaise; nausea; diarrhoea; acneiform and bullous eruptions. Significant Vitamin B12 assay: anti-metabolites and most antibiotics invalidate vitamin B12 interactions assays by microbiological techniques. This assessment is based on the full range of preparation and administration options described in the monograph. Cyclizine | 193 Cyclizine 50mg/mL solution in 1-mL ampoules * Cyclizine lactate is an antihistamine with antimuscarinic activity and mild sedative effects. It may also be used to treat vomiting and attacks of vertigo associated with Meniere’s disease and other vestibular disturbances. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Monitoring Measure Frequency Rationale Improvement in nausea and Periodically * For signs of clinical vomiting or dizziness improvement. Additional information Common and serious Immediate: Anaphylaxis and other hypersensitivity reactions have undesirable effects been reported. Injection/infusion-related: * Too rapid administration: Transient paralysis has been reported. Other: Drowsiness, urticaria, rash, headache, dryness of the mouth, nose and throat, blurred vision, "pulse, urinary retention, constipation, restlessness, nervousness, insomnia and auditory and visual hallucinations. Significant interactions * Cyclizine may "sedative effect of opioid analgesics and other sedating medicines. Action in case of overdose Stop administration and give supportive therapy as appropriate. This assessment is based on the full range of preparation and administration options described in the monograph. Pre-treatment checks * Avoid in acute bacterial endocarditis, major bleeding or high risk of uncontrolled haemorrhage including recent haemorrhagic stroke. If treatment is required beyond 8 days, reduce the dose to either 5000 units (women <80kg, men <70kg) or 7500 units (women! For treatment doses either monitor anti-Factor Xa levels or use unfractionated heparin. For treatment doses either monitor anti-Factor Xa levels or use unfractionated heparin. Dose in hepatic impairment: the manufacturer advises to avoid in severe hepatic impairment. Pinch up a skin fold on the abdominal wall between the thumb and forefinger and hold through- out the injection. Dalteparin sodium | 199 Intravenous infusion via a syringe pump (haemodialysis only) Preparation and administration 1. Technical information Incompatible with No information Compatible with Flush: NaCl 0. In use: Vials should be stored below 30 C and contents used within 14 days of first use. Stability after From a microbiological point of view, prepared infusions should be used preparation immediately; however, the preparation is known to be stable at room temperature for up to 24 hours. Monitoring Measure Frequency Rationale Platelets Alternate days from * Thrombocytopenia can occur in this period of therapy. Serum K After 7 days * Heparins #secretion of aldosterone and so may cause "K (especially in chronic kidney disease). Bleeding Throughout treatment * Low bodyweight: In women <45kg and men <57kg there is a higher risk of bleeding with prophylactic dalteparin doses. Anti-Xa activity If indicated * Not required routinely but may be considered in patients at "risk of bleeding or actively bleeding. Other: Risk of bleeding with organic lesions, invasive procedures, asymptomatic thrombocytopenia during the first days of therapy, clinically significant "K in patients with diabetes or chronic renal failure. This assessment is based on the full range of preparation and administration options described in the monograph. Danaparoid should be started preoperatively; thelast preoperative dose being given a minimum of 1--4 hours before surgery. Pinch up a skin fold on the abdominal wall between the thumb and forefinger and hold through- out the injection. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Intravenous infusion via a syringe pump Preparation of a 200 anti-Factor Xa units/mL infusion with a total volume of 22. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with No information Compatible with Flush: NaCl 0. Monitoring Measure Frequency Rationale Platelet count (patients Daily * To rule out cross-reactivity (#platelets). Signs and symptoms Continuously * If danaparoid is administered in the context of of neurologic peridural or spinal anaesthesia, extreme vigilance impairment (peridural and frequent monitoring must be exercised to or spinal anaesthesia) detect any signs and symptoms of neurologic impairment, such as back pain, sensory and motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction. The risk is increased by the prolonged use of these routes, by the concomitant use of drugs affecting haemostasis, e. Protamine sulfate only partially neutralises overdose the anticoagulant effect of danaparoid and cannot be relied on to reverse bleeding associated with overdosage. This assessment is based on the full range of preparation and administration options described in the monograph. Dantrolene sodium 20-mg dry powder vials * Dantrolene sodium is a muscle relaxant acting directly on skeletal muscle, thus reducing muscle contractility in response to excitation. Pre-treatment checks As soon as the malignant hyperthermia syndrome is recognised, stop all anaesthetic agents. The manufacturers note that a 70-kg man may require approximately 36 vials (to give 10mg/kg) and that such a volume could be administered in approximately 11/2 hours. Further doses are given during anaesthesia if signs of malignant hyperthermia develop. Dantrolene sodium | 205 Intravenous injection Preparation and administration Dantrolene sodium is incompatible with NaCl 0. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Intermittent intravenous infusion Preparation and administration Dantrolene sodium is incompatible with NaCl 0. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Technical information Incompatible with Dantrolene sodium is incompatible with NaCl 0. The powder may have a mottled orange/white appearance or be in the form of loose aggregates; this does not affect the stability of the product.
He would then strain the decoction and reduce the fluid until it was entirely evaporated buy 2 mg detrol. He would roll it up in form of pills and give one of them three or four times a day order detrol with mastercard, improving his cases of dropsy very generally purchase detrol 4mg line. This remedy is considered valuable in the treatment of prostatic disease, chronic enlargement of the prostate, with irritation at the neck of the bladder, urinary irritation from other causes, especially the urinary difficulties of the aged. It is a diuretic, more or less active in proportion to Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 311 the size of the dose. It promotes the absorption and elimination of dropsical effusions in a characteristic manner, especially those of the abdominal cavity. Given to patients suffering from protracted fever, it will make a cooling and pleasant drink, which promotes the elimination of all of the excretions and restores secretion. Felter and Lloyd state that when a frequent desire to urinate is accompanied with a burning pain at the urethral outlet, the urine passed in drops and mixed with a little blood, it is an especially valuable remedy. Therapy—This agent is an important article of commerce in China, being a general domestic remedy and highly prized. It is a mild sedative and tonic to the nerve centers, improving their tone, if persisted in, and increasing the capillary circulation of the brain. It is given in cerebral anemia, and if combined with other tonics is capable of doing some good. It is also prescribed in the failure of digestion incident to nervous prostration and general nerve irritation. Opium is the concrete milky exudation obtained by incising the unripe capsules of the white poppy of Asia Minor. Dose, five Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 312 to twenty minims. A white or colorless crystalline body in shining prismatic crystals; soluble in thirty-six parts of hot alcohol, and in alkalies; almost insoluble in water. A yellowish-white crystalline body, or an amorphous powder, bitter, inodorous except a slight odor of the acetic acid; soluble in two and one- half parts of water. In white feathery, silky crystals, without odor; of an intensely bitter taste; soluble in twenty-one parts of water and in seven hundred parts of alcohol. Muriate of Morphine occurs in white needle-shaped, feathery, lustrous crystals; bitter and odorless; soluble in twenty-four parts of water and in sixty-two parts of alcohol. This is the product of the action of hydrochloric acid on a modified form Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 313 of the alkaloid morphine. It occurs as white or grayish white crystals, without odor, bitter, turning slightly green upon exposure to the air; soluble in forty-five parts of either water or of alcohol. The dose for this purpose is from one-twentieth to one-sixteenth of a grain, although one-eighth of a grain may be given. It may be given to eject bodies from the esophagus to evacuate the stomach after the injection of poisons, and in extreme asthmatic or catarrhal attacks. A field of action has developed for this remedy, outside of its influence as an emetic, which is important. One writer says that in wild delirium, sleep may be induced with this remedy, and a restful quiet. It should be given in doses of from one one-hundredth to one-thirtieth of a grain, hypodermically injected. The dose is less than the emetic dose, and yet sufficient to produce a physiological effect. It is not given until after the patient is undressed and in bed ready to go to sleep. Where it is used for its hypnotic effect alone, and the patient has not previously taken it, it might be well to beg in with a dose as small as the one one hundredth of a grain. The influence of the agent is not protracted, and in some cases it must be repeated in two or three hours. In others it produces a restfulness, which results in sleep, independent of further action of the remedy. In hysterical attacks, the agent is valuable, as it produces general quiet, and refreshing sleep. It may be used in the place of morphine and opium with those who are addicted to a habit for these drugs, and it will produce the same results. The drug is a treacherous one, and consequently dangerous, and must therefore be given with care. In very minute doses, it is given in bronchitis, where there is a deficiency of secretion, or in croup, producing relaxation and expectoration. It is given as an expectorant in cough mixtures, with good results, but its emetic influence should not be induced. One one-hundredth of a grain, repeated every two hours, will be sufficiently large dosage. It produces a Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 314 watery secretion of mucus, which is often undesirable. It should be used only with adults, as stated, as children are too susceptible to its influence. Kinnett has used it in pain from spasms of the pyloris, and others mention its influence for spasmodic pain in severe, acute stomach disorder in sthenic cases. Dice believes apomorphine given in small doses frequently repeated in the initial stage of appendicitis will prevent the development of many cases of this disease. He dissolves also a dram of sulphate magnesium in four ounces of water and gives a teaspoonful every two hours with it. Apomorphine in doses of One-thirtieth of a grain or less, frequently repeated controls some very severe cases of vomiting. In the treatment of alcoholism, this agent is given in sufficient quantity to produce mild nausea; then one-thirtieth of a grain of strychnine or other indicated stimulant is given for its influence upon the nervous system at the same time. Occurrence—An alkaloid of opium closely related to morphine, often, if not carefully prepared, containing a certain proportion of morphine. Character—White octahedral crystals, bitter, odorless, permanent, soluble in eighty parts of water and in three parts of alcohol. Physiological Action—Its influence is that of an anodyne and antispasmodic, more active as an antispasmodic than morphine and much less narcotic. It controls pain without checking secretion to as great an extent as the other alkaloids of opium. Therapy—It has a more marked influence upon pain in the abdomen and in the pelvic organs. Spasms, neuralgia and other painful conditions in these parts are well controlled by codeine. It has been given in doses of fifteen or twenty grains daily for this purpose, in some cases with permanent results. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 315 Codeine has a marked influence upon spasmodic cough.
...or by Phone or Mail
PO Box 800
Buffalo, NY 14231 USA
Toll free 1-800-825-2675
Hours 8:30 am 5:00 pm EST M-F